Martin H. Cohen

CNS metastases in small cell bronchogenic carcinoma. Increasing frequency and changing pattern with lengthening survival

The records of 209 patients with small cell bronchogenic carcinoma were reviewed to define the problem of CNS metastases. CNS metastases were documented in 102 of these patients (49%) and 55 of 85 autopsied patients had CNS metastases (65%). The probability of developing a CNS metastasis increased with lengthening patient survival to a level of 80% after 2 years. As in other series, the cerebrum was the most frequently involved site. In addition, leptomeningeal, spinal, pituitary, and cerebellar metastases, and multiple sites of involvement were far more common than in previously reported series. Patients with bone marrow and liver metastases at initial staging were more likely to develop CNS metastases than those without these metastases. Bone marrow involvement was strongly associated with the development of leptomeningitis. Systemic chemotherapeutic agents which cross the blood brain barrier did not prevent the high frequency of CNS metastases. Pathologic studies suggested cerebral and leptomeningeal metastases may arise via hematogenous spread or via penetrating vessels from bone marrow to the subarachnoid space. Therapy for CNS metastases provided adequate palliation, and the majority of deaths were due to systemic rather than neurologic disease. Nevertheless, prophylactic therapy appears necessary at present to prevent the morbidity associated with these metastases. As further improvements in systemic therapy evolve, CNS prophylaxis may also be required for “cure” of patients with small cell lung cancer.

The clinical behavior of 'mixed' small cell/large cell bronchogenic carcinoma compared to 'pure' small cell subtypes

Biopsy specimens from 19 previously untreated lung cancer patients were prospectively diagnosed as small cell carcinoma with a large cell component. The patients were thoroughly staged and received intensive combination chemotherapy. They represented 12% of all small cell carcinoma cases eligible for aggressive chemotherapy protocols during a 5.5 year period. To determine whether the clinical behavior of this ‘mixed’ histologic variant differed from the other histologic subtypes of small cell lung cancer, we compared these 19 patients to a concurrent group of 103 patients with only small cell cancer in their diagnostic biopsies given equivalent therapy. The ‘mixed’ histology patients were comparable to the ‘pure’ small cell group in age, performance status, extent of disease, and frequency of bone marrow, liver, bone, and central nervous system metastases. Their complete plus partial response rate (58%) was significantly less than the response rate for the ‘pure’ small cell patients (91%), their complete response rate was also lower (16 versus 46%), and their overall survival was significantly shorter (median, 6 versus 10.5 months). Mixed histology small cell/large cell carcinoma represents a distinct pathologic variant of small cell carcinoma of the lung, associated with lower response rates and shorter survival than the ‘pure’ small cell subtypes. Since combination chemotherapy yields some complete responses and long‐term disease‐free survival in these patients, however, aggressive treatment with potentially curative intent should be considered in their management.

Vitamin E in the treatment of chemotherapy-induced mucositis

PURPOSE To determine the efficacy of vitamin E in the treatment of chemotherapy-induced mucositis in patients with malignancy. PATIENTS AND METHODS A randomized, double-blind, placebo-controlled study was performed to evaluate the efficacy of topical vitamin E in the treatment of oral mucositis in patients receiving chemotherapy for various types of malignancy. A total of 18 patients, 17 of whom had solid tumors and one with acute leukemia, were included in this study. Lesions were observed daily prior to and 5 days after topical application of either vitamin E or placebo oil. RESULTS Six of nine patients receiving vitamin E had complete resolution of their oral lesions. In eight of nine patients who received placebo, complete resolution of their oral lesions was not observed. This difference is statistically significant (p = 0.025 by Fishers exact test). No toxicity was observed in this study. CONCLUSION These results suggest that vitamin E may be an effective therapy in patients with chemotherapy-induced mucositis.

Thymosin immunotherapy in patients with small cell carcinoma of the lung: correlation of in vitro studies with clinical course.

