Paul Y. Holoye

Primary chemotherapy of brain metastasis in small-cell lung cancer.

Fourteen patients with brain metastases from previously untreated small-cell lung cancer (SCLC) were treated with three courses of systemic chemotherapy as an initial mode of treatment. Whole brain irradiation was given concurrently with the fourth course of chemotherapy. The chemotherapy consisted of cyclophosphamide, 600 mg/m2 intravenously (IV) on day 1; doxorubicin, 50 mg/m2 IV on day 1; vincristine, 1.5 mg IV days 1 and 5; and etoposide, 60 mg/m2 IV days 3 through 5; all repeated every 3 weeks with dosage adjustments. There were ten men and four women, with a median age of 59 years (range, 47 to 75). Six patients had multiple brain lesions, and the brain was the sole site of distant metastasis in four patients. Three patients were inevaluable for response in the brain, as two died early and the third dropped out of the trial too soon. Brain lesions responded to chemotherapy in nine (one complete remission [CR], eight partial remissions [PR]) of 11 (82%) evaluable patients, and objective responses in ...

Paraneoplastic Cushing's syndrome as an adverse prognostic factor in patients who die early with small cell lung cancer

The potential role of paraneoplastic Cushings syndrome (CS) was assessed on the clinical course of patients with small cell lung cancer. A retrospective comparison was done of complication and survival rates according to the presence or absence of CS in patients with small cell lung cancer who died within 90 days of initial administration of chemotherapy. The setting was a comprehensive cancer center. Eleven patients with clinical and/or biochemical features of CS were identified from among 90 patients who presented between 1979 and 1989 with previously untreated small cell lung cancer. The group with CS and the control patients were compared in terms of clinicopathologic prognostic factors, treatment, and outcome. Patients with CS were comparable to the control patients in all prognostic factors, including tumor stage and cancer treatment. Eight‐two percent of patients with CS (nine of 11) died within 14 days of initiation of chemotherapy compared with 25% of the control patients (19 of 77). The median survival from initiation of chemotherapy was 12 days for the 11 patients with CS and 27 days for the 77 control patients. In 45% of the patients with CS (five of 11), death was attributed to opportunistic fungal or protozoal infection compared with 8% of control patients (six of 77). paraneoplastic CS is a previously unrecognized adverse prognostic factor for patients with small cell lung cancer. Those with both small cell lung cancer and CS have severe opportunistic infections soon after the initiation of chemotherapy, leading to clinical deterioration and death before antineoplastic benefit from chemotherapy can be achieved. Biochemical control of CS for at least 1 to 2 weeks before initiation of chemotherapy may ameliorate the poor prognosis.

Phase I/II clinical trial of didemnin B in non-small-cell lung cancer: neuromuscular toxicity is dose-limiting

SummaryDidemnin B (NSC 325319), a cyclic depsipeptide isolated from a Caribbean tunicate, exhibits potent preclinical antitumor activity. In previous phase I studies, 3.47 mg/m2 was the maximally tolerated dose, with nausea and vomiting being the dose-limiting toxicity. The drug was given in a single bolus infusion over 30 min every 28 days. In the current study, 30 patients presenting with previously treated non-small-cell lung cancer (NSCLC) received 46 courses of the drug at doses ranging from 3.47 to 9.1 mg/m2. Neuromuscular toxicity was dose-limiting. Neusea and vomiting appeared to be correlated with dose levels and were ameliorated by a combination of antiemetics including dexamethasone. Other side effects included a mild rise in hepatic enzymes and an allergic reaction that was preventable by the addition of corticosteroids to the premedication regimen. In all, 2 minor responses were seen among 24 evaluable patients. Because neuromuscular toxicity is dose-limiting, we recommend that routine measurements of creatine kinase and aldolase, a careful neurologic evaluation, and electromyography and muscle biopsy (if indicated) be incorporated into phase II trials. The recommended dose for phase II studies using a single bolus schedule is 6.3 mg/m2, following the premedication of patients with antiemetics.

