Antonius A. Miller

Single-Agent Versus Combination Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The Cancer and Leukemia Group B (study 9730)

PURPOSE We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS A total of 561 eligible patients were randomly assigned to receive paclitaxel alone or in combination with carboplatin. RESULTS The response rate was 17% in the paclitaxel arm and 30% in the carboplatin-paclitaxel arm (P < .0001). Median failure-free survival was 2.5 months in the paclitaxel arm and 4.6 months in the carboplatin-paclitaxel arm (P = .0002). Median survival times were 6.7 months (95% CI, 5.8 to 7.8) and 8.8 months (95% CI, 8.0 to 9.9), and 1-year survival rates were 32% (95% CI, 27% to 38%), and 37% (95% CI, 32% to 43%), respectively. The overall survival distributions were not statistically different: hazard ratio = 0.91 (95% CI, 0.77 to 1.17; P = .25). Hematological toxicity and nausea were more frequent in the combination arm, but febrile neutropenia and toxic deaths were equally low in both arms. There was no significant survival difference in elderly patients. Performance status 2 patients treated with combination chemotherapy had a better survival rate than those treated with single-agent therapy (P = .019). CONCLUSION Combination chemotherapy improves response rate and failure-free survival compared with single-agent therapy, but there was no statistically significant difference in the primary end point of overall survival. The results in elderly patients were similar to younger patients. Performance status 2 patients had a superior outcome when treated with combination chemotherapy.

Randomized Phase II Study of Cisplatin With Gemcitabine or Paclitaxel or Vinorelbine as Induction Chemotherapy Followed by Concomitant Chemoradiotherapy for Stage IIIB Non–Small-Cell Lung Cancer: Cancer and Leukemia Group B Study 9431

PURPOSE To evaluate new drugs in combination with cisplatin in unresectable stage III non-small-cell lung cancer, Cancer and Leukemia Group B (CALGB) conducted a randomized phase II study of two cycles of induction chemotherapy followed by two additional cycles of the same drugs with concomitant radiotherapy. PATIENTS AND METHODS Eligible patients received four cycles of cisplatin at 80 mg/m(2) on days 1, 22, 43, and 64 with arm 1: gemcitabine 1,250 mg/m(2) on days 1, 8, 22, and 29 and 600 mg/m(2) on days 43, 50, 64, and 71; arm 2: paclitaxel 225 mg/m(2) for 3 hours on days 1 and 22 and 135 mg/m(2) on days 43 and 64; and arm 3: vinorelbine 25 mg/m(2) on days 1, 8, 15, 22, and 29 and 15 mg/m(2) on days 43, 50, 64, and 71. Radiotherapy was initiated on day 43 at 2 Gy/d (total dose, 66 Gy). RESULTS One hundred seventy-five eligible patients were analyzed. Toxicities during induction chemotherapy consisted primarily of grade 3 or 4 granulocytopenia. Grade 3 or 4 toxicities during concomitant chemoradiotherapy consisted of thrombocytopenia, granulo-cytopenia, and esophagitis. Response rates after completion of radiotherapy were 74%, 67%, and 73% for arms 1, 2, and 3, respectively. Median survival for all patients was 17 months. One-, 2-, and 3-year survival rates for the patients on the three arms were 68%/37%/28%, 62%/29%/19%, and 65%/40%/23%. CONCLUSION Four cycles of gemcitabine, vinorelbine, or paclitaxel in combination with cisplatin can be administered at these doses and schedules. The observed survival rates exceed those of previous CALGB trials and may be attributable to the use of concomitant chemoradiotherapy. Induction chemotherapy added to concomitant chemoradiotherapy is being evaluated in a phase III randomized trial.

Phase I and Pharmacokinetic Study of Sorafenib in Patients With Hepatic or Renal Dysfunction: CALGB 60301

PURPOSE We sought to characterize the pharmacokinetics (PK) and determine a tolerable dose of oral sorafenib in patients with hepatic or renal dysfunction. PATIENTS AND METHODS Patients were assigned to one of nine cohorts: cohort 1, bilirubin < or = upper limit of normal (ULN) and AST < or = ULN and creatinine clearance (CC) > or = 60 mL/min; cohort 2, bilirubin more than ULN but < or = 1.5x ULN and/or AST more than ULN; cohort 3, CC between 40 and 59 mL/min; cohort 4, bilirubin more than 1.5x ULN to < or = 3x ULN (any AST); cohort 5, CC between 20 and 39 mL/min; cohort 6, bilirubin more than 3x ULN to 10x ULN (any AST); cohort 7, CC less than 20 mL/min; cohort 8, albumin less than 2.5 mg/dL (any bilirubin/AST); and cohort 9, hemodialysis. Sorafenib was administered as a 400-mg dose on day 1 for PK, and continuous daily dosing started on day 8. RESULTS Of 150 registered patients, 138 patients were treated. With the exception of cohorts 6 and 7, at least 12 patients per cohort were assessable, and the dose level with prospectively defined dose-limiting toxicity in less than one third of patients by day 29 was considered tolerable. No significant associations between the sorafenib PK and cohort were found. CONCLUSION We recommend the following empiric sorafenib starting doses by cohort: cohort 1, 400 mg twice a day; cohort 2, 400 mg twice a day; cohort 3, 400 mg twice a day; cohort 4, 200 mg twice a day; cohort 5, 200 mg twice a day; cohort 6, not even 200 mg every third day tolerable; cohort 7, not defined; cohort 8, 200 mg each day; and cohort 9, 200 mg each day.

