U.S. patent application number 09/820523 was filed with the patent office on 2001-10-11 for bone marrow shielding apparatus and method of bone marrow-shielded cancer chemotherapy.
Invention is credited to Kim, Sinil.
Application Number | 20010029389 09/820523 |
Document ID | / |
Family ID | 27491018 |
Filed Date | 2001-10-11 |
United States Patent
Application |
20010029389 |
Kind Code |
A1 |
Kim, Sinil |
October 11, 2001 |
Bone marrow shielding apparatus and method of bone marrow-shielded
cancer chemotherapy
Abstract
The invention provides a variety of bone marrow-shielding
tourniquets and methods for using them to perform bone
marrow-shielded chemotherapy with or without general and without
the need to remove a patient's bone marrow for protection during
the procedure. In the invention method, pressure is applied to at
least one body part of the patient that contains myelopoietic bone
marrow to temporarily occlude arterial flow to the bone marrow
while blood circulation through the remainder of the body is
maintained. Then an effective amount of at least one
myelosuppresive chemotherapeutic agent is administered to the blood
circulation in the remainder of the patient while the arterial flow
through the at least one body part is occluded and so that the
myelosuppresive effect of the agent is substantially dissipated
within the maximum safe period for the occlusion of the arterial
flow, or about three hours. The pressure is removed to restore
blood circulation to the bone marrow when the effect has
substantially dissipated and within the maximum safe period. By the
invention method, a tumor located in the remainder of the body is
treated by the at least one chemotherapeutic agent without
destruction of a substantial portion of the bone marrow in the
occluded body part. The bone marrow shielding tourniquets for use
in the invention chemotherapeutic method are designed to
substantially cover at least the shoulder or hip area of a human so
as to occlude arterial flow therein and include inflatable bladders
that apply the requisite pressure when the tourniquet is applied to
the wearer. The shoulder tourniquet optionally is designed to
occlude arterial flow into the proximal scapula as well as into the
shoulder area. Bilateral tourniquets are also provided for
simultaneous occlusion of bilateral shoulders and, optionally,
bilateral scapulae.
Inventors: |
Kim, Sinil; (Solana Beach,
CA) |
Correspondence
Address: |
June M. Learn
GRAY CARY WARE & FREIDENRICH LLP
Suite 1600
4365 Executive Drive
San Diego
CA
92121-2189
US
|
Family ID: |
27491018 |
Appl. No.: |
09/820523 |
Filed: |
March 28, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09820523 |
Mar 28, 2001 |
|
|
|
09239511 |
Jan 28, 1999 |
|
|
|
6210423 |
|
|
|
|
60080817 |
Apr 6, 1998 |
|
|
|
60075128 |
Feb 14, 1998 |
|
|
|
60074002 |
Feb 9, 1998 |
|
|
|
60073004 |
Jan 29, 1998 |
|
|
|
Current U.S.
Class: |
606/203 |
Current CPC
Class: |
A61F 5/34 20130101; A61B
17/1325 20130101; A61B 17/135 20130101 |
Class at
Publication: |
606/203 |
International
Class: |
A61B 017/00 |
Claims
What is claimed is:
1. A method for bone marrow-shielded chemotherapeutic treatment of
a patient in need thereof, said method comprising: applying
pressure to at least one body part of the patient that contains
myelopoietic bone marrow to temporarily occlude arterial flow to
the bone marrow while blood circulation through the remainder of
the body is maintained, administering to the blood circulation in
the remainder of the body an effective amount of at least one
myelosuppresive chemotherapeutic agent while the arterial flow
through the at least one body part is occluded and so that the
myelosuppresive effect of the agent is substantially dissipated
within the maximum safe period for the occlusion of the arterial
flow, and removing the pressure to restore blood circulation to the
bone marrow when the effect has substantially dissipated and within
the maximum safe period, wherein a tumor located in the remainder
of the body is treated by the at least one chemotherapeutic agent
without destruction of a substantial portion of the bone marrow in
the at least one body part, and without general anesthesia.
2. A method for bone marrow-shielded chemotherapeutic treatment of
a patient in need thereof, said method comprising: applying a bone
marrow shielding tourniquet to at least one body part of the
patient that contains myelopoietic bone marrow to temporarily
occlude arterial flow to the bone marrow while blood circulation
through the remainder of the body is maintained, administering to
the blood circulation in the remainder of the body an effective
amount of at least one myelosuppresive chemotherapeutic agent and
while the arterial flow through the at least one body part is
occluded so that the myelosuppresive effect of the agent is
substantially dissipated within the maximum safe period for the
occlusion of the arterial flow, and removing the bone marrow
shielding tourniquet to restore blood circulation to the bone
marrow when the effect has substantially dissipated and within the
maximum safe period.
3. The method according to claim 2 wherein the chemotherapeutic
agent has a known period of initial half-life and the tourniquet is
removed about 1 minute to about 2 hours after passage of the known
period of initial half life.
4. The method according to claim 2 wherein the method is practiced
without general anesthesia and the maximum safe period is about
three hours.
5. The method according to claim 3 wherein the known period of
initial half-life is about 10 seconds to about 25 minutes and the
removing of the tourniquet is about 15 minutes after passage of the
known period of initial half life.
6. The method according to claim 2 wherein the tourniquet applies a
pressure substantially greater than the systolic blood pressure of
the patient.
7. The method according to claim 6 wherein the pressure is from
about 5mmHg to about 300 mmHg above the systolic blood
pressure.
8. The method according to claim 7 wherein the pressure is from
about 50 mmHg to about 200 mmHg above the systolic blood
pressure.
9. The method according to claim 2 wherein the pressure is
substantially equalized over the body surface covered by the
tourniquet.
10. The method according to claim 2 wherein the method is repeated
at spaced intervals of from eight hours to two months.
11. The method according to claim 10 wherein the repeating is for
up to 20 repeats.
12. The method according to claim 2 wherein the arterial flow is
occluded for a period of from about 5 minutes to about 2 hours.
13. The method according to claim 2 wherein the body part is a
shoulder and/or a hip and the method further comprises
exsanguinating the arm proximal to the shoulder and/or leg proximal
to the hip prior to application of the tourniquet.
14. The method according to claim 13 wherein the exsanguinating
involves applying an Esmarch bandage or gravity drainage of the arm
or leg.
15. The method according to claim 2 wherein the tourniquet is
inflatable and the applying involves inflation of the tourniquet to
apply the pressure around the at least one body part.
16. The method according to claim 2 wherein the at least one body
part is a shoulder and the tourniquet occludes arterial flow into
the proximal upper 1/3 of the humerus of the patient.
17. The method according to claim 15 wherein the at least one body
part includes both shoulders and the tourniquet occludes arterial
flow into the proximal upper 1/3 of the humeri of the patient.
18. The method according to claim 2 wherein the at least one body
part includes a hip and the tourniquet occludes arterial flow into
the proximal upper 1/3 of the femur of the patient.
19. The method according to claim 17 wherein the at least one body
part includes both hips and the tourniquet occludes arterial flow
into the respective proximal upper 1/3 of the femurs of the
patient.
20. The method according to claim 2 wherein the at least one body
part includes a scapula of the patient.
21. The method according to claim 2 wherein the at least one body
part includes both scapulae of the patient.
22. The method according to claim 2 wherein the at least one body
part is selected from the group consisting of an upper femur, an
upper humerus, and a scapula of the patient, and combinations of
two or more thereof.
23. The method according to claim 2 further comprising
administering to the patient an effective amount of one or more
active agents for relieving pain, anxiety, nausea or vomiting.
24. The method according to claim 23 wherein the one or more active
agents are administered before the tourniquet is applied.
25. The method according to claim 2 wherein the chemotherapeutic
agent is cytotoxic against the type of tumor being treated.
26. The method according to claim 25 wherein the chemotherapeutic
agent is mechlorethamine and the effective amount is in the range
from about 0.1 mg/kg to about 1.6 mg/kg of body weight of the
patient.
27. The method according to claim 26 wherein the effective amount
is in the range from about 0.2 mg/kg to about 0.6 mg/kg of body
weight of the patient.
28. The method according to claim 26 wherein the tumor is
associated with a cancer selected from the group consisting of
Hodgkin's disease, lymphoma, sarcoma, and skin, lung, breast,
brain, colon, rectal, uterine, stomach, liver, kidney, pancreas,
prostate, testicular and ovarian cancer.
29. The method according to claim 2 wherein the method further
comprises administering highly oxygenated autologous blood into the
occluded body part while the tourniquet is applied.
30. The method according to claim 2 wherein the method further
comprises chilling the occluded body part during at least a portion
of the time during which the tourniquet is applied.
31. The method according to claim 2 wherein the body part includes
both shoulders and wherein the method further comprises
administering the chemotherapeutic agent via a central venous
catheter.
32. The method according to claim 74 further comprising
administering to the patient an effective amount of a cytokine
selected from the group consisting of Granulocyte-colony
stimulating factor, granulocyte-macrophage-colony stimulating
factor, stem cell factor, erythropoietin, thrombopoietin,
interleukin-11, and suitable combinations thereof.
33. A bone marrow shielding tourniquet adapted to apply pressure
around a shoulder or hip of a human, said tourniquet comprising an
inflatable bladder contoured for covering the shoulder or hip and
having an inner face and an outer face, a fluid-tight connector
attached to the inflatable bladder for attaching the bladder to a
source of fluid pressure, and a substantially inelastic exterior
layer substantially covering the outer face of the bladder so as to
limit expansion of the bladder in the direction of the exterior
layer when the bladder is inflated by fluid from the fluid
source.
34. The tourniquet according to claim 33 wherein the exterior layer
is semi-flexible or inflexible and has a three-dimensional shape
selected to hold the bladder around the shoulder or hip area.
35. The tourniquet according to claim 34 further comprising a
co-operative fastener attached to the tourniquet for releasably
affixing the tourniquet around the hip or shoulder.
36. The tourniquet according to claim 34 further comprising a
flexible interior layer lining the inner face of the bladder.
37. The tourniquet according to claim 36 wherein the exterior layer
and interior layer co-operatively form an envelope for containing
the bladder and wherein inflation of the bladder causes the bladder
to extend the flexible interior layer, and wherein the fastener is
attached to or contiguous with the envelope so formed so that
engagement of the fastener affixes the tourniquet snugly around the
hip or shoulder in contact with the interior layer.
38. The tourniquet according to claim 34 wherein the flexible
bladder has two longer, arcuate sides, and two shorter, straight
sides.
39. The tourniquet according to claim 38 wherein one arcuate side
describes a larger arc than the other and the bladder has an
overall shape described by the difference between the sectors of
two circles having a common center and swept out by a common angle,
but having radii of substantially different length.
40. The tourniquet according to claim 39 wherein the difference in
the length is from about 2 inches to about 10 inches.
41. The tourniquet according to claim 38 wherein the arcuate sides
are substantially equal in length and are arranged in mirror image
to one another so that the tourniquet has an overall hour glass
shape.
42. The tourniquet according to claim 34 wherein the bladder is
pressurizable to at least about 300 mmHg and, when affixed around a
shoulder or hip and inflated, occludes arterial flow to the
myelopoietic bone marrow therein.
43. The tourniquet according to claim 34 further comprising at
least one protuberance on the inner face of the bladder, which
protuberance is sized and located to fill in an anatomical hollow
in the shoulder or hip.
44. The tourniquet according to claim 37 further comprising at
least one protuberance on the interior layer, which protuberance is
sized and located to fill in an anatomical hollow in the shoulder
or hip.
45. The tourniquet according to claim 43 wherein the protuberance
is attached to the surface of the interior layer.
46. The tourniquet according to claim 34 wherein the tourniquet is
adapted for affixation around the shoulder to occlude arterial flow
into the proximal upper 1/3 of the proximal humerus.
47. The tourniquet according to claim 45 wherein the tourniquet is
adapted for affixation to the shoulder of a human and the
protuberance is adapted to fill in an arm pit.
48. The tourniquet according to claim 46 and the tourniquet further
comprises a brace attached to the tourniquet, said brace being
adapted to hold an arm attached to the shoulder at a fixed angle
from the side of the torso to which the shoulder attaches when the
tourniquet is affixed around the shoulder.
49. The tourniquet according to claim 48 wherein the brace is
adapted to elevate the arm proximal to the shoulder at an angle of
from about 45 degrees to about 180 degrees from the proximal side
of the torso when the tourniquet is affixed around the
shoulder.
50. The tourniquet according to claim 48 wherein the brace extends
along the side of the torso proximal the shoulder and wherein the
tourniquet further comprises a brace fastener attached to the
portion of the brace that extends along the proximal side of the
torso for fastening around the torso when the tourniquet is affixed
around the shoulder.
51. The tourniquet according to claim 48 wherein the tourniquet
further comprises a positioning fastener, which positioning
fastener is attached to the tourniquet for fastening around the
torso to prevent migration of the tourniquet from the affixed
position around the shoulder.
52. The tourniquet according to claim 34 wherein the tourniquet is
adapted for affixation around the hip to occlude arterial flow into
the proximal upper 1/3 of the proximal femur.
53. The tourniquet according to claim 52 further comprising a hip
positioning fastener attached to the tourniquet to embrace the
pelvis of a human to prevent migration of the tourniquet from
around the hip.
54. The tourniquet according to claim 53 wherein the hip
positioning fastener comprises a fabric hook and loop fastener
system.
55. The tourniquet according to claim 52 wherein the tourniquet
further comprises a brace attached to the tourniquet, said brace
being adapted to hold a thigh proximal to the hip at a fixed angle
from the proximal side of the torso when the tourniquet is affixed
around the hip.
56. The tourniquet according to claim 55 wherein the brace is
adapted to hold the thigh at an angle of from about 45 degrees to
about 155 degrees from the proximal side of the torso when the
tourniquet is affixed around the hip.
57. The tourniquet according to claim 34 wherein the exterior layer
is made of a material selected from the group consisting of
artificial polymer, leather, plaster of Paris, metal, natural woven
fiber, and combinations thereof.
58. The tourniquet according to claim 34 wherein the tourniquet is
designed for affixation to an extremity and the tourniquet further
comprises an attached brace for holding the extremity at a fixed
angle from the torso.
59. A bilateral bone marrow shielding tourniquet, said bilateral
tourniquet having an anterior and a posterior side and comprising
two tourniquets according to claim 34 in mirror image arrangement
and further comprising a releasable anterior positioning fastener
for releasably joining the anterior portions of the two
tourniquets.
60. The bilateral bone marrow shielding tourniquet according to
claim 59 wherein the anterior positioning fastener comprises two
cooperative parts, each attached to the anterior portion of one of
the tourniquets.
61. The bilateral bone marrow shielding tourniquet according to
claim 59 further comprising a releasable anterior positioning
fastener for releasably joining the posterior portions of the two
tourniquets.
62. The bilateral bone marrow shielding tourniquet according to
claim 59 wherein the anterior positioning fastener comprises two
cooperative parts, each attached to the anterior portion of one of
the tourniquets.
63. The bilateral bone marrow shielding tourniquet according to
claim 59 wherein the bilateral tourniquet is adapted for
simultaneously occluding arterial flow into the proximal upper 1/3
of both upper femurs of a human.
64. The bilateral bone marrow shielding tourniquet according to
claim 59 wherein the bilateral tourniquet is adapted for
simultaneously occluding arterial flow into the proximal upper 1/3
of both humeri of a human.
65. A bilateral hard shell bone marrow shielding tourniquet adapted
for wearing by a human, said tourniquet comprising: a semi-flexible
or inflexible and inelastic carapace in one or more pieces, wherein
the carapace has a three-dimensional shape adapted to substantially
cover at least the bilateral scapular areas and/or shoulder areas
of a wearer while allowing the head, arms, and torso to protrude
from the carapace.
66. The tourniquet according to claim 65 further comprising:
bilateral inflatable bladders attached along the interior surface
of the carapace that, when inflated, apply pressure over at least
the bilateral scapular areas and/or shoulder areas of the wearer,
and a fluid-tight connector on each inflatable bladder for
inflating the bladder, wherein inflation of one or both bladders
causes the tourniquet to exert sufficient pressure upon the
respective covered areas of the wearer to occlude arterial flow
into at least the covered areas.
67. The tourniquet according to claim 66 further comprising at
least one adjustable fastener attached to the carapace for cinching
the carapace about the torso of the wearer.
68. The tourniquet according to claim 67 wherein the carapace is in
two pieces for arranging in mirror image fashion about the wearer
to create the three-dimensional shape.
69. The tourniquet according to claim 67 wherein the two pieces of
the carapace each has an arm hole for receiving an arm of the
wearer and an anterior and a posterior side, and wherein the
arranging involves placing the wearer's arms through the arm holes
and moving the two pieces of the carapace about the shoulders and
scapulae of the wearer to co-operatively substantially cover the
bilateral scapulae and shoulders of the wearer, and cinching the
carapace about the torso of the wearer.
70. The tourniquet according to claim 69 wherein the tourniquet
comprises at least two fasteners, one for joining the anterior
sides of the two pieces across the anterior torso of the wearer and
one for joining the two posterior sides of the two pieces across
the posterior torso of the wearer.
71. The tourniquet according to claim 69 wherein the bilateral
bladders, each substantially cover the respective shoulder area and
proximal scapula of the wearer.
72. The tourniquet according to claim 71 wherein inflation of the
bilateral bladders applies sufficient pressure against the body of
the wearer to bilaterally occlude arterial flow into the upper 1/3
of the proximal humerus and scapula.
73. The tourniquet according to claim 67 wherein the carapace is
semi-flexible and in one piece with a neck/chest opening adapted
for receiving the wearer's head and at least one slit that opens to
enable the tourniquet to be placed about the wearer and closes
about the wearer to assume the three dimensional shape.
74. The tourniquet according to claim 66 wherein the carapace and
the inflatable bladders cover the bilateral scapular areas of the
wearer, but not the bilateral shoulder areas.
75. A hard shell bone marrow shielding tourniquet adapted for
applying pressure to a scapular area of a human wearer, said
tourniquet comprising: a substantially inflexible and inelastic
carapace in one pieces having a three-dimensional shape adapted to
substantially cover at least the scapular area of a wearer while
allowing the head, arms, and torso to protrude from the carapace,
an inflatable scapular bladder attached along the interior surface
of the carapace that, when inflated, applies pressure over the
bilateral scapular area of the wearer, a fluid-tight connector on
the inflatable bladder for inflating the bladder, and at least one
adjustable fastener attached to the carapace for cinching the
carapace about the torso of the wearer, wherein inflation of the
bladder causes the tourniquet to exert sufficient pressure upon the
scapular area of the wearer to occlude arterial flow thereinto.
76. An inflatable bladder comprising an inflatable bladder piece
having a shape adapted to substantially cover the hip area or at
least the shoulder area of a human and a fluid tight connector on
the bladder.
77. The bladder according to claim 76 wherein the bladder piece has
a shape adapted to substantially cover the shoulder area and
proximal scapula of the human.
78. A method for fabricating an individualized bone marrow
shielding tourniquet, said method comprising: (a) wrapping a hip or
shoulder to be compressed for occlusion of arterial blood flow
therein with an inflatable bladder having a fluid-tight connector,
(b) wrapping the inflatable bladder with a softened orthopedic cast
material so as to leave free the connector, and (c) molding the
cast material and the one or more inflatable bladders around the
hip or shoulder under conditions suitable for causing the
orthopedic cast material to harden.
79. The method according to claim 78 wherein the method further
comprises wrapping the shoulder or hip to be compressed with a
cushioning material prior to wrapping the one or more inflatable
bladders around the hip or shoulder.
80. The method according to claim 79 wherein the cushioning
material is moisture absorbent.