Phase II clinical trial of didemnin B in previously treated small cell lung cancer

SummaryDidemnin B (NSC 325319), a cyclic depsipeptide isolated from a Carribean sea tunicate, exhibited potent antitumor activity in preclinical studies. After determining the maximum tolerated dose in our previous phase I/II trial, we conducted a phase II study of this drug in patients with previously treated small cell lung cancer; the starting dose was 6.3 mg/m2 intravenously over 30 min every 28 days. The major side effects were in the neuromuscular system and included severe muscle weakness, myopathy and/or myotonia by electromyography, and elevation of creatine phosphokinase and aldolase levels. We also observed modest increases in bilirubin and alkaline phosphatase levels. There were minimal hematologic toxic effects. No response was observed among 15 evaluable patients, leading us to conclude that didemnin B was toxic but inactive in patients with previously treated small cell lung cancer at the stated dose and schedule. A review of the literature revealed no significant antitumor activity in cancers of the colon, breast, ovaries, cervix, or lung (non-small cell) or in renal cell carcinoma. Further clinical trials for didemnin B may not be warranted at the stated dose and schedule.

Resectability of small-cell lung cancer following induction chemotherapy in patients with limited disease (stage II-IIIb)

A prospective study of multimodality therapy was conducted incorporating adjuvant resection in patients who presented with limited small-cell lung cancer (SCLC). This preliminary report addresses the resectability rate after induction chemotherapy. Twenty-five patients (1 with Stage II, 12 with Stage IIIa, and 12 with Stage IIIb disease) completed the induction regimen of 3 cycles of intravenous cyclophosphamide 750 mg/m2 on day 1, vincristine 2 mg on day 3, cisplatin 20 mg/m2 on days 1–3, and etoposide 100 mg/m2 on days 1–3, (every 3–4 weeks). Patients with complete response or partial response, 10 (40%) and 14 (56%) patients, respectively, were considered for surgical resection. Six were ineligible for surgery because of medical or surgical contraindications, and four refused surgery. Of the 14 patients taken to surgery 10 had resectable disease (40% of the original group of 25). Three pneumonectomies, two bi-lobectomies, two lobectomies, and two wedge resections were performed. In the remaining patient multiple biopsies revealed no residual disease and resection was not performed. Surgery-related complications included one death, one bronchopleural fistula, and one episode of pneumonia. Induction chemotherapy was generally well tolerated. These preliminary data demonstrate that a significant percentage of patients with SCLC, Stages II-IIIb, can feasibly be resected after response to brief induction chemotherapy.

Low-dose continuous infusion cisplatin combined with external beam irradiation for advanced colorectal adenocarcinoma and unresectable non-small cell lung carcinoma

In a dose escalation study, CIS-diamminedichloroplatinum II (cisplatin) was combined with a standard dose of external beam irradiation in 15 patients with localized non-small cell lung cancer (NSCLC) and 16 patients with fixed or recurrent localized adenocarcinoma of the rectum. Cisplatin was given 5 days a week during irradiation using an outpatient portable infusion pump system, at doses of 3.2 mg/m2/24 hr in 15 patients, 4.0 mg/m2/24 hr in 13 patients, and 5.0 mg/m2 24 hr in 3 patients. Twelve of 15 patients with NSCLC received 66 Gy in 33 fractions in 6 1/2 weeks; one received 46 Gy followed by a surgical resection; for the other two patients treatment was discontinued after 50 Gy and 64 Gy, respectively, because they developed distant metastases. The 16 patients with rectal carcinoma received a preoperative dose to the pelvis of 45 Gy in 25 fractions in 5 weeks. Of 12 patients who underwent laparotomy, 10 had a surgical resection, 2 with close or positive surgical margins. Four patients who had resections received an intraoperative electron boost. Of the two patients who did not undergo resection at laparotomy, one received an intraoperative electron boost, the other a boost with interstitial iridium-192. Among the four patients with rectal adenocarcinoma who were not candidates for surgery because of advanced local disease, two had further external beam therapy up to 59.4 Gy, and two had no further therapy. Major toxicity was site-specific, with esophagitis predominating in the patients with NSCLC, diarrhea in the patients with rectal carcinoma, and nausea experienced by both. Cisplatin dose and toxicity seemed to be related. The maximum tolerated dose for low-dose continuous infusion cisplatin given 5 days/week in these patients was 3.2 mg/m2/24 hr combined with 66 Gy in patients with NSCLC and 4.0 mg/m2/24 hr combined with 45 Gy in patients with rectal carcinoma.

