Phase I study of a five-day intermittent schedule for 1,2:5,6-dianhydrogalactitol (NSC-132313).

Because 1,2:5,6-dianhydrogalactitol (NSC-132313 (DAG; the main conversion reaction product of the treatment of dibromodulcitol by mild akali or human serum) showed considerable antitumor activity in various mouse and rat tumor systems, a phase I study in 50 patients was conducted with five daily iv treatments repeated every 6 weeks. Thrombocytopenia was the dose-limiting toxicity. At a dose of 40 mg/m2/day for 5 days, the median platelet nadir was 31,000/mm3 and occurred on day 20; the plate count returned to normal within 8 days. At the same dose, the median white blood cell (WBC) nadir was 2,300/mm3 also on day 20-, the WBC count returned to normal within 7 days. Anemia, nausea, and vomiting were usually mild to moderate. No renal, hepatic, central nervous system, cardiac, or pulmonary toxicity was identified. Antitumor effects of DAG were observed in patients with renal, bladder, and small-cell lung cancers. An iv dose of 20-30 mg/m2/day for 5 consecutive days, repeated every 5-6 weeks, was recommended for phase II studies.

Early clinical study of an intermittent schedule for maytansine (NSC-153858): brief communication.

Maytansine, an ansa macrolide, was evaluated in an early clinical trial in 40 adult patients with various solid tumors. Severe nausea and vomiting, sometimes associated with watery diarrhea and abdominal cramps, and liver function abnormalities, mainly elevation of serum glutamic--oxaloacetic transaminase levels, together constituted what we considered dose-limiting toxicity. Mild hematologic toxicity (mainly thrombocytopenia), neurotoxicity, and possibly cardiac toxicity were also noted. No antitumor effect was seen. An iv dose of 0.750 mg/m2 on days 1, 3, and 5 (total dose, 2.25 mg/m2) repeated every 4 weeks is recommended for Phase II trials.

Disposition and metabolism of pentamethylmelamine and hexamethylmelamine in rabbits and humans.

The disposition and metabolism of pentamethylmelamine (PMM) and hexamethylmelamine (HMM) were studied in the rabbit, and the disposition of PMM was studied in humans. Parent compound and metabolites were identified by thin-layer chromatography, gas chromatography, and gas chromatography/mass spectrometry analyses. Plasma elimination in both species following i.v. administration of each drug was best described by a two-compartment open model. Both compounds were extensively demethylated with less than 1% of the total dose administered recovered in the urine over 24 hr. The areas under the plasma time-concentration curves of PMM and HMM following p.o. administration to rabbits were 5 and 25% of the areas following i.v. administration. Gastrointestinal absorption was rapid and efficient with 75 to 89% of drug equivalents recoverable in the urine after p.o. administration of [ring-14C]PMM or [ring-14C]HMM to rabbits. Reduced bioavailability of PMM and HMM p.o. appears to be a consequence of rapid metabolism presumably in the liver.

Evaluation of prognostic factors in chemotherapy of recurrent brain tumors.

We have evaluated the prognostic significance of several easily obtainable and commonly used factors in patients with primary brain tumors (recurrent after irradiation) undergoing chemotherapy. Age, sex, tumor grade, on-study performance score, time from initial diagnosis to initial postirradiation progression, and prior chemotherapy or no were evaluated for affects on tumor response. None of the six factors significantly correlated with response to therapy. The above six factors plus response to chemotherapy were evaluated for their affects on time to progression and survival. Tumor regression following chemotherapy most strongly correlated with prolonged time to progression and survival. A good on-study performance score (not, or only minimally, symptomatic) significantly correlated with prolonged survival, but not with prolonged time to progression. Surprisingly, tumor grade did not significantly correlate with response, time to progression, or survival. Further study is required, but initial data analyses would suggest that essentially all patients with all grades of recurrent tumor could be used in chemotherapeutic trials with proper pretreatment stratification.

A randomized comparative trial of sequential versus alternating cyclophosphamide, doxorubicin, and cisplatin and mitomycin, lomustine, and methotrexate in metastatic non-small-cell lung cancer.

