Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study.

PURPOSE: Bacillus Calmette-Guerin (BCG) immunotherapy has been widely accepted as the optimal treatment for carcinoma in situ and high grade superficial transitional cell carcinoma. However, controversy remains regarding the role of maintenance therapy, and its long-term effect on recurrence and progression. MATERIALS AND METHODS: All patients in the study had transitional cell carcinoma of the bladder with carcinoma in situ or an increased risk of recurrence. The criteria for increased risk were 2 or more episodes of tumor within the most recent year, or 3 or more tumors within 6 months. At least 1 week following biopsy of carcinoma in situ and resection of any stage Ta or T1 transitional cell tumors 660 patients were started on a 6-week induction course of intravesical and percutaneous Connaught BCG. Three months following initiation of BCG induction therapy 550 consenting patients were stratified by purified protein derivative skin test and the presence of carcinoma in situ, and then randomized by central computer to receive BCG maintenance therapy (maintenance arm) or no BCG maintenance therapy (no maintenance arm). Maintenance therapy consisted of intravesical and percutaneous BCG each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months from initiation of induction therapy. The 384 eligible patients who were disease-free at randomization constitute the primary intent to treat analytic group because they could be followed for disease recurrence. All patients were followed for adverse effects of treatment, recurrence, disease worsening and survival. RESULTS: No toxicities above grade 3 were noted in the 243 maintenance arm patients. The policy of withholding maintenance BCG from patients with increased side effects may have diminished the opportunity to observe severe toxicity. Estimated median recurrence-free survival was 35.7 months (95% confidence interval 25.1 to 56.8) in the no maintenance and 76.8 months (64.3 to 93.2) in the maintenance arm (log rank p<0.0001). Estimated median time for worsening-free survival, defined as no evidence of progression including pathological stage T2 disease or greater, or the use of cystectomy, systemic chemotherapy or radiation therapy, was 111.5 months in the no maintenance and not estimable in the maintenance arm (log rank p = 0.04). Overall 5-year survival was 78% in the no maintenance compared to 83% in the maintenance arm. CONCLUSIONS: Compared to standard induction therapy maintenance BCG immunotherapy was beneficial in patients with carcinoma in situ and select patients with Ta, T1 bladder cancer. Median recurrence-free survival time was twice as long in the 3-week maintenance arm compared to the no maintenance arm, and patients had significantly longer worsening-free survival.

Combination transurethral resection, systemic chemotherapy, and pelvic radiotherapy for invasive (T2-T4) bladder cancer unsuitable for cystectomy: a phase I/II Southwestern Oncology Group study.

OBJECTIVES: Primarily to evaluate the toxicity and, secondarily, the tumor response and patient survival associated with a three-phase combined modality treatment plan for patients with invasive transitional cell carcinoma (TCC) of the bladder (T2-T4,NX-N2, MO) who are medically unsuitable for or who refuse cystectomy. METHODS: Eligible patients initially underwent extensive transurethral resection (TUR) of the primary tumor with the attempt to resect disease totally. Subsequently, they received systemic combination chemotherapy consisting of two cycles of methotrexate, cisplatin, and vinblastine (MCV), followed by cystoscopic re-evaluation of the bladder tumor. Patients then received 6480 cGy radiotherapy to the bladder with concurrent systemic cisplatin. Toxicity, primary tumor response, and overall survival were evaluated. RESULTS: Of 34 eligible patients, 27 patients completed the treatment series. Twenty-two received 80% to 100% of the prescribed doses of MCV and only 2 patients experienced grade 4 hematologic toxicities. The most common toxicities were gastrointestinal (23), hematologic (21), and renal (8). The complete response (CR) rate after all treatment phases was 56% (19 of 34), 10 patients achieving a complete tumor resection of visible tumor at the initial TUR of the bladder (TURB); 3, a CR after MCV; and 6, after radiotherapy and concomitant cisplatin. The median overall survival was 21 months with 6 of 34 (18%) alive at 57 months (range, 36 to 75). Complete resection of tumor by TURB was associated with prolonged overall survival. The bladder was the initial site of recurrence in 85% of patients who had achieved a CR status. CONCLUSIONS: This older age patient group tolerated this combined modality therapy with acceptable toxicities, but the overall survival rate was not improved compared with those reported with radiotherapy alone.

