J. Philip Kuebler

Phase III Trial of Irinotecan/Cisplatin Compared With Etoposide/Cisplatin in Extensive-Stage Small-Cell Lung Cancer: Clinical and Pharmacogenomic Results From SWOG S0124

PURPOSE Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC. PATIENTS AND METHODS Patients were randomly assigned to IP (irinotecan 60 mg/m(2) on days 1, 8, and 15; cisplatin 60 mg/m(2) day 1, every 4 weeks) or EP (etoposide 100 mg/m(2) on days 1 through 3; cisplatin 80 mg/m(2) day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients. RESULTS Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia. CONCLUSION This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.

Oxaliplatin As Adjuvant Therapy for Colon Cancer: Updated Results of NSABP C-07 Trial, Including Survival and Subset Analyses

PURPOSE The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin (FULV) improved disease-free survival (DFS) in patients with stage II or III colon cancer. This analysis is the first publication of overall survival (OS) for the NSABP C-07 study. We updated DFS and examined both end points in clinically relevant patient subsets. PATIENTS AND METHODS Other studies have identified patients age 70 or older and those with stage II disease as patient subsets in which oxaliplatin may not be effective. We investigated toxicity as a driver of divergent outcomes in these subsets. RESULTS In all, 2,409 eligible patients with follow-up were randomly assigned to either FULV (FU 500 mg/m(2) by intravenous [IV] bolus weekly for 6 weeks; leucovorin 500 mg/m(2) IV weekly for 6 weeks of each 8-week cycle for three cycles) or FLOX (FULV plus oxaliplatin 85 mg/m(2) IV on days 1, 15, and 29 of each cycle). With 8 years median follow-up, OS was similar between treatment groups (hazard ratio [HR], 0.88; 95% CI, 0.75 to 1.02; P = .08). FLOX remained superior for DFS (HR, 0.82; 95% CI, 0.72 to 0.93; P = .002). The effect of oxaliplatin on OS did not differ by stage of disease (interaction P = .38 for OS; interaction P = 0.37 for DFS) but did vary by age for OS (younger than age 70 v 70+ interaction P = .039). There was a similar trend for DFS (interaction P = .073). Oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80; 95% CI, 0.68 to 0.95; P = .013), but no positive effect was evident in older patients. CONCLUSION Overall, the addition of oxaliplatin to FULV has not been proven to extend OS in this trial, but the DFS effect remained strong. Unplanned subset analyses suggest a significant OS effect of oxaliplatin in patients younger than age 70.

Pulmonary toxicity induced by mitomycin C is highly responsive to glucocorticoids

The authors have studied five cases of biopsy‐proven pulmonary toxicity caused by the administration of mitomycin C (M), vincristine, and cisplatin in 64 patients with advanced non‐small cell lung cancer. The clinical triad of progressive dyspnea, rales, and pulmonary infiltrates presented in all five cases. In addition, pulmonary function tests showed hypoxemia (four/five), reduced forced vital capacity (three/four), total lung capacity (two/three), and forced expiratory volume (FEV1) (three/four) and very profound reduction in diffusion capacity (three/three). Transbronchial biopsy for tissue examination was necessary to rule out other causes. Characteristics but nonspecific pathologic changes were documented in all five cases. All the patients responded quickly and dramatically to high‐dose glucocorticoids with improvement of hypoxia, dyspnea, exercise tolerance, and sense of well being. In three patients the pulmonary infiltrates cleared. However, abrupt stopping or early withdrawal of steroid resulted in aggravation of dyspnea and pulmonary infiltrate in three cases who improved subsequently with escalation of steroid doses. The authors conclude that the treatment of choice for pulmonary toxicity induced by M or M‐containing chemotherapy regimens is a high dose of glucocorticoid and discontinuation of M at once when suspicion is raised. Cancer 57:2285–2290, 1986.

Prevention of Delayed Nausea: A University of Rochester Cancer Center Community Clinical Oncology Program Study of Patients Receiving Chemotherapy

PURPOSE We conducted a double-blind randomized clinical trial of the following four regimens for controlling delayed nausea (DN): group 1: palonosetron + dexamethasone on day 1 with prochlorperazine on days 2 and 3; group 2: granisetron + dexamethasone on day 1 with prochlorperazine on days 2 and 3; group 3: aprepitant + palonosetron + dexamethasone on day 1 with aprepitant + dexamethasone on days 2 and 3; and group 4: palonosetron + dexamethasone on day 1 with prochlorperazine + dexamethasone on days 2 and 3. PATIENTS AND METHODS Chemotherapy-naive patients received doxorubicin, epirubicin, cisplatin, carboplatin, or oxaliplatin. The primary end point was average nausea assessed four times daily on days 2 and 3. Primary analyses were whether nausea control would be improved by using palonosetron versus granisetron on day 1 (group 1 v group 2); by adding dexamethasone on days 2 and 3 (group 1 v group 4); and by using aprepitant versus prochlorperazine (group 3 v group 4). Statistical significance was set at P = .017. RESULTS Two hundred thirty-four, 234, 241, and 235 evaluable patients were accrued to groups 1, 2, 3, and 4, respectively. Adjusted mean differences for the three planned analyses were as follows: palonosetron versus granisetron: -0.01 (95% CI, -0.23 to 0.20; P = .72); adding dexamethasone on days 2 and 3: 0.20 (95% CI, -0.02 to 0.41; P = .01); and using aprepitant versus prochlorperazine: -0.03 (95% CI, -0.24 to 0.19; P = .56). CONCLUSION The addition of dexamethasone on days 2 and 3 reduced DN. Palonosetron and granisetron have similar effects on DN. The beneficial effect of adding aprepitant for control of DN was the same as adding prochlorperazine.

