Annals of Oncology I: 147-149, 1990. O 1990 Kluwer Academic Publishers. Printed in the Netherlands. Original article Treatment of epidemic Kaposi's sarcoma with combination chemotherapy (vincristine and bleomycin) and zidovudine M.U. Rarick, P.S. Gill, T. Montgomery, M. Bernstein-Singer, B. Jones & A.M. Levine From the Department of Internal Medicine, Division ofHematology, University of Southern California School of Medicine, and the Los Angeles County-USC Medical Center, Los Angeles, USA Summary. Advanced AIDS-associated Kaposi's sarcoma often requires systemic cytotoxic chemotherapy. Despite high response rates, the majority of the patients die of opportunistic infections (OIs). Effective anti-retroviral agents in combina- tion with cytotoxic chemotherapy may be useful in preventing the development of OIs in addition to increasing the tumor response. Twelve patients with extensive EKS were treated with a non-myelosuppressive drug regimen consisting of bleomycin and vincristine (BV) in combination with the anti-retroviral agent, zidovudine (ZDV). The dose of ZDV was 200 mg orally every four hours (full dose) in eight patients (Group I) or 100 mg orally every four hours (half dose) in four patients (Group IT). Toxicity was acceptable with only 3 patients (all from Group I) requiring blood transfusions. ZDV dose reduction due to granulocytopenia was required in 6 patients (5 in Group I and 1 in Group II). Only two patients developed OIs during 27.5 cumulative months of therapy. The overall response rate was 83% in both groups with 4 patients achieving complete remission (CR) and 6 patients achieving a partial remission (PR). We conclude that a combina- tion of (BV) chemotherapy and ZDV can be used safely with high response rates. Prospective studies of such combination regimens are currently in progress. Key words: AIDS, bleomycin, chemotherapy, Kaposi's sarcoma, vincristine, zidovudine (ZDV) Introduction Infection by the Human Immunodeficiency Virus (HIV) results in immune depression that may manifest itself by the development of opportunistic infections (OI), non- Hodgkin's lymphoma, or Epidemic Kaposi's sarcoma (EKS) [1, 2]. Optimal therapy of EKS depends upon the stage, sites, and pace of disease, as well as the underlying immunologic status of the patient. Radiation therapy, Interferon-alpha, and/or chemotherapy, either used as single agents or in combination, have all shown activity in the treatment of EKS [3-9]. Patients with limited EKS and a CD4+ T lymphocyte count greater than 400/mm 3 are the best responders to Interferon-alpha [10]. However, patients with extensive skin disease, lymphedema, or visceral in- volvement usually require combination chemotherapy. Al- though response rates may be high, responding patients often die of intercurrent OL Several studies are currently in progress which use various anti-HTV agents in combination with chemotherapy in the hopes of decreasing the fre- quency of OI and increasing patient survival. Zidovudine (ZDV) is an anti-retroviral agent which inhibits HIV replica- tion and has been shown to increase survival in patients with symptomatic HIV infection [11]. Its major toxicity is myelosuppression, which is often dose limiting and may result in its discontinuation [12,13]. In this setting, effective treatment for EKS with non- myelosuppresive chemotherapy would allow concomitant continuation of ZDV. Two chemotherapeutic agents, bleomycin and vincristine (BV) have only mild myelosup- pressive effects [14] with known anti-tumor activity in patients with EKS [4, 5, 6, 15]. The current report docu- ments our experience with bleomycin, vincristine and ZDV in patients with disseminated EKS and severe immune deficiency secondary to HTV-I. Material and methods Twelve patients were retrospectively studied. All had exten- sive or progressive KS and received ZDV and combination chemotherapy, bleomycin and vincristine (BV) for 4 weeks or greater. Extensive KS was defined as the presence of 25 or more mucocutaneous lesions, development of £ 10 new lesions over one month, or the presence of symptomatic visceral disease. Patients were not excluded if they had constitutional symptoms (weight loss > 10% body weight, fevers of unknown etiology, and night sweats) or chronic diarrhea. Data were collected regarding age, performance status, race, risk factor for HTV infection, history of prior oppor- tunistic infection (OI), and baseline blood counts prior to initiation of BV including hemoglobin (Hgb), absolute granulocyte counts (AGC), and absolute CD4+ lymphocyte counts. The extent and sites of KS including the number of mucocutaneous lesions and presence or absence of visceral
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Treatment of epidemic Kaposi's sarcoma with combination chemotherapy (vincristine and bleomycin) and zidovudineAnnals of Oncology I: 147-149, 1990. O 1990 Kluwer Academic Publishers. Printed in the Netherlands.
