Cancer Investigation, 8(1) 7-12 (1990)
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Vincristine Infusion with CHOP-CCNU in Diffuse Large-Cell Lymphoma Don V. Jackson, Jr., M.D., John B. Craig, M.D., Charles L. Spurr, M.D., Douglas R. White, M.D., Hyman B. Muss, M.D., Julia M. Crur, M.D., Fred Richards, M.D., and Bayard L. Powell, M.D. Piedmont Oncology Association and Cancer Center Wake Forest University Winston.Salem, North Carolina 27103
ABSTRACT
Phase I and II trials of vincristine infusion have demonstrated the safety and efj k a c y of this approach in the treatment of patients with refractory non-Hodgkin 's lymphoma. Subsequently, a trial was designed to evaluate this technique in untreated patients. Repeated 5-day infusions of vincristine 0.25 mg/m2 per day were incorporated into a CHOP-CCNU regimen and administered to 24patients with advanced d i m e large-cell lymphoma. Objective responses occurred rapidly and were observed in 18 (75%)patients in whom 13 (54%)were complete. Toxicity was generally mild to moderate and neurotoxicity appeared to be no worse than typically observed with bolus vincristine. Complete responses have been durable in most patients and 10 (77%)of the complete responders have not relapsed. At this time, 9 (38%)of the total patients remain alive and without evidence of disease from 3.8 to 7.3 years from the start of treatment. One patient died of disseminated gastric cancer at 3.3 years from the start of therapy and there was no evidence of lymphoma art exploratory laparotomy. Infision of vincristine may be safely incorporated into multiagent chemotherapy programs of the CHOP type for non-Hodgkin 's lymphoma. Its potential for protracted nonmyelosuppressive cell kill would appear attractive in designing future trials for this disease.
7 Copyright
0 1990 by Marcel Dekker, Inc.
Jackson et al.
8
METHODS
Cancer Invest Downloaded from informahealthcare.com by University of Otago on 03/14/15 For personal use only.
INTRODUCTION Vincristine has been extensively used in cancer chemotherapy and particularly in non-Hodgkin’s lymphomas for almost three decades (1,2). Conventionally, it has been administered as a rapid intravenous bolus. However, the cytotoxicity of vincristine has been found to be critically dependent on duration of exposure as well as concentration during in vitro studies (3). A Phase I trial of vincristine given as a 5-day infusion was conducted on the premise that prolonged exposure might enhance therapeutic efficacy (4). Objective responses were noted in a variety of malignancies, most notably non-Hodgkin’s lymphoma (partial response in 4 of 6 patients). Interestingly, each of the responding patients had previously received vincristine given as a rapid bolus. The ability to respond to an infusion of this agent following prior exposure of it as a bolus suggested the potential for enhancement of vincristine’s therapeutic effect in this and other tumor types using this technique ( 4 3 . Moreover, pharmacologic analysis conducted during the Phase I trial demonstrated the ability to sustain potentially cytotoxic blood concentrations of vincristine (3)using an infusion which was in contrast to the rapid disappearance observed following bolus administration (6). A Phase I1 trial of vincristine given as a 5-day infusion (0.25 mg/m2/day) was conducted in 25 patients with a variety of non-Hodgkin’s lymphomas (7). Objective responses were observed in 9 (36%)patients in whom 8 were partial and 1 was complete. Each of the responding patients had received vincristine as a bolus injection before entry into the trial. Hematologic toxicity was minimal and nausea or vomiting did not occur. Approximately half of the patients experienced some degree of neurotoxicity, but it was no worse than that typically observed during repetitive bolus injections of vincristine. A Phase In trial was designed to evaluate the infusion of vincristine as a component of a multiagent chemotherapeutic regimen for aggressive non-Hodgkin’s lymphomas. The rapidly proliferating cells typical of the large cell lymphomas might be particularly vulnerable to a protracted infusion of an effective antitumor agent, especially one with the track record of vincristine in the nonHodgkin’s lymphomas.
Subjects Between August 1980 and January 1985, 24 previously untreated patients with Stage I11 or IV diffuse large cell lymphoma were entered into a protocol conducted by the Piedmont Oncology Association. Entry requirements included a white cell count (WBC) of L 4000/mm3and a platelet count of 2 lo0,000/mm3 unless due to bone marrow involvement or splenomegaly, blood urea nitrogen (BUN) I 25 mg%, serum creatinine < 1.5 mg%, serum bilirubin < 1.5 mg % , serum glutamic-oxaloacetic transaminase (SGOT) 5 6 0 IU, presence of measurable disease to be used as an indicator of response, and signed protocol-specific written informed consent. Pretreatment patient characteristics are outlined in Table 1. Performance status was defined using the Zubrod Scale. The Ann Arbor staging system was used.