81. The method according to claim 79 wherein the cushioning
material is stockinet, cast padding, or cotton sheet, or a
combination thereof.
82. The method according to claim 80 wherein the orthopedic cast
material is a knitted substrate impregnated with polyurethane resin
or plaster of Paris.
83. A method for protecting myelopoietic marrow cells from the
effects of chemotherapeutic agents without the need for physical
removal of bone marrow cells from the body of a patient in need
thereof, said method comprising: applying pressure to at least one
body part of the patient that contains myelopoietic bone marrow to
temporarily occlude arterial flow to the bone marrow while blood
circulation through the remainder of the body is maintained,
administering to the blood circulation in the remainder of the body
an effective amount of at least one myelosuppresive
chemotherapeutic agent while the arterial flow through the at least
one body part is occluded and so that the myelosuppresive effect of
the agent is substantially dissipated within about three hours of
commencement of the application of the pressure, and removing the
pressure to restore blood circulation to the bone marrow when the
effect has substantially dissipated and within the three hours.
84. The method according to claim 83 further comprising
administering to the patient an effective amount of a cytokine
selected from the group consisting of Granulocyte-colony
stimulating factor, granulocyte-macrophage-colony stimulating
factor, stem cell factor, erythropoietin, thrombopoietin,
interleukin-11, and suitable combinations thereof.
85. The method according to claim 84 further comprising
administering the chemotherapeutic agent to the via a central
venous catheter.
86. The method according to claim 85 wherein the catheter is placed
into a vein selected from the group consisting of internal jugular,
external jugular, and subclavian veins.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
Provisional Patent Application Ser. No. 60/080,817, filed Apr. 6,
1998; U.S. Provisional Patent Application Ser. No. 60/075,128,
filed Feb. 14, 1998, U.S. Provisional Patent Application Ser. No.
60/074,002, filed Feb. 9, 1998; and U.S. Provisional Patent
Application Ser. No. 60/073,004, filed Jan. 29, 1998.
FIELD OF INVENTION
[0002] This invention pertains to an inflatable tourniquet-like
apparatus or "bone marrow shield" useful for temporary occlusion of
arterial flow into bone marrow of the limbs, shoulder girdle, or
pelvic girdle during administration of cancer chemotherapy, and to
a method of bone-marrow-shielded cancer chemotherapy in humans or
mammals.
BACKGROUND OF THE INVENTION
[0003] One of the most serious side effects of cancer chemotherapy
is myelosuppression-suppression of production of white blood cells,
red cells, and platelets due to damage to the blood-forming
elements of bone marrow in mammals. Myelosuppression can result in
severe infections or bleeding and can result in death.
[0004] Currently, several strategies are employed to reduce this
serious side effect. Granulocyte-colony stimulating factor (G-CSF),
granulocyte-macrophage-colony stimulating factor (GM-CSF), stem
cell factor (SCF), erythropoietin (EPO), thrombopoietin (TPO), or
interleukin-11 (IL-11) is given to stimulate the bone marrow to
produce more white blood cells, red cells or platelets. However,
even with these bone marrow stimulating agents, chemotherapy doses
cannot be high enough to have significant impact upon patient
survival. Therefore, today autologous bone marrow transplant (ABMI)
or peripheral blood stem cell (PBSC) transplant are relied upon to
reconstitute severely damaged bone marrow. Both autologous bone
marrow transplant and autologous peripheral stem cell transplant
involve harvesting the patient's own hematopoietic cells, storing
them outside the body while chemotherapy is administered to the
patient, and then returning the previously-stored cells back to the
patient after the chemotherapeutic agents have largely dissipated
from the body. These methods provide the advantage of reducing the
severity and duration of myelosuppression so that delivery of very
high doses of chemotherapeutic agents can be administered.
[0005] However, these prior art methods are quite complicated and
expensive to perform. Harvesting of a patient's bone marrow cells
usually requires general anesthesia to perform multiple needle
passes into bone marrow of pelvic bones. Harvesting of peripheral
stem cells for PBSC transplant requires multiple apheresis
procedures that are expensive and labor-intensive. The proper
asceptic processing and freezing of harvested bone marrow cells and
peripheral stem cells are also labor intensive and require highly
trained laboratory personnel and special laboratory facilities. For
these reasons, ABMT or PBSC transplant are not routinely performed
in an ordinary oncologist's office making it difficult to perform
multiple cycles of chemotherapy with ABMT or PBSC transplant.
[0006] To enable broad applicability to the general population of
cancer patients, including those without access to expensive and
sophisticated medical technologies, it is desirable to have an
alternative method of reducing the myelosuppresive effect of
chemotherapy that is both less costly and is simple enough to be
performed in an ordinary oncologist's office. In addition, to
derive the maximum benefit from cytotoxic agents, it is quite
desirable to use a procedure that allows administration of multiple
cycles of chemotherapy to the cancer patient.
[0007] Many cancers are confined to the trunk of the body. If it
were possible to restrict arterial flow to the trunk of the body or
to shield at least a portion of the myelopoietic bone marrow in the
limbs while administering a chemotherapeutic agent to the remainder
of the body, the need for removing a portion of the patient's bone
marrow to preserve it from the effects of the chemotherapy could be
avoided. Conrad et al. (Blood, 16:1089-103, 1960), almost 40 years
ago, treated eight cancer patients using a procedure in which
tourniquets were applied to three extremities (one arm plus two
legs) for 15 minutes while nitrogen mustard was being administered.
The chemotherapy involved administration of nitrogen mustard (1.0
to 1.5 mg/kg) under general anesthesia with endotracheal intubation
in an operating room. Out of the eight patients treated, two
patients died within three days, one from pulmonary embolism and
the other from postoperative aspiration pneumonia. All six patients
who survived more than three days postoperatively, suffered severe
side effects, including headache, tinnitus and local
thrombophlebitis, and three of the six patients suffered deafness.
One patient died at 78 days post-operatively with internal and
external hydrocephalus. The symptoms of the latter patient included
aphasia, hemiparesis, papilledema, mental confusion, somnolence,
and weakness.
[0008] Thus, this prior art method of chemotherapy generated severe
side effects. The general anesthesia and intubation used in the
study have risks, including aspiration pneumonia and pulmonary
embolism, from which two of the eight patients succumbed within
three days. Tourniqueting of the lower extremity may have also
contributed to the fatal pulmonary embolism in one patient. Besides
these side effects, the prior art method is expensive. General
anesthesia and intubation are generally performed in an operating
room and require presence of an anesthesiologist, artificial
ventilation, and monitoring equipment, all of which significantly
increase the cost of the chemotherapy treatment.
[0009] In addition, in adults most of the myelopoietic bone marrow
in the upper and lower extremities is confined to the upper 1/3 of
the humerus and femur. Since Conrad et al. appear to have used a
common tourniquet applied in the usual tourniquet position to
practice the prior art method of chemotherapy, it is likely that
the myelopoietic bone marrow in the extremities of the patients
treated was exposed to the myelosuppresive agent.
[0010] Almost 40 years ago in Africa, Duff et al. (British Med J.,
2:1523-8. 1961) also treated patients under general anesthesia on
an operating table in a chemotherapeutic method intended to protect
the bone marrow from the myelosuppresive effects of the
chemotherapeutic method. Sand bags were placed on the patient's
abdomen, directly over the aorta, and then the patient's body was
tightly wrapped with elastic Esmarch bandage while the
chemotherapeutic agent was administered. The occlusion was
maintained for 20 minutes and the treatment was repeated 48 hours
later.
[0011] However, this prior art method of chemotherapy is useful for
only a limited number of patients. External compression of the
abdomen at a pressure high enough to occlude the aorta is only
possible in thin patients and may damage delicate internal organs
and anatomic structures in the abdomen and pelvis, such as the
intestines, kidneys, bladder and ureters. Abdominal pressure high
enough to occlude the aorta would also be likely to occlude the
inferior vena cava, possibly causing formation of thrombus in the
inferior vena cava or other veins in the pelvis and legs,
especially in hypercoagulable cancer patients. In addition to the
risks involved, the use of general anesthesia in Duff s method
would make it expensive and difficult to apply in the modern
era.
[0012] The tourniquets of prior art have design limitations which
make them difficult to apply to the shoulder area or hip area They
have been designed to be applied to part of the limb which is
largely cylindrical or conical, such as the upper arm or thigh
areas. Since the areas of active bone marrow in limbs are normally
limited to the proximal 1/3 of the humerus and femur, blood
circulation must be interrupted in the shoulder area or hip area,
not just in the arm or leg area However, the shoulder and hip areas
are of complex three-dimensional shape, and tourniquets designed to
apply a uniform pressure to these areas do not exist in prior art,
as far as the Applicant is aware. Therefore, methods of tourniquet
application and new tourniquet apparatus are needed that are
designed for application to the shoulder and hip areas.
SUMMARY OF THE INVENTION
[0013] The present invention provides a method for bone
marrow-shielded chemotherapeutic treatment of a cancer patient. The
invention method comprises applying pressure to at least one body
part of the patient that contains myelopoietic bone marrow to
temporarily occlude arterial flow to the bone marrow while blood
circulation through the remainder of the body is maintained,
administering an effective amount of at least one myelosuppresive
chemotherapeutic agent while the arterial flow through the at least
one body part is occluded and so that the myelosuppresive effect of
the agent is substantially dissipated within the maximum safe
period for the occlusion of the arterial flow, and removing the
pressure to restore blood circulation to the bone marrow when the
effect has substantially dissipated and within the maximum safe
period. By the invention method a tumor located in the remainder of
the body is treated by the at least one chemotherapeutic agent
without destruction of a substantial portion of the bone marrow in
the at least one body part, and without general anesthesia.
[0014] In a presently preferred embodiment of the invention method,
a bone marrow shielding tourniquet is used to apply pressure to at
least one body part containing myelopoietic bone marrow so as to
occlude arterial flow to the bone marrow therein. It is presently
preferred that pressure is applied around one or both shoulders
and/or hips of the patient so as to occlude arterial flow to the
bone marrow in the upper 1/3 of the proximal humerus or femur, for
example by surrounding the shoulder(s) and/or hip(s) with a
tourniquet such as is provided herein. The pressure applied (e.g.,
by the tourniquet) is substantially greater than the systolic blood
pressure of the patient, for example from about 5 mmHg to about
300, above the systolic blood pressure to assure complete occlusion
of arterial flow in the shoulder or hip to which the pressure is
applied.
[0015] In another embodiment, the invention provides a bone marrow
shielding tourniquet adapted to apply pressure around a shoulder or
hip of a human. The invention bone marrow-shielding tourniquet
comprises an inflatable bladder contoured for substantially
covering the shoulder or hip of a human and having an inner face
and an outer face, a fluid-tight connector on the inflatable
bladder for attaching the bladder to a source of fluid pressure,
and a substantially inelastic exterior layer substantially covering
the outer face of the bladder so as to limit expansion of the
bladder in the direction of the exterior layer when the bladder is
inflated by fluid from the fluid source.
[0016] The human shoulder and hip are complex three-dimensional
shapes, rather than substantially cylindrical, as is the arm or
thigh. Consequently it is difficult to apply a tourniquet around
these body parts so as to occlude arterial blood flow to the
myelopoietic bone marrow residing therein. Therefore, the shape of
the invention bone marrow-shielding tourniquet contributes
substantially to its ability to apply pressure over the shoulder or
hip area such that all the arteries that supply the proximal upper
one third of the humerus or femur are occluded by the tourniquet.
In some embodiments, the exterior layer is inflexible or
semi-flexible and the invention tourniquet further comprises a
cooperative fastener for fastening the tourniquet around the
shoulder or hip and/or a brace to hold the patient's arm or thigh
at an angle that facilitates placement of the tourniquet and
prevention of migration of the tourniquet during chemotherapy.
[0017] In another embodiment, the invention provides a bilateral
hard shell bone marrow shielding tourniquet adapted for wearing by
a human. The invention hard shell bilateral tourniquet comprises a
semi-flexible or inflexible and inelastic carapace in one or more
parts, wherein the carapace has a three-dimensional shape adapted
to substantially cover at least the bilateral scapulae and shoulder
areas of a wearer while allowing the head, arms, and lower torso to
protrude from the carapace. Optionally the bilateral tourniquet
further comprises bilateral inflatable bladders attached along the
interior surface of the carapace that, when inflated, apply
pressure over at least the bilateral shoulder areas of the wearer,
and a fluid-tight connector on each inflatable bladder for
inflating the bladder. Inflation of one or both bladders in the
invention hard shell bilateral tourniquet exerts sufficient
pressure upon the respective shoulder area of the wearer to occlude
arterial flow into at least the upper 1/3 of the proximal humerus
of the wearer. The invention bilateral hard shell tourniquet
generally further comprises at least one fastener attached to the
carapace for cinching the carapace about the torso of the wearer,
for example the midriff and upper back. In one embodiment, the
carapace is semi-flexible and in one piece with a neck/chest
opening adapted for receiving the wearer's head and at least one
opening, such as a slit, to enable the tourniquet to be placed
about the wearer.
[0018] In another embodiment, the invention provides an inflatable
bladder comprising an expandable bladder piece shaped to
substantially cover a hip area or a shoulder area of a human, and a
fluid-tight connector on the bladder for connecting the bladder to
a source of fluid pressure. When the inflatable bladder is shaped
to substantially cover a shoulder area, it may further
substantially cover the proximal scapula of a human. The invention
inflatable bladder, or two mirror image inflatable bladders, can be
used with the invention hard shell tourniquet to shield a portion
of a wearer's bone marrow during chemotherapy in accordance with
the invention method of chemotherapy.
[0019] In another embodiment, the invention provides a hard shell
bone marrow shielding tourniquet adapted for applying pressure to a
scapular area of a human wearer. In this embodiment, the invention
tourniquet comprises an inflatable bladder contoured for
substantially covering the scapular area and having an inner face
and an outer face , a fluid-tight connector attached to the
inflatable bladder for attaching the bladder to a source of fluid
pressure, a substantially inflexible and inelastic exterior layer
substantially covering the outer face of the bladder and having a
three-dimensional shape selected to hold the bladder against the
scapular area of a human, and at least one fastener attached to the
exterior layer for cinching the tourniquet about the torso of the
wearer. In this embodiment of the invention tourniquet, inflation
of the bladder by fluid from the fluid source exerts a pressure on
the scapular area of the wearer sufficient to substantially occlude
arterial flow into the scapular area of the wearer.
[0020] In another embodiment, the invention provides a method for
fabricating an individualized bone marrow shielding tourniquet The
invention fabrication method comprises wrapping a hip or shoulder
to be compressed for occlusion of arterial blood flow therein with
an inflatable bladder having an attached air-tight tubing, wrapping
the inflatable bladder with an orthopedic cast material so as to
leave free the distal end of the attached tubing, and molding the
cast material and inflatable bladder around the hip or shoulder
under conditions suitable for causing the orthopedic cast material
to harden into an inflexible hard shell.
[0021] It is, accordingly, one object of the present invention to
provide a method for applying a tourniquet to one or both
shoulders, hips, scapulas, or pelvic areas of a human body, for
example, without general anesthesia, to enable temporary occlusion
of arterial flow into myelopoietic bone marrow contained therein
during administration of a chemotherapeutic agent.
[0022] Another objective of the present invention is to provide new
tourniquets contoured to fit the shoulder or hip area of a human
body.
[0023] Another objective of the present invention is to provide a
contoured hard-shell tourniquet for shoulder or hip area of a human
body.
[0024] Another objective of the present invention is to provide a
method of making a custom-fitted hard-shell tourniquet for the
shoulder or hip area of a human body.
[0025] Another objective of the present invention is to provide a
new tourniquet that places and holds the limbs in a preferred
position relative to the torso of a patient's body to effect
compression of blood vessels that supply the proximal ends of femur
or humerus bones.
[0026] Another objective of the present invention is to provide a
new tourniquet with a binding system to affix the tourniquet at a
preferred position at the shoulder or hip while preventing
migration of tourniquet away from the preferred position on the
shoulder or hip.
[0027] Another objective of the present invention is to provide a
method of using the tourniquet to protect myelopoietic bone marrow
cells from the effects of chemotherapeutic agents without the need
for physical removal of bone marrow cells from the patient's body,
i.e. without expensive apheresis or bone marrow aspiration
procedures.
[0028] Another objective of the present invention is to provide a
method of bone marrow-shielded chemotherapeutic treatment of a
patient by administering one or more chemotherapeutic agents while
protecting bone marrow cells in situ using a tourniquet to occlude
arterial blood flow in the bone marrow, for example in one or both
shoulders and hips.
[0029] Another objective of the present invention is to provide a
method of bone marrow-shielded chemotherapeutic treatment of a
patient using the tourniquet apparatus to administer one or more
chemotherapeutic agents, in combination with bone-marrow
stimulating factors.
[0030] Still another objective of the present invention is to
provide a method of bone marrow-shielded chemotherapeutic treatment
of a patient using the tourniquet apparatus in combination with
administration of highly oxygenated autologous blood into an area
of ischemia behind the tourniquet.
[0031] Still another objective of the present invention is to
provide a method of bone marrow-shielded chemotherapeutic treatment
of a patient using the tourniquet apparatus that includes chilling
the limb behind the tourniquet to reduce metabolic rate and thereby
decrease tissue damage caused by ischemia.
[0032] The invention also comprises such other objects, advantages,
and capabilities as will later more fully appear and which are
inherently possessed by the invention. While the accompanying
drawings show certain embodiments of the invention, it should be
understood that the same is susceptible of modification and change
without departing from the spirit of the invention.
BRIEF DESCRIPTION OF DRAWINGS
[0033] FIG. 1 is a see-through drawing showing preferred shoulder
tourniquet placement with an invention shoulder tourniquet placed
around the shoulder area of a patient such that all the arteries
that supply the proximal end of the humerus are occluded by the
tourniquet.
[0034] FIG. 2 is a perspective view of shoulder tourniquet
apparatus of the present invention positioned and affixed on a
patient's shoulder area.
[0035] FIG. 3 is an elevation view of an invention contoured
shoulder tourniquet,
[0036] FIG. 4 is a cross-sectional view taken through line 30-30 of
FIG. 3.
[0037] FIG. 5 is a cross-sectional view taken through line 31-31 of
FIG. 3.
[0038] FIG. 6 is a perspective view of an invention hard-shell
tourniquet.
[0039] FIG. 7 is a drawing showing an invention hard-shell
tourniquet applied onto a cancer patient.
[0040] FIG. 8 is a cross-sectional view of an invention hard-shell
tourniquet with an inflatable bladder at the beginning of the
inflation.
[0041] FIG. 9 is a cross-sectional view of an invention hard-shell
tourniquet with an inflatable bladder inflated further than in FIG.
8.
[0042] FIG. 10 is a perspective view of an invention shoulder
tourniquet in place on a patient's shoulder area, wherein the
tourniquet includes a brace to keep the occluded arm elevated at an
angle away from the patient's torso.
[0043] FIG. 11 is a perspective view of an invention shoulder
tourniquet fitted with a brace and positioning belt.
[0044] FIG. 12 is a perspective view of an invention shoulder
tourniquet affixed on a patient's shoulder area, wherein the
tourniquet includes a positioning belt to aid in affixing the
tourniquet at a preferred position around the shoulder and to
prevent migration of the tourniquet away from the preferred
position around the shoulder.
[0045] FIG. 13 is a perspective view of an invention shoulder
tourniquet fitted with a positioning belt to aid in affixing the
tourniquet at a preferred position on the shoulder.
[0046] FIG. 14 is a perspective view of a "bilateral" tourniquet
apparatus on both of the patient's shoulder areas, the tourniquet
apparatus being fitted with a positioning belt.