Evaluation of low dose continuous infusion 5-fluorouracil in patients with advanced and recurrent renal cell carcinoma. A Southwest Oncology Group Study.

BACKGROUND: The response rate of metastatic renal cell cancer to cytotoxic therapy over the last 10 years has been 5.6%. Low dose continuous 5-fluorouracil (5-FU) has demonstrated efficacy in other cytotoxic refractory tumors, such as pancreas, colorectal, and recurrent breast. The Southwest Oncology Group undertook a Phase II trial of low dose, continuous 5-FU in metastatic renal cell cancer. METHODS: Sixty-one patients were entered in the study to receive 300 mg 5-FU/m2/day for 7 days via a central venous catheter and external programmable pump. The pump was refilled every 7 days. Pyridoxine (50 mg, orally) was administered prophylactically three times a day. RESULTS: A response of 5.2% (one complete response [CR] and two partial responses [PRs]) was achieved. The overall survival was 12 months. The duration of the CR is more than 30 months. Both PRs lasted 6 months. No survival advantage was noted with either prior nephrectomy or biologic therapy. The majority of toxicities were Grade 2: anemia, anorexia, diarrhea, nausea/vomiting, and stomatitis. No toxic deaths occurred. CONCLUSION: Low dose, continuous 5-FU demonstrated minimal activity in metastatic renal cancer.

Phase II study of taxol in patients with untreated advanced non-small-cell lung cancer.

BACKGROUND: Taxol, a complex plant product (a diterpene) extracted from the bark of Taxus brevifolia, has demonstrated substantial anticancer activity in ovarian and breast cancers, malignant melanoma, and acute myelogenous leukemia. Due to allergic reactions in phase I and early phase II studies, use of a 24-hour infusion of taxol with prophylactic dexamethasone, diphenhydramine, and cimetidine has been recommended. PURPOSE: In this phase II study, we attempted to determine the efficacy and toxicity of taxol in patients with advanced (stage IIIB or IV) non-small-cell lung cancer who had never received chemotherapy. METHODS: Patients were not excluded because of prior surgery or because of radiotherapy administered more than 4 weeks before study entry. Taxol was administered in the hospital at a dose of 200 mg/m2 as an intravenous infusion over 24 hours and repeated every 3 weeks, provided that patients had recovered from any toxic effects. Dexamethasone, cimetidine, and diphenhydramine were given before chemotherapy to prevent hypersensitivity reactions. Therapy was continued for at least two courses unless there was rapid disease progression and for at least three courses if no change was observed and no grade 3 or 4 toxic effects occurred. Treatment was continued for six more courses after maximum response or for two more courses after complete remission but was discontinued if disease progressed. RESULTS: Of the 27 patients entered in the study, 25 were assessable for toxic effects and response. One patient had an allergic reaction that was not life threatening. The overall response rate was 24% (one complete response and five partial responses). An additional seven patients (28%) had minor response. Granulocytopenia was the dose-limiting toxic effect, and neutropenic fever occurred in eight of 118 courses. One additional patient developed neutropenic sepsis with hypotension but recovered with intensive treatment. CONCLUSIONS: Taxol appears to have activity against non-small-cell carcinoma of the lung. IMPLICATIONS: A phase II study combining taxol, etoposide, and cisplatin and using hematopoietic stimulating factors is now proposed. The optimal dose for combination chemotherapy has yet to be determined. An important consideration is potential cardiac effects of taxol with other drugs.

Long-term relapse-free survival in adult acute lymphoblastic leukemia.

