Combined cis-platinum plus radiation antitumor activity in locoregionally advanced squamous cell esophageal cancer

The synergistic activity we have observed in vitro in V-79 hamster lung cells after treatment with cis-platinum combined with irradiation, stimulated a pilot study of 31 patients with inoperable locoregionally advanced squamous cell esophageal cancer. The 27 evaluable cases (22 men and 5 women--mean age 59 years) had undergone no prior radiation or cytostatic drug therapy. Histological evidence of the tumor (26 squamous cell, 1 adenocarcinoma) was obtained by endoscopy in all patients before treatment began. The patients were irradiated in two opposite thoracic fields with a total dosage of 3,000-4,000 cGy (200 cGy daily, 1,000 weekly) concurrently with 2 cycles of cis-platinum in the dosage of 30 mg/m2 iv. daily X 4 (120 mg/m2 per cycle). The results showed that cis-platinum combined with radiation showed an evident antitumor activity which included 4 complete clinical remissions and 11 partial remissions with a response rate of 56% (15/27). In two complete responders even a pathologic remission was evident (biopsy specimen) and they are now 16+ and 18+ months free of the disease. The median remission duration has been 8+ months (14+ months in complete responders) and the median survival period for the entire group is 10+ months (for responders 15+ months, p less than 0.05). Toxicity was moderate and reversible, and mainly accounted for radiation mucositis, retrosternal pain and vomiting. A mild bone marrow suppression was observed. In 2 cases esophagotracheal fistulae occurred. The results of this study show that the combination of cis-platinum and radiation might constitute successful palliative or neoadjuvant treatment for squamous cell esophageal cancer.     

Chemotherapy of non-small cell bronchial cancer with mitomycin C, vindesine and cisplatin. Results of a phase II study

Forty-five patients (39 male, 6 female) with inoperable non-small-cell lung cancer were treated with combined mitomycin C, vindesine and cisplatin. All patients had measurable disease and had no previously received chemotherapy. The performance status of all patients was over 60%. Twenty-one patients had limited, 24 extensive disease. The overall remission rate was 53.3% (3 complete and 21 partial remissions) with a median remission duration of 9 months. Adeno- and squamous cell carcinoma responded to the chemotherapy with a remission rate of 63% (7 out of 11 patients) and 58% (14 out of 24 patients), but there were only 30% responders in large cell carcinoma (3 out of 10 patients). The median survival time for responders was 12 months, for those with no change and for patients with progressive disease 6 months. Myelosuppression and renal toxicity of the combination was generally not a treatment problem; subjective tolerance, however, (gastrointestinal upset) was poor.     

Cisplatin, vindesine and bleomycin (CVB) combination chemotherapy of advanced non-small cell lung cancer

Fifty-four patients with advanced squamous, large-cell or adeno-carcinoma of the lung were treated with a three drug regimen of high-dose cisplatin, vindesine and a four-day bleomycin infusion (CVB). All patients had measurable disease; none had previously received chemotherapy. Of 52 patients evaluable for response, 20 (38%) had complete or partial remissions. The median duration of remission was 8 months (range, 6 1/2-19+ months), with eight patients continuing in remission. The median duration of survival for responding patients was 16 months versus five months for nonresponding patients (P greater than 0.001). Toxicity included mild to moderate myelosuppression, peripheral neuropathy, and nephrotoxicity, and was generally manageable. The addition of a four-day bleomycin infusion did not appear to offer a significant advantage over the combination of high-dose cisplatin and vindesine in the treatment of NSCLC. The response rate and survival duration produced by the CVB protocol were similar to those reported for the two-drug combination of vindesine and high-dose cisplatin.     

