Combination chemotherapy for advanced bilharzial bladder carcinoma.

BACKGROUND: Carcinoma of the bilharzial bladder, the most common cancer in Egyptian patients has been, until recently, largely treated by surgery. We have studied the activity of a series of single agents in phase II trials and identified a number of active agents. Here we report the results of a trial in which therapeutic combinations of the most active agents were administered in alternating cycles to patients who had never received chemotherapy. PATIENTS AND METHODS: The study included 30 patients with histologically proven inoperable (20), recurrent (5, 2 of whom subsequently developed metastases), or metastatic disease (5). There were 27 males and 3 females, with a median age of 48.5 years (range 29-65 years). Fourteen patients had squamous cell carcinoma, 12 had transitional cell carcinoma, 2 had adenocarcinoma, and the remaining 2 had undifferentiated carcinoma. Chemotherapy consisted of epidoxorubicin (120 mg/sqm i.v. d1) and vincristine (1.4 mg/sqm i.v., days 1 and 8) alternating with etoposide (100 mg/sqm i.v. infusion over 1 hour, days 1 to 5) and ifosfamide (1800 mg/sqm i.v. infusion over 2 hours, days 1 to 5). Mesna was given as a uroprotector at 40% of the ifosfamide dose at 0, 4, and 8 hours after the ifosfamide infusion. Courses were repeated every 3-4 weeks. RESULTS: Among the 22 evaluable patients, 8 (36.5%) had a partial and one (4.5%), a complete response, giving a response rate of 46%. Three more patients had responses that were less than a partial remission, and 6 patients showed disease stabilisation on chemotherapy. Toxicities were tolerable and consisted mainly of myelosuppression. Results were further analysed in relation to pathologic subtype, disease status at the start of chemotherapy, and the delivered dose intensity. No relationship was found between any of these parameters and response to therapy. CONCLUSION: Advanced bilharzial bladder cancer is relatively sensitive to combination chemotherapy, but complete remission and prolonged survival is rare in this subgroup of patients with advanced disease. Further studies will be needed to determine the relative efficacy of single agents and drug combinations.

Use of ifosfamide in the management of breast cancer.

Ifosfamide, a cytostatic drug highly active in vivo, has slight superiority over cyclophosphamide. It proved effective in experimental tumor systems including the C3H mammary carcinoma. Clinical studies of ifosfamide as monotherapy in breast cancer, begun in 1974 by Ahmann et al., reported a 20% objective response. Subsequent trials were conducted from 1974 through 1977 using ifosfamide as monotherapy, and ifosfamide was also combined with other chemotherapeutic agents. In 1975, Hartwich and coworkers used the combination ifosfamide/vincristine with a 25% overall response. With the introduction of the uroprotector mesna, more studies were instituted. In 1984, using the IMF combination (ifosfamide/methotrexate/5-fluorouracil), we reported a 25% overall response. Other groups also reported good results for ifosfamide-containing combinations, with overall responses ranging from 25% to 79%. Recently, Sanchiz and Milla used high-dose ifosfamide to treat metastatic breast cancer, with a 40% overall response. In conclusion, ifosfamide's efficacy in breast cancer has been confirmed and the drug is highly recommended in combination chemotherapy as a first-line treatment.

Prolonged disease-free survival in pediatric non-Hodgkin's lymphoma using ifosfamide-containing combination chemotherapy.

Pediatric non-Hodgkin's lymphoma (NHL) constitutes 16 per cent of pediatric malignancies reported to the National Cancer Institute (NCI) in Cairo. The adopted treatment for these cases was, from 1982 to July 1985, a modified St Jude's regimen consisting of: vincristine, cyclophosphamide, adriamycin, prednisone and intrathecal methotrexate for the first 6 weeks for induction, followed by cranial irradiation for cranial prophylaxis. Patients in remission received maintenance therapy for 18 months. Of 32 patients complete remission (CR) was achieved in 24 patients (75 per cent); partial remission (PR) in one patient (3 per cent); five patients showed no response (15 per cent) while two patients died during the induction phase. At 60+ months follow-up, 60 per cent of cases are still alive, disease-free, and overall survival is 66 per cent. A new protocol was adopted in 1985, consisting of alternating cycles: A and B, for 4-8 cycles. Cycle A: cyclophosphamide, high dose ara-C, adriamycin, and vincristine. Cycle B: ifosfamide, methotrexate, VP 16, with intrathecal methotrexate. The response in 39 cases is: CR in 31 cases (82 per cent); PR in four cases (10 per cent); no response in three cases (8 per cent). At 60+ months, the disease-free survival is 60 per cent, and overall survival 80 per cent. This new protocol has the advantage of: short duration of therapy and so better patient compliance, no maintenance therapy or cranial irradiation with its sequelae in the future. Moreover, it has a better overall survival.