An intensive treatment program with curative intent was designed for adults with acute lymphoblastic leukemia (ALL). Forty-eight consecutive patients were treated with this protocol and 39 (81%) obtained a complete remission. Although the complete remission rate was high for patients with both null- and T-cell disease, those with null-cell leukemia had a significantly greater median duration of remission (greater than 306 weeks) than patients with T-cell disease (62 weeks). The median survival by life-table analysis for the 48 patients is projected to be greater than 310 weeks, and five patients have finished the 3-year treatment program and have been off therapy for 1-3 years without recurrence of disease. Classification of adult ALL by immune marker status is an important and easily done pretherapy maneuver that identifies subsets of patients with a significantly different prognosis when treated with the protocol described in this study. Those patients for whom leukemic cells had T-cell characteristics had a short median duration of remission. Most importantly, this treatment protocol identifies by therapeutic response a subset of adult patients with ALL whose leukemic blasts are characterized by the absence of immunological markers and who appear, in substantial proportion, to be potentially curable.

Radiotherapy plus razoxane for advanced limited extent carcinoma of the lung.

Forty-four patients with limited extent American Joint Committee on Cancer Stage II-III non-small cell carcinoma of the lung were randomly assigned to potentially curative radiation therapy plus one of two schedules of razoxane. The weekly schedule was 1 gram per square meter body surface area (BSA) every 8 hours for two doses per week, and the daily schedule was a fixed dose of 250 mg per day. The 50% Kaplan-Meier survival estimate for both groups combined was 9 months. There was no survival difference between the two dose-schedules. Toxicity was formidable with an 82% incidence of esophagitis, and a 20% incidence of grade III-IV esophagitis. Fifty-nine percent of patients developed hematologic toxicity. This was greater with the weekly dose-schedule (P = 0.01). Forty-one percent of patients developed radiographic or symptomatic pneumonitis. One patient developed a fatal myelitis. This program is no more effective than irradiation alone, and has substantial morbidity.

Multimodality therapy of favorable prognosis non-Hodgkin's lymphoma.

Twenty-seven previously untreated patients with favorable prognosis non-Hodgkin's lymphoma were treated with a combination of total body irradiation followed by cyclophosphamide - vincristine - prednisone (CVP). The dose of total body irradiation was planned to be 150 rad followed by 6 cycles of chemotherapy. The complete response rate was 59%; the complete plus partial response rate, 93%. The 50% disease-free survival was 8 months. The actuarial projected 5 year survival was 60% and the disease-free survival at 5 years was 27%. The program was well tolerated by the majority of patients. It is possible for some patients with favorable non-Hodgkin's lymphomas to achieve prolonged periods of disease-free survival when treated with combinations of irradiation plus chemotherapy.

Advanced diffuse histiocytic lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) without maintenance therapy.

Thirty-one patients with stage III or IV diffuse histiocytic lymphoma were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) at 3- or 4-week intervals for at least six cycles or until two cycles after complete remission (CR) was achieved. At the completion of therapy, CR was documented by examination of sites known to previously contain disease. After documentation of CR, patients were followed without maintenance therapy. Fifteen patients (48%) achieved CR, four (13%) had equivocal lymphangiograms on restaging but were otherwise free of disease, two (6%) died of unrelated causes during therapy, two (6%) developed central nervous system lymphoma during therapy and despite peripheral remission eventually died of the CNS disease, and eight (26%) had either partial or no response. Twelve of the 15 patients achieving CR remain disease-free with no therapy for 9+ to 43+ months. Three patients relapsed at 3, 4, and 23 months after discontinuation of therapy. Three of the four patients with equivocal restaging lymphangiograms remain without progressive disease with no therapy for 10+ months. The projected median survival time for all patients is 41 months. The risks of long-term (maintenance) chemotherapy are considerable and include the induction of acute nonlymphoblastic leukemia. CHOP without maintenance therapy is able to induce long-term disease-free survival (and probable cure) in a significant number of patients with advanced diffuse histiocytic lymphoma.

cis-dichlorodiammineplatinum(II) with and without ICRF-159 in non-Hodgkin's lymphoma.