Table 1 Pretreatment Patient Characteristics
Number No. of patients Median age (years, range) Sex Male Female Performance status 011
24 55 (19-76)
Percentage (%)
100 -
14
42 58
10
213 Sites of involvement Nodal only
18 6
75 25
12
50
Extranodal Bone marrow Cerebrospinal fluid Stage IIIIIV
12 5 1 12/12
50 21 4 50150
Previous therapy =Radiation or chemotherapy.
0
0
Vincristine Infusion in Lymphoma
9
Cancer Invest Downloaded from informahealthcare.com by University of Otago on 03/14/15 For personal use only.
Treatment Deisgn All patients were treated with the drug combination of CHOP-CCNU (8) in which vincristine was given by infusion rather than bolus as outlined in Table 2. This combination was chosen for the purpose of comparing treatment results obtained within the same institution, and not because CCNU added to the CHOP regimen appeared to be more effective than CHOP alone. The vincristine bolus in the previous trial was given concurrently with the other agents including prednisone. The infusate in the current trial was prepared daily and consisted of the appropriate dose of vincristine in 1000 ml of 5% dextrose and water to which was added 3000 units of heparin and 50 mg of hydrocortisone to reduce phlebitis. The stability of vincristine in this solution has been previously assessed by high-pressure liquid chromatography (4); decomposition was < 10% over a 24-h period. Dosage modifications were based on physical exam and laboratory parameters obtained on the day of therapy. If WBC count was 24000/mm3 and platelets > 100,000/mm3,the patient received the full dose of all drugs; if WBC was 75,000/mm3 but 5 100,000/mm3, the CCNU, cyclophosphamide, and doxorubicin doses were reduced by 50%; if WBC was 1.5 mg% but (3.0 mg% or if the SGOT was 1.5-3 times normal; if they increased to > 3.0 mg% or three times normal, respectively, the doses were decreased by 75 % . If recovery to normal function occurred, full doses were administered. VCR doses were not modified unless loss of imotor function (Grade 111 neurologic toxicity; World Health Organization toxicity scale) occurred. Fifty percent doses were administered as long as motor dysfunction stabilized; if Grade IV neurologic toxicity occurred, the VCR was permanently discontinued.
Statistical Evaluation Standard World Health Organization response criteria were used. Survival was calculated as time from initial treatment to death or last contact date. Response was measured from the time of ithe first noted response until disease progression or last contact date.
RESULTS Response and Survival Since the infusion of vincristine was given before any of the other chemotherapy, changes in the palpable lesions as a consequence of vincristine could be observed momentarily by physical examination. Rapid diminution of adenopathy although not complete resolution, was the rule rather than the exception. Overall, objective responses
Table 2 Treatment Regimena Drug Vincristine
Prednisone Doxor~ bicin
Cyclophosphamide CCNU
Dosage (mg/m2)
Route
Day
Schedule
24-h IV infusion
1-5
q 3 wks x 2 q 6 wks X 2 q 9 wks x 3
40
PO
6-10
q 3 wks
0.2Sb
30
IV
6
q 3 wks
500
IV
6
q 3 wks
50
PO
6
q 6 wks
aTotal duration = 43 weeks. bVincristine 0.5 mg was given as an IV bolus immediately prior to starting each 5-day infusion of vincristine.
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10
Jackson et al.
were eventually observed in 75% of patients (Table 3), in whom complete response occurred in 13 (54%) of the population. The characteristics of patients with a complete response are listed in Table 4. Nine (69%) were female and the median age was 50 years at presentation. All but one patient had nodal disease, and seven (54%) patients had one or more extranodal sites of disease. Of the 13 patients with complete response, 3 subsequently relapsed at 14, 18, and 23 months, respectively, from the start of treatment, leaving 10 (77%) without disease progression. However, one patient died of disseminated gastric cancer 3.3 years from the start of therapy and was without progression of lymphoma as confirmed by exploratory laparotomy. There have been no relapses in the central nervous system to date. Overall, 9 (38%) of the total patients entered into the study are alive and still in complete remission 3.8 to 7.3 years from the start of treatment.
Table 3 Response and Relapse
Patients Complete response (CR) Partial response (PR) CR PR Progression
+
No.