A randomized pilot study of high-dose epirubicin as neoadjuvant chemotherapy in the treatment of cancer of the bilharzial bladder.

Seventy-one patients with T2 and T3 bladder cancer were randomized to receive either two courses of epirubicin 120 mg/m2 i.v. push every 21 days pre-operatively, and four additional courses post-operatively (group I = 34 patients), or radical surgery (group II = 37 patients). At a median follow-up of 24 months (range 22 months to 38 months) 25 patients from group I and 14 patients from group II are still alive and disease-free. The estimated two-year disease-free survival percentages were 73.5 and 37.9%, respectively (P = 0.05). After initial chemotherapy, resected specimens were subjected to histopathological study of chemotherapeutic effects. Necrosis was detected in 95% of cases with squamous cell carcinoma and in 57.3% of cases with transitional cell carcinoma. We conclude that the benefit which was obtained by pre-operative and post-operative chemotherapy with epirubicin is promising and may represent a significant improvement in the treatment of patients with carcinoma of the bilharzial bladder.

Ifosfamide, methotrexate, and 5-fluorouracil: effective combination in resistant breast cancer.

Ifosfamide has definite efficacy in many malignant tumours, including breast cancer. In the present study we substituted cyclophosphamide with ifosfamide in the combination CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) regimen in 25 patients with breast cancer whose disease was refractory to CMF or who had relapsed after previous response. Ifosfamide was given in an i.v. infusion at a dose of 1.2 g/m2 daily for 5 days, together with mesna as a uroprotector (at 20% of the ifosfamide dose). Methotrexate was given at a dose of 40 mg/m2 and 5-fluorouracil was given at 600 mg/m2, both by i.v. push. Courses were repeated every 21 days. The 24 evaluable patients received 3-12 courses (average, 5 courses); results included a complete remission in 3 patients (12.5%) and a partial remission in 3 (12.5%). Among the remaining patients, improvement was seen in 4 (16.6%); stable disease, in 7; and progressive disease, in 7 (29.2%). The complete responses lasted for 11+, 13+, and 15+ months, and partial remissions, for 2, 6, and 9 months. The responses were detected in soft-tissue as well as visceral lesions, but not in bony lesions. The responders remain under follow-up. This study shows the efficacy of ifosfamide-containing chemotherapy in breast cancer. As toxicities were tolerable, higher doses of ifosfamide could safely be used in these patients. Use of this combination as first-line therapy in breast cancer could be considered for a future study.

Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes: 10-year results of a Southwest Oncology Group Study.

Four hundred forty-one women with operable breast cancer with histologically positive axillary nodes were randomized to receive either combination cyclophosphamide (60 mg/m2 orally everyday for 1 year); fluorouracil (300 mg/m2 intravenously [IV] weekly for 1 year); methotrexate (15 mg/m2 IV weekly for 1 year); vincristine (0.625 mg/m2 IV for 10 weeks); prednisone (30 mg/m2 orally days 1 to 14, 20 mg/m2 days 15 to 28, 10 mg/m2 days 29 to 42) (CMFVP) or single-agent melphalan (L-PAM) (5 mg/m2 orally every day for 5 days every 6 weeks for 2 years) chemotherapy after a modified or radical mastectomy between January 1975 and February 1978. Patients were stratified according to menopausal status and number of positive nodes (one to three, more than three nodes) before randomization. Seventy-eight patients were ineligible, most (56) because they were registered more than 42 days from surgery. Maximum duration of follow-up is 12 years, with a median of 9.8 years. The treatment arms were balanced with respect to age, menopausal status, and number of positive nodes. Among eligible patients, disease-free survival and survival were superior with CMFVP (P = .002, .005, respectively). At 10 years, 48% of patients treated with CMFVP remain alive and disease-free and 56% remain alive, compared with 35% alive and disease-free and 43% alive on the L-PAM arm. Disease-free survival and survival were significantly better with CMFVP compared with L-PAM only in premenopausal patients and patients with four or more positive nodes. Both regimens were well tolerated, although toxicity was more severe and more frequent with CMFVP. We conclude that after 10 years of follow-up, adjuvant combination chemotherapy with CMFVP is superior to single-agent L-PAM in patients with axillary node-positive primary breast cancer. The major advantage is in premenopausal women and in patients with more than three positive axillary nodes.

