Teniposide (VM-26) as a single drug treatment for patients with extensive small cell lung carcinoma: a Phase II study of the Southwest Oncology Group.

BACKGROUND: Teniposide (VM-26) was reported to have activity in small cell lung carcinoma (SCLC). The authors performed a Phase II study of teniposide as a treatment for patients with previously untreated extensive SCLC. METHODS: The study was open to patients with a histologic or cytologic diagnosis of extensive SCLC who had not received prior radiation or chemotherapy. Patients with hematologic values below normal were considered eligible if the impaired bone marrow function was directly attributable to disease involvement. Treatment consisted of teniposide 60 mg/m2 given intravenously (i.v.) on Days 1-5 every 3 weeks. RESULTS: This study opened on September 15, 1988, closed permanently on November 15, 1990, and accrued 45 patients identified at 19 academic, military, and Community Clinical Oncology Program institutions affiliated with the Southwest Oncology Group. Of the 45 registered patients, 41 were eligible. Twenty eight (68%) were males and 13 (32%) were females; the median age was 64 years (minimum, 46 years; maximum, 83 years). Twenty-four patients (59%) had a performance status (PS) on the Zubrod scale of 0-1 and 17 cases (41%) had a PS of 2. Of the 41 eligible patients, 10 had confirmed partial responses (24%) (95% confidence interval, 12-40%). The median survival was 7 months. The significant toxicities noted were Grade 4 leukopenia and/or granulocytopenia, experienced by 15 patients; 1 of these patients also had Grade 4 hyponatremia. One patient died of a respiratory infection. CONCLUSIONS: When administered according to the dosage and schedule selected for this study (60 mg/m2 i.v. on Days 1-5 every 3 weeks), teniposide as a single agent had modest activity in extensive small cell lung carcinoma. The toxicities observed in this study were acceptable.

Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease. A Southwest Oncology Group randomized study.

OBJECTIVE: To determine if low-dose involved field radiation after complete remission induction with chemotherapy is effective in preventing relapse and improving survival in patients with stage III or IV Hodgkin disease. DESIGN: A randomized controlled trial with a median follow-up time of 8.1 years. SETTING: A Southwest Oncology Group multi-institutional study. Patients were entered from university- and community-based practices. PATIENTS: 278 adults with clinical or pathologic stage III or IV Hodgkin disease, who achieved complete responses after 6 cycles of MOP-BAP (nitrogen mustard, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine) and who agreed to be randomly assigned to either radiation or no further treatment. INTERVENTION: Patients were assigned to either no further treatment or low-dose radiation to all initially involved sites (radiation dose, 2000 cGy to lymph node areas and 1000 to 1500 cGy to other involved organ sites). MEASUREMENTS: Differences in remission duration, relapse-free survival, and survival. RESULTS: Remission duration, relapse-free survival, and overall survival were similar for the two groups (P = 0.09, P > 0.2, and P = 0.14, respectively). Factors that predicted shorter remission duration in a multivariate analysis were nodular sclerosis histology, bulky disease, and receipt of less than 85% of planned chemotherapy. Low-dose radiation improved remission duration in the subgroups of patients with nodular sclerosis and bulky disease. For the 169 patients with nodular sclerosis, the 5-year remission-duration estimate was 82% for the low-dose radiation group and 60% for the no further treatment group (P = 0.002). For all patients with bulky disease, the 5-year remission-duration estimate was 75% for the low-dose radiation group and 57% for the no further treatment group (P = 0.05). No difference in overall survival was noted between low-dose radiation and no further treatment in all patients or major subgroups. The 5-year survival was 86% for all patients who had a complete response as well as for patients in the nodular sclerosis subgroup. CONCLUSIONS: Low-dose involved field radiation after MOP-BAP chemotherapy in patients with stage III or IV Hodgkin disease did not prolong remission duration or overall survival in randomized patients. However, remission duration was prolonged in several subgroups of patients, most prominently in those with nodular sclerosis histology.