%
Relapse
%
24 13 5 18 6
(100) (54) (21) (75) (25)
3a 5 8
(23) (100) (44)
-
-
aAt 14, 18, and 23 months from the start of treatment.
was noted. Vincristine was discontinued in two patients secondary to Grade I11 neurologic toxicity consisting of disabling paresthesias and mild decreased strength in both, one of whom had juvenile onset diabetes.
Toxicity
DISCUSSION
Overall toxicity is outlined in Table 5 . Hematologic toxicity was modest with only 13 % of patients experiencing Grade IV toxicity; one patient died from leukopeniarelated sepsis. No Grade IV nonhematologic toxicity
The CHOP regimen and some of its variants as used in the SouthwestOncology Group (SWOG) has produced an overall 53% complete response rate among 418 patients with diffuse large cell lymphoma (9). The long-term
Table 4 Characteristics of Patients with a Complete Response
Age (years)
Sex
Initial disease site
Duration of response (months)
E.A. M.B.
42 76
F F
Nodes, pancreas Nodes, chest wall
61 + 64
T.D. A.H.
19 50
F F
Nodes, bowel Nodes, skin
80 + 14
H.I. D.L.
57 47
M F
Nodes Nodes, effusion
22 83
A.L. M.L.a
52 59
F F
Nodes Nodes
40
A.M. C.S.
54 49
M M
Nodes, lung, spleen Liver, spleen, CSF
6 57 +
L.U.
73
F
Nodes
66
H.W.
39
M
Nodes
33
Patient
+
+ 80 +
Sites of relapse
Survival (months)
-
62 + 67 +
-
83
Lung
21
Effusion -
-
+
+
Nodes
+
81 88 + 81 + 40
-
20 60 + 74 +
-
45 +
-
34 F Nodes 53 + 56 + aPatient died due to disseminated gastric carcinoma;there was no evidence of lymphoma during exploratory laparotorny.
S.W.
Vincristine Infusion in Lymphoma
11
Table 5
drug combination when compared with other CHOP regimens. On a positive note, the repeated infusions of vincristine and the entire treatment program appeared to be generally quite well tolerated. Specifically, neurotoxicity was generally mild and perhaps less than was observed in our previous trial using bolus vincristine (8). Further, hematologic toxicity was usually mild to moderate and gastrointestinal side effects did not appear to be increased with this technique. Portable infusion pumps and indwelling venous access devices were used in some patients to facilitate outpatient delivery. It may be possible to use infusion of vincristine to better advantage in multiagent combinations for aggressive non-Hodgkin’s lymphoma than was employed in the current trial. Perhaps it could be given in midcycle as a relatively nonmyelosuppressive agent when nadir blood counts occur and the tumor cells are in a state of increased S-phase activity following exposure to the myelosuppressive agents in the regimen. Recently, the rapid sequencing of drugs appears promising in diffuse large cell lymphoma (10). Also, infusion of vincristine would have the capability for protracted cell kill compared with bolus injection of it. This would seem to be particularly advantageous in a disease characterized by rapid doubling and the potential to regrow between cycles of treatment with myelosuppressive agents. The greatest chance for cure of diffuse large cell lymphoma appears to be linked with the rapid attainment of complete response (1 1). Infusion of vincristine might factor into treatment strategies along this line of thought given the rapidity of response seen with it before the other agents were used in this trial. Furthermore, this technique may have the potential to circumvent drug resistance as suggested by the rapid response of some cases of non-Hodgkin’s lymphoma to infusion of vincristine in the setting of recently progressive disease while receiving bolus treatments with it (2,5,7). Vincristine infusion has been a component of the highly effective COP-BLAM regimen for large cell lymphoma (12) and an integral part of the VAD regimen used in myeloma and a variety of lymphoid malignancies (13). The infusion of vincristine was given concurrently with other chemotherapeutic agents beginning on the first treatment day in both of the latter regimens (12,13).
Cancer Invest Downloaded from informahealthcare.com by University of Otago on 03/14/15 For personal use only.