Chemotherapy in invasive carcinoma of the bladder. A review of phase II trials in Egypt.

Since 1976, a series of phase II studies with screening of various chemotherapeutic agents in invasive bladder cancer have been conducted at the National Cancer Institute, Cairo. Different drugs were screened, one by one, in groups of 20-25 patients with inoperable, metastatic, or recurrent carcinomas. Evaluation was done by clinical bimanual examination, radiography, sonography, cystoscopy, and urine cytology. In these trials bleomycin and doxorubicin were ineffective. Tenoposide, 5-fluorouracil, methotrexate, and cisplatin had minimal or moderate effect (response rates 4-16%). More pronounced effect was found for dibromodulcitol, cyclophosphamide, pentamethylmelamine, etoposide, hexamethylmelamine, ifosfamide, vindesine, vincristine, and epidoxorubicin (response rates 18-60%). Some complete responders remained in response for a period of 3-7 years. Drugs seemed to be more effective in metastatic than in local lesions.

Childhood non-Hodgkin's lymphoma in Egypt: preliminary results of treatment with a new ifosfamide-containing regimen.

Pediatric non-Hodgkin's lymphoma (NHL) constitutes 16% of pediatric malignancies reported to the National Cancer Institute (NCI) in Cairo. Since July 1985, we have treated 39 previously untreated pediatric NHL cases younger than 16 years of age (mean, 7.6 years) with a new protocol consisting of alternating cycles: regimen A comprised cyclophosphamide, high-dose ara-C, Adriamycin and vincristine; regimen B consisted of ifosfamide, methotrexate and VP16, with intrathecal methotrexate. Diagnoses included 20 abdominal masses, 16 peripheral lymphadenopathies and 6 bony lesions. Histopathology according to the working formulation revealed 21 cases of small non-cleaved lymphoma, 6 lymphoblastic, 5 large-cell and 7 unclassified diffuse lymphomas. Responses were complete in 31 cases (82%) and partial in 4 cases (10%), and no response was obtained in 4 cases (8%). Overall survival was 82% in limited disease and 60% in extensive disease at 28+ months. This short-term ifosfamide-containing regimen proved its efficacy, with results matching those of other regimens used in the United States and Europe.

Therapy of recurrent squamous cell carcinoma of the head and neck using combination vincristine, bleomycin, and methotrexate. A Southwest Oncology Group Study.

Fifty-six patients with squamous cell carcinoma of the head and neck were treated with the combination of vincristine, bleomycin, and methotrexate (VBM) on an every 2-week schedule. The overall CR + PR rate was 20%. Median response duration was 10 weeks. The toxicity during this trial was comparable to previously reported VBM regimens. The response rate was less than or no better than those previously reported for VBM or methotrexate alone. Therefore, this regimen offers nothing over methotrexate alone or other VBM regimens.

Ifosfamide in advanced pancreatic cancer. A 5-year experience.

Ifosfamide was studied in advanced pancreatic tumor at the National Cancer Institute, Cairo. Over five years, 25 patients received a daily dose of 1.8 g ifosfamide for five days, courses reported every 21 days. Complete remission was achieved in 1 patient and partial remission in 14 patients, an overall result of 60%, average duration of response being 12+ months. Mesna was used for uroprotection.

Combined modality therapy for first recurrence of breast cancer. A Southwest Oncology Group study.

The Southwest Oncology Group has completed a study of 213 women with the first recurrence of breast cancer. Eligibility included a radical or modified radical mastectomy for cure and recurrence which had received no other form of therapy. Patients were started on tamoxifen (TAM) 20 mg daily (Phase I). Failures, or responders who subsequently failed, had an oophorectomy if the ovaries were intact, and TAM was continued (Phase II). During Phase III, eligible patients underwent an adrenalectomy, and lastly, in Phase IV, patients received chemotherapy. Responses to TAM were seen in 40% of 56 premenopausal patients, 46% of 95 postmenopausal women, and 44% of 62 patients without intact ovaries. Oophorectomy plus TAM gave responses only in premenopausal women who failed to respond on TAM or in postmenopausal patients who had a prior response to TAM. Adrenalectomy was successful in 7 of 21 patients. Chemotherapy resulted in 13% complete and 47% partial responses. Median overall survival was 108, 155, and 115 weeks, respectively, for the three patient groups. The authors believe that until results with chemotherapy improve significantly, hormonal therapy is the preferred first-line management of recurrent breast cancer.