Alternated versus syncopated CHOP-PVB: two studies for the treatment of non-Hodgkin's lymphoma by the Southwest Oncology Group.

Based on a preliminary trial that suggested that CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), and PVB (cisplatinum, vinblastine, bleomycin), are at least partially non-cross-resistant, the Southwest Oncology Group treated patients with unfavorable histology, non-Hodgkin's lymphoma with CHOP and PVB. In the first study, 76 eligible patients were given three courses of CHOP, with complete or partial responders receiving three courses of PVB followed by three further courses of CHOP. Nonresponders after the initial three cycles of CHOP, received six courses of PVB. In the second study, 154 eligible patients were treated with alternating cycles of the two drug regimens. The overall objective antitumor response (CR + PR) was 77% for the first study and 58% for the second. The complete remission rates were 48% and 38%, respectively. The overall survival for both studies is similar. These results are interpreted in terms of the Goldie-Coldman hypothesis.

Comparison of lymphangiography and computed tomography scanning in evaluating abdominal disease in stages III and IV Hodgkin's disease. A Southwest Oncology Group study.

The authors reviewed the records of 139 patients who had laparotomy plus computed tomography (CT) and/or lymphangiograms (LAG) as part of a their staging workup for Hodgkin's disease, in accordance with Southwest Oncology Group (SWOG) protocol 7808. They evaluated the relative ability of CT and LAG to detect disease in the abdomen. Two regions of the abdomen were designated, the upper and the lower, to further examine the capabilities of CT and LAG in the lower abdomen and CT in the upper abdomen. A LAG was more sensitive (P less than 0.05) than CT in detecting positive lower abdominal nodes. In the upper abdomen, CT scan had low sensitivity for detecting positive nodes, liver, or spleen. This study suggests that LAG of the lower abdomen provided more information than CT, and therefore should not be abandoned as a valid method for detecting nodal disease.

VP-16 + adriamycin vs. adriamycin alone in advanced adenocarcinoma of the breast, phase II, a randomized trial: a Southwest Oncology Group Study.

One hundred twenty-two patients with advanced adenocarcinoma of the breast were randomized to receive adriamycin (AD) alone or a combination of VP-16 plus lower dose adriamycin (VAD). The patients were stratified to good and poor risk. The starting dose (day 1) of AD was 60 mg/m2 for good risk and 45 mg/m2 for poor risk. The starting dose of the VAD combination for the good-risk patient was VP-16, 75 mg/m2 daily x 5 plus adriamycin 35 mg/m2. The poor-risk dose for VAD was VP-16, 50 mg/m2 daily x 5 plus adriamycin, 30 mg/m2 on day 1. The total dose of AD was 450 mg/m2 on both arms. The patients who were on the VAD arm continued on VP-16 maintenance. Both arms were repeated every 21 days. There were 54 evaluable patients on the adriamycin arm and 52 evaluable patients on the VAD arm. Both arms were similar with regard to age, menopausal status, performance status, and prior hormonal therapy. More hematologic toxicity was seen in the adriamycin arm. Complete responses were observed on both arms, three (5%) with adriamycin and three (5%) with combination. Eleven (19%) and ten (18%) partial responses were observed with the adriamycin and VP-16 plus adriamycin, respectively. AD produced more stable disease than VAD (41% vs. 29%). Complete responses were seen only in the good-risk patients. Time to progression was delayed on the combination arm (P = 0.02). The survival in both arms was similar. The addition of VP-16 to adriamycin does not offer an important clinical advantage.

Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group Study.

