Phase-I trial of Thiotepa, granulocyte-macrophage colony-stimulating factor and prednisone or pentoxifylline in patients with refractory solid tumors.

In a phase I trial, 13 patients with refractory solid tumors received thiotepa, granulocyte-macrophage colony-stimulating factor (GM-CSF), and either prednisone or pentoxifylline (PTX) on alternate cycles. The prednisone and PTX were administered in an attempt to ameliorate toxicity related to GM-CSF. Of the first six patients treated at a thiotepa dose of 60 mg/m(2), five experienced grade 3 or 4 thrombocytopenia and four grade 2 or greater leukopenia. One of these patients died secondary to E. coli sepsis. Seven patients received a thiotepa dose of 50 mg/m(2), with one experiencing grade 3 thrombocytopenia and another grade 3 leukopenia. The latter patient died secondary to presumed sepsis. The five remaining patients at the 50 mg/m(2) dose did not experience greater than grade 1 hematologic toxicity. Serum tumor necrosis factor levels were not increased by GM-CSF. Patients in this trial were not evaluable for amelioration of GM-CSF toxicity as too few received a second cycle of treatment. We conclude that thiotepa doses greater than 50 mg/m(2) are not tolerated due to severe thrombocytopenia which is not diminished by the administration of GM-CSF.

Sex-associated differences in presentation and survival in patients with lung cancer.

A retrospective study of 478 men and 294 women with primary lung cancer was conducted to characterize sex-associated differences in their presentation and survival. At the time of diagnosis, women were younger than men (mean age, 57.4 +/- 10.4 v 60.2 +/- 9.9 years, respective; P = .0007). Men were more likely to be current or previous smokers (94% v 84%; P less than .005), and in patients with a positive smoking history, cigarette consumption was greater in men (52.2 v 40.2 pack years; P = .0001). The proportion of adenocarcinomas compared with squamous cancers was high in women (45% v 23%), while these cell types were equally represented in men. The majority of patients in both sex groups had regionally advanced or metastatic disease at diagnosis. Survival was related to age, stage at presentation and cell type. In addition, sex was found to be an independent prognostic factor for survival. Women with tumors of all cell types lived longer than their male counterparts (P less than .0001), and survival by stage in patients with nonsmall-cell cancers was greater for women than it was for men. These data demonstrate that important sex-associated differences exist in presentation and survival from lung cancer. Such differences should be considered when planning and analyzing clinical trials.

Adenosquamous lung carcinoma: clinical characteristics, treatment, and prognosis.

Adenosquamous carcinoma of the lung is a rare and poorly described entity. At the University of Chicago between 1974 and 1985, 2.3% (20/873) of patients with lung cancer had well-differentiated adenosquamous carcinoma. As in non-small cell lung cancer, patients with Stage I disease were amenable to operation with 60% (3/5) free from disease between one and six years postoperatively. However, Stage II adenosquamous carcinoma (14 patients) exhibited highly aggressive behavior with rapid progression of disease (mean interval, 2.1 months). Despite combinations of surgery (6 patients), chemotherapy (6 patients, one response), and radiotherapy (10 patients, no response), median survival for patients with Stage III adenosquamous carcinoma was 5.0 months, worse than that for Stage III small cell cancer (9.6 months), adenocarcinoma (9.0 months), and squamous cancer (7.8 months).

Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small-cell carcinoma of the lung.

Combination chemotherapy is frequently used in the therapy of advanced non-small-cell lung cancer (NSCLC), but late complications are rarely recognized because of the short survival of most patients. Of 119 patients with advanced NSCLC treated with cisplatin and other drugs, four patients developed acute nonlymphocytic leukemia (ANLL). All four patients received etoposide and cisplatin with or without vindesine. Leukemia was diagnosed at 13, 19, 28, and 35 months after start of treatment. Three patients had morphologic and/or cytogenetic features of acute leukemia with significant monoblastic involvement; the fourth patient had trilineage dysplasia and cytogenetic abnormalities more commonly associated with therapy-related leukemia. Detailed analysis of the subgroup who survived longer than 1 year (24 patients) suggests that high cumulative doses of etoposide are leukemogenic; the median etoposide dose was 6,795 mg/m2 (first year only) in the four leukemic patients compared with 3,025 mg/m2 in the 20 nonleukemic patients (P less than .01). The rate of ANLL was 0.30 per person-year after the first year (95% confidence limits 0.11 to 0.90), with a cumulative risk of 15% +/- 11% at 2 years, and 44% +/- 24% at 2.5 years. We conclude that high doses of etoposide are potentially leukemogenic, and can induce a syndrome with features of acute monoblastic leukemia de novo that is distinct from other secondary leukemias.

Modified stage I (T1N0M0, T2N0M0), nonsmall cell lung cancer: treatment results, recurrence patterns, and adjuvant immunotherapy.