Original article
Treatment of epidemic Kaposi's sarcoma with combination chemotherapy (vincristine and bleomycin) and zidovudine
M.U. Rarick, P.S. Gill, T. Montgomery, M. Bernstein-Singer, B. Jones & A.M. Levine From the Department of Internal Medicine, Division ofHematology, University of Southern California School of Medicine, and the Los Angeles County-USC Medical Center, Los Angeles, USA
Summary. Advanced AIDS-associated Kaposi's sarcoma often requires systemic cytotoxic chemotherapy. Despite high response rates, the majority of the patients die of opportunistic infections (OIs). Effective anti-retroviral agents in combina- tion with cytotoxic chemotherapy may be useful in preventing the development of OIs in addition to increasing the tumor response. Twelve patients with extensive EKS were treated with a non-myelosuppressive drug regimen consisting of bleomycin and vincristine (BV) in combination with the anti-retroviral agent, zidovudine (ZDV). The dose of ZDV was 200 mg orally every four hours (full dose) in eight patients (Group I) or 100 mg orally every four hours (half dose) in four patients (Group IT). Toxicity was acceptable with only 3 patients (all from Group I) requiring blood transfusions. ZDV dose reduction due to granulocytopenia was required in 6 patients (5 in Group I and 1 in Group II). Only two patients developed OIs during 27.5 cumulative months of therapy. The overall response rate was 83% in both groups with 4 patients achieving complete remission (CR) and 6 patients achieving a partial remission (PR). We conclude that a combina- tion of (BV) chemotherapy and ZDV can be used safely with high response rates. Prospective studies of such combination regimens are currently in progress.
Key words: AIDS, bleomycin, chemotherapy, Kaposi's sarcoma, vincristine, zidovudine (ZDV)
Introduction
Infection by the Human Immunodeficiency Virus (HIV) results in immune depression that may manifest itself by the development of opportunistic infections (OI), non- Hodgkin's lymphoma, or Epidemic Kaposi's sarcoma (EKS) [1, 2]. Optimal therapy of EKS depends upon the stage, sites, and pace of disease, as well as the underlying immunologic status of the patient. Radiation therapy, Interferon-alpha, and/or chemotherapy, either used as single agents or in combination, have all shown activity in the treatment of EKS [3-9]. Patients with limited EKS and a CD4+ T lymphocyte count greater than 400/mm3 are the best responders to Interferon-alpha [10]. However, patients with extensive skin disease, lymphedema, or visceral in- volvement usually require combination chemotherapy. Al- though response rates may be high, responding patients often die of intercurrent OL Several studies are currently in progress which use various anti-HTV agents in combination with chemotherapy in the hopes of decreasing the fre- quency of OI and increasing patient survival. Zidovudine (ZDV) is an anti-retroviral agent which inhibits HIV replica- tion and has been shown to increase survival in patients with symptomatic HIV infection [11]. Its major toxicity is myelosuppression, which is often dose limiting and may result in its discontinuation [12,13].
In this setting, effective treatment for EKS with non- myelosuppresive chemotherapy would allow concomitant
continuation of ZDV. Two chemotherapeutic agents, bleomycin and vincristine (BV) have only mild myelosup- pressive effects [14] with known anti-tumor activity in patients with EKS [4, 5, 6, 15]. The current report docu- ments our experience with bleomycin, vincristine and ZDV in patients with disseminated EKS and severe immune deficiency secondary to HTV-I.