One hundred eight eligible patients with advanced, metastatic non-small-cell lung cancer (NSCLC) were randomized to treatment with either cyclophosphamide, doxorubicin, and cisplatin (CAP) followed by mitomycin, lomustine, and methotrexate (MCM) on progression (sequential, 54 patients) or to CAP alternating with MCM (alternating, 54 patients). The regression rate (30%) was identical for both treatments. In addition, there were no statistically significant differences noted between treatments for regression duration (6.9 months v 7.6 months), time to progression (2.1 months v 4.4 months), or overall survival (5.5 months v 6.9 months). The lack of advantage for the theoretically superior alternating approach was probably due to a combination of relative ineffectiveness of each treatment and lack of complete non-cross resistance.

Prophylactic cranial irradiation in complete responders with small-cell lung cancer: analysis of the Mayo Clinic and North Central Cancer Treatment Group data bases.

PURPOSE: To determine whether prophylactic cranial irradiation (PCI) has an impact on brain failure and survival in patients with small-cell lung cancer (SCLC) who have achieved a complete response to chemotherapy with or without thoracic radiation therapy (TRT). METHODS: Between 1975 and 1990, the Mayo Clinic and North Central Cancer Treatment Group entered 1,617 patients on 15 phase II and III SCLC protocols of chemotherapy with or without TRT and PCI. RESULTS: Of 772 patients with limited disease, 457 (59%) achieved a complete response, compared with 200 of 845 patients (24%) with extensive disease. With follow-up durations of 2 to 17 years (median, 4), the median survival time and 2-, 5-, and 10-year survival rates for the 457 completely responding limited-disease (LD-CR) patients were 19.6 months, 41%, 17%, and 5%, compared with 13.9 months, 26%, 8%, and 5%, respectively, for the 200 completely responding extensive disease (ED-CR) patients (P = .0001). Multiple prognostic factors, including whether the patient did or did not receive PCI (30 to 38 Gy in 2- to 3.6-Gy fractions) were analyzed. In both univariate and multivariate analyses, PCI was not associated with improved (or worsened) survival. The brain relapse rate was 37% for LD-CR patients who did not receive PCI versus 9% for those who did (P = .0001). In ED-CR patients, the brain relapse rate was 31% without PCI and 8% with (P = .009). Essentially all patients who developed brain relapse died within 2 years, with a median survival time of 3.7 months following relapse. Severe, life-threatening, or fatal CNS toxicity occurred in approximately 3% of patients who received PCI. CONCLUSION: The use of PCI remains controversial outside the setting of a clinical trial.

Limited-stage small-cell lung cancer: patterns of intrathoracic recurrence and the implications for thoracic radiotherapy.

PURPOSE: This analysis was performed to determine the most appropriate volume that should be encompassed by thoracic radiation treatments (TRTs) for patients with limited-stage small-cell lung cancer (LSSCLC) who have responded to initial chemotherapy. PATIENTS AND METHODS: A retrospective review of all patients (N = 67) with LSSCLC who were not entered onto a research protocol and were treated at our institution between the years of 1982 and 1990 was performed. Fifty-nine of 67 patients had adequate information regarding the size of the tumor before the start of chemotherapy (computed tomographic [CT] scan of chest or chest x-ray), the size of the tumor before TRT, and the TRT field size based on a simulation radiography. All 59 patients were treated with cyclophosphamide-based chemotherapy, and TRT was generally delivered concomitantly with chemotherapy following two to three cycles of chemotherapy alone. RESULTS: Of 59 patients, 28 were treated with TRT field sizes that encompassed postchemotherapy tumor volumes, and 31 patients were treated with TRT field sizes that encompassed prechemotherapy tumor volumes (defined as a volume that included at least a 1.5-cm margin on the prechemotherapy tumor volume). Nineteen patients had an intrathoracic recurrence of disease as the first site of recurrent small-cell carcinoma: 10 of 31 patients treated with TRT fields that encompassed prechemotherapy tumor volumes and nine of 28 patients treated with TRT fields that encompassed postchemotherapy tumor volumes. For the 28 patients treated with TRT fields that encompassed postchemotherapy tumor volumes, the greatest distance that the prechemotherapy tumor volume (without margins) extended beyond the edge of the TRT field was 0.5 to 5.0 cm, with a median of 2.5 cm. All 19 of the intrathoracic recurrences were in-field failures, although two patients (one prechemotherapy volume and one postchemotherapy volume) did have concurrent pleural effusions. CONCLUSION: These results indicate that the use of TRT fields that encompass postchemotherapy tumor volumes does not increase the risk of marginal failures or intrathoracic failures outside the TRT field.

