William K. Murphy

Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer.

PURPOSE We conducted a phase II study to determine the response to and toxicity of docetaxel (Taxotere; Rhône-Poulenc Rorer Pharmaceuticals, Inc, Collegeville, PA) in patients with advanced non-small-cell lung cancer refractory to prior platinum-containing chemotherapy (PCC) regimens. PATIENTS AND METHODS Forty-four patients with stage IIIb or IV platinum-refractory non-small-cell lung cancer were treated with 100 mg/m2 of docetaxel intravenously over 1 hour every 3 weeks. The responses of 42 of 44 patients were assessable. Most patients had a Zubrod performance status of 1; the predominant histologic type was adenocarcinoma (61%), and 91% of patients had stage IV disease. RESULTS Nine of 42 assessable patients (21%) achieved a partial response to treatment. The median response duration (from response to progression) was 17 weeks, and the projected median survival duration of all patients is 42 weeks (51 weeks for adenocarcinoma and 22 weeks for nonadenocarcinoma). Grade 3/4 neutropenia occurred in 85% of patients and was associated with fever that required intravenous antibiotics in 16% of patients (3% of cycles). Other acute side effects included easily treated hypersensitivity reactions and dermatitis. Cumulative side effects included fluid retention and neuropathy. CONCLUSION Docetaxel administered at 100 mg/m2 intravenously every 3 weeks has notable activity against platinum-refractory non-small-cell lung cancer, with a 21% major response rate. Primary side effects were neutropenia, hypersensitivity, and fluid retention.

Phase II study of docetaxel for recurrent or metastatic non-small-cell lung cancer.

PURPOSE We conducted a phase II study to determine the response and toxicity of docetaxel (Taxotere; Rhône-Poulenc Rorer Pharmaceuticals, Inc, Collegeville, PA) in chemotherapy-naive patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS We treated 41 chemotherapy-naive patients who had stage IIIb or IV non-small-cell lung cancer with 100 mg/m2 of docetaxel intravenously over 1 hour every 3 weeks. Responses were assessed after every one to two treatment courses. Responses of 39 of 41 patients were assessable. The patients median age was 63 years; 90% of patients had a Zubrod performance status of 0 or 1. The predominant histology was adenocarcinoma (54%), and 90% of patients had stage IV disease. RESULTS Thirteen patients (33%) achieved a partial response to treatment, and the median response duration was 14 weeks. Grade 3 or 4 neutropenia occurred in 97% of patient; this was usually of brief duration and was associated with serious infection in 17% of patients. Other acute toxic effects included easily treated hypersensitivity reactions (36% of patients) and dermatitis (74%). We also observed fluid retention (with peripheral edema or pleural effusion or both) in 54% of patients. This was a cumulative side effect that generally occurred late in treatment. CONCLUSION Docetaxel administered at 100 mg/m2 intravenously every 3 weeks has significant activity against non-small-cell lung cancer, with a 33% major response rate. Primary toxicities were neutropenia, hypersensitivity, and fluid retention.

Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan.

PURPOSE This study was designed to assess the anti-tumor activity of topotecan (TPT) in patients with small-cell lung cancer (SCLC) refractory to etoposide. PATIENTS AND METHODS Refractoriness to etoposide was defined as lack of response to etoposide-containing frontline therapy, or progression during or within 3 months of the last dose of etoposide-containing frontline or second-line therapy. Other eligibility criteria were presence of measurable disease, Zubrod scale performance status (PS) < or = 2, < or = two prior chemotherapy regimens, and adequate renal and liver function. TPT was administered at a dose of 1.25 mg/m2/d for 5 days over 30 minutes every 21 days. RESULTS Thirty-two patients were registered, of whom 28 are fully assessable. All patients had been treated with frontline etoposide and cisplatin. Three patients (11%) achieved a partial remission (PR) (durations, 7, 8, and 19 weeks) and two (7%) achieved a minor response; five patients (17%) had stable disease and 18 (65%) had progressive disease. One of the three patients who achieved a PR had failed to respond to frontline cisplatin and etoposide. The overall median survival duration was 20 weeks. Grade 3 to 4 granulocytopenia and thrombocytopenia occurred after 70% and 31% of courses administered, respectively. No grade 3 to 4 non-hematological toxicities were observed. Grade 1 or 2 nonhematological toxicities (in percentage of patients) consisted of nausea (41%, 8%) and vomiting (25%, 11%), and alopecia (100%). CONCLUSION TPT at the dose and schedule used has modest antitumor activity in SCLC patients refractory to etoposide and cisplatin, which indicates that clinical resistance to the topoisomerase II poison etoposide does not confer cross-sensitivity to the topoisomerase I poison TPT. TPT is well tolerated, with myelosuppression of short duration being the most common and limiting toxicity.

Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer.

PURPOSE We conducted a phase I trial of the novel nucleoside analog, gemcitabine, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) to determine the maximum-tolerated dose and efficacy in this population. PATIENT AND METHODS Eligibility requirements included stage III or IV NSCLC, performance status < or = 1, and no prior chemotherapy. Gemcitabine was administered as a 30-minute intravenous infusion weekly for 3 weeks every 4 weeks. We enrolled patients at doses that ranged from 1,000 to 2,800 mg/m2/wk (three patients per cohort). Responses were assessed after every two courses (8 weeks). RESULTS We treated 33 chemotherapy-naive patients with stage III (n = 5) or IV (n = 28) NSCLC. Most had performance status 1, and 67% had adenocarcinoma. Eight of 32 assessable patients (25%) achieved a partial response. The projected median survival duration (all patients) is 49 weeks. The maximum-tolerated dose was 2,200 mg/m2/wk for 3 weeks every 4 weeks; dose-limiting toxicity was myelosuppression and reversible transaminase elevation. Other side effects were consistently mild. The maximum dose-intensity achieved with the first two cycles was 2,362 mg/m2/wk for 3 weeks every 4 weeks, which is a feasible phase II starting dose. CONCLUSION This study estimates a phase II starting dose of gemcitabine in chemotherapy-naive patients to be 2,400 mg/m2/wk for 3 consecutive weeks every 4 weeks; this is much higher than that previously reported in heavily pretreated patients. Twenty-five percent of patients with advanced NSCLC achieved a partial response to gemcitabine. This significant activity in conjunction with a very favorable toxicity profile supports the further evaluation of gemcitabine in combination with other active agents.

The natural history of resectable metastatic melanoma (Stage IVA Melanoma)

One‐hundred‐two patients with malignant melanoma who had distant metastases surgically resected and were judged to be clinically free of disease (M. D. Anderson Stage IVA melanoma) were studied. The median survival for all the patients from time of diagnosis of stage IVA disease was 18 months. The site of the resected metastases did not appear to influence survival, being approximately the same for the brain (15 months), lung (16 months), intraabdominal (18 months), and skin and/or lymph nodes (23 months). The site of the resected metastases also did not influence the median disease‐free interval. Patients who had metastases resected from several organs at the same time had a median survival of 15 months, which was similar to that of patients with one resected site. Patients who were rendered Stage IVA on several occasions by surgical excisions had a median survival of 36 months. Thirty‐five patients received surgery only and 67 patients received adjuvant chemotherapy, immunotherapy, or combined chemoimmunotherapy after surgery. For the group treated with surgery only, the median disease‐free interval and survival from diagnosis of stage IVA disease were 6 months and 16 months, respectively, and for the adjuvant group 6 months and 21 months, respectively. Specifically, by the type of adjuvant therapy, the median disease‐free interval and survival from stage IVA for 23 patients receiving Corynebacterium parvum were 6.9 and 19 months; for 39 patients receiving BCG, eight months and 26 months; for 24 patients receiving BCG + DTIC, eight and 17.4 months; and for all 51 DTIC treated patients 6.3 and 17.8 months, respectively. Patients receiving BCG had a median survival superior to the surgery only group (P = 0.02). An increase in survival was seen predominantly in patients who achieved IVA status more than once and received BCG. Patients with recurrent soft‐tissue metastases appeared to benefit most from BCG in prolonging the disease‐free interval. Only 1/10 treated by surgery alone had a disease‐free interval longer than 1 year, compared with 9/16 who received BCG (P = 0.01). Stage IVA melanoma appears to be distinctly different in prognosis from Stage IVB melanoma and should be classified separately. Patients with recurrent soft‐tissue disease may benefit significantly from treatment with BCG.