In 1979 we initiated a phase III study in the Southwest Oncology Group (SWOG) which was designed to determine the value of chest radiation in limited-stage small-cell lung cancer patients achieving complete response after induction chemotherapy, and to test the use of wide-field v more limited-volume radiation in patients with partial responses (PRs) and patients with stable disease (SD). The induction chemotherapy (VMV-VAC) consisted of vincristine, 2 mg intravenously (IV) every week for six doses; methotrexate, 60 mg/m2 IV days 1 and 43; VP-16, 50 mg/m2/d IV days 1 to 5 and 43 to 47; doxorubicin, 60 mg/m2 IV days 22 and 64; and cyclophosphamide, 1,000 mg/m2 IV days 22 and 64. Four hundred ninety-four patients were registered, of whom 473 were eligible. Of 466 response-evaluable patients, 153 (33%) achieved complete disease remission (CR) with chemotherapy. A total of 387 patients entered the consolidation phase of treatment after chemotherapy and response determination. CR patients were prospectively randomized to receive chest radiation, consisting of 4,800 rad administered in a split-course scheme, or to continue chemotherapy without interruption. The treatment volume was based on tumor extent before the induction chemotherapy. Maintenance chemotherapy consisted of cyclophosphamide and VP-16 administered for four cycles before a period of reinduction chemotherapy consisting of VMV-VAC as described above. Patients receiving chest radiation therapy were given the same maintenance and reinduction chemotherapy programs following completion of the chest radiation. One hundred ninety-one eligible patients achieving PR or SD status after induction chemotherapy were randomized to a preinduction treatment volume or to a postinduction reduced tumor volume, with treatment portals designed according to tumor extent before or after induction chemotherapy, respectively. After completion of the entire treatment plan, there were 218 (47%) CRs and 121 (26%) PRs. These figures represent the greatest response achieved at any point in the treatment program. The median survival for all eligible patients was 57 weeks (74 weeks for CRs). Overall survival for CR patients was not different for patients who did or did not receive chest radiation. However, patterns of tumor relapse were affected by the chest radiation, as 38 of 42 relapsing patients who did not receive radiation had intrathoracic recurrences in comparison to only 20 of 36 radiated patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Thyroid lymphoma with gastrointestinal involvement: report of three cases.

Three elderly females are reported who presented with high-grade lymphoma of the thyroid and subsequently were found to have extensive gastrointestinal (GI) lymphoma that dominated their clinical courses. One of the patients remains free of disease 30+ months after extensive resection of involved bowel and combination chemotherapy. Two died from disseminated lymphoma. Optimal delivery of therapy in both of the latter patients was impeded by massive gastrointestinal hemorrhage. A review of previously reported cases of thyroid lymphoma, plus those described here, suggests a predilection for these tumors to involve the GI tract independent of other organ metastases.

Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience.

To study the influence of chronologic age on treatment outcome in patients with advanced, diffuse large-cell (histiocytic) lymphoma (DHL), we reviewed the results of two recent Southwest Oncology Group (SWOG) clinical trials. From 1974 to 1982, members entered 307 eligible patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without bleomycin, and CHOP with or without immunotherapy using BCG, levamisole, or both. Complete response (CR) rates declined progressively with advancing age: 65% in those under 40, 60% in the 40 to 54 age group, 55% in the 55 to 64 age group, and 37% in those 65 and older (P = .001). Likewise, survival decreased significantly in older patients: medians were 101 +, 52, 34, and 16 months, respectively (P less than .001). Treatment guidelines included an initial dose reduction of 50% for patients aged 65 or older and for younger patients with bone marrow compromise. Despite protocol specifications, 23 of 81 patients aged 65 or older received initial full-dose therapy. When these patients were compared with younger patients on whom full-dose chemotherapy was started, survival curves, but not CR rates, were still significantly different. There were no significant differences in duration of CR or frequency of treatment complications. These data suggest that older age is associated with a worse prognosis in advanced DHL. Moreover, the initial dose reduction for patients aged 65 or older may have contributed to their inferior outcomes.

Bisantrene hydrochloride in gastric adenocarcinoma: a Southwest Oncology Group Study.