Clinical comparison of adriamycin and a combination of methyl-CCNU and imidazole carboxamide in disseminated malignant melanoma.

The effects of adriamycin were compared to a combination program of methyl-CCNU and imidozole carboxamide (DTIC) in 44 patients with disseminated malignant melanoma. There were objective clinical responses in 6 of 21 patients with the combination of DTIC and methyl-CCNU who received this program as primary treatment and none in 23 patients receiving adriamycin as primary treatment. Secondary responses were not observed with either treatment regimen. Toxicity with the combination program included leukocyte depression (less than 3,000/cu mm) in 25% and platelet depression (less than 100,000/cu mm) in 40% compared to 52% leukocyte depression and 16% platelet depression after adriamycin. There were no responses after the combination treatment program in the absence of myelosuppression. There was nausea and vomiting in virtually all patients, which was moderately severe in one third of the patients receiving the combination and in only 10% of those receiving adriamycin. Alopecia developed in all who received adriamycin but in only 15% of the combination treatment group. The combination treatment response of 28% was of the same order as most response rates previously reported in this disease. This randomized controlled clinical trail found adriamycin without clinical benefit and not worthy of further trial in patients with disseminated malignant melanoma.

Delayed leukoencephalopathy in survivors with small cell lung cancer.

Six patients with small cell lung cancer developed a slowly progressive neurologic syndrome characterized by apathy, abulia, memory loss, gait ataxia, and corticospinal tract signs 26 to 50 months (mean, 35.2 months) after prophylactic cranial irradiation and systemic chemotherapy. In each case this was accompanied by CT and/or MRI evidence of changes in the periventricular white matter. These patients are long-term survivors (41 to 69 months) and do not have CNS metastases.

Results of combination chemotherapy and thoracic radiation therapy for unresectable non-small cell carcinoma of the lung.

From October 1979 to December 1982, 126 patients with locally advanced unresectable or inoperable Stage II (7 patients), Stage IIIA (81 patients), and Stage IIIB (38 patients) non-small cell carcinoma of the lung were treated in a prospective randomized trial using five cycles of CAP (Cytoxan, Adriamycin, and cisplatin), T-CAP (triazinate plus CAP), or V-CAP (VP-16 plus CAP) chemotherapy with thoracic radiation therapy (TRT). TRT consisted of 40 Gy in 10 fractions (split-course) with cycles 3 and 4 of chemotherapy. The treatment field included the primary tumor, ipsilateral hilum, mediastinum, and ipsilateral supraclavicular fossa. All patients were followed until death or for a minimum of 5 years for survivors. The evaluable subgroup consisted of 102 patients who completed TRT. Median and 5-year survivals for the entire group were 14.0 months and 10%, respectively; for the evaluable subgroup, they were 14.8 months and 12%, respectively. There was a trend toward better survival with V-CAP plus TRT than with CAP plus TRT (p = 0.08). Median and 5-year survivals were 16.2 months and 18%, respectively, with V-CAP plus TRT. Of eight prognostic variables analyzed for their association with survival, only Eastern Cooperative Oncology Group performance status (0,1 versus 2) (p = 0.02) and weight loss (less than or equal to 10% versus greater than 10%) (p = 0.05) were significant. Sex, age, T stage, N stage, overall stage, and histologic type were not significantly associated with survival. Failure analysis revealed 83 patients (81%) with identifiable first failures. The median time to first failure was 9.8 months, and the median survival after first failure was 4.7 months. Failure patterns included local failure alone (19%), local and distant (20%), and distant alone (43%). Nineteen percent of patients had no documented progression. Total failure patterns were local in 39% and distant in 63%. Twenty-three patients (23%) had failure in the brain; they accounted for 31% of all distant failures. In 20 of these patients (20% of all patients), this was the only site of failure. There were eight (8%) initial nodal failures in 96 untreated contralateral supraclavicular fossae. No initial failures were seen in any of 101 untreated contralateral hila. The data suggest the following: (a) Combined treatment with V-CAP and TRT yielded excellent results (median survival, 16.2 months; 5-year survival, 18%).(ABSTRACT TRUNCATED AT 400 WORDS)

Meningeal carcinomatosis in patients with primary breast or lung cancer.

