Daniel C. Ihde

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.

Possible enhancement of vincristine neuropathy by VP-16

Eleven consecutive patients with small cell carcinoma of the lung treated intensively with a combination chemotherapy regimen cyclophosphamide, Adriamycin, VP‐16, and vincristine experienced peripheral neuropathy. Four of the 11 patients had severe (Grade III) neuropathy, leaving them virtually bedridden; the remaining seven patients had mild to moderate neuropathy. Only 8 of the 14 patients treated less intensively with vincristine and VP‐16 had Grade I and II neuropathy. Predisposing factors for severe neuropathy included advanced age and preexisting peripheral neuropathy. All patients performance status declined and all lost much weight before developing neuropathy. From accumulated treatment experience of small cell carcinoma with vincristine alone or with vincristine, Adriamycin, cyclophosphamide combinations, the authors feel that the severe neuropathy observed was due to an interaction of vincristine and VP‐16. This conclusion is supported by electron microscopic observation of electron‐opaque granular degeneration of the myelin lamellae of affected nerve fibers.

Hepatic involvement in the cutaneous T-cell lymphomas. Results of percutaneous biopsy and peritoneoscopy

Forty‐three patients with cutaneous T‐cell lymphomas (mycosis fungoides and the Sezary syndrome) underwent routine staging procedures to assess extent of disease prior to therapy. Evaluation of the liver included physical examination, liver function tests, 99mTc‐liver‐spleen scans, percutaneous liver biopsy, and peritoneoscopy with multiple liver biopsies. Seven patients (16%) had biopsy‐documented hepatic lymphoma, histologically defined as focal aggregates of atypical convoluted lymphocytes in portal zones or hepatic lobules. The liver was the most frequently involved visceral site. Involvement of peripheral blood, leukocytosis, and generalized erythroderma were significantly associated with hepatic lymphoma. Biopsy examination was the only accurate method of detecting hepatic involvement, and peritoneoscopy with multiple biopsies appeared to be more sensitive than a single percutaneous biopsy, since the yield of positive biopsies increased from three to seven. In order to better understand the natural history of the cutaneous T‐cell lymphomas and the relation of hepatic involvement to survival, histologic evaluation of the liver in patients with the cutaneous lymphomas should be carried out prior to therapy.

Effective treatment of hormonally-unresponsive metastatic carcinoma of the prostate with adriamycin and cyclophosphamide: methods of documenting tumor response and progression.

Combination chemotherapy with Adriamycin and cyclophosphamide was administered to 22 men with progressive tumor following hormonal treatment for metastatic carcinoma of the prostate. Objective partial response was documented in 7 patients (32%); an additional four (18%) had stable disease for a minimum of four months, and 11 (50%) were non‐responders. Patients with partial response had a median survival of 14 months and lived significantly longer than those with no response (median five months); survival of men with stable disease approximated that of partial responders. Serial utilization of mutiple staging procedures during chemotherapy demonstrated that although no single test allowed identification of all patients with objective tumor response or progression, improvement in a median of five parameters could be documented in responding patients. In patients adequately studied at the time of disease progression, deterioration in a median of six tests was found. Serum acid phosphatase, radionuclide bone scan, and plasma carcinoembryonic antigen were the most sensitive procedures which detected both objective tumor response and progression. Toxicity of chemotherapy was acceptable except in patients with prior radiation therapy. Administration of Adriamycin and cyclophosphamide was associated with clinical benefit in half of our patients with hormone‐resistant prostatic cancer. Tumor response and progression can best be objectively assessed if several staging procedures are serially employed during treatment.

Cardiac candidiasis in cancer patients

Histologically proven infection of the heart by Candida organisms occurred in 17 (10%) of 168 cancer patients with candidiasis studied at necropsy. All 17 patients were among the 85 patients with disseminated Candida infection; none of the 83 patients with localized candidiasis had involvement of the heart. Abscesses in the myocardium were present by histologic examination in all 17 patients and in 8 were evident on gross inspection as well. The mural endocardium was also affected in 5 patients from direct extension of a myocardial abscess. The valves were uninvolved. Pericardial infection was detected in 2 patients. The 17 patients with cardiac Candida infection had a higher frequency of positive premortem blood and cerebrospinal fluid cultures and of presence of Candida in the hearts blood than did the 68 patients with disseminated candidiasis but without involvement of the heart. Symptoms or signs of cardiac dysfunction resulting from the cardiac Candida infection were not readily detected in any patient. The clinical and pathologic features of cardiac candidiasis in cancer patients are distinct from those observed in Candida endocarditis.

