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.

Thymoma.

Thymomas and thymic carcinomas are thymic epithelial tumors that constitute approximately 15% of all mediastinal masses. From 28 to 66% of thymomas cause chest symptoms as the initial manifestation; the rest are discovered on routine chest roentgenograms or during investigations prompted by the presence of a paraneoplastic syndrome. Forty percent of patients with thymoma have one or more paraneoplastic syndromes, including myasthenia gravis, pure red cell aplasia, and hypogammaglobulinemia. Extrathymic malignant lesions develop in up to 20% of patients. Traditional histologic classifications have not accurately predicted tumor behavior; a recently developed classification based on cellular differentiation toward thymic medullary or cortical epithelium may correlate better with prognosis. Nevertheless, the prognosis is best predicted by stage of the tumor determined intraoperatively and is poorer in patients with incomplete resection than in those with complete resection of the thymoma. In addition to surgical intervention, irradiation and chemotherapy have important roles in the management of thymomas, particularly in advanced stages. In this article, the clinical manifestations, diagnosis, pathologic features, staging, and treatment of thymomas are reviewed, and the prognosis of affected patients is discussed.

Wegener's granulomatosis. Anatomic correlates, a proposed classification.

Based on a 10-year experience with 50 patients who had Wegener's granulomatosis, a new classification is proposed based on anatomic site of involvement: upper airway or ear, nose, and throat (designated E), lung (L), and kidney (K). All combinations of ELK were seen. The system is offered as a unifying concept to embrace the terms midline granuloma, generalized or classic Wegener's granulomatosis, and limited Wegener's granulomatosis. Fourteen patients have died despite the use of corticosteroids and immunosuppressant therapy. Thirteen patients with renal involvement have survived for periods as long as 114 months; all were taking immunosuppressive agents.

Roentgenologic features of pulmonary blastomycosis.

In 35 cases of pulmonary blastomycosis, the roentgenologic features were as follows: consolidation 26%, mass 31%, intermediate-sized nodules 6%, miliary pattern 11%, solitary cavity 9%, fibrotic and cavitary changes 6%, interstitial pattern 6%, diffuse alveolar involvement 3%, and mixed alveolar and interstitial infiltrate 3%. All symptomatic cases of consolidation were acute (symptoms for less than 1 month), and most were in young patients (mean age, 34 years). Consolidation constituted 58% of the acute cases in this series. Two of the nine cases of consolidation were asymptomatic epidemic cases detected by screening. A pulmonary mass was the most common initial manifestation in this series; it tended to occur in patients with chronic symptoms (more than 1 month). The mass was considered suggestive enough of bronchogenic carcinoma to necessitate resection in 55% of cases. The military form of pulmonary blastomycosis occurred in older patients with disseminated disease. Fibrotic and cavitary disease was chronic in nature. The presence of intermediate-sized nodules elsewhere in the lung proved to be a helpful diagnostic finding in several patients with consolidation, mass, or cavitary disease. Hilar adenopathy, postinfectious calcification, chest wall invasion, and pleural effusion occurred infrequently or not at all in this series.

Gossypibomas mimicking echinococcal cyst disease of the lung.

Gossypibomas, masses of retained cotton materials, may produce a variety of postoperative complications. This case report of hemoptysis of 18 months' duration and cavitating chest masses in a 62-year-old man with previous cardiac operations illustrates several salient features about the presentation, differential diagnosis, and management of gossypibomas.

Colchicine in the treatment of pulmonary fibrosis.

There is no standard or known optimal treatment for idiopathic pulmonary fibrosis. Corticosteroids have been used with widely variable benefit. Colchicine has been reported to suppress fibroblast growth factors and to inhibit collagen deposition. A potential role has been proposed for colchicine in the treatment of fibrotic pulmonary diseases. We retrospectively assessed the outcome of 23 patients with idiopathic pulmonary fibrosis in whom colchicine was used as empiric treatment. Eighteen patients had received prior corticosteroid therapy. By clinical and pulmonary function criteria, five patients (22 percent) improved following colchicine, nine (39 percent) remained stable, and nine (39 percent) worsened. The average duration of follow-up was 22 months. Despite limitations of this retrospective analysis, colchicine may be of benefit in pulmonary fibrosis and should be considered for further clinical trials.