[0047] FIG. 15 is a see-through drawing showing tourniquet
placement with an invention hip tourniquet placed around the hip
area of a patient such that all the arteries that supply the
proximal end of the femur are occluded by the tourniquet.
[0048] FIG. 16 is another see-through drawing showing tourniquet
placement with an invention hip tourniquet placed around the hip
area of a patient and showing details of arteries that supply the
proximal end of the femur.
[0049] FIG. 17 is a perspective view of an invention hip tourniquet
that is fitted with a positioning belt to keep the tourniquet at a
preferred position around the hip and to prevent migration of the
tourniquet away from the preferred position around the hip.
[0050] FIG. 18 is another perspective view of FIG. 17, showing the
invention hip tourniquet about to be placed around the hip area of
a patient.
[0051] FIG. 19 is another perspective view of FIG. 17, showing the
invention hip tourniquet in place around a hip of a patient.
[0052] FIG. 20 is a perspective view of an invention hip tourniquet
that is fitted with a brace to keep the to keep the occluded leg
extended at a fixed angle toward the patient's torso.
[0053] FIG. 21 is a perspective view of an invention hip tourniquet
affixed around a patient's hip area, the hip tourniquet being
fitted with a brace to keep the occluded leg extended at a fixed
angle toward the patient's torso.
[0054] FIG. 22 is a perspective view of an invention hard shell
bilateral tourniquet placed around a wearer's upper torso and
substantially covering both humeri, and both scapulae.
[0055] FIG. 23A is a frontal elevation view of an invention hard
shell bilateral tourniquet having a two piece carapace with the two
pieces assembled, but with the fasteners on the anterior and
posterior exterior of the tourniquet not cinched. The carapace is
designed to cover bilateral shoulder and bilateral scapular areas
of the wearer. A torso opening is shown at the bottom of the
tourniquet. The dotted lines show hidden portions of the bilateral
bladders and of the torso opening at the bottom of the
tourniquet.
[0056] FIG. 23B is a frontal elevation view of the invention hard
shell bilateral tourniquet having a two piece carapace as
illustrated in FIG. 23A, except that the carapace is designed to
cover the bilateral scapular areas of the wearer, but not the
bilateral shoulder areas.
[0057] FIG. 24 is a frontal elevation view of the tourniquet of
FIG. 23 with the two pieces assembled and cinched together by the
fastener.
[0058] FIG. 25 is a frontal elevation view showing bilateral
inflatable bladders for applying pressure to the wearer's bilateral
shoulder areas and scapulae that line the interior surface of the
invention tourniquet carapace of FIGS. 22-24.
[0059] FIG. 26 is a frontal elevation view of an invention hard
shell bilateral tourniquet having a one piece semi-flexible
carapace with under arm openings drawn together and cinched by a
plurality of fasteners. The bottom of the tourniquet has a torso
opening. Bilateral inflatable bladders for applying pressure to the
wearer's bilateral shoulder areas and scapulae are shown lining the
interior surface of the invention tourniquet carapace above the
bottom torso opening. Hidden portions of the torso opening and
bladders are shown in dotted lines.
[0060] FIG. 27 is a frontal elevation view of an invention hard
shell bilateral tourniquet having a one piece, front-opening,
semi-flexible carapace that the wearer puts on like a vest. Two
fasteners join the left and right sides of the back of the carapace
across the chest of the wearer. Bilateral inflatable bladders for
applying pressure to the wearer's bilateral shoulder areas and
scapulae are shown lining the interior surface of the invention
tourniquet carapace with hidden portions shown as dotted lines.
[0061] FIG. 28 is a frontal elevation view of an invention hard
shell bilateral tourniquet having a one piece, back-opening,
semi-flexible carapace that the wearer puts on like a hospital
gown. Two fasteners (shown in cross-hatching) join the left and
right sides of the back opening of the tourniquet above a bottom
torso opening. Bilateral inflatable bladders for applying pressure
to the wearer's bilateral shoulder areas and scapulae are shown
lining the interior surface of the invention tourniquet carapace.
Hidden portions of the bottom torso opening and of the bladders are
shown as dotted lines.
[0062] FIG. 29 is a frontal elevation view of an invention hard
shell bilateral tourniquet having a two piece carapace with the two
pieces hinged at the top of the shoulder and with under arm
openings drawn together and cinched by a plurality of fasteners.
The bottom of the carapace has a torso opening. Bilateral
inflatable bladders for applying pressure to the wearer's bilateral
shoulder areas and scapulae are shown lining the interior surface
of the invention tourniquet carapace. Hidden portions of the bottom
torso opening and of the bladders are shown as dotted lines.
[0063] FIG. 30 is a frontal elevation view of an invention hard
shell tourniquet having a one-piece inflexible carapace adapted to
fit about a wearer so as to cover the scapular area (but not the
shoulder cap or arm pit) and a portion of the chest. An inflatable
scapular bladder for applying pressure to the triangular scapular
area of a human (i.e., the shoulder blade), but not the shoulder
area, is shown lining the interior surface of the carapace. Hidden
portions of the bottom torso opening and of the bladders are shown
as dotted lines.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0064] In adults, active marrow is located primarily in the axial
skeleton, including the vertebral bodies, pelvis, sternum, ribs,
scapulae, and to a variable extent, the skull. In the limbs, active
bone marrow is restricted to the proximal one third of the femurs
and humeri (with more peripheral extension of marrow seen in
children). In fact, the proximal humerus contains hematopoietic
marrow in 99% of adult patients, with some patchy extension to the
epiphysis in 62% of adults. Surprisingly, the adult humerus
contains a larger quantity of hematopoietic marrow than the femur,
despite its smaller size.
[0065] Accordingly, in the present invention there are provided
method(s) for bone marrow-shielded chemotherapeutic treatment of a
patient in need thereof. The invention method(s) comprise applying
pressure to at least one body part of the patient that contains
myelopoietic bone marrow to temporarily occlude arterial flow to
the bone marrow while blood circulation through the remainder of
the body is maintained, administering to the blood circulation in
the remainder of the body an effective amount of at least one
myelosuppresive chemotherapeutic agent while the arterial flow
through the at least one body part is occluded so that the
myelosuppresive effect of the agent is substantially dissipated
within the maximum safe period for the occlusion of arterial flow,
and removing the pressure to restore blood circulation to the bone
marrow when the effect has substantially dissipated and within the
maximum safe period. By the invention method, a tumor located in
the remainder of the body is treated by the at least one
chemotherapeutic agent without destruction of a substantial portion
of the bone marrow in the at least one body part. The invention
method(s) can be practiced either with or without general
anesthesia.
[0066] The term "substantially dissipated" as used herein means
that the myelosuppresive effect of the chemotherapeutic agent has
subsided sufficiently in the circulating blood that irreparable
damage to a substantial portion of the bone marrow in the occluded
body part will not occur when the blood circulation is restored to
the body part. As those of skill in the art will appreciate, the
period of time required for the chemotherapeutic (i.e.,
myelosuppresive) effect to be substantially dissipated will depend
upon the pharmokinetics of the particular chemotherapeutic agent
used, or of the combination of chemotherapeutic agents used, and
can be selected by the skilled practitioner when taking into
account such factors as the initial half-life and residual effects
of the chemotherapeutic agent or combination of therapeutic agents,
as well as the size and general health of the patient.
[0067] In a presently preferred embodiment of the invention
method(s), a bone marrow shielding tourniquet is used to apply
pressure to at least one body part that contains myelopoietic bone
marrow so as to occlude arterial flow to the myelopoietic bone
marrow. Use of the invention bone marrow shielding tourniquet in
practice of the invention method(s) greatly facilitates practice of
the methods with or without general anesthesia as explained more
fully herein.
[0068] The most convenient body parts to be shielded during
chemotherapy in a human adult are the shoulder and hip. The term
"shoulder" or "shoulder area" as used in the description and claims
herein means the part of the body formed by the lateral portions of
a scapula and clavicle, at least the head of the proximal humerus,
and the flesh covering them (including the areas commonly referred
to as the shoulder cap and the arm pit). Similarly, the term "hip"
or "hip area" as used in the description and claims herein means
the part of the body formed by the pelvis, at least the head of the
femur, and the flesh covering them (including the areas commonly
referred to as the "hip bone" and groin). As used herein, the term
"shoulder tourniquet" means a tourniquet shaped to conform to and
fit around the shoulder area of a human so as to substantially
cover the shoulder area, and the term "hip tourniquet" means a
tourniquet apparatus shaped to conform to and fit around the hip
area of a human so as to substantially cover the hip area. The term
"scapula" or "scapular area" as used herein means the substantially
flat, triangular bone commonly known as the shoulder blade and the
flesh covering it, but does not necessarily include the spine. The
term "nutrient artery" or nutrient arteries" as used herein means
the arteries supplying blood into bone and bone marrow that enter
the body (or shaft) of a long bone, in this case the humerus or
femur. The arteries supplying the ends of the humerus and femur
have individual names as provided herein.
[0069] The term "bone-marrow shielding" as used herein means a
process of temporarily occluding arterial blood flow into a body
part containing myelopoietic bone marrow, such as a shoulder or
hip, for example, during administration of cancer chemotherapy. The
term "occludes," "occluded" and "occluding" as used herein mean
temporary occlusion of arterial blood flow into the affected body
part. Whether arterial blood flow has been occluded in a shoulder
or hip can be empirically determined by determining the absence of
a pulse in the adjacent limb, for example the pulse of the dorsalis
pedis artery in the foot or the radial artery in the wrist. The
term "bone-marrow shield" is defined as an apparatus, such as an
invention tourniquet, that performs bone-marrow shielding.
[0070] Preferably, the occluding pressure is applied to the body
part using an inflatable, releasable tourniquet that occludes
arterial flow to the body part, preferably completely, such as the
invention tourniquet(s) described herein. However, the pressure is
applied, it is essential that the pressure not be inadvertently
released to allow arterial flow into the shielded bone marrow while
the myelosuppresive effect of the chemotherapeutic agent(s) is
substantially present in the circulating blood, as such an accident
could result in serious injury to the patient. When the bone marrow
shielding pressure is applied to a shoulder area, it is therefore
essential that arterial flow into the proximal upper 1/3 of the
humerus of the patient be substantially occluded, preferably
completely occluded. Similarly, when the bone marrow shielding
pressure is applied to a hip area, it is essential that arterial
flow into the proximal upper 1/3 of the femur of the patient be
substantially occluded, preferably completely. Since bone marrow
shielding of the shoulder or hip areas requires substantial
occlusion of the arteries into these body parts, the invention is
best understood by reference to the anatomy of the body parts to be
shielded. FIG. 1 illustrates cancer patient 1 with an arm 10 in a
preferred elevated position with shoulder tourniquet 20 placed in a
preferred shoulder area location. For the upper limb, the arteries
supplying the upper end of the humerus 12 include anterior and
posterior humeral circumflex arteries 8 and 9, which are typically
the last branch of the axillary artery 4, which is the direct
continuation of the subclavian artery. The deltoid branch of
thoraco-acromial artery 2 also supplies the upper end of the
humerus in some patients. The nutrient artery of the humerus is a
thin branch that arises from the brachial artery 5 about the middle
of the upper arm and enters the anteromedial surface of the middle
third part of the humerus. To interrupt blood circulation into the
upper humerus it is critical for the tourniquet to compress not
only the main artery supplying the limb (axillary artery 4 which
continues on as brachial artery 5), but also smaller branch
arteries of the upper humerus, such as the anterior and posterior
humeral circumflex arteries 8 and 9 and the deltoid branch of
thoraco-acromial artery 2. FIGS. 8 and 9 show cross-sections
through the upper humerus bone with an invention shoulder
tourniquet in position before and after inflation,
respectively.
[0071] The tourniquet compresses the main artery, brachial artery
58 against the humerus to occlude arterial flow, but median nerve
57, ulnar nerve 60 and radial nerve 61 will also be compressed
against the humerus. It is important to the practice of the
invention that the pressure applied to occlude arterial flow into
the upper humerus be as evenly distributed over the surface of the
shoulder area as possible to avoid damage to these nerves.
Therefore, in the invention method(s) the pressure is preferably
applied over the entire shoulder area and the pressure applied, for
example by a tourniquet, is preferably substantially equalized over
the shoulder area. Similarly, the invention bone marrow-shielding
shoulder tourniquet is contoured to extend over the shoulder area
so as to substantially equalize the pressure applied to the
delicate nerves and arteries within the shoulder area.
[0072] It is preferred that the arm 10 is in an elevated position
to enable preferred placement of tourniquet 20 in shoulder area
when the invention shoulder tourniquet is used in practice of the
invention bone marrow shielded chemotherapy method. Therefore, as
shown in FIG. 1, the angle 3 formed by the patient's arm 10 and the
proximal side of the patient's torso 11 is preferably between 45
degrees and 180 degrees, more preferably between 75 degrees and 160
degrees, and most preferably between 85 degrees and 140 degrees in
practice of the invention method.
[0073] The anatomy of the hip area, is illustrated in FIGS. 15 and
16, which show the blood supply of the femur 13 consisting of
multiple arteries entering each end of the femur, and one or two
nutrient arteries entering the body or shaft of the femur. The
nutrient arteries are usually derived from upper perforating
branches of the profunda femoris 18; and they enter the femur close
to the linea aspera and run up and down in the marrow cavity.
Although the nutrient arteries in the femur anastomose with the
vessels at the two ends of the femur, the upper perforating
branches of the profunda femoris 18 are the chief supply of
nutrients to the human femur.
[0074] The arteries to the upper end of the femur are derived
mostly from the medial 17 and lateral 16 femoral circumflex
arteries; which provide numerous branches to the trochanters. The
artery of the ligament of the femoral head, derived from the
obturator 15 (see FIG. 16) or the medial femoral circumflex 17,
enters the head through the ligament of the head and supplies a
variable amount of bone adjacent to the fovea. Otherwise, the head
and neck are supplied by branches of the two circumflexes 16 and
17. These branches approach the bone at the level of attachment of
the capsule of the hip joint, pierce the capsule, and then run
upward along the neck deep into the synovial membrane that is
reflected upward around the neck to the cartilage of the head. To
occlude arterial circulation into the upper femur, it is important
for the tourniquet to compress not only the main femoral artery 6,
but the smaller branches that supply the upper femur such as the
medial and lateral femoral circumflex arteries 16 and 17 and the
artery of the ligament of the head 19.
[0075] The scapulae of adult humans also contain myelopoietic bone
marrow. Therefore, in an alternative embodiment of the invention
method(s), a bone marrow shielding pressure is applied to one or
both scapulae in a manner that occludes arterial flow thereinto.
There are three main arteries that supply the scapulae. The first
is the suprascapular artery, which arises from the thyrocervical
trunk in the neck. The suprascapular artery courses backward above
the scapular notch on the superior border of the scapula and
supplies blood to the back (dorsal) surface (facie) of the scapula.
The second is the subscapular artery, which arises from the
axillary artery. The subscapular artery supplies the front (costal)
surface of the scapula and then branches into the scapular
circumflex artery, which swings around the lower border of the
scapula and supplies arterial blood to the back (dorsal) surface of
the scapula. The third is the transverse cervical artery, which
also arises from the thyrocervical trunk in the neck. The
transverse cervical artery runs along the medial margin of the
scapula and supplies both the back (dorsal) and front (costal)
surfaces of the scapula. Application of sufficient pressure over
the back (dorsal) surface of the scapula will compress the arteries
supplying the back surface of the scapula Such a pressure upon the
back surface of the scapula can transmit the pressure to the
posterior rib cage, further compressing the arteries between the
front surface of the scapula and the rib cage.
[0076] Therefore, in practice of the invention method, the at least
one body part is selected from the group consisting of an upper
femur, an upper humerus, and a scapula of the patient, and
combinations of two or more thereof.
[0077] To assure that arterial flow is substantially occluded to
the bone marrow to be shielded, the pressure applied, for example
by the invention tourniquet, is substantially greater than the
systolic blood pressure of the patient, preferably at the point of
application of the tourniquet, for example from about 5 mmHg to
about 300 mmHg above the systolic blood pressure, such as from
about 20 mmHg to about 250 mmHg, and preferably about 50 mmHg to
about 200 mmHg above systolic blood pressure. Alternatively,
pressure of about 280 mmHg may be used. Preferably, the tourniquet
is applied around or over the body part so that the occluding
pressure is substantially equalized over the entire area.
[0078] Once the pressure has been applied, and occlusion of
arterial flow is assured, one or more chemotherapeutic agents
selected to treat the type of tumor under treatment can be
administered, for example, by injection of the chemotherapeutic
agent(s) into the blood circulation to treat a tumor that lies
within the trunk or within any part of the body in which the
circulation of blood has been maintained. Any myelosuppresive 20
chemotherapeutic agent known in the art can be safely administered
in the standard dosage, or in a higher dosage, so long as the
myelosuppresive effect of the agent(s) is substantially dissipated
before removal of the occluding pressure and any
non-myelosuppresive side-effect is not dose-limiting. Given the
present understanding in the medical arts concerning methods for
extending the maximum safe period, the arterial flow can be
occluded before irreversible cell damage to the occluded body part
(e.g., extremity) occurs, the occluding pressure is removed in
practice of the invention method within the maximum safe period for
occluding arterial flow, generally about three hours, or preferably
two hours, of commencement of the application of the occluding
pressure to the body part.
[0079] Therefore the chemotherapeutic agent(s) are selected to have
the property that their myelosuppresive effect will be
substantially dissipated before the occluded body part sustains
irreversible damage caused by the occlusion.
[0080] Generally, the chemotherapeutic agent or combination of
chemotherapeutic agents is selected to have a half life of from
about 10 seconds to about 25 minutes. However, many
chemotherapeutic agents continue to have myelosuppresive effect for
a period equal to three or more half-lives, and their
chemotherapeutic effect is generally maximized when the activity of
the agent(s) is allowed to substantially dissipate by the natural
operation of bodily processes, as is known to those of skill in the
art Therefore in practice of the invention method the general rule
is that the chemotherapeutic agents used are selected and the
method of administration (i.e. whether bolus, drip or infusion) is
selected so that the myelosuppresive effect of the agent(s) will
have substantially dissipated (i.e., at least to a level that will
not irreparably harm bone marrow) within three hours, or preferably
two hours, of application of the occluding pressure to the body
part of the patient. It is not presently possible to extend the
period of occlusion for substantially longer than about three hours
even when secondary measures such as chilling of the occluded body
part or infusion of oxygenated blood into the occluded body part
are taken, as explained more fully hereafter. Generally, the
chemotherapeutic agent(s) is selected and administration of the
chemotherapeutic agent(s) is timed so the level of toxicity of the
chemotherapeutic agent to myelopoietic bone marrow has dissipated
to a safe or acceptable level within no more than about two hours
of occlusion of arterial blood flow to the body part.
Alternatively, in some cases, a known neutralizing agent that
lowers the toxicity of the chemotherapeutic agent(s) can be
administered so that circulation can be restored to the occluded
body part within a safe time period. The invention therapeutic
treatment method can be repeated at spaced intervals of from eight
hours to two months for up to 20 repeats, depending upon the choice
of the chemotherapeutic agent.
[0081] Many chemotherapeutic agents have a known in vivo initial
half life of about 25 minutes or less, as shown in Table I herein
below. When such an agent is used in the practice of the invention
method(s), the pressure can be removed to restore blood circulation
to the protected bone marrow about 15 minutes after passage of the
known period of initial half life of the chemotherapeutic
agent.