Growth of lung cancer colonies from bronchoscopy washings

Cells from bronchoscopy washings from 30 patients with lung cancer were plated in tissue culture using a human tumor stem cell assay technique. These culture results were subsequently compared to routine ctyology readings carried out on the same specimens. The stem cell culture showed colony growth from 9 of 11 cytologically positive bronchoscopy washing specimens. More colonies grew from cytologically positive specimens (average of six colonies per plate) than from cytologically negative specimens (average of 0.8 colonies per plate). With additional refinements, the stem cell culture system could be used to improve the diagnostic yield of bronchoscopy washings. However, at present, the low number of tumor colonies grown from the washings precludes performing chemosensitivity studies on tumor cells from the bronchoscopy washing specimens.

Abdominal computed tomography in small cell lung cancer: assessment of extent of disease and response to therapy.

Abdominal computed tomography (CT) was performed as part of the initial staging evaluation in 77 patients with small cell carcinoma (SCC) of the lung. CT scans revealed mass lesions in 26 patients (34%). Abnormalities were confined to the liver in 15 patients and to retroperitoneal structures (lymph nodes, adrenal glands, psoas muscle region masses) in eight, and occurred in both areas in three. However, only three of 29 patients otherwise staged as having limited disease (confined to one hemithorax and regional nodes) had evidence of abdominal metastases on CT scan. Most (23/26) positive studies were in patients already known to have more extensive tumor dissemination. In 71 patients with pathologic confirmation of liver status, CT had a sensitivity of 63%, specificity of 91%, and overall accuracy of 85% in assessing the liver. Comparison of radionuclide liver scan findings with hepatic biopsies gave similar results. During therapy, 65 follow‐up CT scans were obtained in 46 patients. Scan abnormalities improved or disappeared in 11/12 cases with tumor response documented in other ways, appeared or worsened in 5/13 cases of tumor progression that was diagnosed by other tests, and only rarely (2/65 scans) improved at the time of documented tumor progression, or vice versa. In only three patients, however, did CT scan provide the sole site of evaluable disease during treatment or detect either the only area of residual disease in a patient in otherwise complete remission or the initial evidence of tumor progression. Although abdominal CT scans in SCC can demonstrate metastatic dissemination not evaluable by other means, they provide relatively little therapeutically relevant information beyond that obtained with standard staging procedures.

Evaluation of response to chemotherapy with fiberoptic bronchoscopy in non-small cell lung cancer

Fiberoptic bronchoscopy was performed before and during administration of chemotherapy in 32 patients with unresectable non‐small cell carcinoma of the lung. Pretreatment findings varied with the histologic cell type. Direct visual and/or pathologic evidence of cancer was obtained in 11 of 11 patients with epidermoid, in 5 of 7 with large cell, and in 9 of 14 with adenocarcinoma. In 5 of the 32 patients, intrathoracic tumor was documented at bronchoscopy but not by chest x‐ray. During chemotherapy, one of five episodes of response and eight of 21 episodes of chest tumor progression were detected solely by bronchoscopy, while in an additional two objective responses and six progressions, bronchoscopic and radiographic findings simultaneously improved or deteriorated. The likelihood of documenting disease progression by bronchoscopy also depended upon the histologic type of cancer. Enlarging chest tumor found solely by chest x‐ray occurred exclusively in patients with large cell carcinoma and adenocarcinoma. During chemotherapeutic treatment of our patients, addition of serial bronchoscopic examinations to standard means of assessing tumor response frequently allowed the earlier discontinuation of an ineffective drug regimen.

High-dose methotrexate with leucovorin rescue in patients with unresectable non-small cell carcinoma of the lung.

Thirty‐one patients with unresectable non‐small cell carcinoma of the lung (19 adenocarcinoma, 7 large cell carcinoma, 4 squamous cell carcinoma, 1 mixed histology) were treated with one of two intravenous infusion schedules of high dose methotrexate with leucovorin rescue. First, 14 patients received methotrexate in escalating doses from 1.5 to 12 g/m2 over 6 hours followed immediately with leucovorin 15 mg/m2 for 12 doses every 6 hours; there were no complete or partial responses among these 14 patients. Then, 17 patients were treated with a loading bolus of 50 mg/m2 intravenous methotrexate followed by a 30‐hour continuous infusion of 1.5 g/m2. Leucovorin 15 mg/m2 every 6 hours for 12 doses was begun at the end of the infusion. There were 3 partial responses among the 17 patients in this group. The results demonstrate that both 6‐ and 30‐hour infusions of high‐dose methotrexate regimens can be given safely to middle aged adult patients, but the overall 10% response rate does not appear to be significantly different than the results with standard‐dose methotrexate.