Material and methods
Twelve patients were retrospectively studied. All had exten- sive or progressive KS and received ZDV and combination chemotherapy, bleomycin and vincristine (BV) for 4 weeks or greater. Extensive KS was defined as the presence of 25 or more mucocutaneous lesions, development of £ 10 new lesions over one month, or the presence of symptomatic visceral disease. Patients were not excluded if they had constitutional symptoms (weight loss > 10% body weight, fevers of unknown etiology, and night sweats) or chronic diarrhea.
Data were collected regarding age, performance status, race, risk factor for HTV infection, history of prior oppor- tunistic infection (OI), and baseline blood counts prior to initiation of BV including hemoglobin (Hgb), absolute granulocyte counts (AGC), and absolute CD4+ lymphocyte counts. The extent and sites of KS including the number of mucocutaneous lesions and presence or absence of visceral
148
involvement at baseline and maximum tumor response on BV and ZDV were recorded.
Response criteria
Complete remission (CR) was defined as a complete flatten- ing of all known mucocutaneous disease and a negative biopsy confirmation of one representative residual pig- mented cutaneous lesion. In addition, patients with known visceral lesions were required to have repeat bronchoscopy or endoscopy for pulmonary and gastrointestinal involve- ment respectively, to document CR. Partial remission (PR) was defined as the complete flattening of over 50% of all mucocutaneous lesions, with improvement of visceral dis- ease upon repeat evaluation. Responses less than PR were defined as minor response (MR), and development of new lesions was defined as progressive disease (PD).
Treatment regimen
Bleomycin (10 U/m2) and vincristine (2 mg) were adminis- tered intravenously in two week cycles. Dose adjustments of the chemotherapy were not made in the presence of peripheral blood cytopenias. However, vincristine was reduced by 50% for Grade II neuropathy, and held in the presence of Grade DI or IV neuropathy (USC Comprehensive Cancer Center Toxicity Grading Scale). ZDV was given either at 200 mg (full dose) or 100 mg (half dose) every four hours, by mouth in accordance to the dose of ZDV they were tolerating prior to the initiation of chemotherapy. Full dose ZDV was reduced for hematologic toxicity as follows: for an absolute granulocyte count (AGQ of < 1,000/mm3 the ZDV dose was reduced by 50%; for AGC < 500/mm3, ZDV was held. When the AGC rose above 500/mm3, ZDV was restarted at the 50% dose level. No modification of ZDV dose was made for anemia, and patients received blood transfusions as clinically indi- cated. The half dose ZDV regimen was modified as fol- lows: for an AGC of < 500/mm3 the ZDV was discontinued and restarted at the same dose when the AGC rose above 500/mm3
For prophylaxis against Pneumocystis carinii pneumo- nia, 7/12 (58%) received aerosolized pentamidine, 2 received trimethoprim/sulfamethoxazole, 1 received sul- fadiazine/pyrimethamine and 2 did not receive any prophylaxis.
Results
Twelve male patients with a median age of 38 years (range 30-57 years) were treated Eight patients (67%) received full dose ZDV (200 mg every 4 hours, Group I) and four (33%) received half dose (100 mg every 4 hours, Group II). The patient characteristics at study entry are summarized in Table 1. Median performance status was the same in both groups, as were tumor extent, prior use of ZDV and history of OIs. Only one patient (in Group IT) had a history of chronic diarrhea. There was no difference in the baseline
Table I. Clinical characteristics: 12 patients.
Group I Group II Full dose ZDV + BV 50% ZDV dose + BV (2O0mgq4hr) (100mgq4hr)
Number of patients Median Kamofsky performance
Status Tumor extent (KS) at entry (# cases)
Skin involvement (> 25 lesions) Mucous membrane involvement Other visceral sites
Prior OIs PCP Others
Prior use of ZDV (# cases) Duration of prior ZDV use (months)
Median Range
Table 2. Hematologic toxicity: Bleomycin, vincristine and zidovudine.