Long-term follow-up with ABDIC salvage chemotherapy of MOPP-resistant Hodgkin's disease

Thirty-six consecutive patients with advanced recurrent Hodgkin's disease resistant to chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) were treated with doxorubicin (Adriamycin), bleomycin, (dacarbazine) DTIC, (lomustine) CCNU, and prednisone (ABDIC). Among the 34 patients evaluable for response, complete remission occurred in 35% and partial remission in 35%. The achievement of complete remission during primary MOPP induction was a statistically significant prognostic factor that predicted complete remission with ABDIC (p less than 0.01). The median time to complete remission was 2 months (range 1-11 mo). The median relapse-free survival time for complete responders is 47 months, and an estimated 53% of all patients who achieve complete remission are projected to be alive, free of disease off therapy at 3 years from initiation of ABDIC. The median survival of all patients is 24 months. The median survival of complete responders, partial responders, and nonresponders is 70, 17, and 4 months, respectively. The survival curve for complete responders is significantly different from that for partial responders (p less than 0.01); the survival curve for partial responders is also significantly different from that of nonresponders (p less than 0.01). Toxicity of ABDIC was acceptable; only one patient died from complications of myelosuppression. Our results indicate that ABDIC is a potentially curative regimen for a fraction of patients with MOPP-resistant Hodgkin's disease who achieve complete remission with prior MOPP therapy. It also prolongs the survival of patients who do not achieve complete remission with prior MOPP therapy.     

HOAP-Bleo as salvage therapy for diffuse aggressive non-Hodgkin's lymphoma

Summary A total of 30 patients with recurrent or unresponsive diffuse, aggressive non-Hodgkin's lymphoma, who had previously received doxorubicin, cyclophosphamide, vincristine, and prednisone with or without bleomycin were treated with a combination of doxorubicin, vincristine, ara C, prednisone, and bleomycin (HOAP-Bleo). Complete remissions were achieved in 33.3% of the patients and partial remissions in 13.3%. Four of the ten complete responders relapsed at 4, 10, 11, and 18 months. Myelosuppression was the major toxicity and nonhematological toxicities were acceptable. Their median survival from the date of first relapse was only 4–5 months.     

A randomized prospective comparison of methotrexate with a combination of methotrexate, bleomycin, and cisplatin in head and neck cancer

Combination chemotherapy with methotrexate, bleomycin, and cis-diamminedichloroplatinum (II) was compared to weekly therapy with methotrexate alone in a randomized prospective trial in 163 patients with recurrent or metastatic squamous cancer of the mucous membranes of the head and neck. The combination produced responses in 48% compared to 35% for methotrexate alone, with 16% complete remissions versus 8%, respectively. The difference in overall and complete remission rates is significant (P = 0.04) using a one-sided binary regression test. Median time to disease progression among responders was 5.8 months for the combination and 5 months for methotrexate, and median survival was 5.6 months in each group. Toxicity was similar in the two groups. Ambulatory patients, those without fixed neck nodes and those without distant metastases, responded more often. Poor performance status, distant metastases, history of heavy smoking, and adjacent organ invasion by the primary tumor were associated with shorter survival, as were weight loss, the presence of tumor in the neck, and heavy alcohol consumption. The addition of bleomycin and cisplatin to methotrexate produces more remissions, and especially complete remissions, but has not made a major impact on the course of far-advanced head and neck cancer.     

Diffuse well-differentiated lymphocytic lymphoma: chemotherapy with BCNU, cyclophosphamide, vincristine, melphalan and prednisone

Twenty patients with stage III and IV diffuse well-differentiated lymphocytic lymphoma were treated with combination chemotherapy consisting of BCNU, cyclophosphamide, vincristine, melphalan and prednisone (M-2). Treatment was given every 5 weeks for 11 cycles in responding patients. The median age of the patients was 62 years (range 45-76). There were 12 complete remissions and 6 partial remissions for an overall response rate of 90%. The median duration of remission was 24 months (range 12-79 months) and was identical for complete responders and partial responders. All but 2 responding patients have been subsequently retreated for relapse. The median survival was 84 months (range 1-108 months). Myelosuppression was mild. Nausea/vomiting, neuropathy, alopecia and gastrointestinal symptoms from prednisone were seen in the minority of patients. One patient expired from sepsis/neutropenia during the first cycle of therapy. The M-2 protocol produces effective remissions in diffuse well-differentiated lymphocytic lymphoma. The relapse and survival pattern are similar to the results achieved with other chemotherapy regimens in low-grade lymphoma.     