Life-threatening bleomycin pulmonary toxicity with ultimate reversibility.

A 60-year-old man with advanced seminoma was treated with four cycles of a cisplatin, etoposide and bleomycin. He then developed severe pulmonary toxicity with diffuse infiltrates as evidenced on a chest x-ray film. The room air PaO2 value was 32 mm Hg. The patient was treated with steroids and oxygen supplementation, including a high FIo2 for several days, and survived and eventually experienced marked improvement in his pulmonary status. Aggressive management of severe bleomycin-induced pneumonitis appears justified.

Differing response rates and survival between squamous and non-squamous non-small cell lung cancer. Comparison of CAP versus MAP.

One hundred and thirty patients with advanced non-small cell lung cancer were treated in a randomized study with either CAP (cyclophosphamide, doxorubicin, and cisplatin) or MAP (mitomycin C, doxorubicin, and cisplatin). Among all patients, regardless of cell type, the regression rate was slightly higher for MAP (46%) than CAP (34%) but no differences were detected in time to progression and overall survival. However, differences were apparent by treatment when patients were divided into two groups: squamous cell (SQC) and non-squamous cell (non-SQC). MAP, compared to CAP, was associated with a significantly superior regression rate (60% vs. 33%), time to progression, and overall survival in SQC. On the other hand, CAP, compared to MAP, was associated with a significantly longer overall survival in non-SQC. This apparent difference among subtypes of non-small cell lung cancer in response to chemotherapy regimens differing only in one drug, if confirmed, will need to be kept in mind in designing future studies.

Cyclophosphamide, etoposide, and infusion cisplatin in refractory small cell lung cancer. A preliminary report.

Twelve patients (three with limited and nine with extensive disease) with small cell carcinoma of the lung who had plateaued or progressed on their chemotherapeutic regimens were switched to a program of combination chemotherapy consisting of cyclophosphamide, etoposide, and a 5-day continuous infusion of cisplatin. Nine of the 12 patients (75%) showed further tumor reduction, including four patients who achieved a clinical complete response. Also noted was a patient who previously failed on a regimen of short infusion cisplatin who responded to the continuous infusion platinum regimen. Toxicity was quite acceptable, considering the amount of prior treatment given these patients. Further studies seem warranted to confirm these encouraging preliminary results.

Leukoencephalopathy in small cell lung cancer patients receiving prophylactic cranial irradiation.

The cases of 283 small cell lung cancer patients who received treatment with combination chemotherapy with or without prophylactic cranial irradiation (PCI) were reviewed to determine the incidence of leukoencephalopathy. The overall incidence was 10%. Of all patients receiving PCI, 17% developed neurotoxicity, and of those receiving PCI and surviving greater than or equal to 1.5 years, 37% suffered neurologic sequelae. In those receiving PCI but surviving less than 1.5 years, the incidence of neurotoxicity was 4%. The mean time interval between the end of PCI and the onset of neurotoxicity was 17 months (range 2-63 months). The PCI dose ranged from 2600-3600 cGy. None of the patients not receiving PCI developed neurotoxicity. The incidence of neurotoxicity in long-term survivors (greater than or equal to 1.5 years) with respect to PCI dose was less than or equal to 3000 cGy (25%), 3200 cGy (56%), 3600 cGy (36%). Almost all of the patients getting PCI also received lomustine, an agent associated with DNA repair inhibition and synergism with DNA damaging agents such as ionizing radiation or alkylating agents. Under the conditions of our study, PCI was associated with an unacceptable risk of neurotoxicity. Until further information is forthcoming, one should proceed with caution when using PCI in conjunction with lomustine.

Pleural effusion. A diagnostic dilemma.