Group I ZDV Group II Full dose ZDV + BV 50% ZDV dose + BV (200mgq4hr) (100mgq4hr)
Hb(gm/dl) Entry median (range)
< 10 gm/dl(# cases) Transfusion
< 1000/cumm (# cases) Nadir (/cumm) median (range)
< 1000/cumm (# cases)
T4 Lymphocyte counts Entry (/cumm) median (range)
< 200 (/cumm) (# cases)
1/4
hemoglobin (Hgb), absolute granulocyte count (AGC), or platelet count between the two groups, as shown in Table 2. Because this was a retrospective analysis, the prior duration of ZDV use was variable, but with no significant difference between the two groups. Patients in Group I received a mean of 5.4 cycles of BV (range 3-10) while group II received a mean of 4.2 cycles (range 3—7), which represented 27.5 months of cumulative chemotherapy treat- ment in all twelve patients.
In Group I, five patients (63%) achieved a complete remission, while three (37%) attained a partial remission. No patient in Group II achieved a complete remission while two (50%) achieved a partial remission. The overall response rate (CR and PR in both groups) was 83%. The median duration of response was 2 months (range 1-10 months).
149
Toxicity
Varied hematologic toxicity was seen in the two groups as shown in Table 2. A drop in mean Hgb (< 10 mg/dl) was seen in four patients (50%) in Group I. This drop occurred at a median of 7 weeks following the initiation of chemotherapy (range 6-10 weeks). Blood transfusions were required in three of these patients because of symptomatic anemia. Two patients (50%) in Group II also had a drop in Hgb (< 10 gm/dl), although neither required blood transfusions. There was a fall in the AGC (< 1,000/mm3) in five patients (63%) in Group I and three patients in Group II. ZDV modification was required due to neutropenia in five patients in Group I (63%) and one in Group II (25%). There was only one patient who had a drop in platelet count during the treatment, going from 117,000/mm3, at baseline to 61,000/mm3. Two patients experienced paraesthesia due to vincristine of which one was grade II requiring a 50% dose reduction.
Only two patients developed infections during chemotherapy, including one with amebic dysentery and one with cytomegalovirus colitis.
Discussion
Combination chemotherapy for extensive epidemic Kaposi's sarcoma, as reported herein, has resulted in a major response in 83% of our patients. Usually, survival of these patients is limited by the development of OI. The anti-retroviral agent, ZDV, has been shown to increase survival of patients with severe HIV infection, and to decrease the incidence and severity of OIs [11]. In our study the combination of BV and ZDV was relatively well tolerated, although dose limiting toxicity was observed, consisting of granulocytopenia (< 1000/mm3) which re- quired a dose reduction of ZDV in half of the patients receiving full dose ZDV therapy. Interestingly, however, only 2/12 patients developed infections while on therapy. Prior reports of patients receiving chemotherapy alone for EKS have described development of OI's in as many as 60% of treated patients [5].
As expected, development of significant anemia was seen in approximately half of our patients, one quarter of whom required blood transfusions. This anemia may be related to long term ZDV use in conjunction with chemotherapy, and was seen following six to ten weeks of therapy.
Although the overall response rate was high in our patients, the majority of responses occurred in those who received full dose ZDV. Since this was an uncontrolled study, the objective contribution of ZDV to the response rate is not known. Moreover, the response rate of approximately 80% is similar to our experience with bleomycin and vincristine used alone [15]. Thus, prospec- tive clinical trials utilizing ZDV in combination with chemotherapy will be required to demonstrate if ZDV in fact reduces the frequency of OI's in these patients, with prolongation of survival.
Acknowledgement
We wish to thank Laurie Hornor for the typing and prepara- tion of this manuscript
References
1. Gottlieb MS, Groopman JE, Weinstein WM, Faley JL, Detels R. The acquired immunodeficiency syndrome Ann Intern Med 1983; 99: 208.
2. Ziegler JL, Beckstead JA, Volberding PA et aL Non-Hodgkin's lymphoma in 90 homosexual men. NEJM 1984; 311: 565.
3. Volberding PA, Abrams DI, Conant M et al. Vinblastine therapy for Kaposi's sarcoma in the Acquired Immunodeficiency Syndrome. Ann Intern Med 1985; 103: 335-8.