We reviewed the records of 35 patients with meningeal carcinomatosis and primary lung or breast cancer in an effort to identify prognostic factors. No definite associations were found. The prognosis for these patients continues to be poor; the median duration of survival after the diagnosis of meningeal carcinomatosis was 43 days in our study group.

Metastatic bronchioloalveolar carcinoma and metastatic adenocarcinoma of the lung: comparison of clinical manifestations, chemotherapeutic responses, and prognosis.

Between 1975 and 1985, 25 patients with metastatic bronchioloalveolar carcinoma and 223 patients with metastatic adenocarcinoma of the lung received experimental cisplatin-based chemotherapy at the Mayo Clinic. The chemotherapeutic response rates were 32% and 33%, respectively. The median times to progression of disease were identical (3 months in both groups). The median survival times were 4 months and 6 months, respectively. Metastatic bronchioloalveolar carcinoma is an aggressive disease that is associated with a poor prognosis, similar to metastatic adenocarcinoma of the lung.

Carcinosarcoma of the lung: Mayo Clinic experience and response to chemotherapy.

The clinical presentation, clinical course, and results of various treatment modalities of 17 patients with carcinosarcoma of the lung were reviewed. This group of patients was 0.2% of all Mayo Clinic patients with lung cancer who had been treated between 1971 and 1982. Most patients were men in the sixth decade of life who had a history of smoking. Ten of 17 neoplasms were located in the upper lobes. Noninvasive diagnostic tests had a low yield in detecting carcinosarcomas. Pulmonary resection with curative intent was performed in 15 of 17 patients; however, only 4 patients were alive at 6, 8, 28, and 39 months, respectively, postoperatively. The median survival was 1 year. Doxorubicin-based chemotherapeutic programs produced an objective response in two of four patients.

Management of regionally advanced (stage III) non-small cell lung cancer. LCSG 831.

Patients with regionally extensive non-small cell lung cancer (predominantly by virtue of metastases to mediastinal lymph nodes, less commonly by direct extension into the mediastinum) were treated predominantly with chest radiation therapy alone until the early 1980s. At that time, because of the high local recurrence rate, the higher likelihood of distant metastases, and the poor 5-year survival rates, studies were begun in these patients attempting to substitute a different local treatment modality (surgery) or to use both radiation therapy and surgery to decrease local recurrence rates and to add chemotherapy as a systemic therapy to decrease distant metastases. LCSG 831 explored the use of CAP (cyclophosphamide, doxorubicin, cisplatin) chemotherapy plus radiation therapy as preoperative or neoadjuvant therapy. Thirty-nine patients entered this phase 2 trial with 33 undergoing resection. Median survival was 11 months, and 1-year survival was 43%. These results are compared with the results of other similar trials. Explanations for the poor and differing results are suggested as are possible ways to improve study design and results.

Pleural lavage after pulmonary resection for bronchogenic carcinoma.

A cytologic examination of pleural fluid was performed on a pleural lavage specimen collected at the completion of operation after pulmonary resection in 135 of 599 patients undergoing curative pulmonary resection for a non-small cell carcinoma of the lung between 1977 and 1982. The cytologic results of lavage was positive for malignant cells in 12 of the 135 patients (8.9%). The incidence of positive results was correlated with lymph node status (N2 greater than N1 greater than N0), cell type (adenocarcinoma greater than other non-small cell lung cancers), stage (III greater than II greater than I), and visceral pleural status (invaded greater than not invaded). No positive cytologic results were noted in 39 patients having a diagnostic excisional pulmonary biopsy prior to more definitive resection. The disease has recurred in nine of the 12 patients with positive cytologic results (only two in the ipsilateral pleural space), and eight have died. The prognostic role of pleural lavage cytology needs more study.

Modern thirty-day operative mortality for surgical resections in lung cancer.