Because "the standard" chemotherapy for advanced gastric adenocarcinoma, the FAM combination of 5-fluorouracil, adriamycin, and mitomycin, is only minimally effective, there is a clear need for other choices. Therefore, the Southwest Oncology Group tested the new adriamycin analog, bisantrene, hoping that it might be more effective than the "parent drug." Twenty-six patients with gastric adenocarcinoma were treated on a program of every-3-week 2-hour bisantrene infusions. The starting dose was 260 mg/m2 (208 if poor risk), with subsequent doses based on prior toxicity. The regimen caused sufficient toxicity (especially local phlebitis with pain and swelling) to assure an adequate test. One person (3.8% of eligible patients) experienced a clinically useful 3-month response. He had previously had progressive disease on FAM. Nevertheless, we conclude that bisantrene is not an addition to the small list of drugs useful in the management of gastric adenocarcinoma.

Abnormal immunoregulation in remission Hodgkin disease.

Peripheral blood mononuclear cells from 11 patients with remission Hodgkin disease and 20 normal controls were incubated with irradiated allogeneic lymphocytes in one-way mixed lymphocyte cultures. Simultaneously, modified assays were performed by adding supplemental irradiated PBM, T lymphocytes, or adherent cells autologous to the responders. Baseline allogeneic responsiveness of patients and controls was not different. However, significant suppression (p less than .01) was demonstrated when the cultures were supplemented with patient mononuclear cells or adherent cells, an effect not found with similar supplemental cells from controls. Conversely, T-cell supplementation of control cultures produced more than twofold increases in proliferation but significantly less augmentation in the patients' cultures (p less than .01). T-cell subset analysis in six patients showed decreased helper: suppressor cell ratios. Hodgkin disease patients have adherent suppressor cells, which persist during remission, as well as a defect in T-cell helper function.

Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone alone or with levamisole or with levamisole plus BCG for malignant lymphoma: a Southwest Oncology Group Study.

Between 1977 and 1983 the Southwest Oncology Group (SWOG) evaluated chemotherapy alone (cyclophosphamide, doxorubicin, vincristine, prednisone; CHOP) or chemoimmunotherapy (CHOP-levamisole or CHOP-levamisole-BCG) in a randomized prospective clinical trial involving 715 eligible patients with all types of malignant lymphoma (ML). Of 281 evaluable patients with favorable histologic types of ML, 171 (61%) achieved complete remission (CR) and there was no difference in CR rate, CR duration, or survival according to the type of initial treatment. Of 388 evaluable patients with unfavorable histologic types of ML, 194 (50%) achieved CR. Levamisole appeared to adversely affect CR rates in nodular mixed and nodular large-cell lymphoma and CR duration in patients with unfavorable histology ML. Chemoimmunotherapy with levamisole or levamisole-BCG offers no advantage in terms of CR rates, CR duration, or survival compared to CHOP chemotherapy alone, and levamisole may have had an adverse impact on outcome in certain subtypes of ML.

Vocal cord paralysis and recovery with thyroid lymphoma.

Vocal cord paralysis has been reported in 33 patients with thyroid lymphoma for an estimated overall incidence of 17%. There is little expectation of vocal cord function recovery, both because neoplastic invasion is believed irreversible and since surgery often necessitates sacrifice of the recurrent laryngeal nerve. Unlike in most well differentiated thyroid malignancies, external radiation therapy plays a vital role in the treatment of thyroid lymphoma. The patient presented here had complete recovery of vocal cord function following radiation therapy for a large thyroid lymphoma associated with vocal cord paralysis. This is the first reported case of such recovery following treatment for a thyroid neoplasm. The rather rapid and complete recovery of neural function suggests that, at least in some, paralysis is caused by reversible compression rather than by neural invasion or tumor-induced neurolysis.

Long-term survival and toxicity in small cell lung cancer. Southwest Oncology Group study.