We analyzed 96 patients who had surgery with T1N0M0 or T2N0M0 nonsmall cell lung cancer (NSCLC) to identify survival rates and recurrence patterns in well-staged patients and to evaluate adjuvant therapy. Preoperative staging included chest x-ray, gallium 67 scanning, and bronchoscopy in all patients. At thoracotomy, multiple mediastinal lymph node sites were routinely sampled. The results included an operative mortality rate of 5.2%, and the actuarial 5-year survival rate of all patients was 70.0%. Survival of T1N0 (n = 44) and T2N0 (n = 47) patients was 72.1% and 68.3%, respectively (p = NS). Survival was not affected by type of surgery, cell type, sex, age, or race. Late death was due to recurrence in 12 patients, a new airway malignancy in three, and a noncancer problem in six. Disease recurred in 15 patients: four (9.1%) T1N0 patients versus 11 (23.4%) T2N0 patients, p less than 0.05. Recurrence was local in four patients and distant in 11. Second lung cancers developed in six patients at a mean interval of 65.7 months after resection. A prospective, randomized trial of systemic immunotherapy with bacillus Calmette-Guerin (BCG) skin scarification was carried out in 29 patients. Survival in those patients receiving BCG was 85.9% compared with 63.9% for control subjects (p = 0.075) and 69.6% for patients not in the study (p = 0.077). The following conclusions can be made: Resection for well-staged, modified stage I NSCLC results in a 5-year survival rate of 70%. Nearly half the deaths are unrelated to recurrence of the original cancer. Recurrences are more frequent in T2N0 patients, but there is no survival difference compared with T1N0 patients. Systemic recurrences are more frequent than local recurrences, and there is an appreciable incidence of second lung cancers. Adjuvant chemotherapy or radiation therapy does not seem justified, but systemic immunotherapy holds sufficient promise to warrant further investigation.

Pleural involvement in stage IIIM0 non-small-cell bronchogenic carcinoma. A need to differentiate subtypes.

Forty-one patients with two subtypes of stage IIIM0 non-small-cell lung cancer treated over a 7-year period were evaluated. The first group of 20 patients had ipsilateral parietal pleural involvement not contiguous with the primary tumor but no distant metastases. Fifteen had positive pleural fluid cytology, seven with positive pleural biopsy in addition; four had extensive pleural studding or a positive biopsy but no effusion; and one had negative pleural fluid cytology. Treatment consisted of radiation therapy followed by combination chemotherapy in all. Due to symptoms, eight patients first had fluid drainage with or without sclerosis and two patients had a pleurectomy. Nine had progressive pleural disease despite the local treatment. To all modalities of therapy, only two patients had a partial response. One patient who had a pleurectomy lived 25 months. Median survival was 6.9 months. Cause of failure involved local progression in 17 patients. There was no difference in median survival by age, sex, histology, side of effusion, location of nodal disease, or use of local therapy. The second group of 21 patients had localized involvement of the parietal pleura by the primary tumor. There was deeper chest wall invasion in nine. All patients were rendered free of known disease by surgical resection, were stage T3N0-2M0, and received radiation and chemotherapy in addition to resection. The median survival was 13.5 months. There was local recurrence in nine patients but only one developed an effusion. Five patients were alive at 29-82 months. No variable unfavorably influenced survival except a central versus peripheral primary. Thus, the median survival of the patients in the first group with multiple sites of pleural involvement was similar to that of patients with distant metastases but with the cause of failure primarily local progression. In the majority of patients in the second group, parietal pleural and chest wall involvement, even with nodal metastases, did not translate into local failure, and long-term survival was possible.

Protochemotherapy in non-small cell lung carcinoma. An attempt to increase surgical resectability and survival. A preliminary report.

Twenty patients with Stage IIIM0 (T3N2) non-small cell lung cancer were treated with vindesine, etoposide, and Platinol (cisplatin) (ELETOP) chemotherapy in an attempt to decrease tumor size and increase resectability and survival. ELETOP chemotherapy induced a 70% response rate (all partial responses) within 6 weeks, and three patients were able to undergo curative resection. Toxicities with ELETOP were moderately severe, with leukocyte and platelet nadirs on day 15. This pilot study demonstrates the feasibility of protochemotherapy in non-small cell lung cancer.

CAMP chemotherapy for metastatic non-oat cell bronchogenic carcinoma. A 7-year experience (1975-1981) with 160 patients.

Between January 1975 and December 1981, 160 patients with metastatic non-oat cell bronchogenic carcinoma (MNOBC) were treated with cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP), or with a CAMP-like regimen. Forty-two (26%) of these patients demonstrated an objective response to the chemotherapy with a median survival of 61 weeks. Thirty-nine (24%) patients had stable disease (SD) with a median survival of 45 weeks. Seventy-nine patients (49.4%) were nonresponders with a median survival of 15 weeks. There was a significant difference in survival times between the responders and the SD patients, and between the responders and SD patients and the nonresponders. Responses were seen in 11% of the patients with squamous cell carcinoma and in 37% of the patients with adenocarcinoma. There was a significant difference in the response and SD categories in favor of adenocarcinoma over squamous cell carcinoma. Once a response was achieved, the median survival of the patients with adenocarcinoma was not significantly longer than that of the patients with squamous cell carcinoma.