Previous studies suggest that the mechanism of action of thymosin is reconstitution of immune defects rather than augmentation of relatively normal levels of cellular immunity. To test this hypothesis, we correlated in vitro assays with clinical course in 55 patients with bronchogenic carcinoma who were randomized to receive subcutaneous inoculations of thymosin 60 mg/m2 (T60), thymosin 20 mg/m2 (T20), or no thymosin (P) twice weekly during the first six weeks of an intensive chemotherapy program. Overall tumor response did not differ significantly among the three treatment groups (p >.12); however, survival of the T60 group was significantly greater than that of the P group (p =.017). Duration of response for patients achieving a complete remission was significantly longer in the T60 group than in the P group (p =.02). In an attempt to define an association between the increased survival of the T60 group and in vitro assays that show changes with tumor presence and extent, comparisons were made between survival and pretreatment peripheral blood levels of carcinoembryonic antigen (CEA), α2HS‐glycoprotein (α2HS), and total thymus‐dependent lymphocytes (T cells). Independent of therapy, pretreatment CEA levels correlated directly with tumor extent (p=.004) and inversely with degree of tumor response (p=.006) and survival (p=.006). The effect of T60 compared with the P group on survival was similar in patients with pretreatment CEA levels >4 Ng/ml and those with levels >4 Ng/ml. However, among those with pretreatment total T‐cell and α2HS levels below the median for all patients, survival of the T60 group was significantly greater than that of the P group (p=.006 and p=.036, respectively); for patients with higher pretreatment total T‐cell and α2HS levels, survival did not differ significantly between the T60 and P groups (p=.28 and p=.17, respectively). Analysis by tests of interaction shows that the effect of T60 on survival depended on pretreatment levels of α2HS (p=.046) and, to some extent, total T‐cells (p=.17). Thus the association between survival and type of treatment may be related to pretreatment levels of these two parameters of cellular immunity. These results support the hypothesis that patients with relatively low levels of immunity benefit most from administration of thymosin. Additional studies with larger patient populations and other tumors are needed to confirm these findings. Cancer 43:863–870, 1979.

Non-small-cell lung cancer. Major cause of late mortality in patients with small cell lung cancer☆

Among 360 patients with small cell lung cancer treated in National Cancer Institute therapeutic trials from 1973 to 1982, 40 were two-year cancer-free survivors. Of these 40 patients, six had later development of non-small-cell lung cancer at 3.5 to 8.0 years (median 5.1) after the diagnosis of small cell lung cancer. Three had the second malignant tumor in the contralateral lung, one in a different lobe, and two in the same lobe as the initial small cell lung cancer. Ten patients had relapses of small cell lung cancer at 2.1 to 6.2 years (median 3.2) from diagnosis. Three recurrences were in the same site or lobe as the initial lesion, four in the same lobe and in sites outside the thorax, and three solely in sites outside the thorax. It is concluded that these non-small-cell lung cancers usually represent second primary lung tumors and that most late small cell lung cancers represent relapses occurring up to 6.2 years from diagnosis. In this study, the risk of development of non-small-cell lung cancer after two years of disease-free survival following small cell lung cancer is 4.4 percent per person-year, approximately 10 times higher than the rate of 0.5 percent previously determined in screening studies of men at high risk for lung cancer. Non-small-cell lung cancer represents more than a third of lung cancer deaths in patients with small cell lung cancer surviving beyond two years from diagnosis and more than half of lung cancer deaths beyond three years. It is recommended that all patients treated for small cell lung cancer discontinue smoking.

Calcitonin as a marker for bronchogenic cancer. A prospective study

A prospective study was done of serum calcitonin (HCT) levels in 61 patients with bronchogenic cancer. Initially, 52% of patients had hypercalcitonemia. Hypercalcitonemia was not confined to patients with any particular histologic type. Seventy‐eight percent of those with high calcitonin remained normocalcemic. There was no correlation between high calcitonin levels and osseous metastases. Selective thyroid venous sampling delineated two types of hypercalcitonemia: thyroidal and ectopic. To date, the ectopic type has been associated with the small cell bronchogenic carcinoma. High initial calcitonin levels decreased significantly in 75% of patients on antitumor therapy. In 13 evaluable patients calcitonin levels mirrored clinical status changes 67% of the time. Calcitonin may be a useful marker to assess the results of therapy in patients with bronchogenic cancer. Cancer 44:680‐684, 1979.