In the first study of combined chemotherapy and radiation therapy for small cell lung cancer by the Southwest Oncology Group, 17 patients survived more than five years after treatment was initiated (4.6 percent). Late relapse, or a second primary malignancy three to six years after diagnosis, accounted for death in five of these patients. Late recurrences involved the chest, bone, and liver; none occurred in the central nervous system. Disease-free survival continues in 10 patients (6 percent of those with limited disease and 1 percent of those with extensive-stage diseases) at a minimal follow-up in excess of six years. One definite case of chronic treatment-related toxicity occurred: congestive cardiomyopathy after 450 mg/m2 of doxorubicin, successfully managed with digitalis and diuretics. One severe neurologic problem (orthostatic hypotension with preterminal dementia) and two less severe neurologic complications (occasional falling episodes without documented cause and cerebrovascular accident) may be treatment-related. Progressive pulmonary disability, post-herpetic pain syndromes, organic brain syndrome, and hematologic abnormalities have not been observed to date. Nitrosourea administration and/or co-administration of a nitrosourea or methotrexate during the induction phase of treatment with radiotherapy to the brain may account for the higher incidence of complications observed by others in long-term survivors.

Vindesine, carmustine, doxorubicin, and prednisone (EBAP) in recurrent lymphomas: a Southwest Oncology Group study.

Seventy-eight patients with Hodgkin's disease and non-Hodgkin's lymphoma who had failed prior chemotherapy or radiation therapy were treated with a combination of vindesine, carmustine, doxorubicin, and prednisone (EBAP). Outpatient therapy was administered at 21-day intervals. Complete and partial responses were seen in 32 patients (41%). The response rate was higher for Hodgkin's disease (59%) than for non-Hodgkin's lymphoma (31%). The median duration of response was 31 weeks in both groups, with a median survival of all patients of 35 weeks (responders, 122 weeks; nonresponders, 16 weeks). Myelotoxicity was greater using EBAP than in the earlier reported program with vincristine, carmustine, doxorubicin, and prednisone, and in the absence of higher response rates does not support the use of vindesine over vincristine in combination programs using nitrosoureas, anthracyclines, and prednisone.

Multiagent chemotherapy in relapsing ovarian cancer.

A multiagent regimen (vinblastine, bleomycin, hexamethylmelamine, and cis-platinum) partly designed on the basis of data from a human tumor stem cell assay was used to treat 36 patients with relapsing epithelial ovarian cancer. All patients included in this study had previously received alkylating agent therapy, and 78% (28/36) had also received Adriamycin. Thirty-five patients were clinically evaluable for response; eight achieved complete clinical remission, and nine achieved partial remission, for an overall response rate of 49%. The median duration of response was 10 months, and three of the complete responders are in remission at 10+, 17+, and 22+ months. Mild to moderate peripheral neuropathy was the major side effect, occurring in 11% (4/35) of patients. Myelotoxicity was well tolerated. We conclude that this four-drug regimen is effective in the treatment of relapsing ovarian cancer patients and should be considered for study as a front-line combination chemotherapy for previously untreated patients.

Improved complete remission rates and survival for patients with large cell lymphoma treated with chemoimmunotherapy. A Southwest Oncology Group Study.

Between 1974 and 1977, 652 patients with non-Hodgkin's lymphoma without prior chemotherapy were randomized to 1 of 3 combination chemotherapy programs designed to induce complete remission (CR): COP-bleomycin (180 patients), CHOP-bleomycin (232 patients) or CHOP plus immunotherapy with Bacillus Calmette Guerin (BCG) (240 patients). With mature follow-up, the major effect of BCG immunotherapy was observed in patients with large cell lymphomas (diffuse or nodular "histiocytic") and not in other common lymphoma subtypes. CR rate for 65 patients with large cell lymphoma treated with CHOP-BCG was 68% compared to 48% in 61 patients treated with CHOP-bleomycin (P = 0.02) (two-tailed test) or 44% for 45 patients treated with COP-bleomycin (P = 0.02). CR duration for both CHOP-based regimens was similar and superior to that produced by COP-bleomycin (P = 0.03). Survival of patients with large cell lymphoma treated with CHOP-BCG was better than that observed with CHOP-bleomycin (P = 0.02) or COP-Bleomycin (P = 0.002). Although the explanation for the favorable effect of BCG remains unclear, further clinical trials to evaluate the combination of chemotherapy and other "biologic response modifiers" is warranted for patients with lymphoma.