Randomized Phase II Trial of Induction Chemotherapy Followed by Concurrent Chemotherapy and Dose-Escalated Thoracic Conformal Radiotherapy (74 Gy) in Stage III Non-Small-Cell Lung Cancer : CALGB 30105

PURPOSE To evaluate 74 Gy thoracic radiation therapy (TRT) with induction and concurrent chemotherapy in stage IIIA/B non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with stage IIIA/B NSCLC were randomly assigned to induction chemotherapy with either carboplatin (area under the curve [AUC], 6; days 1 and 22) with paclitaxel (225 mg/m(2); days 1 and 22; arm A) or carboplatin (AUC, 5; days 1 and 22) with gemcitabine (1,000 mg/m(2); days 1, 8, 22, and 29; arm B). On day 43, arm A received weekly carboplatin (AUC, 2) and paclitaxel (45 mg/m(2)) while arm B received biweekly gemcitabine (35 mg/m(2)) both delivered concurrently with 74 Gy of TRT utilizing three-dimensional treatment planning. The primary end point was survival at 18 months. RESULTS Forty-three and 26 patients were accrued to arms A and B, respectively. Arm B was closed prematurely due to a high rate of grade 4 to 5 pulmonary toxicity. The overall response rate was 66.6% (95% CI, 50.5% to 80.4%) and 69.2% (95% CI, 48.2% to 85.7%) on arm A and B, respectively. The median survival time (MST) and 1-year survival rate was 24.3 months (95% CI, 12.3 to 36.4) and 66.7% (95% CI, 50.3 to 78.7) and 12.5 months (95% CI, 9.4 to 27.6) and 50.0% (95% CI, 29.9 to 67.2) for arms A and B, respectively. The primary toxicities included esophagitis, pulmonary, and fatigue. CONCLUSION Arm A reached the primary end point with an estimated MST longer than 18 months and will be compared with a standard dose of TRT in a planned randomized phase III trial in the United States cooperative groups.

Intravenous pamidronate disodium treatment of bone metastases in patients with breast cancer. A dose-seeking study

Background. Treatment of the symptoms of bone metastases currently involves the use of narcotic medication, radiation therapy, or hormonal therapy. Pamidronate disodium, a bisphosphonate, may prove helpful in the palliative treatment of bone metastases in patients with breast cancer as demonstrated in this multicenter, dose‐ranging trial.

Schedule dependency of 21-day oral versus 3-day intravenous etoposide in combination with intravenous cisplatin in extensive-stage small-cell lung cancer: a randomized phase III study of the Cancer and Leukemia Group B.

PURPOSE This was a randomized phase III study to test the schedule dependency of etoposide given as a conventional 3-day intravenous (IV) regimen versus a prolonged 21-day oral regimen for extensive-stage small-cell lung cancer (SCLC). Both regimens contained IV cisplatin. The objectives were to compare survival (primary end point) and to establish response rates, failure-free survival, and toxicity (secondary end points). PATIENTS AND METHODS Patients with untreated measurable or assessable disease and normal organ function were eligible. Randomization was stratified according to performance status 0 versus 1 or 2. Treatment consisted of etoposide 130 mg/m2/d IV for 3 days and cisplatin 25 mg/m2/d IV for 3 days every 21 days for eight courses (schedule 1) versus etoposide 50 mg/m2/d orally for 21 days and cisplatin 33 mg/m2/d IV for 3 days every 28 days for six courses (schedule 2). In 1990, bioavailability of oral etoposide was assumed to be 50%, and the study was designed to deliver the same total doses of etoposide and cisplatin on both regimens over 24 weeks without the use of growth factors. RESULTS Between December 1990 and October 1993, 306 eligible patients were entered. Of these, 69% were male and 66% were > or = 60 years of age; 21% had a performance status of 0, 47% a performance status of 1, and 32% a performance status of 2; 156 were randomized to receive schedule 1 and 150 to receive schedule 2. Overall median survival estimates were 9.5 and 9.9 months (difference not significant) for schedule 1 and schedule 2, respectively. The 95% confidence interval (CI) for overall survival, 8 to 11 months, was the same for both schedules, with 126 and 117 deaths on schedule 1 and 2, respectively. Both schedules also resulted in the same median failure-free survival estimate of 7 months (95% CI, 6 to 8 months on either schedule). Complete and partial responses were observed in 15% and 42% of patients on schedule 1 and 14% and 47% on schedule 2, respectively. The overall maximal hematologic toxicities grade 3 and 4 for leukocytes, neutrophils, platelets, and hemoglobin were, respectively, as follows: schedule 1, 62%, 85%, 32%, and 32%; schedule 2, 83%, 83%, 52%, and 53%. Lethal toxicity due to neutropenia and infection occurred in 4% of patients on schedule 1 and 10% on schedule 2 (difference not statistically significant). CONCLUSION The two schedules of etoposide in combination with cisplatin did not result in differences in treatment outcome with respect to tumor response and survival. However, a significantly greater rate of severe or life-threatening hematologic toxicity was noted on the 21-day oral etoposide treatment schedule.

Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

Whole body FDG-PET for the evaluation and staging of small cell lung cancer: a preliminary study

[F18]-2-deoxy-2fluoro-D-glucose positron emission tomography (FDG-PET) is increasingly used in the diagnosis and staging of lung cancer. Despite its positive performance characteristics in non-small cell lung cancer (NSCLC), the role of FDG-PET in the staging of small cell lung cancer (SCLC) remains to be determined. We designed a prospective study to address this question. Eighteen patients with SCLC were enrolled prospectively to undergo total body FDG-PET in addition to conventional staging procedures (chest computed tomography (CT), abdominal CT, cranial CT or magnetic resonance imaging (MRI), and bone scan/bone marrow biopsy). The agreement between FDG-PET and conventional staging modalities in identifying the presence or absence of metastatic disease was compared using the Veterans Administration (VA) cooperative staging system for staging. Overall staging by FDG-PET agreed with conventional staging exams in 15/18 (83%) patients (kappa=0.67), which included eight extensive and seven limited cases. FDG-PET showed more extensive disease in two of the three patients for which FDG-PET and conventional staging disagreed. These data suggest that total body FDG-PET may be useful in the staging, treatment planning, and prognostication of SCLC. Whether FDG-PET will replace other more established staging modalities remains to be determined by larger prospective randomized controlled studies.

The risk of death from heart disease in patients with nonsmall cell lung cancer who receive postoperative radiotherapy: analysis of the Surveillance, Epidemiology, and End Results database.

This study was designed to investigate whether the mortality from heart disease, a manifestation of intercurrent disease after postoperative radiotherapy (PORT), has decreased over time for patients with nonsmall cell lung cancer (NSCLC).

Prospective Evaluation of the Relationship of Patient Age and Paclitaxel Clinical Pharmacology: Cancer and Leukemia Group B (CALGB 9762)

PURPOSE To prospectively evaluate the pharmacokinetics and toxicity profile of paclitaxel in relation to patient age in adults > or = 55 years old. PATIENTS AND METHODS Paclitaxel was administered at 175 mg/m2 for 3 hours to 153 patients, 46 of whom were > or = 75 years of age. Pharmacokinetic and toxicity assessments were performed. Data were analyzed by cohort (cohort 1, age 55 to 64 years; cohort 2, age 65 to 74 years; cohort 3, age > or = 75 years). RESULTS Paclitaxel concentration versus time (AUC) and total-body clearance (CL(tb)) data were available for 122 patients (cohort 1, 46 patients; cohort 2, 44 patients; cohort 3, 32 patients). Mean paclitaxel AUC increased across cohorts (P = .01). Mean (SE) AUCs were 22.4 (2.5) micromol/L x hour, 26.2 (2.8) micromol/L x hour, and 31.7 (5.6) micromol/L x hour for cohorts 1, 2, and 3, respectively. There was a corresponding significant (P = .007) age-related decrease in mean (SE) paclitaxel CL(tb) (cohort 1, 11.0 [0.7] L/h/m2; cohort 2, 9.3 [0.6] L/h/m2; cohort 3, 8.2 [0.6] L/h/m2). Patients in cohort 3 experienced significantly lower absolute neutrophil count nadirs than did younger groups (P = .02). There was also a significant increase in percentage of patients with > or = grade 3 neutropenia across age cohorts (cohort 1, 22%; cohort 2, 35%; cohort 3, 49%; P = .006). However, the increased exposure of patients to paclitaxel and increased neutropenia were not reflected in adverse clinical sequelae such as hospitalization for toxicity (P = .82), receiving intravenous antibiotics (P = .21), or experiencing a temperature more than 38 degrees C (P = .45). CONCLUSION Although paclitaxel CL(tb) decreases with increasing patient age, there is great interpatient variability. Cooperative group studies to evaluate the effect of aging on pharmacokinetics are feasible.