Combination chemotherapy followed by an immunotoxin (anti-B4-blocked ricin) in patients with indolent lymphoma: results of a phase II study

The purpose of this article was to evaluate the antitumor effects of a combination chemotherapy program based on ProMACE (prednisone, methotrexate, doxorubicin [Adriamycin], cyclophosphamide, etoposide) followed by a B cell-specific immunotoxin in the treatment of patients with advanced-stage indolent histology non-Hodgkin's lymphomas. We performed a prospective phase II clinical trial in a referral-based patient population. After confirmation of diagnosis and staging evaluation, 44 patients (10 small lymphocytic lymphoma, 27 follicular lymphoma, 7 mantle cell lymphoma; 30 without prior therapy, 14 previously treated) received six cycles of ProMACE-CytaBOM (cytarabine, bleomycin, vincristine [Oncovin], mechlorethamine) combination chemotherapy (with etoposide given orally daily for five days) followed by a 7-day continuous infusion of anti-B4-blocked ricin immunotoxin at 30 microg/kg/day given every 14 days for up to six cycles. A complete response was achieved in 25 of 44 patients (57%), 21 from the chemotherapy alone, 3 converted from partial to complete response with the immunotoxin, and 1 patient became a complete responder after a surgical procedure to remove an enlarged spleen that was histologically negative for lymphoma. With a median follow-up of 5 years, 14 of 25 complete responders have relapsed (56%); median remission duration was 2 years, and overall survival was 61%. Forty-two percent of the complete responders have been in continuous remission for more than 4 years. The median number of courses of immunotoxin delivered was two usually because of the development of human anti-ricin antibodies. ProMACE-CytaBOM plus anti-B4-blocked ricin does not produce durable complete remissions in the majority of patients with indolent lymphoma. However, the remissions appear quite durable (> 4 years) in about 40% of the complete responders.     

FAM2 regimen in disseminated gastric cancer

Forty-four previously untreated patients with advanced inoperable and/or disseminated gastric carcinoma were given an i.v. combination (FAM2) chemotherapy of 5-fluorouracil, 400 mg/m2 on days 1, 2 and 3, and 21, 22 and 23; adriamycin, 40 mg/m2 on days 2 and 22; and mitomycin C, 10 mg/m2 on day 1, with a recycle on day 42 (1 cycle = 41 days). Forty patients have completed 2 cycles and are evaluable (median number of cycles 5; range 3 to 8): 26 of these achieved a partial remission, with a response rate of 65%; 4 (10%) gained a stable situation for 3 to 6 months, and 10 (25%) showed progression of disease. Median duration of partial remissions was 10 months, and median survival was 15 months for responders and 5 months for nonresponders. A fall in WBC (less than 2500/microliter) occurred in 7% and of platelets (less than 80,000/microliter) in 4.5%. Total alopecia occurred in 20 of 40 patients and nausea and or weakness were common findings. No drug-related infection, bleeding or death was observed. Patients with advanced gastric carcinoma can derive useful palliation from FAM2 chemotherapy.     

Treatment of low-grade and intermediate-grade lymphoma with intensive combination chemotherapy results in long-term, disease-free survival.

To define the role of intensive combination chemotherapy in the treatment of low-grade or intermediate-grade lymphomas, the authors report results in 49 patients treated with intermediate-dose or high-dose methotrexate, bleomycin, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cytoxan (cyclophosphamide), vincristine, and dexamethasone (m/M-BACOD) with long-term follow-up. The complete response rate was 59% (29 of 49), including 67% (eight of 12) with low-grade and 57% (21 of 37) with intermediate-grade disease. The median survival for the entire group was 81 months. The 29 complete responders had a long median survival of 131 months. Forty-five percent (13 of 29) of the complete responders, 27% of the entire group, continue in remission with a median disease-free survival of 76 months. This includes five of 19 patients with diffuse poorly differentiated lymphoma, a disease generally characterized by early relapse. Twelve patients achieved a partial response and had a shorter median survival of 53 months, whereas nonresponders survived a median of less than 5 months. Late relapse was noted in patients with low-grade and intermediate-grade disease. Age (younger than or older than 60 years) was the only predictor of long-term survival. These data indicate very long disease-free survival can be achieved in low-grade and intermediate-grade lymphomas after attaining a complete remission. Intensive doxorubicin containing chemotherapy can be considered as an option for patients with advanced low-grade lymphoma but can only be proven to be superior to single-agent chemotherapy or no initial therapy by controlled randomized trails.     