Modern postoperative mortality rates for resectional operations for lung cancer are not readily available. In recent publications estimating the risk factors for surgical resection, mortality rates of 10% to 15% for pneumonectomy and 5% to 7% for lobectomy are frequently quoted. In order to determine modern operative mortality rates (up to 30 days postoperatively), the Lung Cancer Study Group (LCSG) analyzed the surgical mortality rates of the various participating centers during the years 1979 to 1981. A total of 2,200 resections for lung cancer were available for analysis. Of the 2,220 resections performed, 1,058 were lobectomies, 569 were pneumonectomies, and 143 were lesser resections (segmental or wedge). Eighty-one postoperative deaths occurred from among the 2,220 resections (3.7%). The mortality rate for pneumonectomy was 6.2% and for lobectomy, 2.9%. Lesser resections carried a 1.4% mortality rate, not statistically different from lobectomy. In patients under the age of 60 years, the mortality rate was 1.3%, 60 to 69 years, 4.1%, and over 70 years, 7.1%, all significantly different (p less than 0.01). The postoperative mortality rate for patients 70 years or older was 7.1% (pneumonectomy 5.9% and lobectomy 7.3%). It is obvious that greater care was taken in selection among the older pneumonectomy patients. The striking similarity of postoperative mortality rates for resectional operations for lung cancer among the various centers of the LCSG and among the various institutions within these centers suggest that these data are a reasonably accurate analysis of modern surgical mortality rates in the treatment of lung cancer.

Chemotherapy for malignant mesothelioma; CAMEO.

Twelve patients with a tissue diagnosis of malignant mesothelioma were treated with combination chemotherapy (CAMEO) every 4-5 weeks, with or without hemithoracic radiation. Mean survival from the time of tissue diagnosis an start of protocol treatment was 15.7 and 12.6 months, respectively. Median survival from the time of tissue diagnosis and start of protocol treatment was 11 and 6.5 months, respectively. Two patients were long-term survivors (32 and 45 months), one of whom is alive without evidence of recurrent disease. Toxicity from this regimen was moderate.

Phase II study of the three-drug combination of mitomycin C, CCNU, and methotrexate (MCM) in advanced non-small cell lung cancer.

Ninety-two patients with advanced non-small cell lung cancer, 51 without prior chemotherapy exposure, were treated with the combination of mitomycin C, lomustine (CCNU), and methotrexate (MCM). Overall, the regression rate was 33%, the median regression duration 4.9 months, and the median survival 4.9 months. Patients with ECOG performance scores (PSs) of 0-1 had a statistically significant higher regression rate than did patients with ECOG PSs of 2-3 (43% versus 15%; p = 0.005) as did patients without prior chemotherapy (41% versus 22%; p = 0.05). Cell type and prior chemotherapy exposure did not affect regression duration, time to progression, nor survival. Subjective toxicity was quite acceptable. Cumulative myelosuppression was the most significant objective toxicity. MCM is a relatively effective combination chemotherapy regimen, even in patients with prior chemotherapy exposure (predominantly doxorubicin and cisplatin-based chemotherapy).

Lack of value for cisplatin added to mitomycin-doxorubicin combination chemotherapy for carcinoma of unknown primary site. A randomized trial.

Fifty-five patients with metastatic carcinomas of unknown primary site (50 adenocarcinomas) were randomized, after stratification, to treatment with either mitomycin and doxorubicin (MA) or mitomycin, doxorubicin, and cisplatin (MAP). There was a moderate but nonsignificant improvement in regression frequency (14 vs. 27%) and a slight but also nonsignificant worsening of survival (median 5.5 months vs. median 4.6 months) by the addition of cisplatin at 60 mg/m2 to the MA regimen.

Preliminary communication--treatment of primary brain tumors recurrent after irradiation with aziridinylbenzoquinone (AZQ;NSC-182986).

Twenty-nine patients with primary brain tumors recurrent or progressive after cerebral irradiation were treated with AZQ. Twenty of the 29 patients had also failed prior chemotherapy. CT scan-documented tumor regressions were noted in 17.2% (5/29) and ranged from 15.0% (3/20) in patients with prior chemotherapy to 22.2 (2/9) in patients without prior chemotherapy. Myelosuppression was the only significant toxicity noted. AZQ is worthy of further studies in patients with primary brain tumors.