1TABLE 1 Myelosuppresive Chemotherapeutic Agents with Short
Half-Lives Cancer Initial Terminal Drugs T1/2 T1/2 Toxicities
Common Indications Dose Mechlor- .about.1 min. hematologic, N/V
Hodgkin's dis. lymphoma, 0.1 to 1.6 mg/kg ethamine lung, breast,
ovary cancers IV Doxorubicin 5 min 10 hrs hematologic, breast,
ovary, lymphoma, lung 5 to 75 mg/m.sup.2 IV cardiac cancers 5-FU +
16 min* hematologic, Colon, breast, rectal, stomach, 300 to 1200
mg/m.sup.2 leucovorin diarrhea, ovary, cervix, bladder, liver, IV
5-FU + 500 stomatitis pancreatic, head and neck mg/m.sup.2 IV LV
cancers 5-fluoro- 16 min* hematologic, Colon, breast, rectal,
stomach, 300 to 1200 mg/m.sup.2 uracil (5-FU) stomatitis ovary,
cervix, bladder, liver, IV pancreatic, head and neck cancers
Dactino- 2 min 36 hrs hematologic; Wilm's tumor, 0.2-2.5 mg/m.sup.2
IV mycin mucositis rhabdomyosarcoma, Swing's sarcoma, trophoblastic
neoplasms, testicular, Kaposi's sarcoma, melanoma, breast, ovary
cancers, and regional isolation perfusion Mitomycin- 6-17 min
hematologic, 2% Breast, stomach, pancreas, 5-10 mg/m.sup.2 IV C
renal, HUS, colon, rectum, H&N, lung, pulmonary. cervix.
Streptozocin 5 min 35-40 25-70% renal, Pancreatic islet cell,
carcinoid, 200-500 mg/m.sup.2 IV min mild hematologic. Hodgkin's
disease, colorectal, hepatoma, melanoma. Mito- 9 min 29 hrs
moderate Leukemia, prostate 4-75 mg/m.sup.2 IV xantrone
hematologic, cholestasis, cardiac BCNU 6 min 68 min hematologic,
Brain tumors, multiple 50-225 mg/m.sup.2 IV pulmonary myeloma,
lymphoma, Hodgkin's disease, melanoma, gastero-intestinal tumors,
breast, lung Cytarabine 7-20 min hematologic Leukemia, lymphomas.
20-3000 mg/m.sup.2 IV Melphalan 10 min 75 min hematologic Multiple
myeloma, ovarian, 2-8 mg/m.sup.2 IV breast, prostate, melanoma,
isolation perfusion. Thiotepa 8 min 2.4 hr hematologic Breast,
ovary, lymphoma, lung, 0.1-0.4 mg/kg IV DTIC (da- 10 min 5 hrs
hematologic Melanoma, lymphoma, soft- 200 mg/m.sup.2 IV carbazine)
tissue sarcomas, neuroblastomas. 5-fluoro- 16 min* hematologic,
Colon, breast, rectal, stomach, 5-20 mg/m.sup.2 IV deoxyuridine
stomatitis ovary, cervix, bladder, liver, pancreatic, head and neck
cancers 5-Aza- 2-5 min hematologic; Leukemia 200 mg/m.sup.2 IV
citidine neurotoxicity, mucositis *Shorter half-life with smaller
doses
[0082] The list of useful chemotherapeutic agents in Table 1 is
merely exemplary and is not intended to be limiting in any way.
Additional useful intravenous agents not included in Table 1,
agents being developed, or agents yet to be developed, and
combinations thereof, are just as useful provided they exhibit the
following desirable characteristics: 1) the chemotherapeutic
agent(s) and their active metabolic products have sufficiently
short half-lives following intravenous administration so that the
concentration of the active drug or active metabolic products are
at a clinically safe level when the occluding pressure is released;
2) the agent(s) have hematological toxicity; and 3 ) the agent(s)
have cytotoxic activity against the type of tumor being
treated.
[0083] It is also possible to combine a myelosuppresive drug, such
as those in Table 1, with a less myelosuppresive drug in practice
of the invention. Table 2 below lists chemotherapeutic agents that
are less myelosuppresive than those in Table 1, but which can be
combined with myelosuppresive drugs, such as those in Table 1, for
combination chemotherapy. Of course, drugs in Table 1 may also be
combined among themselves for combination chemotherapy.
2TABLE 2 Less-Myelosuppresive Chemotherapeutic Agents for
Combination Chemotherapy. Cancer Initial Drugs T1/2 Toxicities
Indications Dose Cisplatin 30 min moderate hematologic, Testicular,
lung, ovary, 20-100 mg/m.sup.2 IV severe nausea/vomiting, bladder,
head and neck, renal cervical cancers. Vincristine 2.6 hr mild
hematologic; Leukemia, Hodgkin's disease, 1-1.4 mg/m.sup.2 IV
neuropathy lymphoma, sarcomas, small cell lung, breast, Kaposi's
sarcoma, multiple myeloma, renal cell Hemamethyl- 5 hrs mild
hematologic, Ovarian cancer 150 mg/m.sup.2 PO qd X melamine**
neurotoxicity 14 days Bleomycin 2 hr mild hematologic; skin;
Testicular, lymphomas, 2-15 U/m.sup.2 IV qwk pulmonary fibrosis,
fever Hodgkin's disease, head and neck cancers **Available in per
oral formulation
[0084] Thus, it can be seen that the period of time after
administration of the chemotherapeutic agent that the pressure is
maintained on the occluded body part is determined by two
factors--by the in vivo clearance rate of the chemotherapeutic
agent, or the combination of the agents, and by the maximum safe
period for stoppage of arterial flow into the body part under the
treatment conditions (i.e., whether the occluded body part is being
chilled and/or infused with pre-oxygenated autologous blood during
the occlusion period). Generally, the occluding pressure is removed
about 1 minute to about 2 hours after passage of a known period of
initial half life so that the arterial flow is occluded for a
period of from about 5 minutes to about 2 hours. For example, where
the known period of initial half life is about 10 seconds to about
25 minutes, the removing of an invention tourniquet to release the
pressure on the occluded body part is about 15 minutes after
passage of the known period of initial half life. Whatever the
pharmacokinetics or the treatment conditions, under existing
technology the period of occlusion is limited to about 3 hours.
However, it is anticipated that the maximum safe period of
occlusion may be extended by future development in the art.
[0085] It is usually preferred, to minimize the period of occlusion
of a body part, not only for safety, but for the comfort of the
patient to alleviate such symptoms as anxiety, nausea, pain, and
the like, caused by the combined physiological and psychological
effects of the drugs and the occlusion of arterial flow. Therefore,
the selection of the chemotherapeutic agent is guided, as much as
possible (so long as the other two above-listed required
characteristics are met) by giving preference to a chemotherapeutic
agent having the shortest initial half-life. Nitrogen mustard
(mechlorethamine) and 5-azacitidine have the shortest in vivo
half-lives following intravenous administration in humans of all
chemotherapeutic agents presently known. Because of the short
half-lives of these drugs, it is safe to release the pressure on
the occluded body part as soon as 10 minutes after administration
of the drug(s) while substantially shielding the bone marrow within
the occluded body part, although a somewhat longer period of
post-administration occlusion, for example, 15 to 30 minutes or
even up to 2 hours may increase the bone marrow protection to a
further extent. When the chemotherapeutic agent is mechlorethamine,
the effective amount is in the range from about 0.1 mg/kg to about
1.6 mg/kg, for example, in the range from about 0.2 mg/kg to about
0.6 mg/kg of body weight of the patient.
[0086] In addition to the short half-life, nitrogen mustard also
has the advantage of having a broad spectrum activity against a
variety of cancers, such as Hodgkin's disease, lymphoma, sarcoma
and skin, lung, breast, brain, colon, prostate, testicular and
ovarian cancers, and the like. Nitrogen mustard also has the
property of being neutralized by sodium thiosulfate. Therefore, it
is possible to neutralize the remaining activity of the drug
remaining before removing the pressure (e.g. releasing the
tourniquet) to allow arterial blood flow into the occluded body
part. Due to this combination of properties, nitrogen mustard is
currently the chemotherapeutic agent preferred for use in the
invention method of treatment of these cancers.
[0087] The chemotherapeutic agent 5-azacitidine, which is a
nucleoside analogue that has somewhat narrow spectrum of activity
compared to nitrogen mustard, has an initial active half life of 2
to 5 minutes, making it an especially useful for use in the
invention method wherein general anesthesia is not used. With the
shielding of bone marrow according to the invention, as illustrated
in Example 13 below, an escalation of dose intensity is now
possible, for example to as high as 200 mg/m.sup.2 of treated body
surface. At such elevated dosage, this chemotherapeutic agent may
have activity against a wider spectrum of cancers.
[0088] Doxorubicin is a DNA intercalator with very rapid initial
half-life (about 5 minutes) followed by longer terminal half-life
(about 10 hours or more). Because of the rapid initial half-life,
substantial shielding of occluded bone marrow occurs when the
occluding pressure is maintained for a period as short as about 15
minutes to 1 hour post administration of the doxorubicin, although
a longer period of tourniquet application can further shield the
bone marrow and further reduce myelosuppression therein. This agent
has very broad spectrum of activity against cancers arising from
breast, lung, ovary, and lymphoma. There are several different
types of suitable dosing for use of doxorubicin in practice of the
invention methods. For example, smaller doses such as about 5 m
m.sup.2to about 20 mg/m.sup.2 of treated body surface can be given
frequently, for example daily for about 2 to about 5 times. Another
method less frequently, is to give a larger dose, such as about 21
mg/m.sup.2 to about 75 mg/m.sup.2 of treated body surface, for
example about 5 mg/m.sup.2 to about 75 mg/m.sup.2; 10 mg/m.sup.2 to
about 50 mg/m.sup.2; or preferably, about 50 mg of doxorubicin per
m2 of treated body surface.
[0089] 5-Fluorouracil (5-FU), alone or in combination with the
vitamin leucovorin, and/or 5-fluorodeoxyuridine (both are
pyrimidine nucleoside analogues) has a broad spectrum of activity
against the commonly occurring malignancies, such as breast, head
and neck, colon, and other cancers arising from the
gastrointestinal tract. These primitive nucleoside analogues have
relatively short half-lives of some 16 minutes, which is
dose-dependent. That is, smaller doses have shorter half-lives,
even as short as 8 minutes. Therefore, smaller, frequent doses
allow use of shorter tourniquet times. Maximal tourniquet
post-dosage duration, such as 1 to 2 hours, is most preferred to
maximize bone marrow shielding, but a shorter duration of
occlusion, such as about 30 minutes to about 59 minutes will still
give substantial protection from the myelosuppresive effects of
these drugs. However, these drugs can cause well known side
effects, such as stomatitis, which can be reduced by ice chips in
the mouth for a 30-minute period during bolus injection therapy.
When 5-FU is given with leucovorin, diarrhea from enterocolitis can
assume life-threatening proportions. This severe diarrhea usually
responds to therapy, for example with octreotide acetate; however
the fluid loss caused by diarrhea generally must be replaced by
aggressive fluid replacement.
[0090] Dactinomycin (or actinomycin D) is a DNA intercalator whose
antitumor and toxic effect may be proportional to peak drug
concentration rather than to the prolonged exposure to low
concentration. This agent also has very rapid initial distribution
half-life of 2 minutes and very slow terminal half-life. Toward the
end of the initial distribution phase, when the pharmacokinetic is
beginning to be dominated by the slow terminal half-life, the
plasma concentration usually drops below the concentration that is
irreversibly damaging to human cells. Therefore, a post-dosage
tourniquet duration of about 15 minute to about 1 hour, is
sufficient time for the major part of initial rapid half-life
distribution phase to run its course and to allow the drug
concentration in plasma to drop close to or below a therapeutic
concentration. Nevertheless, a longer tourniquet duration of about
1 to about 2 hours may be further beneficial for shielding the
occluded bone marrow from myelosuppression. Several different
suitable dosing regimens can be used in practice of the invention
method using dactinomycin. For example, about 0.2 to about 0.5
mg/m.sup.2 of affected body area can be administered at spaced
intervals, for example daily for about 2 to 5 times. Alternatively,
a larger dose, such as about 0.6 to about 2.5 mg/m.sup.2, can be
administered less frequently. Use of dactinomycin in the invention
method is illustrated herein in Example 17 below.
[0091] Mitomycin-C is an agent with a fairly broad spectrum of
activity against breast, stomach, pancreas, colon, rectum, head and
neck, lung, and cervical cancers and has a half-life of 6-17
minutes. Since hematologic toxicity is severe with this drug, a
tourniquet duration of 1 to 2 hours is preferred. Nevertheless, a
shorter duration of tourniquet application, such as 30 minutes to
59 minutes, may provide additional shielding from myelosuppresive
effects to the bone marrow within the circulation-isolated part of
the body. Non-hematological toxicity, especially hemolytic uremic
syndrome and pulmonary toxicities, are rare, but potentially dose
limiting and fatal. The usual intravenous dose is from about 10 to
about 20 mg/m.sup.2 of treated body surface.
[0092] Streptozocin has chemotherapeutic activity against such
cancers as Hodgkin's disease and pancreatic islet cell or carcinoid
colorectal cancers, hepatoma, and melanoma and the like. Because
this drug is cleared by the liver, Streptozocin may cause problems
when the drug is combined with other drugs metabolized by the
liver, such as doxorubicin. Also, because of potential renal
toxicity, this drug is generally not combined with other
nephrotoxic drugs, such as cisplatin. The hematologic toxicity of
streptozocin is relatively mild as compared with other
chemotherapeutic drugs. Therefore, the recommended post-dosage
duration of occlusion is from about 30 minutes to about 60 minutes.
Example 19 below is an example of the invention method employing
Streptozocin.
[0093] Mitoxantrone is a DNA intercalator with rapid initial
half-life of 9 minutes and a long terminal half-life of 29 hours.
As is the case with actinomycin D, plasma concentration of
mitoxantrone drops below the lethal concentration for human cells
at the end of the initial rapid-half-life (i.e., the distributive
phase of pharmacokinetics) so that the period of occlusion
necessary to substantially shield bone marrow from myelosuppresive
effects is about 30 minute to about 1 hour post-dosage.
Nevertheless, a longer post-dosage tourniquet duration of about 1
to about 2 hours may be further beneficial for reducing
myelosuppression in the shielded bone marrow. There are several
different types of suitable dosing. Smaller doses such as about 4
mg/m.sup.2 to about 20 mg/m.sup.2 of treated body surface can be
given frequently, for example daily for 2 to 5 times.
Alternatively, a larger dose, such as about 21 mg/m.sup.2 to about
75 mg/m.sup.2 of treated body surface can be administered less
frequently. Example 20 below illustrates use of mitoxantrone in the
invention method.
[0094] BCNU (carmustin) has a somewhat broad spectrum of activity
against brain tumor, multiple myeloma, lymphoma, melanoma,
gastero-intestinal tumors and breast and lung cancers. The main
toxicities are hematologic and pulmonary. The pulmonary toxicity
can be ameliorated by concurrent administration of prednisone.
Because the plasma half-life of BCNO is 15-20 minutes, bone marrow
is generally shielded by maintaining the occluding pressure for
about 1 to about 2 hours following administration of the BCNU.
However, a shorter duration of 30 minutes to 1 hour also provides
some protection to the bone marrow within the circulation-isolated
part of the body. Example 21 below illustrates use of BCNU in
practice of the invention method.
[0095] Cytarabine is mainly useful for treatment of leukemia and
lymphoma However, it has synergistic activity against solid tumors
when given with other agents, such as cisplatin. In addition, when
administered in frequent small doses, this agent has significant
activity against a broad spectrum of solid tumors in its own right.
Cytarabine has fairly short half-life in circulation, about 7-20
minutes. Thus, in practice of the invention method, the shielding
is preferably continued for about 1 to about 2 hours after
administration of cytarabine to maximize bone marrow protection,
but a shorter duration of shielding, such as about 30 minutes to
about 1 hour will reduce the myelosuppresive effect, especially
when the cytarabine is given in smaller doses within this range.
This drug has hematologic toxicity as the main side-effect. Use of
cytarabine in the invention method is illustrated in Example 22
below.
[0096] Melphalan has a biphasic pharmacokinetic profile following
intravenous administration in humans. The initial half-life is
quite short, about 10 minutes, but the terminal half-life is quite
long at about 75 minutes. Therefore, in practice of the invention
method, the occluding pressure is preferably maintained for about 1
to about 2 hours following administration of melphalan. However,
shielding for a shorter duration, such as about 30 minutes to about
1 hour post-dosage, is beneficial in protecting the shielded bone
marrow against the myelosuppresive effects of melphalan. Use of
melphalan in the invention method is illustrated in Example 23
below.
[0097] Thiotepa is a polyfinctional alkylating agent with a wide
spectrum of anti-cancer therapeutic activity, for example against
breast, ovarian, and lung cancers, as well as against lymphomas.
Following intravenous administration, the serum concentration of
thiotepa declines rapidly with a half-life of about 8 minutes
during the initial distributive phase of pharmacokinetics (i.e.,
the initial half-life). Therefore, when thiotepa is used as the
therapeutic agent in practice of the invention method, maintaining
the occluding pressure for about 15 to about 60 minutes after
administration of the drug is generally sufficient to provide
substantial protection against myelosuppression to the shielded
bone marrow. Nevertheless, longer tourniquet duration such as about
1 to about 2 hours post-dosage may further decrease the exposure of
the shielded bone marrow to myelosuppresive effects of the drug.
Use of thiotepa in the invention method is illustrated in Example
24 below.
[0098] Dacarbazine (DITC) is a synthetic analogue of the naturally
occurring purine precursor, 5-amino-1H-imidazole4-carboxamine, but
this drug works as an alkylating agent and has a spectrum of
activity against melanoma, lymphoma, soft-tissue sarcomas, and
neuroblastomas. The initial distributive phase half-life is quite
short at about 10 minutes. Therefore, applying pressure to occlude
arterial blood flow to the shielded body part for about 30 to about
60 minutes postdosage provides substantial protection against
myelosuppression therein. Applying the occluding pressure for a
longer period, such as about 1 to about 2 hours, may further reduce
myelosuppression in the shielded bone marrow. An illustration of
the invention method using dacarbazine as the chemotherapeutic
agent in the invention method is provided in Example 25 below.
[0099] When the invention bone marrow shielding tourniquet is used
to occlude arterial blood flow to both shoulder areas, the
chemotherapeutic drug is most conveniently administered via a
central venous catheter, such as a Port-A-Cath.RTM., Hickman
catheter, Groshong catheter, Pick line, or Broviac catheter. The
catheter is preferably placed into a vein selected from the group
consisting of internal jugular vein, external jugular vein, and the
subclavian vein.
[0100] In patients undergoing the chemotherapy according to the
invention method, the venous blood pH prior to tourniquet
activation is generally between 7.33 to 7.37 with an average of
approximately 7.35; pO.sub.2 is 43-53 mmHg (48 mmHg average),
pCO.sub.2 is 38-43 mmHg (average of 41 mmHg), and lactic acid
concentration is 3 to 9 mg/dl. When arterial flow is occluded, for
example, by inflation of the invention tourniquet, the oxygen is
initially consumed fairly rapidly by continued aerobic metabolic
activity, generating carbon dioxide. As hypoxia deepens, the cells
largely convert into an anaerobic metabolic pathway, which does not
consume oxygen, but generates lactic acid, which in turn lowers the
blood pH. Following the initial 30 minutes of tourniquet inflation,
the venous blood pH drops to 7.24-7.30, pO.sub.2 drops to 25-30
mmHg (average 27 mmHg), pCO.sub.2 rises to 48-56 mmHg, and lactic
acid rises to 20 to 30 mg/dl. After 60 minutes of total tourniquet
time, the blood pH drops further to an average of 7.14 (range:
7.11-7.17), pO.sub.2 drops slightly further to 22-25 mmHg (average
23 mmHg), pCO.sub.2 rises further to 63-69 mmHg (average 65 mmHg),
and lactic acid continues to rise precipitously to 50-70 mg/dl. At
90 minutes of total tourniquet time, the blood pH drops further to
an average of 6.99 (range: 6.97-7.05), pO.sub.2 drops further to
9-19 mmHg (average 13 mmHg), pCO.sub.2 rises further to 83-91 mmHg
(average 88 mmHg), and lactic acid continues to rise precipitously
to 60-80 mg/dl. At 120 minutes of total tourniquet time, the blood
pH is now very acidotic with average pH of 6.90 (range: 6.88-6.96),
pO.sub.2 drops very low to 3-9 mmHg (average 7 mmHg), pCO.sub.2
rises even further to 95-113 mmHg (average 107 mmHg), and lactic
acid is now 80-100 mg/dl.