Combination of 4-epi-doxorubicin and irradiation--a new approach in the treatment of locoregionally advanced inoperable esophageal cancer

The synergistic activity observed in vitro in V-79 hamster lung cells after treatment with 4-epi-doxorubicin (4-epi-DX) combined with irradiation stimulated a pilot study of 38 patients with inoperable locoregionally advanced squamous cell esophageal cancer. The patients (30 males, 8 females; mean age 60 years) had undergone no prior radiation or cytostatic drug therapy. Twenty tumors were localized in the middle third of the esophagus, and the remainder in the upper or lower third. Histological evidence of the tumor was obtained in all patients before treatment by endoscopy. The 33 evaluable cases included 30 squamous cell carcinomas, 2 anaplastic (squamous cell) carcinomas and 1 adenocarcinoma. The patients were irradiated in two opposite thoracic fields (Betatron-Siemens) with a total dosage of 3600-4000 cGy (200 cGy daily, 1000 weekly). The patients were concurrently administered 4-epi-DX at the dose of 50 mg/m2 i.v. daily on days 1, 2, 22 and 23; the total 4-epi-DX dosage was 200 mg/m2. The results showed that 4-epi-DX combined with irradiation had a pronounced antitumorigenic activity, since the 33 evaluable patients included 11 complete and 12 partial remissions, with a response rate of 70% (23/33). A minor regression (less than 50%) was observed in 6 cases, and progression of the disease in 4. The median duration of the remissions was 9 + months (14 + months in complete responders). In 8 patients with a complete clinical response even the endoscopic biopsy samples were negative. Toxicity was moderate and reversible, and mainly accounted for by radiation mucositis and retrosternal pain, alopecia and mild bone marrow suppression. Transient ECG changes were observed in 3 cases. The results of the pilot study show that the combination of 4-epi-DX and irradiation might constitute successful palliative treatment for squamous cell esophageal cancer.     

Five-year survival of patients with disseminated nonseminomatous testicular cancer treated with cisplatin, vinblastine, and bleomycin

Ninety-one patients with disseminated testicular non-seminomas were treated with 3 to 4 cycles of cisplatin, vinblastine, and bleomycin (PVB) induction chemotherapy followed by cisplatin and vinblastine maintenance therapy for 1 year. The follow-up of these patients ranges from 24 to 66 months. Forty-nine (54%) patients achieved complete remission by chemotherapy alone and 14 (15%) were rendered free of tumor by surgery after chemotherapy, for a total complete remission rate of 69%. Three complete responders relapsed within 13 months, and two died. One additional complete responder died of a noncancer-related cause. One of the surgical complete responders relapsed and died. Overall, 58 (64%) patients remain free of disease. The 5-year survival is 95% for complete responders, 32% for partial responders, and 72% overall. This combination regimen has significantly improved the survival of disseminated testicular cancer patients, equaling that of Stage II patients in older literature.     

The role of cytosine arabinoside maintenance in acute nonlymphoblastic leukemia.

A series of 30 unselected patients with acute nonlymphoblastic leukemia (ANLL) was treated with combination chemotherapy, including three courses of cytosine arabinoside (Ara-C) by 5-day continuous i.v. infusion, vincristine i.v. weekly, and prednisone daily to complete remission. Ara-C was administered alone as a 5-day continuous i.v. infusion monthly for maintenance. Ten (33%) achieved a complete remission (CR). The remaining 30 (67%), including temporary partial remissions, hematologic improvements, inadequate trials, and early deaths, were all considered failures. The CR rate was 57% in those 17 cases receiving an adequate trial. After After 5 1/2 years' followup, the overall median survival, including cases failing to achieve CR, was 3.1 months. For those having adequate trials the median survival was 16.6 months, and for those achieving a CR, 36.6 months. Two patients are still alive, one at 55.2 months on maintenance therapy, and the other at 62.8 months, currently unmaintained.     