Phase II study of topotecan in patients with advanced non-small-cell lung cancer previously untreated with chemotherapy.

PURPOSE This study was designed to assess the anti-tumor activity of topotecan (TPT) in patients with advanced non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy. PATIENTS AND METHODS Patients with stage IIIB or IV NSCLC with measurable disease in nonradiated fields were eligible. Other eligibility criteria were Zubrod performance status (PS) < or = 2 and adequate renal and liver function. TPT was administered at a dose of 1.5 mg/m2/d for 5 days over 30 minutes every 21 days. Of 48 registered patients, 40 were fully assessable. Nineteen patients had adenocarcinoma (AD), 14 squamous carcinoma (SCC), and seven poorly differentiated carcinoma. RESULTS Six patients (15%) achieved a partial remission (PR) (durations: 8, 14, 18, 28, 56, and 61 weeks) and four patients a minor response; 10 patients had stable disease and 20 patients progressive disease. The PR rate was 36% (five of 14 patients) in patients with SCC versus 4% (one of 26 patients) in those with other histologies (P = .014). The overall median survival time was 38 weeks and 30% of patients were alive at 1 year. Grade 3 to 4 granulocytopenia and thrombocytopenia occurred after 76% and 10% of courses administered, respectively. No grade 3 to 4 nonhematologic toxicities were observed. Grade 1 or 2 nonhematologic toxicities consisted of nausea (46% and 5%), vomiting (31% and 7%), and fatigue (53% and 16%). CONCLUSION TPT at the dose and schedule used has moderate antitumor activity in NSCLC; its activity is mostly limited to patients with SCC. TPT is well tolerated, with myelosuppression of short duration being the most common and limiting toxicity.

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 ...

β‐Lactam regimens for the febrile neutropenic patient

A total of 535 evaluable febrile episodes in neutropenic patients were randomly assigned to treatment with ticarcillin‐clavulanate plus vancomycin (TV), ceftazidime plus vancomycin (CV), or all three antibiotics (TCV). The TCV regimen was significantly more effective than TV, considering all evaluable episodes, documented infections, gram‐negative infections, and infections in patients with persistent severe neutropenia (< 100 neutrophils/mm3). The results with CV were intermediate between TV and TCV. The toxicities were similar with all three regimens and consisted primarily of skin rashes. The TCV regimen is effective for empiric therapy of fever in neutropenic patients and probably should be utilized in preference to CV or TV, although its superiority over CV in this study was inconclusive.

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.

Protected environment–Prophylactic antibiotic program for malignant sarcomas: Randomized trial during remission induction chemotherapy

Fifty‐one evaluable patients with malignant sarcomas were randomly allocated to receive three courses of remission induction chemotherapy with cyclophosphamide, vincristine, Adriamycin, and dimethyl triazeno imidazole carboxamide (CYVADIC) on the protected environment‐prophylactic antibiotic (PEPA) program24 or as controls.27 The complete remission rate was 33% for the PEPA group and 15% for the control group (P = 0.22). The response rates (complete plus partial) were 71% and 67%, respectively. The durations of response were similar for both groups of patients, but the PEPA patients survived substantially longer (median, 84 weeks vs. 58 weeks). The frequency of infection was significantly lower among the PEPA patients, and the doses of CYVADIC could be escalated more often among these patients. Dosage escalation was associated with a higher complete remission rate and lower fatality rate.