Intrapleural etoposide for malignant effusion

SummaryThe pharmacology, toxicity, and therapeutic effectiveness of etoposide (VP-16) given by the intrapleural route were examined in a phase I trial. Ten patients with malignant pleural effusion received 100, 150, or 225 mg/m2 VP-16 infused over 2 h into the pleural space after drainage of pleural fluid. The administration of VP-16 was tolerated well, with no local pain, increase in cough, dyspnea, or infection. Myelosuppression was mild at doses of 150 mg/m2 or less but severe at 225 mg/m2. Drug levels were followed in both plasma and pleural fluid for up to 12 h. Clearance of VP-16 from the pleural cavity was low at 2 ml/min m2. Peak pleural-fluid drug levels in patients receiving 225 mg/m2 exceeded 300 µg/ml, whereas peak drug concentrations in corresponding plasma samples obtained at the same time amounted to <10 µg/ml. Serial chest X-rays showed no disappearance of pleural effusion in nine evaluable patients. However, follow-up investigation of pleural fluid characteristics [carcinoembryonic antigen (CEA), lactic dehydrogenase (LDH), and cytologic examination] suggested some evidence of local therapeutic benefit.

The role of adjuvant surgery in the combined modality therapy of small-cell bronchogenic carcinoma after a chemotherapy-induced partial remission.

Twenty-six patients with a limited-disease presentation of small-cell bronchogenic carcinoma (SCBC) had surgery after achieving a partial remission with three cycles of chemotherapy. Persistent SCBC was found in 15 patients (58%), non-small-cell bronchogenic carcinoma (NSCBC) in six patients (23%), and no malignancy in five patients (19%). Twelve patients have died since surgery. Tumor-node-metastasis (TNM) staging prior to or after chemotherapy was not predictive of outcome, but an N0 status found at pathological examination of the surgical specimen was predictive of long-term survival. Median survival for this group of patients was 25 months. Adjuvant surgery is feasible and may be beneficial.

Ifosfamide with mesna uroprotection in the management of lung cancer

Fourteen patients with extensive disease small cell bronchogenic carcinoma (SCBC) received ilbsfamide at 2.000 mg/ m2/day for 5 consecutive days with simultaneous mesna and vineristine while 26 patients with extensive disease non-small- cell bronchogenic carcinoma (N-SCBC) received the same regimen without vincristine. Eight partial responses (57%) were observed with a 40-week median survival in the case of SCBC and four partial remissions (15%) with a 31 -week median survival in N-SCBC. Ciranulocytopenia was the doselimiting toxicity. whereas urotoxicity was well controlled with mesna. Neuropsychiatric toxicity consisted of anxiety, agitation, confusion, and hallucination. Neurobehavioral testing detected worsened performance during ifosfamide treatment. Ifosfamide is one of the few active agents in N-SCBC.

Phase II trial of trimetrexate for unresectable or metastatic non-small cell bronchogenic carcinoma

SummaryWe treated 34 chemotherapy-naive patients with stage IIIb or IV non-small cell lung cancer with trimetrexate 150–200 mg/m2 intravenously over 30 minutes every two weeks. Six of 31 evaluable patients (19%) achieved a partial response. The major toxic effects from this regimen were myelosuppression, nausea/vomiting, and skin rash. We conclude that this well-tolerated schedule of trimetrexate has significant activity as a single agent against non-small cell lung cancer.