Hexamethylmelamine in advanced head and neck cancer. A phase II study.

The results of hexamethylmelamine therapy in 20 patients with advanced squamous cell head and neck cancer are reported. No patient had previously received chemotherapy. The dose of hexamethylmelamine was 8 mg/kg/day p.o. There was partial response in 3/20 (15%) patients. The duration of the response was 6-10 weeks. Twelve of 20 (12/20) patients had stable disease for a median of 8 weeks (range: 4-18 weeks). Hexamethylmelamine was well tolerated with the only significant toxicity being mild nausea and vomiting. This drug deserves further evaluation in the treatment of head and neck cancer.

Preoperative adjuvant chemotherapy in relatively advanced head and neck cancer.

Thirty patients with locally advanced primary squamous cell carcinoma of the head and neck were treated with two courses of cis-platinum chemotherapy (50 mg/m2 every 3 weeks). Twenty-three of thirty patients had either partial remission, improvement, or stable disease. Chemotherapy was well tolerated. Follow-up of all patients was done in greater than 36 months. Seven of 23 patients remain in complete remission after chemotherapy plus surgery. Of these seven patients, four of seven were partial responders to chemotherapy, two of seven were improved, and one of seven had stable disease or chemotherapy. Preoperative adjuvant chemotherapy needs further evaluation in head and neck cancer.

Pediatric Hodgkin's disease in Egypt.

A consecutive group of 242 children with Hodgkin's disease attending the National Cancer Institute, Cairo during the years 1975-1980 were studied. Males predominated representing 76.85% of cases. Age distribution was similar to other African countries with an earlier presentation than the US. The most common histopathologic types was the mixed cellularity 60.74% of patients. Late Stages III and IV represented 63.22%, with a high tumor burden. Celiotomy in 154 cases detected more tissue involvement than clinical assessment. Its results coincided with lymphography in 68% of the cases. It showed 7 cases with schistosomal hepatic fibrosis. As schistosomal infestation is still prevalent in rural areas of Egypt, celiotomy seems mandatory in the cases studied to accomplish proper staging.

Analysis of human urine for mutagens associated with carcinoma of the bilharzial bladder by the Ames Salmonella plate assay.

The Ames Salmonella plate assay was employed to test urine samples from bladder cancer patients and controls living in Egypt for the presence of chemical mutagens. Urine from five groups of Egyptian adults were tested, including individuals with (1) neither bilharziasis nor bladder cancer, (2) urinary bilharziasis and normal urinary cytology, (3) urinary bilharziasis and atypical urinary cytology, (4) carcinoma of the bilharzial bladder, and (5) bladder cancer without bilharziasis. Plates treated with histidine dependent bacteria, S-9 mix, beta-glucuronidases and 0.3 ml sterile urine from all five groups yielded 50 to 150 percent more colonies than plates treated with saline instead of urine. These differences were highly statistically significant for all groups except subjects with bladder cancer without bilharziasis. Gross and microscopic inspection suggested, however, that plates containing urine had heavier bacterial lawns than plates treated with saline. A procedure for quantitating viable bacteria in the lawn was devised which demonstrated that the increase in colonies on urine treated plates could be attributed to increased numbers of viable bacteria in the bacterial lawn on those plates. There was, therefore, no convincing evidence for the presence of mutagenic substances in these urine samples.

Phase II evaluation of rubidazone (NSC-164011) in advanced carcinoma of the breast. A Southwest Oncology Group study.

The SWOG carried out a Phase II evaluation of rubidazone in patients with advanced breast cancer. Good risk patients were given rubidazone 150 mg/m2 IV every three weeks. Poor risk patients were given a 25% dose reduction at the start of treatment. Rubidazone dose was increased or decreased depending on toxicity. One patient went into complete remission, four had partial remission and nine had stable disease. Forty-two patients showed increased disease on treatment. No cardiotoxicity was seen, but other common toxicities noted included mostly mild to moderate myelosuppression, nausea, vomiting and alopecia. This study failed to indicate significant antitumor activity of rubidazone in patients with advanced breast carcinoma.