The cause of pleural effusion in 108 of 133 patients was determined by laboratory tests and clinical examination; it was indeterminate in 25, even after complete diagnostic evaluation. In 164 diagnostic thoracenteses, 136 cytologic examinations were done; the results were positive for cancer in 20 (15%). Five of 19 patients (26%) with bronchogenic cancer, 13 of 25 (52%) with metastatic cancer of the lung, and two of 20 (10%) with lymphoma had positive results on cytologic examination. Of 143 routine bacterial cultures, only five were positive (3%). Of 103 mycobacterial and 76 fungal cultures, only one was positive in each instance. Despite the high incidence of indeterminate diagnoses, we recommend that only measurement of protein content and cytologic examination be ordered routinely. Our algorithm provides a logical, cost-effective approach to the diagnostic problem of pleural effusion.

Evaluation of cyclophosphamide (NSC-26271) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU; NSC-409962) in the treatment of patients with inoperable or disseminated lung cancer.

Forty-eight patients with nonlocalized bronchogenic carcinoma were randomly selected and treated with either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or cyclophosphamide (or both). Five of the 48 patients (three who had received BCNU and two who had received cyclophosphamide) responded to initial treatment. Crossover treatment with the alternate drug after unsuccessful treatment with the initial drug resulted in no additional responses. Toxic effects included gastrointestinal upset and myelosuppression and, in general, were acceptable. There was one death after a course of BCNU that was attributable to the myelosuppressive effects of this agent. The medain survival time of the patients who died after treatment was 18 weeks, and the mean survival time was 15 weeks. Survival times were virtually the same for both treatment groups.

Continuous five-drug versus alternating three-drug and two-drug chemotherapy after five-drug or three-drug induction in extensive small cell lung cancer.

Fifty-six patients with extensive small cell lung cancer were treated with vincristine, doxorubicin, cisplatin, etoposide, and cyclophosphamide in a prospective randomized trial using all five drugs together or as three-drug (cisplatin, etoposide, cyclophosphamide) and two-drug (doxorubicin, vincristine) combinations given sequentially, then alternatively. The five-drug combination was associated with a higher overall regression rate (p = 0.03), higher complete regression rate (p = 0.09), prolonged time to first progression (p = 0.03), more nervous system initial failures (p = 0.07), more anemia requiring transfusion (p = 0.04), but no prolongation of overall survival (median 332 days for five-drug, median 303 days for three-drug and two-drug). Until more and better chemotherapeutic agents become available, little or no advantage is likely to be gained for patients with small cell lung cancer given sequential, or alternating chemotherapy.

An evaluation of low-dose cisplatin as part of combined modality therapy of limited small cell lung cancer.

Sixty-two patients with previously untreated limited stage small cell lung cancer were treated in a prospectively randomized trial comparing thoracic irradiation plus combination chemotherapy with VP-16-213, vincristine (Oncovin), cyclophosphamide, and Adriamycin (VOCA) or those same four drugs plus low-dose (40 mg/m2) cisplatin (VOCAP). The addition of the cisplatin in eight courses of planned chemotherapy did not significantly improve either time to tumor progression of survival or alter sites of disease progression. It did, however, worsen the degree and frequency of nausea, vomiting, and myelosuppression. We did not identify any benefit from the usage of low-dose cisplatin as employed in this study.

Treatment toxicities in long-term survivors of limited small cell lung cancer.

A total of 211 patients with limited small cell lung cancer were assessed retrospectively for long-term toxicities, treatment-related deaths, and second primaries. All had received treatment with various combinations of doxorubicin, vincristine, cisplatin, lomustine, cyclophosphamide, and etoposide with or without split-course thoracic radiotherapy (4,000 cGy/10 fractions) and/or split-course prophylactic cranial irradiation (3,600 cGy/10 fractions). Sixty-eight (32%) of the patients survived longer than 1.5 years and formed the basis of this study. Debilitating pulmonary, cardiac, and neurologic toxicity was noted in 12%, 14%, and 15%, respectively, of long-term survivors. These complications were the result of aggressive combined modality therapy. Certain drugs appeared to cause additive toxicity when combined with radiation. Three patients developed new primary tumors of squamous cell origin. Attention must be directed to defining the safest way to employ aggressive combined modality treatment for these patients.