Toxicity (World Health Organization Scale)
Grade 2
Grade 3
WBC
7 (29%)
6 (25%)
3 (13%)a
Platelets N euro1og ic Mucositis Nausea Vomiting
1 (4%)
3 (13%)
4 (17%)
2 (8%)b
2 (8%) 0 (0%)
1 (4%)
3 (13%) 3 (13%) 1 (4%)
4 (17%)
5 (21%)
Grade 4
0 (0%) 0 (0%) 0 (0%)
aWBC < 1000/mm3or platelets
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Vincristine Infusion with CHOP-CCNU in Diffuse Large-Cell Lymphoma Don V. Jackson, Jr., M.D., John B. Craig, M.D., Charles L. Spurr, M.D., Douglas R. White, M.D., Hyman B. Muss, M.D., Julia M. Crur, M.D., Fred Richards, M.D., and Bayard L. Powell, M.D. Piedmont Oncology Association and Cancer Center Wake Forest University Winston.Salem, North Carolina 27103
ABSTRACT
Phase I and II trials of vincristine infusion have demonstrated the safety and efj k a c y of this approach in the treatment of patients with refractory non-Hodgkin 's lymphoma. Subsequently, a trial was designed to evaluate this technique in untreated patients. Repeated 5-day infusions of vincristine 0.25 mg/m2 per day were incorporated into a CHOP-CCNU regimen and administered to 24patients with advanced d i m e large-cell lymphoma. Objective responses occurred rapidly and were observed in 18 (75%)patients in whom 13 (54%)were complete. Toxicity was generally mild to moderate and neurotoxicity appeared to be no worse than typically observed with bolus vincristine. Complete responses have been durable in most patients and 10 (77%)of the complete responders have not relapsed. At this time, 9 (38%)of the total patients remain alive and without evidence of disease from 3.8 to 7.3 years from the start of treatment. One patient died of disseminated gastric cancer at 3.3 years from the start of therapy and there was no evidence of lymphoma art exploratory laparotomy. Infision of vincristine may be safely incorporated into multiagent chemotherapy programs of the CHOP type for non-Hodgkin 's lymphoma. Its potential for protracted nonmyelosuppressive cell kill would appear attractive in designing future trials for this disease.
7 Copyright
0 1990 by Marcel Dekker, Inc.
Jackson et al.
8
METHODS
Cancer Invest Downloaded from informahealthcare.com by University of Otago on 03/14/15 For personal use only.
INTRODUCTION Vincristine has been extensively used in cancer chemotherapy and particularly in non-Hodgkin’s lymphomas for almost three decades (1,2). Conventionally, it has been administered as a rapid intravenous bolus. However, the cytotoxicity of vincristine has been found to be critically dependent on duration of exposure as well as concentration during in vitro studies (3). A Phase I trial of vincristine given as a 5-day infusion was conducted on the premise that prolonged exposure might enhance therapeutic efficacy (4). Objective responses were noted in a variety of malignancies, most notably non-Hodgkin’s lymphoma (partial response in 4 of 6 patients). Interestingly, each of the responding patients had previously received vincristine given as a rapid bolus. The ability to respond to an infusion of this agent following prior exposure of it as a bolus suggested the potential for enhancement of vincristine’s therapeutic effect in this and other tumor types using this technique ( 4 3 . Moreover, pharmacologic analysis conducted during the Phase I trial demonstrated the ability to sustain potentially cytotoxic blood concentrations of vincristine (3)using an infusion which was in contrast to the rapid disappearance observed following bolus administration (6). A Phase I1 trial of vincristine given as a 5-day infusion (0.25 mg/m2/day) was conducted in 25 patients with a variety of non-Hodgkin’s lymphomas (7). Objective responses were observed in 9 (36%)patients in whom 8 were partial and 1 was complete. Each of the responding patients had received vincristine as a bolus injection before entry into the trial. Hematologic toxicity was minimal and nausea or vomiting did not occur. Approximately half of the patients experienced some degree of neurotoxicity, but it was no worse than that typically observed during repetitive bolus injections of vincristine. A Phase In trial was designed to evaluate the infusion of vincristine as a component of a multiagent chemotherapeutic regimen for aggressive non-Hodgkin’s lymphomas. The rapidly proliferating cells typical of the large cell lymphomas might be particularly vulnerable to a protracted infusion of an effective antitumor agent, especially one with the track record of vincristine in the nonHodgkin’s lymphomas.
Subjects Between August 1980 and January 1985, 24 previously untreated patients with Stage I11 or IV diffuse large cell lymphoma were entered into a protocol conducted by the Piedmont Oncology Association. Entry requirements included a white cell count (WBC) of L 4000/mm3and a platelet count of 2 lo0,000/mm3 unless due to bone marrow involvement or splenomegaly, blood urea nitrogen (BUN) I 25 mg%, serum creatinine < 1.5 mg%, serum bilirubin < 1.5 mg % , serum glutamic-oxaloacetic transaminase (SGOT) 5 6 0 IU, presence of measurable disease to be used as an indicator of response, and signed protocol-specific written informed consent. Pretreatment patient characteristics are outlined in Table 1. Performance status was defined using the Zubrod Scale. The Ann Arbor staging system was used.