Combination chemotherapy of esophageal carcinoma using cisplatin, vindesine, and bleomycin

Sixty-one patients with epidermoid carcinoma of the esophagus have been treated with a three drug combination of cisplatin, vindesine, and bleomycin. Of 53 patients currently evaluable for response, 29 (55%) have had partial remissions: 7/16 with metastatic, and 22/37 with local-regional disease. The median duration of response in metastatic patients is eight months. Of 28 patients treated preoperatively, 23 (82%) had resectable disease. The major toxicities seen were nephrotoxicity and myelosuppression. Cisplatin, vindesine and bleomycin is an effective combination in the treatment of esophageal carcinoma. Effects on long-term survival cannot yet be evaluated.     

Treatment of epidemic Kaposi's sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine

An epidemic of disseminated Kaposi's sarcoma in male homosexuals has recently been described. Forty-one evaluable patients with epidemic Kaposi's sarcoma were treated with etoposide. The majority of these patients had early stage disease, no prior opportunistic infections, and no prior therapy. Twelve patients (30%) achieved complete remission, 19 (46%) partial remission, and ten (24%) no response. With follow-up time to 31 months, the median response duration is nine months. The median survival of patients with complete and partial remissions has not been reached. A combination of doxorubicin (Adriamycin, Adria Laboratories, Columbus, Ohio), bleomycin, and vinblastine (ABV) was used in 31 evaluable patients with epidemic Kaposi's sarcoma. The majority of these patients had late stage disease, prior opportunistic infections, or had failed prior treatment. Seven patients (23%) achieved complete remission, 19 (61%) partial remission, and five (61%) no response. With follow-up time to 24 months, the median response duration is eight months. The projected median survival for all patients treated with ABV is nine months. Both regimens were well tolerated, with an overall response rate of 76% for etoposide and 84% for ABV. However, while successfully treating the Kaposi's sarcoma, the underlying immune deficiency in these patients has persisted. Future treatments of Kaposi's sarcoma will need to focus on reversing the underlying immune incompetence as well as controlling the malignant manifestations of Kaposi's sarcoma arising in relation to the acquired immune deficiency syndrome.     

Sequential methotrexate and 5-fluorouracil with bleomycin and cisplatin in the chemotherapy of advanced squamous cancer of the head and neck

A bolus intravenous dose of 5-fluorouracil of 600 mg/M2 was added exactly 1 hour after methotrexate administration in an established combination program including bleomycin and cisplatin for advanced squamous cell cancer of the head and neck. Results were no better than those observed previously with the three drugs, and hematologic and mucosal toxicities were slightly worse. The overall response rate was 41% in 34 patients with recurrent or metastatic disease, with only 6% complete remissions. Median time to disease progression for responding patients was 14 weeks, compared with 10 weeks for nonresponders. Partial response had little impact on survival. Among 12 patients with far-advanced disease confined above the clavicles without prior radiotherapy, 9 (75%) achieved partial remission, but the median survival, even with later surgery or irradiation, was only 34 weeks.     

Chemo-immunotherapy of advanced AIDS-related Kaposi's sarcoma

AIMS AND BACKGROUND: Kaposi's sarcoma (KS) is the most common neoplastic complication of HIV infection and AIDS. Multiple cytotoxic chemotherapy regimens have been used with various response rates. We have evaluated the efficacy and toxicity of low-dose chemotherapy in patients with poor-prognosis AIDS-related KS and the role of interferon alpha (IFN-alpha) in complete responders. METHODS: Twenty-five previously untreated patients with advanced KS received bleomycin (BL) 10 mg/m2 and vinblastine (VB) 6 mg/m2 on days 1 and 15 every two weeks. After six cycles, patients in complete remission received IFN-alpha (3 million U s.c. 3 times/week) combined with antiretroviral therapy. All patients were evaluated for toxicity using the World Health Organization (WHO) toxicity schedule. Both Eastern Cooperative Oncology Group (ECOG) and AIDS Clinical Trials Group (ACTG) response criteria were used to evaluate response and survival. RESULTS: The overall response rate was 84% (95% confidence interval, 51-117%) with six complete remissions (24%) and 15 partial remissions (60%) by ECOG criteria, and 92% (95% confidence interval: 58-128%) with 17 partial remissions (68%) by ACTG criteria. The median duration of response on IFN-alpha treatment was 4.5 months (range, 2-10). The overall median survival duration for all 25 patients was 9 months (range 2-39). Grade 3-4 anemia was observed in five patients and grade 3-4 neutropenia in two patients. No other clinically significant (> or = grade 3) toxicities were observed. CONCLUSIONS: Combination of BL and VB is effective and well tolerated, even if new therapeutic options are developing. This disease remains a challenging problem, so larger studies using the combination of chemotherapy and/or IFN-alpha with antiretroviral treatment are warranted.     