Effect of oral prophylactic broad spectrum nonabsorbable antibiotics on the gastrointestinal absorption of nutrients and methotrexate in small cell bronchogenic carcinoma patients

Patients with small cell bronchogenic carcinoma, in a study utilizing laminar‐air‐flow‐protected environments, oral prophylactic broad spectrum non‐absorbable antibiotics (PNAA), and intensive combination chemotherapy, were examined to determine the effects of PNAA on serum biochemical values and on gastrointestinal absorption of both nutrients and methotrexate. With use of PNAA the following abnormalities were observed; serum carotene and folate decreased, D‐xylose absorption was impaired, fat globules and muscle fibers were demonstrable in the stool, and the mean weight loss in 6 weeks was 10.2% as compared with 4.3% in patients not treated with antibiotics. Methotrexate absorption decreased from a mean of 69% prior to antibiotic use to 44% on PNAA. Thus, PNAA causes malabsorption of both nutrients and drugs. It appears unwise to treat patients on PNAA with oral antineoplastic drugs. Nutritional status must also be closely monitored and supplemental nutrition, either intravenously or with elemental diets, must be considered.

Elevated alpha1-Antitrypsin serum levels in lung cancer patients.

A deficiency of serum alpha1‐antitrypsin has been associated with a predisposition to obstructive pulmonary disease. To determine if a similar association exists with lung cancer, serum alpha1‐antitrypsin levels were measured in 73 patients with nonresectable lung cancer. Elevated alpha1‐antitrypsin levels were found. Patients with primary cancer at other sites also had elevated levels. Thus, malignancy is one of several exogenous and endogenous factors that increase serum alpha1‐antitrypsin. Prospective studies to determine the serum levels of alpha1‐antitrypsin in patients with precanerous lesions of the respiratory tract are in progress, as are studies to determine if levels of alpha1‐antitrypsin change with successful treatment of the malignancy.

Clinical pharmacology of isophosphamide

The alkylating activity in the urine was measured in patients receiving a new antineoplastic cyclophosphomide analog, isophosphamide (IP), at doses of 2,900 to 5,000 mg per square meter body surface area (BSA) and compared with that of patients receiving 1,100 mg per square meter of cyclophosphamide (CP). Total excretion of alkylating activity after CP (1,l00 mg per square meter) lay between values for the 3,800 mg per square meter dose and the 5,000 mg per square meter dose of IP. The concentration of urinary alkylating activity was higher in patients who developed cystitis than in those who did not. Alkylating activity in the urine was unaltered by acetylcysteine bladder washout. Plasma alkylating activity was more persistent after 5,000 mg per square meter IP than after 1,100 mg per square meter CPo After [HC] IP 5,000 mg per square meter, the plasma half‐life was 13.79 hours, and the urinary recovery of radioactivity was 81.6%, of which 61.6% was unchanged drug. These values differ markedly from those published for CPo IP penetrated the blood‐brain barrier, but its metabolites did not. The greater propensity of IP than of CP to cause cystitis at apprOXimately equitoxic doses may be related to larger amounts of alkylating activity in urine of patients receiving IP. The greater dose of IP than of CP required to produce the same alkylating activity in urine correlates well with the differences in Km of the two drugs in an isolated microsomal enzyme system in vitro previously reported.

MACC chemotherapy for adenocarcinoma and epidermoid carcinoma of the lung. Low response rate in a cooperative group study

The MACC (methotrexate, adriamycin, cyclophosphamide, CCNU) regimen was administered to 43 patients with advanced epidermoid and adenocarcinoma of the lung. Only 5 patients (12%), all of whom were ambulatory, responded with partial remissions. Median time to progression for the 5 responders was 20 weeks from start of treatment. Median survival was 15.5 weeks for patients with epidermoid cancer and 14.4 weeks for those with adenocarcinoma. Hematologic toxicity was severe, with 2 treatment‐related deaths during profound myelosuppression. White blood counts below 2000/μl were reported in 47%, and below 1,000/μl in 26%. Since the activity of this regimen, given as it was in full doses, is not superior to that achieved with standard doses of single agents which are less toxic, further employment of the MACC regimen is not recommended, either for advanced disease or as a surgical adjuvant.