4. Kaplan L, Abrams D, Volberding P. Treatment of Kaposi's sarcoma in Acquired Immunodeficiency Syndrome with an alternating Vincristine - Vinblastine regimen. Cancer Treat Rep 1986; 70: 1121-2.
5. Laubenstein LJ, Krigel FL, Odajnk CM et al. Treatment of Kaposi's sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine. J Clin Oncol 1984; 2: 1115-20.
6. Gill PS, Krailo M, Slater L et aL Results of a randomized trial of ABV vs A advanced epidemic KS. Int Conf AIDS, Stockholm, June 1988.
7. Krown SE, Real FX, Cunningham-Rundles S et al. Preliminary observations on the effect of recombinant leukocyte A interferon in homosexual men with KS. NEJM 1983; 308: 1071.
8. Volberding PA, Mitsuyasu R. Recombinant interferon alpha in the treatment of acquired immune deficiency syndrome related KS. Seminars Oncol 1985; 12: 2.
9. Chak LY, Gill PS, Levine AM et aL Radiation therapy for acquired immunodeficiency syndrome related Kaposi's sarcoma. J Clin One 1988; 6: 863.
10. Lane C, Feinberg J, Davey V et al. Anti-retroviral effects of Interferon-alpha in AIDS-associated Kaposi's sarcoma. Lancet 1988; 1218-22.
11. Fischl M, Grieco MH, Richman DD et aL The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind placebo controlled trial. N Engl J Med 1987; 317: 185-91.
12. Richman DD, Fischl MA, Grieco MH et al. The toxicity of Azidothymidine (AZT) in the treatment of patients with AIDS and AIDS related complex. N Engl J Med 1987; 317: 192-7.
13. Gill PS, Rarick M, Brynes RK et al. Azidothymidine associated with bone marrow failure in the Acquired Immunodeficiency Syndrome (AIDS). Ann Intern Med 1987; 107: 502.
14. Chabner BA, Myers CE. Clinical Pharmacology of Cancer Chemotherapy. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer principles and practice of oncology. Chapter 14. Philadel- phia: JB Lippincott Co, 1985; 287-328.
15. Gill PS, Rarick M, Bernstein-Singer M. Treatment of advanced Kaposi's sarcoma using a combination of bleomycin and vincrisUne. Am Journal of Clin One (in press).
Received 20 September 1989; accepted 31 October 1989.
Original article
Treatment of epidemic Kaposi's sarcoma with combination chemotherapy (vincristine and bleomycin) and zidovudine
M.U. Rarick, P.S. Gill, T. Montgomery, M. Bernstein-Singer, B. Jones & A.M. Levine From the Department of Internal Medicine, Division ofHematology, University of Southern California School of Medicine, and the Los Angeles County-USC Medical Center, Los Angeles, USA
Summary. Advanced AIDS-associated Kaposi's sarcoma often requires systemic cytotoxic chemotherapy. Despite high response rates, the majority of the patients die of opportunistic infections (OIs). Effective anti-retroviral agents in combina- tion with cytotoxic chemotherapy may be useful in preventing the development of OIs in addition to increasing the tumor response. Twelve patients with extensive EKS were treated with a non-myelosuppressive drug regimen consisting of bleomycin and vincristine (BV) in combination with the anti-retroviral agent, zidovudine (ZDV). The dose of ZDV was 200 mg orally every four hours (full dose) in eight patients (Group I) or 100 mg orally every four hours (half dose) in four patients (Group IT). Toxicity was acceptable with only 3 patients (all from Group I) requiring blood transfusions. ZDV dose reduction due to granulocytopenia was required in 6 patients (5 in Group I and 1 in Group II). Only two patients developed OIs during 27.5 cumulative months of therapy. The overall response rate was 83% in both groups with 4 patients achieving complete remission (CR) and 6 patients achieving a partial remission (PR). We conclude that a combina- tion of (BV) chemotherapy and ZDV can be used safely with high response rates. Prospective studies of such combination regimens are currently in progress.