High-dose medroxyprogesterone acetate in advanced breast cancer. Clinical and pharmacokinetic study with a combined oral and intramuscular regimen

Seventy-five patients with advanced and intensively pretreated breast cancer received high-dose medroxyprogesterone acetate (MPA) using a schedule consisting of an intramuscular (IM) loading dose (1 g MPA IM days 1 to 10) and an oral maintenance treatment (200 mg/day three times a day) thereafter. A reinduction was performed in part of the responding patients at time of early relapse (1 g MPA IM for 10 consecutive days). MPA serum levels above 100 ng/ml were achieved during induction treatment and maintained for 3 to 4 months during the oral phase of therapy before decreasing to approximately 50 ng/ml. Two complete remissions (duration, 17.2 and 62 months), 15 partial remissions (median duration, 7 months), and 21 cases of disease stabilization (median duration, 5.5 months) were achieved. The median survival time was significantly longer for responders (19.9 months) than nonresponders (4.8 months). Although a higher proportion of postmenopausal patients responded, the remission duration in premenopausal women was remarkably long. Favorable sites of response were soft tissue, lymph nodes, and bone lesions. Reinduction treatment yielded a second response (two partial remissions, three no change) in five of six patients indicating that high-dose conditions were necessary to maintain response. This schedule allows to restrict higher doses of MPA on a long-term basis to responding patients.     

Combination chemotherapy of MOPP-resistant Hodgkin's disease with adriamycin, bleomycin, dacarbazine and vinblastine (ABDV).

Twenty-four patients with advanced Hodgkin's disease, resistant to the MOPP regimen, were treated with a combination of Adriamycin, bleomycin, dacarbazine and vinblastine (ABDV). Fifteen (63%) achieved objective remission, 14 partial remissions and one complete remission. The median duration of remission in this group of patients was 6.5 months; four of the 15 patients are still in remission (8+, 8+, 9+, 10+ months). Objective remission occurred rapidly within 1.5 months. Regression was evident in disease within nodes, lung, liver and bone. Toxic manifestations caused by ABDV were well tolerated and reversible. In one patient death was directly attributed to drug toxicity. This combination has produced a better rate and duration of remission than that reported with single agent chemotherapy in MOPP-resistant patients with Hodgkin's disease. In our hands, ABDV did not equal the recent results reported with Bleomycin-CCNU-Velban in a seemingly similar group of patients.     

Bleomycin infusion followed by cyclophosphamide, methotrexate, and 5-fluorouracil in advanced squamous carcinoma of the head and neck

Twenty-seven patients with squamous cell carcinoma of the head and neck were treated with bleomycin 7.5 U/m2/day continuous infusion X 3 days (days 1-4, 8-11), followed by cyclophosphamide 300 mg/m2, methotrexate 30 mg/m2 and 5-fluorouracil 300 mg/m2 on days 5 and 12 (bleo-CMF). Treatment was repeated every 28 days. All but two had a performance status of 0-2 and all but 3 patients had received prior surgery, radiotherapy, and/or chemotherapy. Of 24 evaluable patients, 1 had a complete remission (1.9 months) and 4 had partial remissions (3.7, 3.9, 3.9, 4.1 months, respectively) for an overall response rate of 21%. If one excludes 7 patients with prior chemotherapy, the response rate is 5 of 17 (29%). All responders had received both radiotherapy and surgery. The median survival was 4.4 months for the responders and 3.5 months for the nonresponders. Marked hematologic toxicity occurred in eight patients, and contributed to the death of two. Severe pulmonary toxicity occurred in two patients and caused the death of one. Bleo-CMF did not produce a higher response rate than historical single-agent trials and caused significant toxicity. Furthermore, there was no important difference in the survival of responders and nonresponders.