Two studies of cis-dichlorodiammineplatinum(II) (CDDP) were conducted. The single-agent phase II study revealed that three of ten patients with non-Hodgkin's lymphoma treated with CDDP alone achieved objective partial remission of 7-15 weeks' duration. Eight patients were treated with CDDP plus ICRF-159. None of these eight patients achieved an objected response. CDDP is active as a single agent in non-Hodgkin's lymphoma. The combination of CDDP plus ICRF-159 does not appear to be a promising salvage program for non-Hodgkin's lymphoma.

An abbreviated phase II trial of thalicarpine.

Thalicarpine, a plant alkaloid of novel structure, was evaluated in a phase II clinical trial. Fourteen previously treated patients with advanced malignant disease were given thalicarpine at a dose of 1100 mg/m2 weekly as a constant 2-hour iv infusion. Common toxic effects included nausea, ECG changes, arm pain, and lethargy; less frequent effects included vomiting, tachycardia, hypotension, pain distant from infusion site, urticaria, chills, diarrhea, and mydriasis. There was no hematologic, hepatic, or renal toxicity. There were no complete or partial objective responses. Although the drug's true response rate in any given tumor type cannot be determined, its absence of activity in man, to date, and the recent closing of its IND, make further clinical investigation with thalicarpine unlikely.

Clinical usefulness and reproducibility of histologic subclassification of advanced diffuse histiocytic lymphoma.

Thirty-one patients with stage III and IV diffuse histiocytic lymphoma (DHL) were treated uniformly with cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP). The patients were subclassified independently by two hematopathologists into groups with predominantly large noncleaved cells (eight patients), predominantly large cleaved cells (seven patients), a mixture of large cleaved cells and large noncleaved cells (11 patients), tumors with the characteristics of immunoblastic sarcomas (two patients) and unclassified (three patients). The concurrence rate on applying the subclassification was 85 per cent. Survival in patients with large noncleaved cells was superior to that of the other patients as a group (p less than 0.001), and to that of those with large cleaved cells (p less than 0.05) and large cleaved and large noncleaved cells (p less than 0.025). All the patients with large noncleaved cells are alive and "off" therapy without evidence of progressive disease. This histologic subclassification seems to identify a subgroup of patients with advanced diffuse histiocytic lymphoma having large noncleaved cells who have an excellent prognosis when treated with CHOP.

Phase II study of cis-dischlorodiammineplatinum(II) in stage IVB Hodgkin's disease.

A broad phase II study of cis-dichlorodiammineplatinum(II) was conducted. Eight patients with stage IVB Hodgkin's disease were studied. Four of these patients attained an objective partial remission of 7--19+ weeks' duration. The usual time to the occurrence of a greater than 25% response was 1 week. This drug is active in far-advanced Hodgkin's disease with a projected lower limit of response rate from 19% to 21%.

Erythema annulare centrifugum and Hodgkin's disease: association with disease activity.

The skin lesions of erythema annulare centrifugum developed in a 58-year-old woman who had Hodgkin's disease. Response of the neoplasm to vinblastine sulfate was accompanied by disappearance of the skin lesions. When therapy was discontinued, both disorders recurred, and both responded to reinstitution of vinblastine therapy. To our knowledge, this case is the first reported association of erythema annulare centrifugum and Hodgkin's disease. The cutaneous manifestation in this patient were a nonneoplastic concomitant of her neoplastic disorder.

Myeloid metaplasia and osteolytic lesions.

The case of a patient with myelofibrosis and painful osteolytic lesions is described. Biopsy of the involved bone demonstrated myeloid proliferation. Foci of myeloid metaplasia may occasionally result in clinical disability, with bone pain and rarefaction. Myeloid metaplasia should be considered when these symptoms and signs occur in the setting of myelofibrosis. The role of radiation therapy as a palliative maneuver remains uncertain.