Key words: AIDS, bleomycin, chemotherapy, Kaposi's sarcoma, vincristine, zidovudine (ZDV)
Introduction
Infection by the Human Immunodeficiency Virus (HIV) results in immune depression that may manifest itself by the development of opportunistic infections (OI), non- Hodgkin's lymphoma, or Epidemic Kaposi's sarcoma (EKS) [1, 2]. Optimal therapy of EKS depends upon the stage, sites, and pace of disease, as well as the underlying immunologic status of the patient. Radiation therapy, Interferon-alpha, and/or chemotherapy, either used as single agents or in combination, have all shown activity in the treatment of EKS [3-9]. Patients with limited EKS and a CD4+ T lymphocyte count greater than 400/mm3 are the best responders to Interferon-alpha [10]. However, patients with extensive skin disease, lymphedema, or visceral in- volvement usually require combination chemotherapy. Al- though response rates may be high, responding patients often die of intercurrent OL Several studies are currently in progress which use various anti-HTV agents in combination with chemotherapy in the hopes of decreasing the fre- quency of OI and increasing patient survival. Zidovudine (ZDV) is an anti-retroviral agent which inhibits HIV replica- tion and has been shown to increase survival in patients with symptomatic HIV infection [11]. Its major toxicity is myelosuppression, which is often dose limiting and may result in its discontinuation [12,13].
In this setting, effective treatment for EKS with non- myelosuppresive chemotherapy would allow concomitant
continuation of ZDV. Two chemotherapeutic agents, bleomycin and vincristine (BV) have only mild myelosup- pressive effects [14] with known anti-tumor activity in patients with EKS [4, 5, 6, 15]. The current report docu- ments our experience with bleomycin, vincristine and ZDV in patients with disseminated EKS and severe immune deficiency secondary to HTV-I.
Material and methods
Twelve patients were retrospectively studied. All had exten- sive or progressive KS and received ZDV and combination chemotherapy, bleomycin and vincristine (BV) for 4 weeks or greater. Extensive KS was defined as the presence of 25 or more mucocutaneous lesions, development of £ 10 new lesions over one month, or the presence of symptomatic visceral disease. Patients were not excluded if they had constitutional symptoms (weight loss > 10% body weight, fevers of unknown etiology, and night sweats) or chronic diarrhea.
Data were collected regarding age, performance status, race, risk factor for HTV infection, history of prior oppor- tunistic infection (OI), and baseline blood counts prior to initiation of BV including hemoglobin (Hgb), absolute granulocyte counts (AGC), and absolute CD4+ lymphocyte counts. The extent and sites of KS including the number of mucocutaneous lesions and presence or absence of visceral
148
involvement at baseline and maximum tumor response on BV and ZDV were recorded.
Response criteria
Complete remission (CR) was defined as a complete flatten- ing of all known mucocutaneous disease and a negative biopsy confirmation of one representative residual pig- mented cutaneous lesion. In addition, patients with known visceral lesions were required to have repeat bronchoscopy or endoscopy for pulmonary and gastrointestinal involve- ment respectively, to document CR. Partial remission (PR) was defined as the complete flattening of over 50% of all mucocutaneous lesions, with improvement of visceral dis- ease upon repeat evaluation. Responses less than PR were defined as minor response (MR), and development of new lesions was defined as progressive disease (PD).
Treatment regimen
Bleomycin (10 U/m2) and vincristine (2 mg) were adminis- tered intravenously in two week cycles. Dose adjustments of the chemotherapy were not made in the presence of peripheral blood cytopenias. However, vincristine was reduced by 50% for Grade II neuropathy, and held in the presence of Grade DI or IV neuropathy (USC Comprehensive Cancer Center Toxicity Grading Scale). ZDV was given either at 200 mg (full dose) or 100 mg (half dose) every four hours, by mouth in accordance to the dose of ZDV they were tolerating prior to the initiation of chemotherapy. Full dose ZDV was reduced for hematologic toxicity as follows: for an absolute granulocyte count (AGQ of < 1,000/mm3 the ZDV dose was reduced by 50%; for AGC < 500/mm3, ZDV was held. When the AGC rose above 500/mm3, ZDV was restarted at the 50% dose level. No modification of ZDV dose was made for anemia, and patients received blood transfusions as clinically indi- cated. The half dose ZDV regimen was modified as fol- lows: for an AGC of < 500/mm3 the ZDV was discontinued and restarted at the same dose when the AGC rose above 500/mm3
For prophylaxis against Pneumocystis carinii pneumo- nia, 7/12 (58%) received aerosolized pentamidine, 2 received trimethoprim/sulfamethoxazole, 1 received sul- fadiazine/pyrimethamine and 2 did not receive any prophylaxis.