[0101] The invention method may further comprise steps designed to
counteract the build up of hypoxia in the tissue of the bone
marrow-shielded body part. For example, the invention method may
further comprise chilling the occluded body part during at least a
portion of the time during which the occluding pressure is applied.
Hypothermia of the occluded limb decreases the metabolic rate
within the limb, which results in decreased consumption of oxygen
and other nutrients while decreasing production of harmful
metabolic products in the absence of arterial blood flow. Chilling
a limb during temporary occlusion of circulation therein results in
slower development of metabolic disequilibrium within the limb
(i.e., slowing of the rate of decline of blood pH and pO.sub.2, and
slowing of the rise in pCO.sub.2 and lactic acid concentration.
Thus, damage to tissues during the transient regional ischemia is
reduced.
[0102] Yet another embodiment of the invention method(s) comprises
administering highly oxygenated autologous blood into the occluded
body part while the occluding pressure (e.g., the tourniquet) is
applied. The highly oxygenated autologous whole blood can be
prepared and infused as is known in the art, and as described in
Example 11 hereinbelow.
[0103] In another embodiment of the invention method(s) wherein
arterial blood flow is to be occluded in a shoulder or hip, the
affected extremity is exsanguinated prior to application of
pressure to occlude arterial flow therein. Exsanguination can be
accomplished by such well known methods as application of gravity
drainage, or by use of a bandage designed to progressively press
blood from an extremity towards the trunk of a patient, such as an
Esmarch bandage.
[0104] In another embodiment, the invention method further
comprises administering to the patient an effective amount of one
or more cytokines, such as G-CSF, GM-CSF, Stem cell factor,
Thrombopoietin, IL-12, EPO, and the like, and suitable combinations
thereof, to stimulate various components of blood-forming elements,
or other cytokines that result in expansion of myelopoiesis in
myelopoietic bone marrow and into peripheral areas of bone marrow.
The cytokines can be administered prior to and/or after the
chemotherapy. For example, about 2 to about 10 days, or about 4 to
about 7 days, and preferably about 5 days, prior to administration
of the chemotherapeutic agent, one or more of such cytokines are
given daily or twice weekly to expand the bone marrow. Then
chemotherapy is administered as described herein. Administration of
the cytokine(s) can be repeated following chemotherapy. This
embodiment of the invention method is illustrated in Example 4
below. Alternatively, starting with the administration of
chemotherapy or following the administration of chemotherapy, the
patient can be administered the cytokine daily by subcutaneous
injections for about 7 to about 30 days (for example, about 10 to
about 20 days, and preferably about 14 days) to stimulate the bone
marrow.
[0105] To combat discomfort and anxiety in the patient during the
practice of the invention method, the method may further comprise
premedicating the patient prior to application of the occluding
pressure by administering to the patient an effective amount of one
or more active agents for relieving pain, anxiety, nausea or
vomiting, and the like, and suitable combinations of any two or
more thereof. This additional step is particularly recommended when
the invention method of bone marrow shielded chemotherapy is
practiced without the use of general anesthesia The use of such
active agents in conjunction with particular chemotherapeutic
agents is illustrated in the Examples below.
[0106] The chemotherapeutic agent and/or cytokine is administered
in an "effective amount." An effective amount is the quantity of a
chemotherapeutic agent necessary to prevent, to cure, or at least
partially arrest growth of a tumor, or of a symptom of cancer
associated therewith. An effective amount of a cytokine is the
quantity of a cytokine necessary to stimulate growth of bone marrow
in a subject. A patient or human is any mammal having a
human-shaped shoulder or hip area, preferably a human. Amounts
effective for therapeutic use will, of course, depend on the
severity of the disease and the weight and general state of the
subject as well as the mode or regimen of administration (i.e.,
whether multiple smaller doses are preferred over bolus injection
of the maximum recommended dose, and the like). Since individual
subjects may present a wide variation in severity of symptoms and
each therapeutic agent has its unique therapeutic characteristics,
it is up to the practitioner to determine a subject's response to
treatment and vary the dosages accordingly. In addition to the
considerations pertaining to the pharmacokinetics of the
chemotherapeutic agents, various considerations in arriving at an
effective amount are described, e.g., in Goodman And Gilman's: The
Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press,
1990; and Remington's Pharmaceutical Sciences, 17th ed., Mack
Publishing Co., Easton, Pa., 1990, each of which is herein
incorporated by reference in its entirety.
[0107] The chemotherapeutic agent can be administered either as a
bolus injection, drip, or continuous infusion. Buffers,
preservatives, antioxidants, and the like, can be incorporated as
required.
[0108] In another aspect, the invention provides a bone marrow
shielding tourniquet adapted to apply pressure around a shoulder or
hip of a human. The invention tourniquet comprises an inflatable
bladder contoured for substantially covering the shoulder or hip
and having an inner face and an outer face, a fluid-tight connector
on the bladder for connecting the bladder to a source of fluid
pressure, and a substantially inelastic exterior layer
substantially covering the outer face of the bladder so as to limit
expansion of the bladder in the direction of the exterior layer
when the bladder is inflated by fluid from the fluid source. The
exterior layer can be semi-flexible or inflexible. When the
exterior layer is inflexible, the exterior layer has a
three-dimensional shape selected to hold the bladder around the
shoulder or hip area. The invention tourniquet can optionally
further comprise a co-operative fastener attached to the tourniquet
for releasably affixing the tourniquet around the hip or shoulder,
although the tourniquet can be lashed around the shoulder or hip
using any suitable type of tie or belt that does not form a part of
the tourniquet. No matter how the tourniquet is affixed around the
body part to be occluded, it is important that the fastener not be
subject to inadvertent release during the practice of the invention
method to prevent potentially lethal damage to the patient's bone
marrow.
[0109] In a presently preferred embodiment, the invention
tourniquet further comprises a flexible interior layer lining the
inner face of the bladder. The exterior layer and interior layer
may co-operatively form an envelope for containing the bladder such
that inflation of the bladder causes the bladder to extend the
flexible interior layer. In this embodiment, the invention
tourniquet can further comprise a fastener attached to or
contiguous with the envelope so formed so that engagement of the
fastener affixes the tourniquet with the interior layer in contact
with the body parts such as a hip or shoulder. In any event, when
the tourniquet is in position around the hip or shoulder and fluid
pressure is introduced into the bladder through the fluid-tight
connector attached thereto, the constraining force exerted by the
semi-flexible or inflexible, substantially inelastic exterior layer
causes the bladder to expand towards the shoulder or hip that the
tourniquet surrounds.
[0110] Since the invention tourniquet is adapted to apply an
occluding pressure around a shoulder or hip area of a human, the
overall shape of the tourniquet must be selected to substantially
cover, or wrap around, at least the shoulder or hip so as to cut
off arterial flow into the upper 1/3 of the proximal humerus or
femur. To facilitate this requirement, in a presently preferred
embodiment, the invention tourniquet has two longer, arcuate sides,
and two shorter, straight sides. One arcuate side describes a
larger arc than the other so that the bladder has an overall shape
described by the difference between the sectors of two circles
having a common center and swept out by a common angle, but having
radii of substantially different length. To adequately cover the
shoulder or hip area of the human, the difference in the length of
the radii describing the arcuate sides of the tourniquet is
generally from about 2 inches to about 10 inches, although the
exact difference will depend upon the general body size of the
patient and whether the invention tourniquet is intended to be
positioned around a shoulder or a hip.
[0111] This embodiment of the invention tourniquet is illustrated
in FIGS. 3, 4 and 5, which show an invention contoured shoulder
tourniquet 20 having larger and smaller arcuate sides 36 and 35,
respectively, two shorter straight ends 66, and a two-part
cooperative fastener (of hooks and loops), with one part 34 located
on the interior layer 67 and one part 33 (shown in dotted outline
in FIG. 3) located on the exterior layer 68 of the tourniquet. The
interior and exterior layers form an envelope to contain inflatable
bladder 37 having an inner face 69 and an outer face 70. Air pump
21, pressure gauge 22, air feed tube 23, are in fluid communication
with inflatable bladder 37. FIG. 4 is a cross-sectional view taken
through line 30-30 of FIG. 3; FIG. 5 is a cross-sectional view
taken through line 31-31 of FIG. 3.
[0112] The connector on the inflatable bladder is in fluid
communication with a source of fluid pressure. As shown in the
Figures herein, the source of fluid pressure includes an air pump
bulb 21, air pressure gauge 22, air pressure tubing 23, and
pressure relief valve 29. However, as used in the description and
claims herein the term "source of fluid pressure" is intended to
include any type of fluid pump known in the art, including a
self-inflating air bag, which may be contained within the
tourniquet itself. The fluid pump can be adapted to supply fluid
pressure to two or more of the bladders simultaneously and/or
independently.
[0113] An optional protuberance 32 also contained within the
envelope is contoured and located so that the protuberance fits
into the arm pit of the patient when the invention shoulder
tourniquet is positioned around the shoulder area. The protuberance
32, which equalizes pressure distribution over the shoulder area
decreases likelihood of tissue damage caused by the tourniquet
itself, can be either located on the surface of the bladder itself,
or, when the tourniquet comprises an interior layer, the
protuberance can be located either on the interior layer or under
the interior layer on the inner face of the bladder (i.e., within
the envelope that encloses the bladder). Although FIGS. 3, 4 and 5
show a preferred embodiment of the optional fastener, a fabric hook
and loop fastener system 33 and 34, the fastener can also be a belt
buckle system, strong snaps, ties, and the like, or any type of
device known in the art for securely, but releasably fastening
together two different objects or parts of a continuous object.
[0114] In another embodiment of the invention tourniquet, the
arcuate sides are substantially equal in length and are arranged in
mirror image to one another so that the tourniquet has an overall
hour glass shape.
[0115] The inflatable bladder contained in the invention tourniquet
is pressurizable to at least about 300 mmHg and is configured so
that, when affixed around a shoulder or hip and inflated, the
tourniquet occludes arterial flow to the upper 1/3 of the proximal
humerus or femur (as well as to the extremities containing them)
and thereby shields the myelopoietic the bone marrow therein. FIG.
1, which is a "see-through" figure, illustrates the invention
shoulder tourniquet in position on cancer patient 1 with an arm in
a preferred elevated position. Shoulder tourniquet 20 is positioned
in a preferred shoulder area location to enable occlusion of
arterial flow through not only the major arterial trunk, axillary
artery 4 and brachial artery 5, but also the smaller branch
arteries such as anterior humeral circumflex artery 8 posterior
humeral circumflex artery 9 and deltoid branch of thoraco-acromial
artery 2 that supply blood to proximal humerus.
[0116] FIG. 2 is an alternate view of shoulder tourniquet 20 of the
present invention position at a preferred location of a cancer
patient's 1 shoulder area, with an arm 10 in a preferred elevated
position, to enable occlusion of arterial flow through not only the
major arterial trunk, axillary artery and brachial artery, but also
the smaller branch arteries such as anterior humeral circumflex
artery 8, posterior humeral circumflex artery 9, and deltoid branch
of thoraco-acromial artery 2 that supply blood to proximal humerus
as shown in FIG. 1.
[0117] In another embodiment shown in FIGS. 10-11, the invention
shoulder tourniquet further comprises a brace, preferably rigid,
attached to the tourniquet (e.g., to the exterior of the
tourniquet). The brace is shaped to hold an arm attached to the
shoulder at a fixed angle from the side of the torso to which the
shoulder attaches when the tourniquet is affixed around the
shoulder. Optionally, the invention shoulder tourniquet can still
further comprise a brace fastener, such as a strap, attached to the
portion of the brace that extends along the torso and adapted to
fasten around the torso of a human. FIG. 10 shows a shoulder
tourniquet 20 having a rigid elevating brace 40, which keeps the
arm elevated at an angle 3 away from the patient's torso. The angle
3 formed by the patient's arm and proximal side of the torso is
generally between 45 degrees and 180 degrees, for example between
75 degrees and 160 degrees, and preferably between 85 degrees and
140 degrees. As shown in FIG. 10, The elevating brace 40 is held
firmly in place by physical attachment to the tourniquet 20 and by
brace strap 41, which is adapted to encircle and fasten around the
patient's torso as shown. The brace strap 41 includes a fabric hook
and loop fastener system 42 for securing the brace strap around the
torso of the patient. FIG. 11 is a perspective view of the
invention shoulder tourniquet that includes a rigid or stiff
elevating brace 40 and brace strap 41.
[0118] The invention tourniquet optionally further comprises a
positioning fastener, which positioning fastener is attached to the
tourniquet for fastening around the torso to prevent migration of
the tourniquet from the affixed position around the shoulder or
hip. FIGS. 12 and 13 show a shoulder tourniquet, in which the
positioning fastener is a positioning fastener 43, shown here as a
belt, positioned to keep the shoulder tourniquet at a preferred
position around the shoulder area of the patient and to prevent
migration of the tourniquet away from the preferred location around
the shoulder. As shown in FIGS. 12 and 13, belt 43 is sewn onto the
fabric cover 38 of the shoulder tourniquet 20, and is tightly
fastened with a two-part fabric hook and loop fastener system 34
and 33. The belt loops around the chest to keep shoulder tourniquet
in a preferred position even without the elevating brace shown in
FIG. 11.
[0119] FIGS. 15-17 illustrate an embodiment of the invention
tourniquet 50 adapted for affixation around the hip area of a
patient. FIG. 15 shows an invention hip tourniquet 50 applied to
cancer patient 1 with a thigh 26 in a preferred extended position
to facilitate position of hip tourniquet 50 around the hip area so
as to enable occlusion of arterial flow through not only the major
arterial trunk, external iliac artery 7, and femoral artery 6, but
also the smaller branch arteries such as lateral femoral circumflex
artery 16 and medial femoral circumflex artery 17 that supply blood
to proximal femur. The angle 25 formed by the patient's thigh 26
and the patient's torso 11 is generally between 45 degrees and 155
degrees, for example, between 75 degrees and 155 degrees, and
preferably between 90 degrees and 145 degrees.
[0120] As shown in FIGS. 17-19, the hip tourniquet can include a
hip positioning fastener 51 (shown here as belt 51 sewn to the
exterior of tourniquet 50 and having a two-part fabric hook and
loop fastener system 33 and 34) for fastening around the pelvis of
the patient to prevent migration of the tourniquet from the affixed
position around the hip. The hip tourniquet may also optionally
include a brace 52 attached to the tourniquet (shown in FIGS. 20
and 21) for holding the patient's thigh at a fixed angle to the
proximal side of the patient's torso.
[0121] In an alternative embodiment, the exterior layer of the
tourniquet is semi-flexible or inflexible and has a
three-dimensional shape selected to hold the bladder around the
body part to be occluded, such as the hip area, or shoulder and/or
scapular area. The hard shell exterior can be fabricated in several
different sizes to accommodate a broad range of body builds. The
exterior layer of this "hard shell" tourniquet is generally
fabricated from a material selected from the group consisting of an
artificial polymer, leather, plaster of Paris, metal, natural woven
fiber, and the like, and combinations thereof. The preferred
material is an artificial polymer (e.g., a plastic) such as
polyethylene, poly propylene, polycarbonate, ethacrylate, acrylic,
and the like.
[0122] FIG. 6 illustrates an invention hard-shell tourniquet 45 for
the shoulder area. The inflexible exterior layer 46 loosely
conforms to the contour of the body part to which it is to be
applied, in this case, the shoulder. In FIG. 6, the hard shell is
shown striped to demonstrate the surface contour. Attached to, and
lining the inside surface of the hard shell, is the inflatable
bladder 37 with fabric interior layer 38 that comes in contact with
the skin of the patient. The inflatable bladder 37 is connected to
a source of fluid pressure via an attached fluid-tight connector,
shown here as the air pressure tubing 23, air pressure gauge 22,
and air pump bulb 21. FIG. 7 shows a hard-shell tourniquet applied
onto the shoulder of a cancer patient 1. To apply the hard shell
tourniquet, the patient's arm 10 is slipped through the hard-shell
tourniquet and positioned as shown. When the inflatable bladder is
pressurized with air pump 21, the bladder 37 balloons only in the
central direction, toward the patient's arm. This results in
relatively uniform distribution of pressure over the entire
shoulder area so that blood vessels are occluded without excessive
pressure, resulting in decreased pain and decreased risk of tissue
damage during the period of tourniquet inflation.
[0123] FIG. 8 is a cross section through the shoulder tourniquet of
FIG. 7 at line 65, and shows a cross section through the upper
humerus bone 12 having myelopoietic bone marrow 47 contained
within. This cross sectional view shows the inflexible exterior
layer 46 that loosely conforms to the contour of the body part to
be applied, in this case, the shoulder, and the inflatable bladder
37 in the beginning stage of inflation with smaller amount of air
within the bladder cavity 39. In FIG. 9, the inflatable bladder 37
of FIG. 8 is inflated further. As the inflatable bladder 37 is
inflated above the blood pressure, the blood vessels would be
completely collapsed and occluded, until the pressure is relieved.
This cross sectional view also shows bone marrow within humerus 47,
deltoid muscle 48, biceps muscle 49, triceps muscle 54, pectoralis
major muscle 55, musculocutaneous nerve 56, median nerve 57,
brachial artery 58, brachial vein 59, ulnar nerve 60, radial nerve
61, teres major muscle 62, subcutaneous fat 63, and
coracobrachialis muscle 64.
[0124] Still another embodiment of the present invention is a
hard-shell tourniquet for the hip area that is analogous to that
shown in FIGS. 6 through 9, except the contour of the hard-shell
follows that of the hip area. Again, the inelastic and inflexible
hard shell directs pressure of the inflatable bladder towards the
center, resulting in relatively uniform distribution of pressure
over the hip area. As a result, less pressure is required to
occlude the blood vessels, which in turn results in decreased pain
and decreased risk of tissue damage during the period of tourniquet
inflation.
[0125] In another embodiment, the invention provides a bilateral
hard shell bone marrow shielding tourniquet adapted for wearing by
a human. The invention bilateral hard shell tourniquet comprises a
semi-flexible or inflexible and inelastic exterior carapace in one
or more pieces, wherein the carapace has a three-dimensional shape
adapted to substantially cover at least the bilateral scapular
areas and/or shoulder areas of a wearer while allowing the head,
arms, and lower torso to protrude from the carapace. Bilateral
inflatable bladders can be attached along the interior surface of
the carapace that, when inflated, apply pressure over at least the
bilateral scapular areas and/or shoulder areas of the wearer, and a
fluid-tight connector on each inflatable bladder for inflating the
bladder, wherein inflation of one or both bladders exerts
sufficient pressure upon the respective covered areas of the wearer
to occlude arterial flow into at least the covered areas.
Alternatively, the bilateral bladders can be separate from the
tourniquet and applied to the wearer before the carapace is placed
around the wearer. Generally the bilateral hard shell tourniquet
further comprises at least one fastener attached to the carapace
for cinching the carapace about the chest of the wearer. This
embodiment of the invention is illustrated in FIGS. 22-29.