Table 1 Pretreatment Patient Characteristics
Number No. of patients Median age (years, range) Sex Male Female Performance status 011
24 55 (19-76)
Percentage (%)
100 -
14
42 58
10
213 Sites of involvement Nodal only
18 6
75 25
12
50
Extranodal Bone marrow Cerebrospinal fluid Stage IIIIIV
12 5 1 12/12
50 21 4 50150
Previous therapy =Radiation or chemotherapy.
0
0
Vincristine Infusion in Lymphoma
9
Cancer Invest Downloaded from informahealthcare.com by University of Otago on 03/14/15 For personal use only.
Treatment Deisgn All patients were treated with the drug combination of CHOP-CCNU (8) in which vincristine was given by infusion rather than bolus as outlined in Table 2. This combination was chosen for the purpose of comparing treatment results obtained within the same institution, and not because CCNU added to the CHOP regimen appeared to be more effective than CHOP alone. The vincristine bolus in the previous trial was given concurrently with the other agents including prednisone. The infusate in the current trial was prepared daily and consisted of the appropriate dose of vincristine in 1000 ml of 5% dextrose and water to which was added 3000 units of heparin and 50 mg of hydrocortisone to reduce phlebitis. The stability of vincristine in this solution has been previously assessed by high-pressure liquid chromatography (4); decomposition was < 10% over a 24-h period. Dosage modifications were based on physical exam and laboratory parameters obtained on the day of therapy. If WBC count was 24000/mm3 and platelets > 100,000/mm3,the patient received the full dose of all drugs; if WBC was 75,000/mm3 but 5 100,000/mm3, the CCNU, cyclophosphamide, and doxorubicin doses were reduced by 50%; if WBC was 1.5 mg% but (3.0 mg% or if the SGOT was 1.5-3 times normal; if they increased to > 3.0 mg% or three times normal, respectively, the doses were decreased by 75 % . If recovery to normal function occurred, full doses were administered. VCR doses were not modified unless loss of imotor function (Grade 111 neurologic toxicity; World Health Organization toxicity scale) occurred. Fifty percent doses were administered as long as motor dysfunction stabilized; if Grade IV neurologic toxicity occurred, the VCR was permanently discontinued.
Statistical Evaluation Standard World Health Organization response criteria were used. Survival was calculated as time from initial treatment to death or last contact date. Response was measured from the time of ithe first noted response until disease progression or last contact date.
RESULTS Response and Survival Since the infusion of vincristine was given before any of the other chemotherapy, changes in the palpable lesions as a consequence of vincristine could be observed momentarily by physical examination. Rapid diminution of adenopathy although not complete resolution, was the rule rather than the exception. Overall, objective responses
Table 2 Treatment Regimena Drug Vincristine
Prednisone Doxor~ bicin
Cyclophosphamide CCNU
Dosage (mg/m2)
Route
Day
Schedule
24-h IV infusion
1-5
q 3 wks x 2 q 6 wks X 2 q 9 wks x 3
40
PO
6-10
q 3 wks
0.2Sb
30
IV
6
q 3 wks
500
IV
6
q 3 wks
50
PO
6
q 6 wks
aTotal duration = 43 weeks. bVincristine 0.5 mg was given as an IV bolus immediately prior to starting each 5-day infusion of vincristine.
Cancer Invest Downloaded from informahealthcare.com by University of Otago on 03/14/15 For personal use only.
10
Jackson et al.
were eventually observed in 75% of patients (Table 3), in whom complete response occurred in 13 (54%) of the population. The characteristics of patients with a complete response are listed in Table 4. Nine (69%) were female and the median age was 50 years at presentation. All but one patient had nodal disease, and seven (54%) patients had one or more extranodal sites of disease. Of the 13 patients with complete response, 3 subsequently relapsed at 14, 18, and 23 months, respectively, from the start of treatment, leaving 10 (77%) without disease progression. However, one patient died of disseminated gastric cancer 3.3 years from the start of therapy and was without progression of lymphoma as confirmed by exploratory laparotomy. There have been no relapses in the central nervous system to date. Overall, 9 (38%) of the total patients entered into the study are alive and still in complete remission 3.8 to 7.3 years from the start of treatment.
Table 3 Response and Relapse
Patients Complete response (CR) Partial response (PR) CR PR Progression
+
No.