Results
Twelve male patients with a median age of 38 years (range 30-57 years) were treated Eight patients (67%) received full dose ZDV (200 mg every 4 hours, Group I) and four (33%) received half dose (100 mg every 4 hours, Group II). The patient characteristics at study entry are summarized in Table 1. Median performance status was the same in both groups, as were tumor extent, prior use of ZDV and history of OIs. Only one patient (in Group IT) had a history of chronic diarrhea. There was no difference in the baseline
Table I. Clinical characteristics: 12 patients.
Group I Group II Full dose ZDV + BV 50% ZDV dose + BV (2O0mgq4hr) (100mgq4hr)
Number of patients Median Kamofsky performance
Status Tumor extent (KS) at entry (# cases)
Skin involvement (> 25 lesions) Mucous membrane involvement Other visceral sites
Prior OIs PCP Others
Prior use of ZDV (# cases) Duration of prior ZDV use (months)
Median Range
Table 2. Hematologic toxicity: Bleomycin, vincristine and zidovudine.
Group I ZDV Group II Full dose ZDV + BV 50% ZDV dose + BV (200mgq4hr) (100mgq4hr)
Hb(gm/dl) Entry median (range)
< 10 gm/dl(# cases) Transfusion
< 1000/cumm (# cases) Nadir (/cumm) median (range)
< 1000/cumm (# cases)
T4 Lymphocyte counts Entry (/cumm) median (range)
< 200 (/cumm) (# cases)
1/4
hemoglobin (Hgb), absolute granulocyte count (AGC), or platelet count between the two groups, as shown in Table 2. Because this was a retrospective analysis, the prior duration of ZDV use was variable, but with no significant difference between the two groups. Patients in Group I received a mean of 5.4 cycles of BV (range 3-10) while group II received a mean of 4.2 cycles (range 3—7), which represented 27.5 months of cumulative chemotherapy treat- ment in all twelve patients.
In Group I, five patients (63%) achieved a complete remission, while three (37%) attained a partial remission. No patient in Group II achieved a complete remission while two (50%) achieved a partial remission. The overall response rate (CR and PR in both groups) was 83%. The median duration of response was 2 months (range 1-10 months).
149
Toxicity
Varied hematologic toxicity was seen in the two groups as shown in Table 2. A drop in mean Hgb (< 10 mg/dl) was seen in four patients (50%) in Group I. This drop occurred at a median of 7 weeks following the initiation of chemotherapy (range 6-10 weeks). Blood transfusions were required in three of these patients because of symptomatic anemia. Two patients (50%) in Group II also had a drop in Hgb (< 10 gm/dl), although neither required blood transfusions. There was a fall in the AGC (< 1,000/mm3) in five patients (63%) in Group I and three patients in Group II. ZDV modification was required due to neutropenia in five patients in Group I (63%) and one in Group II (25%). There was only one patient who had a drop in platelet count during the treatment, going from 117,000/mm3, at baseline to 61,000/mm3. Two patients experienced paraesthesia due to vincristine of which one was grade II requiring a 50% dose reduction.
Only two patients developed infections during chemotherapy, including one with amebic dysentery and one with cytomegalovirus colitis.