[0126] FIG. 22 shows cancer patient 1 wearing an invention
bilateral hard-shell tourniquet 70 having a two part inflexible
carapace and attached bilateral flexible bladders designed to apply
pressure to bilateral humeri and bilateral scapulae of a patient
when the tourniquet is assembled around and "worn" by the patient
placing an arm 76 through each arm hole 73 and moving the two
pieces of the carapace about the shoulders and scapulae to
co-operatively substantially cover the bilateral scapulae and
shoulders of the wearer, and cinching the carapace 70 about the
chest of the wearer using fasteners 77. The wearer's head 80, arms
76 and torso 81 protrude from the tourniquet and neck/chest opening
82 defined the two pieces of the carapace is large enough to
facilitate blood circulation in the part of the wearer's body that
is not occluded by the tourniquet. As further shown in FIGS. 23-25,
carapace parts 71 and 72 each have an armhole 73 for receiving an
arm of the wearer and anterior 74 and posterior 75 sides. At least
one adjustable fastener 77 (shown here as two belts, each with an
end attached to the anterior side of one of the two carapace
pieces, and each with a fabric hook and loop fastener system) joins
the anterior sides 74 of the two carapace pieces across the chest
of the wearer. At least one additional adjustable fastener 78
(shown in FIGS. 23 and 24 as two belts (in cross-hatching)) joins
the two posterior sides 75 of the two carapace parts across the
back of the wearer.
[0127] As can further be seen in FIGS. 23 and 24, the posterior
sides 75 of the carapace pieces are shaped to co-operatively create
a bottom torso opening 79. Similarly, the two anterior sides 76 of
the carapace pieces co-operatively form a neck/chest opening 82.
Cushions can be placed under the anterior sides 74 of the carapace
to facilitate breathing and blood circulation in the non-occluded
parts of the wearer while the tourniquet is worn and the bladders
are inflated. A chemotherapeutic agent(s) is administered
intravenously through central line catheter 91.
[0128] Two mirror image inflatable bladders 85 have a shape and are
attached to and positioned along the interior surface of the
corresponding carapace pieces to substantially cover the respective
shoulder area and proximal scapula of the wearer when the
tourniquet is cinched around the chest of the wearer. Each bladder
has a fluid-tight connector for attaching the inflatable bladder to
a source of fluid pressure for inflating the bladder, shown in
FIGS. 22-25 as including an air pump bulb 21, air pressure gauge
22, air pressure tubing 23, and pressure relief valve 29. The
preferred shape of the bilateral inflatable bladders 85 (shown in
detail in FIG. 25) is designed to exert sufficient pressure upon
the respective shoulder area and proximal scapula of the wearer to
occlude arterial flow in the covered area and proximal extremity.
Preferably, the tourniquet is cinched about the chest of the wearer
before the bladders are inflated. As shown by a comparison of FIGS.
23A and 24, fasteners 77 and 78 are adjustable to cinch the two
pieces about the wearer by drawing the two pieces of the carapace
about the upper torso of the wearer.
[0129] As illustrated in FIG. 23B, the carapace optionally covers
the bilateral scapular areas of the wearer without covering the
bilateral shoulder areas. FIG. 23B shows two carapace pieces 71 and
72 abbreviated in the extension over the shoulder caps as compared
with the carapace of FIG. 23A. In this embodiment of the invention,
the mirror image inflatable bladders 85 are similarly contoured to
cover the surface of a human scapula (the triangular shoulder blade
bone) to occlude arterial flow therein, but not to cover the
shoulder area sufficiently to occlude arterial flow in the shoulder
area.
[0130] Variations of the invention bilateral hard shell inflatable
tourniquet are described with reference to FIGS. 26-28. Instead of
having a carapace made of two pieces that are cinched together
around the wearer, the carapace shown in FIGS. 26-28, is made of a
single piece and therefore is generally semi-flexible to facilitate
placing the tourniquet about the wearer. The one-piece carapace is
provided with at least one opening to further facilitate
application of the tourniquet to the body of the wearer. As shown
in frontal view in FIG. 26, one-piece carapace 71 has slits 86
running from the underneath of each arm hole 73 to the bottom edge
87 of the carapace and a plurality of adjustable side fasteners 89
for holding the sides formed by the slit together when the
tourniquet is worn. In this embodiment, the bilateral inflatable
bladders 85 attached to the interior of the carapace have
corresponding slit to allow opening of the carapace. The sides of
the slits in the bilateral inflatable bladders are brought together
and held in position by cinching of the carapace about the wearer
so that the bladders substantially surround the shoulder areas of
the wearer (the sides of the slits may overlap) when the side
fasteners are cinched.
[0131] Alternatively, as shown in FIG. 29, the tourniquet with an
opening under each arm (described above with reference to FIG. 26)
can also have a relatively inflexible carapace of two pieces that
are joined by a hinging mechanism 89 along each upper shoulder. In
this embodiment, the bilateral tourniquet opens like a "bivalve"
and is applied over the head of the wearer. The bilateral bladders
85, also each have a slit under the arm. The edges of the slits are
overlapped and then the adjustable side fasteners 89 are secured to
cinch the tourniquet around the torso of the wearer before the
bilateral bladders are inflated.
[0132] In another embodiment of the invention bilateral tourniquet
having a one-piece carapace, shown in FIG. 27, the sides of the
carapace do not have an opening, (e.g. slits), but the carapace is
semi-flexible and has a front opening such that the tourniquet has
the appearance of, and can be donned by the wearer, like a vest.
Adjustable fasteners 77 attached to the carapace at either side of
the front opening are used to cinch the carapace about the chest of
the wearer. In this embodiment, the mirror image bilateral bladders
85 attached to the interior surface of the carapace are configured
as shown in FIG. 25.
[0133] In another embodiment of the invention bilateral tourniquet
having a one-piece carapace, shown in FIG. 28, the carapace is
semi-flexible and the opening is at the midline of the back, formed
by a slit running from top to bottom of the carapace. In this
embodiment, the tourniquet has the appearance of, and can be donned
by the wearer, like a short, back-opening hospital gown. Adjustable
back fasteners 78 attached to the carapace at either side of the
back opening are used to cinch the carapace about the chest of the
wearer. In this embodiment, the mirror image bilateral bladders 85
are also configured as shown in FIG. 25.
[0134] In another embodiment, the invention provides a hard shell
bone marrow shielding tourniquet adapted for applying pressure to a
scapular area of a human wearer. In this embodiment, the invention
tourniquet comprises a substantially inflexible and inelastic
carapace in one piece having a three-dimensional shape adapted to
substantially cover at least the scapular area of a wearer while
allowing the head, arms, and torso to protrude from the carapace,
an inflatable scapular bladder attached along the interior surface
of the carapace that, when inflated, applies pressure over the
scapular area of the wearer, a fluid-tight connector on the
inflatable bladder for inflating the bladder, and at least one
adjustable fastener attached to the carapace for cinching the
carapace about the torso of the wearer. Inflation of the bladder
causes the tourniquet to exert sufficient pressure upon the
scapular area of the wearer to occlude arterial flow thereinto.
[0135] As illustrated in FIG. 30 in frontal view, one-piece
carapace 93 has a shape adapted to fit about a wearer so as to
cover the scapular area (but not the shoulder cap or arm pit) and a
portion of the chest. Inflatable scapular bladder 95, which is
attached to the interior of the carapace posterior, is shaped to
cover the triangular scapular area of a human (i.e., the shoulder
blade), but not the shoulder area. Two adjustable and releasable
fasteners 98 attach to the anterior and posterior sides of carapace
93 and are designed to loop around the torso of the wearer to cinch
the inflexible carapace against the torso. When fasteners 98
(illustrated here as each including a fabric hook and loop fastener
system 42) are fastened around the torso of the wearer, inflation
of scapular bladder 95 according to the invention method exerts
sufficient pressure upon the exterior of the scapular area of the
wearer to substantially occlude arterial flow into the
myelosuppresive bone marrow contained therein.
[0136] The carapace can be fabricated in several different sizes to
accommodate a broad range of body builds. If the carapace is
slightly too large on a patient for the inflatable bladder(s) to
exert the requisite pressure to occlude arterial flow to the
desired body part(s), the fit can be improved by padding carapace
and/or the body part with a relatively incompressible, but
flexible, padding, such as a rubber, textile, or other soft
material.
[0137] The carapace is generally fabricated from a material
selected from the group consisting of an artificial polymer,
leather, plaster of Paris, metal, natural woven fiber, and the
like, and combinations thereof. The preferred material is an
artificial polymer (e.g., a plastic) such as polyethylene, poly
propylene, polycarbonate, ethacrylate, acrylic, and the like, which
is injection molded using techniques known in the art, to obtain a
thin shell having the desired bodily shape and degree of
flexibility as taught herein. Alternatively, a custom-fitted
carapace can be prepared using a polymer splinting material known
as Aquaplast.RTM. splinting material (Smith & Nephews, Inc.),
which is softened in hot water, molded around a body part, for
example, by hand, and which will harden at body temperature into a
semiflexible shell, as is described in U.S. Pat. No. 4,240,415,
which is incorporated herein by reference in its entirety.
[0138] In still another embodiment of the invention, a method is
provided for fabricating a custom-fitted hard-shell tourniquet that
is made to fit an individual patient, much as an orthopedic cast is
applied to a shoulder or hip. The invention fabrication method
comprises substantially covering a body part of a patient to be
compressed for occlusion of arterial flow therein with one or more
inflatable bladders having a fluid-tight connector; wrapping the
one or more inflatable bladders with a softened orthopedic cast
material so as to leave free the connectors on the bladders, and
molding the cast material and inflatable bladder around the body
part under conditions suitable for causing the orthopedic cast
material to harden.
[0139] For comfort of the patient, the method can further comprise
wrapping the body part to be compressed with a soft cushioning
material, such as stockinet, cast padding (Webril.RTM.), and/or
cotton sheet, prior to wrapping the one or more inflatable bladders
around the body part. The cushioning material helps to decrease the
pain caused by inflation of the inflatable bladder(s) and also
helps to absorb moisture, such as perspiration generated by the
body part during fabrication of the hard-shell tourniquet and/or
during its use.
[0140] During use, the connector on the bladder is attached to a
fluid source such as an air pump, and inflated to a pressure
substantially above the systolic blood pressure of the patient as
disclosed herein. Preferably, the connector, and/or gas source
includes a mechanism for regulating gas pressure within the one or
more inflatable bladders, including such parts as a pressure gauge,
a pressure relief valve, and the like.
[0141] The preferred orthopedic cast material for making the
invention hard shell tourniquet is a knitted substrate impregnated
with polyurethane resin, for example, Delta-Lite.RTM. Polyester
Casting Tape (Johnson & Johnson), but other material, such as
plaster of Paris may be used. Delta-Lite.RTM. Fiberglass Casting
Tape and plaster of Paris are activated by water. As the casting
tape hardens, heat is evolved, which can be felt by patient. The
hard shell made from Delta-Lite.RTM. sets in approximately 3 to 5
minutes and is load-bearing in about 20 minutes after setting.
Therefore, the custom-fitted hard-shell tourniquet can be used the
same day as its fabrication. After completing the first session of
chemotherapy using the custom-fitted hard-shell tourniquet, the
custom-fitted hard-shell tourniquet may be left in place for
subsequent doses after the bladder(s) are deflated, but it is
preferable that the tourniquet be compressed loosely enough about
the body part of interest that it can be slipped off after the
chemotherapy session is completed and reused for one or more
subsequent sessions. If it is not possible to slip the
custom-fitted hard-shell tourniquet off from the patient, to enable
its removal, the hard-shell portion of the tourniquet may be slit
open using a standard cast saw so as to loosen the hard-shell. When
such a use is contemplated, it is important that the inflatable
bladder within the tourniquet be positioned so that it will not be
slit when the hard shell is slit open. Breathing dust formed by
cutting the hard shell should be avoided, as this may cause
respiratory irritation or sensitization. Alternatively, the
hard-shell portion may be cut "bivalved" longitudinally into
"half-shells". With careful cutting of the hard-shell, preferably
to avoid destroying the inflatable bladders underneath, the
hard-shell can be saved and reused for subsequent doses of
chemotherapy by firmly lashing the custom-fitted hard-shell
tourniquet onto the patient's body.
[0142] FIG. 14 is a perspective view of a "bilateral" shoulder
tourniquet comprising shoulder tourniquets 20 and 20' fitted on
both of the patient's shoulder areas in mirror image arrangement
and fitted with a releasable anterior positioning fastener for
releasably joining the anterior portions of the two tourniquets,
shown in FIG. 14 as belt 44. The belt 44 is sewn onto the fabric
cover 38 of the shoulder tourniquet 20, and is tightly fastened
with fabric hook and loop fastener system 42. Optionally, in a
preferred embodiment, there is a mirror-image releasable posterior
positioning fastener, shown here as belt 44' (indicated by the
dotted lines behind the patient 1), that releasably joins the
shoulder tourniquet across the back of the patient when the two
tourniquets 20 and 20' are in place. The anterior and posterior
positioning fasteners (belts 44 and 44') keep the shoulder
tourniquets in position around the shoulder area of the patient and
prevent migration of tourniquet away from the preferred location on
the shoulder during use.
[0143] FIG. 17 is yet another embodiment of hip tourniquet 50, for
placement around a patient's hip area. Hip tourniquet 50 is fitted
with a tourniquet positioning fastener (illustrated here as a belt
having anterior portion 51 and posterior portion 51') to keep the
hip tourniquet in position around the hip and prevent migration of
tourniquet away from the preferred position. As illustrated here,
the positioning belt 51 is sewn onto the fabric cover 38 of the hip
tourniquet 50, and is tightly fastened with fabric loop fastener 33
and fabric hook fastener 34 attached to the exterior of tourniquet
50. The hip positioning fastener is adapted to loop around the
patient's pelvis to keep hip tourniquet 50 from slipping down, away
from the preferred position where occlusion of the arteries
supplying the proximal femur is possible. The hip tourniquet 50
further comprises bladder 37 in fluid communication with a source
of fluid pressure, which is shown here as comprising air pump 21,
pressure gauge 22, pressure relief valve 29, and air feed tube 23.
In the embodiment shown in FIG. 17, the hip tourniquet further
comprises a fastener for securing the tourniquet around the hip of
the patient, such as a fabric hook and loop fastener system. FIG.
18 shows the hip tourniquet 50 of FIG. 17 about to be fastened on
the hip of a patient, and FIG. 19 shows hip tourniquet 50 of FIGS.
17 and 18 now firmly fastened around the patient's hip area.
[0144] In another embodiment of hip tourniquet 50, for placement on
a patient's hip area (FIG. 20), the hip tourniquet is fitted with a
hip extension brace 52 that keeps the thigh extended at an angle
toward the patient's torso. The hip extension brace is made of
relatively inflexible material. The brace is held firmly in place
by the attachment to hip tourniquet 50 as well as by the thigh belt
53.
[0145] FIG. 21 is another perspective view of hip tourniquet fitted
with a hip extension brace now shown firmly fastened on the
patient's hip area. The hip tourniquet 50 is fitted with a hip
extension brace 52, that keeps the thigh extended at an angle
toward the patient's torso. The hip extension brace is made of
relatively inflexible material. The brace is held firmly in place
by the attachment to hip tourniquet 50 as well as by the thigh belt
53. The angle, 25, formed by the patient's thigh, 26, and the
patient's torso, 11, is generally between about 45 degrees and
about 155 degrees, for example, between about 75 degrees and about
155 degrees, and most preferably between about 90 degrees and about
145 degrees.
[0146] The invention will now be described in greater detail by
reference to the following non-limiting examples.
EXAMPLE 1
[0147] A central line catheter by subclavian or jugular approach is
placed in a patient with cancer if the patient is to undergo
bilateral shoulder tourniquet procedure. Alternately, a peripheral
intravenous line is placed in a neck vein (external jugular),
taking care that the catheter does not get dislodged at any time
during the entire procedure. If the patient is to undergo a
unilateral shoulder tourniquet procedure, a central line catheter
or intravenous line in the neck are not necessary since
chemotherapy can be infused into the contralateral arm. On the day
of chemotherapy, a complete blood count, and test of levels of
serum Creatinine, Bilirubin, Serum Glutamic Oxaloacetic
Transaminase (SGOT), Serum Glutamic Pyruvic Transaminase (SGPT),
and alkaline phosphatase are performed. The white blood cell count
should be higher than 4000 per cu. mm., and the platelet count
should be higher than 100,000 per cu. mm.
[0148] Prior to application of a tourniquet, the patient is
premedicated with 1 mg of lorazepam given orally or intravenously
for anxiety, 10 mg of ondansetron intravenously for
nausea/vomiting, and 100 mg of meperidine, or equivalent,
intravenously for pain. Webril.RTM. is applied to the upper arm and
shoulder area to protect the skin, and the tourniquet is placed
over the Webril.RTM. to cover the shoulder area, making certain
that the entire shoulder or hip area is encircled by the tourniquet
The extremity to be occluded is exsanguinated using an Esmarch
bandage and/or gravity drainage, then the tourniquet is inflated to
a pressure high enough to substantially occlude, and preferably
completely occlude, the covered arteries, which is at least 5 to 10
mmHg above systolic blood pressure, preferably at the limb, for
example 5 to 300 mmHg above systolic blood pressure, or between 50
to 200 mmHg above systolic blood pressure, and preferably about 100
mmHg above systolic blood pressure. Alternately, pressure of 280
mmHg may be used. The Esmarch bandage is removed and the absence of
radial artery pulsation is determined.
[0149] 0.4 mg/kg of body weight mechlorethamine is injected through
the central line catheter. Five minutes to 2 hours, for example 5
minutes to 1 hour, and preferably 5 minutes to 15 minutes following
the administration of the chemotherapeutic agent, the tourniquet is
deflated.
EXAMPLE 2
[0150] The following is an example of process of using the
invention tourniquet to occlude arterial flow into the upper leg so
that the bone marrow within the femur, tibia, fibula, ankle bones,
and feet bones are not exposed to high concentration of cytotoxic
chemotherapeutic drugs.
[0151] The procedure described in Example 1 above is followed
except that the patient is administered 40 .mu.g/kg of body weight
of granisetron intravenously for nausea/vomiting and the
Webril.RTM. is applied to the upper leg and buttock area to protect
skin prior to placing the tourniquet around the hip area and the
absence of pulse is determined in the dorsalis pedis artery.
[0152] As chemotherapeutic agent, 10 mg mechlorethamine is injected
intravenously and 5 minutes to 2 hours, for example 5 minutes to 1
hour, and preferably 5 minutes to 15 minutes, following the
administration of the chemotherapeutic agent, the tourniquet is
deflated.
EXAMPLE 3
[0153] Prior to the administration of chemotherapy, the patient is
given 10 .mu.g/day of granulocyte-colony stimulating factor (G-CSF
or filgrastim) daily by subcutaneous injections to stimulate the
bone marrow. The patient's white blood cell count (WBC) is
monitored during this period to avoid producing too high a WBC
count About 24 hours following the final dose of G-CSF, the patient
undergoes chemotherapy as described in Examples 1 or 2 herein.
EXAMPLE 4
[0154] The procedure described in Example 3 above is followed
except that prior to administration of chemotherapy in the place of
G-CSF the patient is administered 5 .mu.g/kg body weight/day of
granulocyte macrophage-colony stimulating factor (GM-CSF) daily by
subcutaneous injection for 2 to 10 days to stimulate the bone
marrow.