%
Relapse
%
24 13 5 18 6
(100) (54) (21) (75) (25)
3a 5 8
(23) (100) (44)
-
-
aAt 14, 18, and 23 months from the start of treatment.
was noted. Vincristine was discontinued in two patients secondary to Grade I11 neurologic toxicity consisting of disabling paresthesias and mild decreased strength in both, one of whom had juvenile onset diabetes.
Toxicity
DISCUSSION
Overall toxicity is outlined in Table 5 . Hematologic toxicity was modest with only 13 % of patients experiencing Grade IV toxicity; one patient died from leukopeniarelated sepsis. No Grade IV nonhematologic toxicity
The CHOP regimen and some of its variants as used in the SouthwestOncology Group (SWOG) has produced an overall 53% complete response rate among 418 patients with diffuse large cell lymphoma (9). The long-term
Table 4 Characteristics of Patients with a Complete Response
Age (years)
Sex
Initial disease site
Duration of response (months)
E.A. M.B.
42 76
F F
Nodes, pancreas Nodes, chest wall
61 + 64
T.D. A.H.
19 50
F F
Nodes, bowel Nodes, skin
80 + 14
H.I. D.L.
57 47
M F
Nodes Nodes, effusion
22 83
A.L. M.L.a
52 59
F F
Nodes Nodes
40
A.M. C.S.
54 49
M M
Nodes, lung, spleen Liver, spleen, CSF
6 57 +
L.U.
73
F
Nodes
66
H.W.
39
M
Nodes
33
Patient
+
+ 80 +
Sites of relapse
Survival (months)
-
62 + 67 +
-
83
Lung
21
Effusion -
-
+
+
Nodes
+
81 88 + 81 + 40
-
20 60 + 74 +
-
45 +
-
34 F Nodes 53 + 56 + aPatient died due to disseminated gastric carcinoma;there was no evidence of lymphoma during exploratory laparotorny.
S.W.
Vincristine Infusion in Lymphoma
11
Table 5
drug combination when compared with other CHOP regimens. On a positive note, the repeated infusions of vincristine and the entire treatment program appeared to be generally quite well tolerated. Specifically, neurotoxicity was generally mild and perhaps less than was observed in our previous trial using bolus vincristine (8). Further, hematologic toxicity was usually mild to moderate and gastrointestinal side effects did not appear to be increased with this technique. Portable infusion pumps and indwelling venous access devices were used in some patients to facilitate outpatient delivery. It may be possible to use infusion of vincristine to better advantage in multiagent combinations for aggressive non-Hodgkin’s lymphoma than was employed in the current trial. Perhaps it could be given in midcycle as a relatively nonmyelosuppressive agent when nadir blood counts occur and the tumor cells are in a state of increased S-phase activity following exposure to the myelosuppressive agents in the regimen. Recently, the rapid sequencing of drugs appears promising in diffuse large cell lymphoma (10). Also, infusion of vincristine would have the capability for protracted cell kill compared with bolus injection of it. This would seem to be particularly advantageous in a disease characterized by rapid doubling and the potential to regrow between cycles of treatment with myelosuppressive agents. The greatest chance for cure of diffuse large cell lymphoma appears to be linked with the rapid attainment of complete response (1 1). Infusion of vincristine might factor into treatment strategies along this line of thought given the rapidity of response seen with it before the other agents were used in this trial. Furthermore, this technique may have the potential to circumvent drug resistance as suggested by the rapid response of some cases of non-Hodgkin’s lymphoma to infusion of vincristine in the setting of recently progressive disease while receiving bolus treatments with it (2,5,7). Vincristine infusion has been a component of the highly effective COP-BLAM regimen for large cell lymphoma (12) and an integral part of the VAD regimen used in myeloma and a variety of lymphoid malignancies (13). The infusion of vincristine was given concurrently with other chemotherapeutic agents beginning on the first treatment day in both of the latter regimens (12,13).
Cancer Invest Downloaded from informahealthcare.com by University of Otago on 03/14/15 For personal use only.
Toxicity (World Health Organization Scale)
Grade 2
Grade 3
WBC
7 (29%)
6 (25%)
3 (13%)a
Platelets N euro1og ic Mucositis Nausea Vomiting
1 (4%)
3 (13%)
4 (17%)
2 (8%)b
2 (8%) 0 (0%)
1 (4%)
3 (13%) 3 (13%) 1 (4%)
4 (17%)
5 (21%)
Grade 4
0 (0%) 0 (0%) 0 (0%)
aWBC < 1000/mm3or platelets