Discussion
Combination chemotherapy for extensive epidemic Kaposi's sarcoma, as reported herein, has resulted in a major response in 83% of our patients. Usually, survival of these patients is limited by the development of OI. The anti-retroviral agent, ZDV, has been shown to increase survival of patients with severe HIV infection, and to decrease the incidence and severity of OIs [11]. In our study the combination of BV and ZDV was relatively well tolerated, although dose limiting toxicity was observed, consisting of granulocytopenia (< 1000/mm3) which re- quired a dose reduction of ZDV in half of the patients receiving full dose ZDV therapy. Interestingly, however, only 2/12 patients developed infections while on therapy. Prior reports of patients receiving chemotherapy alone for EKS have described development of OI's in as many as 60% of treated patients [5].
As expected, development of significant anemia was seen in approximately half of our patients, one quarter of whom required blood transfusions. This anemia may be related to long term ZDV use in conjunction with chemotherapy, and was seen following six to ten weeks of therapy.
Although the overall response rate was high in our patients, the majority of responses occurred in those who received full dose ZDV. Since this was an uncontrolled study, the objective contribution of ZDV to the response rate is not known. Moreover, the response rate of approximately 80% is similar to our experience with bleomycin and vincristine used alone [15]. Thus, prospec- tive clinical trials utilizing ZDV in combination with chemotherapy will be required to demonstrate if ZDV in fact reduces the frequency of OI's in these patients, with prolongation of survival.
Acknowledgement
We wish to thank Laurie Hornor for the typing and prepara- tion of this manuscript
References
1. Gottlieb MS, Groopman JE, Weinstein WM, Faley JL, Detels R. The acquired immunodeficiency syndrome Ann Intern Med 1983; 99: 208.
2. Ziegler JL, Beckstead JA, Volberding PA et aL Non-Hodgkin's lymphoma in 90 homosexual men. NEJM 1984; 311: 565.
3. Volberding PA, Abrams DI, Conant M et al. Vinblastine therapy for Kaposi's sarcoma in the Acquired Immunodeficiency Syndrome. Ann Intern Med 1985; 103: 335-8.
4. Kaplan L, Abrams D, Volberding P. Treatment of Kaposi's sarcoma in Acquired Immunodeficiency Syndrome with an alternating Vincristine - Vinblastine regimen. Cancer Treat Rep 1986; 70: 1121-2.
5. Laubenstein LJ, Krigel FL, Odajnk CM et al. Treatment of Kaposi's sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine. J Clin Oncol 1984; 2: 1115-20.
6. Gill PS, Krailo M, Slater L et aL Results of a randomized trial of ABV vs A advanced epidemic KS. Int Conf AIDS, Stockholm, June 1988.
7. Krown SE, Real FX, Cunningham-Rundles S et al. Preliminary observations on the effect of recombinant leukocyte A interferon in homosexual men with KS. NEJM 1983; 308: 1071.
8. Volberding PA, Mitsuyasu R. Recombinant interferon alpha in the treatment of acquired immune deficiency syndrome related KS. Seminars Oncol 1985; 12: 2.
9. Chak LY, Gill PS, Levine AM et aL Radiation therapy for acquired immunodeficiency syndrome related Kaposi's sarcoma. J Clin One 1988; 6: 863.
10. Lane C, Feinberg J, Davey V et al. Anti-retroviral effects of Interferon-alpha in AIDS-associated Kaposi's sarcoma. Lancet 1988; 1218-22.
11. Fischl M, Grieco MH, Richman DD et aL The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind placebo controlled trial. N Engl J Med 1987; 317: 185-91.
12. Richman DD, Fischl MA, Grieco MH et al. The toxicity of Azidothymidine (AZT) in the treatment of patients with AIDS and AIDS related complex. N Engl J Med 1987; 317: 192-7.
13. Gill PS, Rarick M, Brynes RK et al. Azidothymidine associated with bone marrow failure in the Acquired Immunodeficiency Syndrome (AIDS). Ann Intern Med 1987; 107: 502.
14. Chabner BA, Myers CE. Clinical Pharmacology of Cancer Chemotherapy. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer principles and practice of oncology. Chapter 14. Philadel- phia: JB Lippincott Co, 1985; 287-328.
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Received 20 September 1989; accepted 31 October 1989.
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