Malignant superior vena cava obstruction reconsidered: the role of diagnostic surgical intervention.

The cases of 42 patients with malignant superior vena cava (SVC) obstruction were reviewed to evaluate clinical dogmas of prohibitive risk for invasive diagnostic procedures and need for urgent radiotherapy. Thirty-nine had carcinoma (35, bronchogenic and 4, other), and 3 had lymphoma. Lung cancer histology was squamous cell in 11, adenomatous in 10, large cell in 7, and small cell in 7. The SVC obstruction was always symptomatic, usually causing facial or cervical swelling, but there was no instance of SVC obstruction causing life-threatening problems such as cerebral or laryngeal edema. Twenty-two patients underwent bronchoscopy (11 flexible and 11 rigid) prior to radiotherapy without respiratory complications, and diagnostic tissue was obtained in 8. Also prior to radiotherapy, 29 invasive diagnostic procedures were performed: thoracotomy (1), mediastinotomy or mediastinoscopy (11), supraclavicular or scalene node biopsy (15), and percutaneous lung needle biopsy (2). Neither excessive blood loss nor serious complications occurred, and diagnostic tissue was obtained in 22 patients who received individualized therapy. Eight patients had urgent radiotherapy, which delayed diagnosis and specific therapy for two weeks to 6 months. For the 33 patients who underwent radiotherapy after development of the SVC obstruction, the obstruction clinically resolved spontaneously within fourteen days, independently of whether radiotherapy was begun immediately or was delayed. Median survival was 5.0 months and was not influenced by the dose or timing (early or late) of radiotherapy. We reached the following conclusions. First, although a grim prognostic sign, SVC obstruction is rarely life-threatening and typically resolves spontaneously, probably by development of venous collaterals.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined modality therapy for Stage IIIMO non-small cell lung cancer. A five-year experience.

Between 1975 and 1980, 101 patients with inoperable Stage IIIMO non-small cell lung carcinoma were entered into combined radiotherapy and chemotherapy trials at Michael Reese Hospital and University of Chicago Hospital. Sixty-four percent of the patients responded. Median survival for all patients was 8.8 months. Responders survived 13.7 months and nonresponders 4.6 months (P = 0.002). Patients treated with 4200 rad had a higher response rate than those treated with 3000 rad (74% versus 54%, P = 0.04) but there was no difference in survival. Although all patients with squamous cell carcinoma died by 30 months, 18% of patients with adenocarcinoma and 20% of patients with large cell carcinoma are long-term survivors. Brain metastases occurred more frequently in patients with large cell or adenocarcinoma than in patients with squamous cell carcinoma (P = 0.02). The prognostic effect of age, initial performance status, sex, histology, and tumor extent are examined. Toxicity was substantial with a 13% treatment-related mortality. Combined modality therapy may benefit selected patients with non-squamous cell types, but more effective chemotherapeutic agents are needed. Prophylactic cranial irradiation in patients with large cell carcinoma or adenocarcinoma may decrease the incidence of subsequent brain metastases.

Trial of vindesine, etoposide, and cisplatin in patients with previously treated, advanced-stage, non-small cell bronchogenic carcinoma.

Twenty-two patients with advanced-stage, non-small cell bronchogenic carcinoma were treated in a pilot study with a combination of vindesine, etoposide, and cisplatin (VEDDP). All patients had been previously treated with a non-cisplatin-containing regimen and had documentation of progressive disease. Median duration of VEDDP therapy was 2.6 months. Only one patient had a minor response. Median survival from start of protocol therapy was 3.7 months; the overall survival from start of primary therapy was 13.5 months. The only significant variable possibly affecting survival was achieving a minor response or stable disease (5.0 months for minor response/stable disease from start of VEDDP vs 3.2 months for progressive disease, P = 0.016). Hematologic toxicity was moderate to severe in 14 patients and prevented completion of two full cycles in seven patients. We conclude that VEDDP is ineffective in inducing a response in patients with refractory, advanced-stage non-small cell bronchogenic carcinoma in the dose and kinetic schema used in this pilot study.

Serum thyroglobulin in the management of patients with thyroid cancer.

We have reviewed our experience with the management of patients with thyroid cancer to assess the potential benefits of employing the serum thyroglobulin assay in patient management programs and to determine the optimal conditions for this application. Serum thyroglobulin levels were found to be more reliable when obtained from hypothyroid patients. Levels of thyroglobulin greater than 10 ng/mL appeared to be abnormally elevated in both thyroidectomized patients prior to radioactive iodine therapy (group 1) and in thyroidectomized patients after radioactive iodine therapy (group 2). Elevated thyroglobulin levels were found to be useful indicators of the presence of metastatic disease, whereas normal thyroglobulin levels were reliable indicators of the absence of metastases. In group 1 patients, elevated thyroglobulin levels reliably predicted the presence of important total body scan uptake. In group 2 patients, normal thyroglobulin levels reliably predicted the absence of total body scan uptake. The serum thyroglobulin assay can substantially reduce the need for repetitive total body scanning in the follow-up of group 2 patients with thyroid cancer.