EXAMPLE 5
[0155] The procedure described in Example 3 or 4 above is followed
except that the cytokine administered prior to the administration
of chemotherapy is 100 .mu.g of stem cell factor (SCF) daily by
subcutaneous injection for 2 to 10 days.
EXAMPLE 6
[0156] In place of G-CSF, GM-CSF, or SCF administration as in
Examples 3, 4, and 5, erythropoietin (EPO), thrombopoietin (TPO),
IL-12, or other cytokines are given prior to, during, or after the
administration of chemotherapy to stimulate bone marrow.
EXAMPLE 7
[0157] The procedure described in Example 1 above is followed
except that the patient's arm is chilled to extend the time that
the arterial flow is occluded to the arm. Prior to application of
the Webril.RTM., the arm to be occluded is chilled to a skin
temperature of about 5 to about 35.degree. C., for example, to a
skin temperature of about 15 to about 25.degree. C., and preferably
to a skin temperature of about 18 to about 22.degree. C., using
"cold packs" (Riker 3M) or a cooling blanket with circulating
chilled water. Once the desired temperature is attained,
Webril.RTM. is applied and the procedure of Example 1 is carried
out while continuing to chill the arm except that the pressure is
maintained on the shoulder area for about 5 minutes to 2 hours, for
example 5 minutes to 1 hour, and preferably 5 minutes to 15
minutes, following the administration of the chemotherapeutic
agent, before the tourniquet is deflated and the cooling blanket or
cooling packs are removed.
EXAMPLE 8
[0158] The procedure described in Example 8 above is followed
except that the patient's leg is chilled rather than an arm, and
the tourniquet is applied around the hip area rather than around
the shoulder area.
EXAMPLE 9
[0159] This example illustrates an embodiment of the invention
method wherein the patient's blood is collected for oxygenation
prior to application of the tourniquet and the oxygenated blood is
administered to the occluded body part as a means of safely
extending the period of occlusion. The procedure described in
Example 1 above is followed, except as follows: Prior to
exsanguination, a standard blood collection bag is prepared for
collecting autologous whole blood by first injecting 100 ml of pure
oxygen gas into the bag. Then a portion of a
preservative-anticoagulant solution, such as ACD
(acid-citrate-dextrose), CPD (citrate-phosphate-dextrose), or
CPDA-1 (CPD with adenine), which is generally already in the bag,
is removed so that 14-15 ml of the solution remains in the blood
collection bag for each 100 ml of whole blood to be collected.
[0160] A blood collection needle is inserted into the arm of the
patient to undergo bone marrow shielding, and about 100 to about
300 ml of the patient's own (i.e. autologous) blood is then
collected into the bag prior to premedication of the patient for
pain, anxiety, and the like, and prior to application of the
tourniquet.
[0161] The collection bag containing the blood is placed upon a
continuously tilting machine to gently mix the blood with pure
oxygen gas so that each 100 ml of whole blood absorbs as much blood
as possible, up to a maximum of about 20 ml of pure oxygen gas. The
needle through which the autologous blood is collected is kept in
place, later to be used for transfusion of the oxygenated blood
back into the same arm.
[0162] About thirty minutes or about one hour after the tourniquet
is applied, the autologous blood collected previously and exposed
to pure oxygen gas is infused back into the patient's arm while the
tourniquet remains inflated. At about 90 minutes to about 2 hours
following the application of the tourniquet, the tourniquet is
deflated.
EXAMPLE 10
[0163] This example illustrates a procedure for neutralizing the
myelosuppresive effect of a chemotherapeutic agent used in practice
of the invention method before the pressure is removed from the
occluded body part, allowing administration of an increase in the
dosage of the chemotherapeutic agent.
[0164] The procedure described in Example 1 above is followed
except that as follows: The patient is administered 10 mg of
mechlorethamine as an intravenous bolus dose through the central
line catheter as the chemotherapeutic agent. Fifteen minutes
following the administration of the chemotherapeutic agent, 1000 mg
of sodium thiosulfate is administered intravenously. Three to five
minutes after administration of the sodium thiosulfate dose, the
tourniquet is deflated.
EXAMPLE 11
[0165] This example illustrates the use of 5-azacitidine, a
nucleoside analogue that has somewhat narrow spectrum of activity
compared to nitrogen mustard, in the invention bone marrow shielded
chemotherapy method. The procedure described in Example 1 above is
followed except that the patient is administered 200 mg/m.sup.2 of
5-azacitidine, intravenously as the chemotherapeutic agent, and the
pressure on the occluded body part is maintained from about 10
minutes to 2 about hours, for example, about 15 minutes to about 1
hour, and preferably about 15 minutes to about 30 minutes,
following the administration of the chemotherapeutic agent.
EXAMPLE 12
[0166] The following example illustrates use of doxorubicin, a DNA
intercalator with very rapid initial half-life (5 min) followed by
longer terminal half-life (10 hr), in the invention bone
marrow-shielded chemotherapy method. The procedure described in
Example 1 above is followed except that the patient is premedicated
with 2 mg of granisetron intravenously for nausea/vomiting, and 1
to 2 mg of hydromorphone intravenously for pain. Doxorubicin in an
amount of 50 mg/m.sup.2 of body surface treated is administered
intravenously as the chemotherapeutic agent, and 30 minutes to 1
hour following the administration of the chemotherapeutic agent,
the tourniquet is deflated.
EXAMPLE 13
[0167] The following example illustrates use of 5-fluorouracil in
the invention bone marrow-shielded chemotherapy method. The
procedure described in Example 1 above is followed except for the
following: The patient is premedicated with 1 mg of lorazepam
orally or intravenously for anxiety, ondansetron is omitted since
5-FU does not cause significant nausea/vomiting, and 100 mg of
meperidine is given intravenously for pain. 5-fluorouracil is
administered intravenously as the chemotherapeutic agent at a
dosage of 300 mg/m.sup.2 of treated body surface, and the
tourniquet is deflated 30 minutes following the administration of
the chemotherapeutic agent. This procedure is repeated daily for a
total of 5 days.
EXAMPLE 14
[0168] An alternate method of using 5-fluorouracil in the invention
method follows the procedure of Example 13 except that the
5-fluorouracil is administered together with leucovorin, a folate
vitamin that potentiates 5-fluorouracil. The procedure in Example
15 is followed, except that the patient is administered 370
mg/m.sup.2 of 5-fluorouracil plus 20 mg/m.sup.2 of leucovorin in
the place of the daily 5-fluorouracil of Example 13.
EXAMPLE 15
[0169] The procedure described in Example 1 above is followed
except that administration of ondansetron is omitted since
dactinomycin does not cause significant nausea/vomiting and as the
chemotherapeutic agent the patient is administered 5-dactinomycin
intravenously at a dosage of 2 mg/m.sup.2 of body surface. Thirty
minutes following the administration of the chemotherapeutic agent,
the tourniquet is deflated.
EXAMPLE 16
[0170] The procedure described in Example 15 above is followed
except that the chemotherapeutic agent administered intravenously
is mitomycin-C at a dosage of 10 mg/m.sup.2 of body surface treated
and the tourniquet is deflated about 30 minutes to 1 hour following
the administration of the chemotherapeutic agent.
EXAMPLE 17
[0171] The procedure described in Example 15 above is followed
except that as the chemotherapeutic agent the patient is
intravenously administered streptozocin at a 2 dosage of 10 mg/rn
of body surface treated and the tourniquet is deflated about 30
minutes to 1 hour following the administration of the
chemotherapeutic agent.
EXAMPLE 18
[0172] The procedure described in Example 1 above is followed
except that the patient is intravenously administered 50 mg/m.sup.2
of body surface of mitoxantrone as the chemotherapeutic agent.
About 30 to about 60 minutes following administration of the
chemotherapeutic agent, the tourniquet is deflated.
EXAMPLE 19
[0173] The procedure described in above example 18 is followed,
except that 200 mg/m.sup.2 of body surface of BCNU is used in place
of mitoxantrone in Example 18.
EXAMPLE 20
[0174] The procedure described in above example 13 is followed,
except that 30 mg/m.sup.2 of body surface of cytarabine is used in
place of 5-FU in Example 13.
EXAMPLE 21
[0175] The procedure described in above example 18 is followed,
except that 5 mg/m.sup.2 of body surface of melphalan is used in
place of mitoxantrone in Example 18.
EXAMPLE 22
[0176] The procedure described in Example 18 above is followed
except that the patient is administered 0.2 mg/kg of body weight of
thiotepa in place of mitoxantrone in Example 18.
EXAMPLE 23
[0177] The procedure described in above example 18 is followed,
except that 200 mg/m.sup.2 of treated body surface of DTIC is used
in place of mitoxantrone in Example 18.
EXAMPLE 24
[0178] The procedure described in Example 1 above is followed
except that as the chemotherapeutic agent the patient is
administered as the following chemotherapeutic agents according to
the following schedule, each administration with the tourniquet in
place: 600 mg/m.sup.2 of body surface of 5-FU (weekly), 50
mg/m.sup.2 of body surface of doxorubicin (every 4 weeks), and 10
mg/m.sup.2 of body surface of mitomycin-C (every 8 weeks), through
the central line catheter. For each dosage, 15 minutes to 2 hours,
but preferably 30 minutes to 2 hours, and most preferably 30
minutes to 1 hour, following the administration of the
chemotherapeutic agent, the tourniquet is deflated.
EXAMPLE 25
[0179] The procedure described in above Example 24 is followed,
except that 0.5 mg/kg of body weight of mechlorethamine is used in
place of mitomycin-C in Example 24.
EXAMPLE 26
[0180] The procedure described in above Example 24 is followed,
except that 0.5 mg/kg of body weight of mechlorethamine, and 2
mg/m.sup.2 of body surface of dactinomycin are substituted for
mitomycin-C and doxorubicin in Example 24.
EXAMPLE 27
[0181] The procedure described in above Example 24 is followed,
except that 45 mg/M.sup.2 of body surface of mitoxantrone and 0.4
mg/kg of body weight of thiotepa are substituted for doxorubicin,
mitomycin, and 5-FU.
EXAMPLE 28
[0182] The procedure described in Example 1 above is followed
except that as the chemotherapeutic agent the patient is
administered by injection a combination of chemotherapeutic agents,
such as 0.3 mg/kg of body weight of mechlorethamine (every 4
weeks), 50 mg/m.sup.2 of body surface of doxorubicin (every 4
weeks), and 375 mg/m.sup.2 of body surface of DTIC (every 2 weeks),
through the central line catheter. For each dosage, 15 minutes to 2
hours, but preferably 30 minutes to 2 hours, and most preferably 30
minutes to 1 hour, following the administration of the
chemotherapeutic agent, the tourniquet is deflated. Separately from
the tourniquet procedure, the remaining drug in this combination
regimen, 1.5 mg/m.sup.2 of body surface (maximum of 2 mg) of
vincristine is administered weekly throughout the regimen. The
vincristine is administered separately without application of the
tourniquet, since this drug causes minimal damage to bone
marrow.
EXAMPLE 29
[0183] The procedure described in Example 28 above is followed
except that as the chemotherapeutic agent a combination of 50
mg/m.sup.2 of body surface of doxorubicin and 50 mg/m.sup.2 of body
surface of cisplatin is administered instead of mechlorethamine,
doxorubicin, and DTIC, and vincristine is omitted.
EXAMPLE 30
[0184] The procedure described in Example 28 above is followed,
except that the combination of chemotherapeutic agents administered
is 200 mg/m.sup.2 of body surface of BCNU and 2 mg/m.sup.2 of body
surface of dactinomycin instead of mechlorethamine, doxorubicin,
and DTIC in Example 28, and vincristine is administered as in
Example 28.
EXAMPLE 31
[0185] The procedure described in above example 28 is followed,
except that the combination of chemotherapeutic agents administered
is 0.3 mg/kg of body weight of mechlorethamine, 50 mg/m.sup.2 of
doxorubicin and 50 mg/m.sup.2 of body surface of cisplatin instead
of mechlorethamine, doxorubicin, and DTIC and vincristine is
omitted.
EXAMPLE 32
[0186] The procedure described in Example 1 above is followed
except that as the chemotherapeutic agent used during the
tourniquet procedure, the patient is administered 6 mg/m.sup.2 of
body surface of mechlorethamine intravenously and the tourniquet is
applied (on days 1 and 8 of a 14 day regimen). Fifteen minutes to 2
hours, but preferably 30 minutes to 2 hours, and most preferably 30
minutes to 1 hour, following the administration of the intravenous
chemotherapeutic agent, the tourniquet is deflated.
[0187] In addition, further chemotherapeutic agents are
administered separately from the tourniquet procedure as follows.
On days 1 and 8 of the 14 day regimen, at least 30 minutes to 60
minutes prior to the above shoulder tourniquet procedure, 1.4
mg/m.sup.2 of body surface (maximum of 2 mg) of vincristine are
administered intravenously; and on days 1 through 14 of the 14 day
regimen, 100 mg/m.sup.2 of body surface of procarbazine and 40
mg/m.sup.2 of body surface of prednisone are administered
orally.
EXAMPLE 33
[0188] The procedure described in above Example 32 is followed,
except that 25 mg/m.sup.2 of body surface of doxorubicin, 6
mg/m.sup.2 of body surface of vinblastine, and 375 mg/m.sup.2 of
body surface of DTIC are substituted for mechlorethamine of Example
32. In the place of vincristine, procarbazine, and prednisone given
separately from the tourniquet procedure in Example 32, bleomycin
is administered separately from the tourniquet procedure at a
dosage of 10 mg/m.sup.2 of body surface.
EXAMPLE 34
[0189] The procedure described in above Example 32 is followed,
except that 750 mg/m.sup.2 of body surface of cyclophosphamide and
50 mg/m.sup.2 of body surface of doxorubicin are substituted for
mechlorethamine of Example 32. The three drugs (i.e. vincristine,
procarbazine, and prednisone) given separately from the tourniquet
procedure in Example 34, are substituted by 1.4 mg/m.sup.2 of body
surface (maximum of 2 mg) of vincristine and 60 mg/m.sup.2 of body
surface of prednisone (per oral daily for 5 days).
EXAMPLE 35
[0190] The procedure described in above Example 32 is followed,
except that 25 mg/m.sup.2 of body surface of doxorubicin (given on
days 1 and 8) and 650 mg of cyclophosphamide (given on days 1 and
8) are substituted for mechlorethamine of Example 32. The three
drugs (i.e. vincristine, procarbazine, and prednisone) given
separately from the shoulder tourniquet procedure in Example 32,
are substituted by bleomycin, 5 units/m.sup.2 of body surface
(given on days 15 and 22), vincristine 1.4 mg/m.sup.2 of body
surface (maximum of 2 mg, given on days 1 and 8), and 60 mg of
prednisone (given daily from day 15 to 28).
EXAMPLE 36
[0191] The procedure described in above Example 32 is followed,
except that 50 mg/m.sup.2 of body surface of doxorubicin, 500
mg/m.sup.2 of body surface of 5-fluorouracil (given on days 1 and
8), and 500 mg/m.sup.2 of body surface of cyclophosphamide are
substituted for mechlorethamine of Example 32. The three drugs
(i.e. vincristine, procarbazine, and prednisone) given separately
from the tourniquet procedure in Example 32, are omitted.
EXAMPLE 37
[0192] The procedure described in above Example 32 is followed,
except that 45 mg/m.sup.2 of body surface of doxorubicin, and 500
mg/m.sup.2 of body surface of cyclophosphamide are substituted for
mechlorethamine of Example 32. The three drugs (i.e. vincristine,
procarbazine, and prednisone) given separately from the tourniquet
procedure in Example 32, are omitted.
EXAMPLE 38
[0193] The procedure described in above Example 32 is followed,
except that 10 mg/m.sup.2 of body surface of mitomycin-C (given on
days 1 and 22, then every 6 weeks) and vindesine 3 mg/m.sup.2 of
body surface (given weekly for 5 times, then every 2 weeks) are
substituted for the mechlorethamine of Example 32. The three drugs
(i.e. vincristine, procarbazine, and prednisone) given separately
from the tourniquet procedure in Example 32, are omitted.
EXAMPLE 39
[0194] The procedure described in above Example 32 is followed,
except that 8 mg/m.sup.2 of body surface of mitomycin-C (given on
days 1, 29, and 71 only), vindesine 3 mg/m.sup.2 of body surface
(given weekly for 5 times, then every 2 weeks), and cisplatin 120
mg/m.sup.2 of body surface (given on days 1, 29, then every 6
weeks) are substituted for mechlorethamine of Example 32. The three
drugs (i.e. vincristine, procarbazine, and prednisone) given
separately from the tourniquet procedure in Example 32, are
omitted.
EXAMPLE 40
[0195] The procedure described in above Example 32 is followed,
except that 8 mg/m.sup.2 of body surface of mitomycin-C (given on
days 1, 29, and 71 only), vinblastine 4.5 mg/m.sup.2 of body
surface (given weekly for 5 times, then every 2 weeks), and
cisplatin 120 mg/m.sup.2 of body surface (given on days 1, 29, then
every 6 weeks) are substituted for mechlorethamine of Example 32.
The three drugs (i.e. vincristine, procarbazine, and prednisone)
given separately from the tourniquet procedure in Example 32, are
omitted.
EXAMPLE 41
[0196] The procedure described in above Example 32 is followed,
except that 8 mg/M2 of body surface of mitomycin-C (given on days
1, 29, and 71 only), vinblastine 4.5 mg/m.sup.2 of body surface
(given weekly for 5 times, then every 2 weeks), and cisplatin 120
mg/m.sup.2 of body surface (given on days 1, 29, then every 6
weeks) are substituted for mechlorethamine of Example 32. The three
drugs (i.e. vincristine, procarbazine, and prednisone) given
separately from the tourniquet procedure in Example 32, are
omitted.
EXAMPLE 42
[0197] The procedure described in above Example 32 is followed,
except that 45 mg/m.sup.2 of body surface of doxorubicin, 50
mg/m.sup.2 of body surface of etoposide (given daily for 5 days),
and 1000 mg/m.sup.2 of body surface of cyclophosphamide are
substituted for the mechlorethamine of Example 32. The three drugs
(i.e. vincristine, procarbazine, and prednisone) given separately
from the tourniquet procedure in Example 32, are omitted.
EXAMPLE 43
[0198] The procedure described in above Example 32 is followed,
except that 1000 mg/m.sup.2 of body surface of cyclophosphamide and
45 mg/m.sup.2 of body surface of doxorubicin are substituted for
the mechlorethamine of Example 32. The three drugs (i.e.
vincristine, procarbazine, and prednisone) given separately from
the tourniquet procedure in Example 32, are substituted by 1.4
mg/m.sup.2 of body surface (maximum of 2 mg) of vincristine.
EXAMPLE 44
[0199] The procedure described in above Example 32 is followed,
except that 1000 mg/m.sup.2 of body surface of cyclophosphamide and
50 mg/m.sup.2 of body surface of doxorubicin are substituted for
the mechlorethamine of Example 32. The three drugs (i.e.
vincristine, procarbazine, and prednisone) given separately from
the tourniquet procedure in Example 32, are substituted by 1.4
mg/m.sup.2 of body surface (maximum of 2 mg) of vincristine and 60
mg/m.sup.2 of body surface of etoposide (given daily for 5
days).
EXAMPLE 45
[0200] A human study was performed to assess the effectiveness of a
shoulder tourniquet for transiently occluding blood supply to bone
marrow of a humerus. An invention shoulder tourniquet was applied
to the right shoulder of a human adult male and inflated to 280 mm
Hg. Eight millicuries of technetium-99 m sulfur colloid was then
injected intravenously into the contralateral left arm vein. A
gamma camera (Model NXT Maxi Camera 400 AC) with LEAP collimator
was used to monitor blood perfusion to the head, neck, and
bilateral upper arms. With the tourniquet inflated, images were
collected every minute for the first 20 minutes, beginning 1 minute
following the injection, with 60 seconds of accumulated exposure
for each image. At 20 minutes post injection, the tourniquet was
deflated to restore the pressure on the occluded shoulder to
atmospheric pressure, and then at the 22 minute point another image
was collected over a 60 second period. In total, 64.times.64 images
were processed and stored in a Sophy computer system.
[0201] Visual examination of the images showed that inflation of
the invention shoulder tourniquet to 280 mm Hg is very effective
for transiently occluding arterial flow into the humerus bone,
including the upper 1/3 of the humerus while perfusion to the head
and contralateral arm was unimpaired. The images also show that
within two minutes of deflation of the tourniquet, perfusion was
reestablished in the treated shoulder and arm.
EXAMPLE 46
[0202] This example illustrates the utility of the invention bone
marrow shielding tourniquet during administration of a standard
dose of mechlorethamine (0.4 mg/kg) to a human patient with breast
cancer. This patient responded favorably to the invention method of
treatment by having decreased pain in her back even though the
mechlorethamine was administered at a dosage no higher than the
standard dosage.
[0203] The patient (Patient # 1), a 46 year old female, had been
diagnosed two years earlier as having a high-grade lobular
carcinoma (5.times.3.times.3 cm) in the left breast with invasion
of capillary and lymphatic vessels (38 of 41 axillary nodes were
positive for cancer). A mastectomy was performed followed by
chemotherapy with 6 cycles of CEF (epirubicin, 5-FU, and
cyclophosphamide). The patient also received radiation therapy to
the left chest wall and axilla. Approximately two years
post-radiation and chemotherapy, the patient was found to have
metastatic recurrence to spine, pelvis and lung. In treatment of
the recurrence, the patient received 2500 rads of x-ray radiation
over 5 weeks to T10-L2 spine and to right coxofemoral joint,
followed by two cycles of chemotherapy with CEF. Because of the
high total dose of epirubicin, the patient could receive no further
CEF chemotherapy. At the time of enrollment in treatment using the
invention method and device, the patient was experiencing back pain
of level 2 on a 10 level pain scale.
[0204] In the first cycle of treatment according to the invention,
a standard dose of 0.4 mg/kg of body weight of mechlorethamine was
administered without use of the invention bone marrow shielding
tourniquet. As premedication the patient received intravenously 16
mg dexamethasone and 2 mg Kytril and 1 mg lorazepam orally. Then
the dose of mechlorethamine was administered intravenously without
bone marrow shielding and without GM-CSF. The nadirs of the
patient's white blood count (WBC), absolute neutrophil count (ANC),
and platelet count were 1200 (day 12), 840 (day 12), and 48,000
cells/cu mm (day 15), respectively. By day 22, the patient's WBC
(white blood count), ANC (absolute neutrophile count), and platelet
count recovered to 4000, 3400, and 164,000 cells/cu mm,
respectively and the patient reported symptomatic improvement of
back pain after the first cycle.
[0205] In a second cycle of treatment, a bone marrow shielded
standard dose mechlorethamine was administered 31 days after the
first cycle of treatment. An invention bone marrow shielding
tourniquet was applied to the right humerus at a pressure of 260
mm/Hg for 15 minutes, while a dose of 0.4 mg/kg of body weight of
mechlorethamine was administered in the left arm vein. The nadirs
of the patient's WBC, ANC, and platelet count were 1000 (day 10),
600 (day 12), and 20,000 cells/cu mm (day 17), respectively. By day
19 post second cycle treatment, the patient's WBC, ANC, and
platelet count had recovered to 3100, 1860, and 54,000 cells/cu mm,
respectively.
[0206] In a third cycle of treatment 35 days after the second cycle
of treatment, an invention bone marrow shielding tourniquet was
applied to bilateral humeri and one scapula at 260 mm Hg for 4
minutes and then 180 mm Hg for 11 minutes while the standard dose
of mechlorethamine was administered through a Groshong catheter
inserted into the right subclavian vein. The nadirs of the
patient's WBC, ANC, and platelet count were 900 (day 12), 459 (day
12), and 19,000 cells/cu mm (day 19), respectively. By day 22,
patient's WBC, ANC, and platelet count recovered to 3200, 2240, and
26,000 cells/cu mm, respectively.
[0207] In a fourth cycle of treatment 28 days after the third cycle
of treatment, an invention bone marrow shielding tourniquet was
applied to bilateral humeri and one scapula at 260 mm Hg for 4
minutes and then 180 mm Hg for 11 minutes while the standard dose
of mechlorethamine was administered through a Groshong catheter
inserted into the right subclavian vein. The nadirs of the
patient's WBC, ANC, and platelet count were 500 (day 12), 360 (day
12), and 17,000 cells/cu mm (day 23), respectively. By day 30, the
patient's WBC, ANC, and platelet count had recovered to 3350, 2546,
and 150,000 cells/cu mm, respectively.
EXAMPLE 47
[0208] In this Example, a patient (patient #2) with brain cancer, a
notoriously difficult tumor to treat with chemotherapy, was treated
using the invention method and apparatus. Patient # 2, a 49 year
old female, had been diagnosed with high-grade glioma of the right
hemisphere of the brain about four and a half years earlier. At
that time she underwent a craniotomy and subsequently received
radiation therapy to the brain over a period of 5 weeks. Patient #2
did well for about 51 months, but thereafter experienced
convulsions and vomiting. Upon examination, the patient was found
to have a recurrence and was treated by a second resection of the
glioma via a craniotomy. At the time of enrollment in the present
treatment regimen, patient #2 had no symptoms except for a mild
weakness in her left arm and a healed craniotomy scar from ear to
ear on her scalp.
[0209] In the first cycle of chemotherapy according to the present
invention, patient #2 was administered 16 mg dexamethasone
intravenously, and 2 mg Kytril and 1 mg lorazepam orally as
premedications. Then 0.4 mg/kg of body weight of mechlorethamnine
was administered intravenously into the right arm vein in standard
fashion without the use of the invention bone marrow shielding
tourniquet. The nadirs of the patient's WBC, ANC, and platelet
count were 2100, 300, and 174,000 cells/cu mm, respectively, the
first two occurring on day 17 and the last occurring on day 12. By
day 19, the patient's WBC, ANC, and platelet count had recovered to
3000, 1000, and 332,000 cells/cu mm, respectively.
[0210] In a second cycle of treatment 21 days after the first cycle
of treatment, an invention bone marrow shielding tourniquet was
applied only to the patient's right humerus at 260 mm Hg pressure
and the doses of medication of the first cycle were repeated. The
nadir of the patient's WBC, ANC, and platelet count were 1100 (day
15), 266 (day 17), and 135,000 cells/cu mm (day 12), respectively.
By day 19, the patient's WBC, ANC, and platelet count had recovered
to 2300, 825, and 249,000 cells/cu mm, respectively.
[0211] A third cycle of treatment was administered on days 18 and
19 following completion of the second cycle at twice the standard
dose using the invention bone marrow shielding tourniquet and with
a supplemental administration of GM-CSF. Patient #2 was
premedicated with 8 mg dexamethasone IV, 16 mg dexamethasone IV,
and 2 mg Kytril, 1 mg lorazepam, and 0.3 mg of buprenorphine
orally. Then, the invention bone marrow shielding tourniquet was
applied to the patient's bilateral humeri and bilateral scapulae at
a pressure of 260 mm Hg prior to administration of 0.4 mg/kg of
body weight of mechlorethamine given IV through a Groshong catheter
placed into the patient's left subclavian vein. The bone marrow
shielding tourniquet was kept inflated for 15 minutes following the
injection of mechlorethamine, except for the left scapula bladder,
which was deflated 3 minutes after injection of mechlorethamine.
This regimen of chemotherapy was repeated the next day for a total
of 2 days. On day 2, Patient #2 was started on a daily supplemental
dosage of 400 .mu.g of GM-CSF subcutaneously for a total of 14
days. The nadirs of the patient's WBC, ANC, and platelet count were
1000 (day 11), 580 (day 15), and 36,000 cells/cu mm (day 17),
respectively. By day 19 post-treatment, the patients WBC and
platelet count had recovered to 2500 and 69,000 cells/cu mm,
respectively.
[0212] In the fourth cycle of treatment, started 35 days after
commencement of the third cycle, the patient was premedicated with
8 mg of dexamethasone IV, and 16 mg of Zofran IV, 2 mg of lorazepam
orally, 0.3 mg of buprenorphine IV, and Benadryl 20 mg IV. The
invention bone marrow shielding tourniquet was applied to bilateral
humeri and bilateral scapulae for 15 minutes at 280 mmHg while 0.4
mg/kg of body weight of mechlorethamine was administered through a
Groshong catheter as above. This regimen of chemotherapy was
repeated the next day for a total of 2 days. The patient was not
given any GM-CSF until she developed fever, which was successfully
managed with an outpatient IV antibiotic and daily subcutaneous
GM-CSF. The nadirs of the patient's WBC, ANC, and platelet count
were 300 (day 13), 0 (day 15), and 9,000 cells/cu mm (day 22),
respectively. By day 22, the patient's WBC and ANC had recovered to
1400 and 1232 cells/cu mm, respectively. CT scan of brain showed a
substantial decrease in tumor size.
EXAMPLE 48
[0213] In this Example, a patient with rectal cancer, another very
difficult type of cancer to treat with chemotherapy, receives one
cycle of mechlorethamine with Bone marrow shielding tourniquet
applied to one humerus and two cycles of mechlorethamine with Bone
marrow shielding tourniquet applied to bilateral humeri and
bilateral scapulae, all given without GM-CSF.
[0214] Patient # 3, a 48 year old male, had been diagnosed three
years prior as having adenocarcinoma of the rectum. At that time, a
resection of the rectal cancer was performed with an anastomosis of
the rectum. About three years post-surgery, the patient had
symptoms of recurrence and was found to have a large tumorous mass
in the rectum, which was determined to be unresectable due to its
size. Instead, the patient was administered radiation therapy at
5000 rads to the pelvis in 20 fractions and two months later
underwent diverting colostomy for 70% obstruction of the rectum
caused by the very large size of the tumor remaining after the
radiation therapy. At the time of enrollment in the present
treatment regimen, patient #3 was suffering from pain in the rectum
and took Darvon for the pain.
[0215] Some three months after the colostomy, in a first cycle of
treatment according to the present invention, an intravenous line
was place in right arm vein and patient #3 was administered 16 mg
dexamethasone IV, and 2 mg Kytril and 1 mg lorazepam orally as
premedications followed by 0.4 mg/kg of body weight of
mechlorethamine IV while an invention bone marrow shielding
tourniquet was applied to left humerus alone at 260 mm Hg for 15
minutes. No GM-CSF was given. The nadirs of the patient's WBC and
ANC were 2900 (day 15), 1537 cells/cu mm (day 15), respectively. By
day 19 post-treatment, the patient's WBC and ANC had recovered to
3000, and 1890 cells/cu mm, respectively.
[0216] In the second cycle administered 41 days later, patient #3
was administered 16 mg dexamethasone IV, and 2 mg Kytril orally, 1
mg lorazepam orally, and 0.3 mg of buprenorphine IV as
premedications. An invention bone marrow shielding tourniquet was
applied to the patient's bilateral humeri and bilateral scapulae at
a pressure of 260 mm Hg while 0.4 mg/kg of body weight of
mechlorethamine (twice the standard dose) was given IV through a
Groshong catheter placed into patient's right subclavian vein. The
bone marrow shielding tourniquet was kept inflated for 15 minutes
following the injection of mechlorethamine. This chemotherapy
regimen was repeated the next day for a total of 2 days. Patient #3
was not given any GM-CSF. The nadirs of the patient's WBC, ANC, and
platelet count were 1800 (day 19), 918 (day 19), and 130,000
cells/cu mm (day 22), respectively. By day 26 post-treatment, the
patient's WBC, ANC, and platelet count had recovered to 2700, 1863
and 240,000 cells/cu mm, respectively. After the second cycle, the
patient's rectal pain was completely resolved and the patient was
able to return to work as a mechanic. CT (computerized axial
tomography) scan showed "no disease" whereas previous CT scan had
shown very large tumor obstructing the rectum.
[0217] In a third cycle of treatment commencing 37 days after the
second cycle, the patient was administered 8 mg dexarnethasone IV,
and 16 mg Zofran IV, 2 mg Ativan, 20 mg Benadryl orally, but no
buprenorphine, as premedication, and a standard dose of 0.4 mg/kg
of body weight of mechlorethamine was given IV through the Groshong
catheter with the invention bone marrow shielding tourniquet
applied to bilateral humeri and bilateral scapulae at 280 mm/Hg for
15 minutes on the right side, but only 4 minutes on the left side.
On the second day of the third cycle, the chemotherapy was repeated
with the invention bone marrow shielding tourniquet applied to
bilateral humeri and scapulae for 15 minutes. The nadirs of the
patient's WBC, ANC, and platelet count were 2300 (day 10), 1372
(day 15), and 170,000 cells/cu mm (day 21), respectively. By day 31
post-treatment, the patient's WBC, ANC, and platelet count had
recovered to 4800, 2448, and 225,000 cells/cu mm, respectively.
[0218] Some two weeks after the third cycle of treatment, the
patient underwent sigmoidoscopy, which showed markedly smaller
tumor mass. As a result, the patient was presented at a local tumor
board and a recommendation was made to have the patient undergo
resection of the tumor, which was successfully performed.
[0219] The resected surgical specimen showed only necrotic mass
without any detectable cancer under microscopic histopathology
examination.
EXAMPLE 49
[0220] The next example is a very young patient with breast cancer,
who developed metastatic disease after receiving standard surgical
and chemotherapeutic treatments. She received her first cycle of
mechlorethamine at 4 times the standard dose (0.4 mg/kg of body
weight.times.4) with the Bone marrow shielding tourniquet applied
to bilateral humeri and bilateral scapulae and daily GM-CSF for 21
days. The patient tolerated chemotherapy well with a degree and
duration of myelosuppression that was equivalent to that associated
with standard dose mechlorethamine.
[0221] Patient # 4, a 28 year old female, had been diagnosed with
breast cancer involving almost all of the right breast about two
years prior. At that time the patient underwent preoperative
chemotherapy with Cytoxan, 5-FU, and epirubicin (120 mg/sq m) for 4
cycles, with partial response (80%), followed by modified radical
mastectomy about one year post-diagnosis. Patient #4 had more than
10 positive lymph nodes and received post-operative radiation
therapy to her chest wall. Following the mastectomy, the patient
had an additional 4 cycles of the chemotherapy, except with a lower
dose of epirubicin (80 mg/sq m). The patient started to have back
pain within a few months and underwent radiation therapy to the L
spine for 10 days. The pain improved and the patient had a slight
pain in her back at the time of enrollment in the present treatment
regimen. However, one month later, patient #4 was found to have
liver metastases, multiple lesions, on both lobes, as diagnosed by
ultrasound. At the time of enrollment (about five months after
radiation therapy), patient #4 also had numerous 0.5 cm to 1 cm
hard skin nodules over the right chest wall (over the mastectomy
site).
[0222] In a first cycle of chemotherapy according to the invention,
patient #4 was administered 8 mg dexamethasone IV, and 16 mg Zofran
IV, 1 mg lorazepam, 0.3 mg of buprenorphine and 30 mg of benadryl
orally as premedications. A bone marrow shielding tourniquet was
applied to the patient's bilateral humeri and bilateral scapulae at
a pressure of 280 mm Hg while 0.4 mg/kg of body weight of
mechlorethamine was administered IV through a Hickman catheter
placed into patient's left subclavian vein. The invention one
marrow shield was kept inflated for 15 minutes following the
injection of mechlorethamine. This chemotherapy was repeated daily
through Hickman catheter for a total of 4 days. On the second day
of chemotherapy, patient #4 was started on a daily subcutaneous
dose of GM-CSF (400 .mu.g) for 21 days. The nadirs of the patient's
WBC, ANC, and platelet count were 400, 164, and 14,000 cells/cu mm,
respectively, all occurring on day 14. By day 19, patient's WBC,
ANC, and platelet counts had partially recovered to 1800, 1170, and
22,000 cells/cu mm, respectively.
EXAMPLE 50
[0223] The patient in this example, a breast cancer patient who
developed metastatic disease after receiving standard surgical and
chemotherapeutic treatments, received her first cycle of
mechlorethamine at 4 times the standard dose (0.4 mg/kg of body
weight.times.4) with the invention bone marrow shielding tourniquet
applied to bilateral humeri and bilateral scapulae and daily GM-CSF
for 13 days. The patient tolerated chemotherapy well with a degree
and duration of myelosuppression that was much milder than that
associated with standard doses of mechlorethamine that are
administered without bone marrow shielding according to the
invention method. In addition, the tumor mass on the patient's
skull almost disappeared after one cycle of the invention
chemotherapy with the bone marrow shielding tourniquet.
[0224] Patient #5 is a 54 year old female who had been diagnosed
with an advanced stage of cancer (6.times.4 cm in size) of the left
breast about two years prior. At that time the patient underwent
preoperative chemotherapy with Cytoxan, 5-FU and epirubicin at
regular dose for 3 cycles, with a partial response, followed by
modified radical mastectomy some four months later. As 29 of 30 of
the lymph nodes were positive for cancer, following the mastectomy,
patient had radiation therapy to the left chest wall and left
axilla with some skin damage from radiation. An additional 3 cycles
of Cytoxan, 5-FU and epirubicin were given post-operatively. The
patient's surgeon tried to implant a silicon prosthesis, but the
implant was not successful so the breast prosthesis was eventually
removed. About 26 months after the mastectomy, the patient
developed pain in her left leg. A bone scan showed multiple
metastatic lesions in pelvis, ribs, and skull. The patient
consequently received radiation to her hips in 10 fractions,
resulting in improvement of the pain.
[0225] At the time of enrollment in the present study, the patient
used a cane to walk with slight pain in her left hip area and was
taking Tamoxifen and prednisone at 30 mg every other day. There was
darkened skin with a linear horizontal scar over the mastectomy
site, with apparent radiation burn, resulting in some dried exudate
from the scar. In addition, the patient had a firm and slightly
tender tumorous mass (3 cm.times.3.5 cm) over the left parietal
bone of her skull.
[0226] A first cycle of chemotherapy according to the present
invention was commenced about 291/2 months after the mastectomy. An
invention bone marrow shielding tourniquet was applied to the
patient's bilateral humeri and bilateral scapulae at a pressure of
280 mm Hg while 0.4 mg/kg of body weight of mechlorethamine was
given IV through a Hickman catheter placed into patient's right
subclavian vein. The bone marrow shielding tourniquet was kept
inflated for 15 minutes following the injection of mechlorethamine.
This chemotherapy regimen was repeated daily through a Hickman
catheter for a total of 4 days. On the third day of chemotherapy,
the patient was started on a daily dose of GM-CSF (400 .mu.g
subcutaneously) for 13 days. The nadirs of the patient's WBC, ANC,
and platelet count were 2100 (day 8), 1197 (day 8), and 90,000
cells/cu mm (day 15), respectively. By day 17, the patient's WBC,
ANC, and platelet count recovered to 3900, 2379, and 99,000
cells/cu mm, respectively. After the first cycle of chemotherapy
with the bone marrow shielding tourniquet in place, the patient's
tumor mass in her left parietal bone of skull has almost
disappeared.
[0227] It will be apparent to those skilled in the art that various
changes may be made in the invention without departing from the
spirit and scope thereof, and therefore, the invention encompasses
embodiments in addition to those specifically disclosed in the
specification, but only as indicated in the appended claims.
* * * * *