Prospective Multicenter Study of the Impact of Oncotype DX Colon Cancer Assay Results on Treatment Recommendations in Stage II Colon Cancer Patients

The Oncotype DX colon cancer assay is a clinically validated predictor of recurrence risk in stage II colon cancer patients. This prospective study evaluated the impact of recurrence score (RS) results on physician recommendations regarding adjuvant chemotherapy in T3, mismatch repair-proficient (MMR-P) stage II colon cancer patients. Patients and Methods. Stage IIA colon cancer patients were enrolled in 17 centers. Patient tumor specimens were assessed by the RS test (quantitative reverse transcription-polymerase chain reaction) and mismatch repair (immunohistochemistry). For each patient, the physicians recommended postoperative treatment plan of observation, fluoropyrimidine monotherapy, or combination therapy with oxaliplatin was recorded before and after the RS and mismatch repair results were provided. Results. Of 221 enrolled patients, 141 patients had T3 MMR-P tumors and were eligible for the primary analysis. Treatment recommendations changed for 63 (45%; 95% confidence interval: 36%-53%) of these 141 T3 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy decreased from 73 patients (52%) to 42 (30%), following review of RS results by physician and patient. Increased treatment intensity was more often observed at higher RS values, and decreased intensity was observed at lower values (p = .011). Conclusion. Compared with traditional clinicopathological assessment, incorporation of the RS result into clinical decision making was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients in this prospective multicenter study. Use of the RS assay may lead to overall reduction in adjuvant chemotherapy use in this subgroup of stage II colon cancer patients.

Severe enteropathy among patients with stage II/III colon cancer treated on a randomized trial of bolus 5-fluorouracil/leucovorin plus or minus oxaliplatin: a prospective analysis.

Cases of severe gastrointestinal toxicity were monitored prospectively during NSABP C‐07, a randomized clinical trial of adjuvant therapy for patients with stage II/III colon cancer.

Evaluation of the Combination of Docetaxel/Carboplatin in Patients with Metastatic or Recurrent Squamous Cell Carcinoma of the Head and Neck (SCCHN): A Southwest Oncology Group Phase II Study

Carboplatin/docetaxel chemotherapy was evaluated in advanced squamous cell carcinoma of the head and neck (SCCHN). Eligibility included patients with recurrent, persistent, or metastatic SCCHN with Zubrod performance status 0–2. Docetaxel 65 mg/m2 and carboplatin (AUC of 6) were given IV in a 21-day cycle to 68 patients. Response probability was 25 percent (95%CI: 15–38). The major toxicity observed was neutropenia, with 36 patients (61 percent) experiencing Grade 3 or worse. Median progression-free survival was 3.8 months (95%CI, 3.1–4.8) Median overall survival was 7.4 months (95%CI, 6.2–8.9). The results of this study suggest this regimen is active for outpatient treatment of recurrent SCCHN patients with good performance status.

Evaluation of Gemcitabine in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: A Southwest Oncology Group Phase II Study

A phase II trial of gemcitabine(Gemzar®), a nucleoside analogue with broadactivity in solid tumors, was performed inpatients with recurrent or metastaticsquamous cell carcinoma of the head andneck. A total of 26 eligible patients wereregistered to receive a dose of1250 mg/m2 weekly for 3 weeks,followed by a 1 week rest. Toxicity wasevaluable in 26 patients. Nausea andvomiting occured in 11 and 6 patients,repectively. Grade 3 or 4 hematologictoxicities were infrequent. Two patientsdeveloped neutropenic infections. Onepatient developed fatal liver failure whichwas thought due to progressive livermetastases or infection 14 days after asingle dose of gemcitabine. There were noobjective treatment responses (95% CI0–13%), with a median survival of 6 monthsin this highly resistant diseasepopulation. Gemcitabine is not consideredactive enough as monotherapy for furtherevaluation in this disease population.

Phase ii evaluation of a combination of mitomycin C, vincristine, and cisplatin in advanced non‐small cell lung cancer

The combination treatment of mitomycin C (M), vincristine (V), and cisplatin (P) (MVP) in 63 patients with advanced non‐small cell lung cancer (NSCLC) were evaluated for their potential synergistic cytotoxicity. The overall response rate was 43% (27/63); in the 54 eligible and evaluable patients, the response rate was 50% (27/54). Responses were observed in all cell types and disease sites. Cell type; performance status of 0, 1, or 2; sex; and age younger or older than 60 years did not significantly influence the response rate. However, patients with prior radiation had significantly more treatment failure than those without. The dose‐limiting side effects in these 54 patients were myelosuppression (40%), pulmonary fibrosis (9%), peripheral neuropathy (6%), and intractable nausea and vomiting (4%). The degree of leukopenia (P < 0.01) but not of thrombocytopenia increased significantly in patients who had received prior radiotherapy. One patient died ofMarked thrombocytopenia and one of fulminant hepatitis. Patients who responded lived significantly longer than those who did not (P < 0.004). Amajority of the responders (82%) also achieved symptomatic palliation. With appropriate dose modification and supportive care, MVP was tolerable. Further trials with this regimen or a modified version are worth consideration.

Effect of interferon alpha, interferon beta, and interferon gamma on the in vitro growth of human renal adenocarcinoma cells

Interferon-α, interferon-β, and interferon-γ differ in their antiproliferative effects for several cell lines. Interferons were thus assessed for their activity in inhibiting proliferation of three renal cell carcinoma cell lines. The malignant epithelial phenotype of each of these cell lines was confirmed by electron microscopy, histology, karyotype and tumorigenicity. When compared on an anti-viral unit basis, naturally produced interferon-β was more effective than natural interferon-α for all cell lines and clones. Proliferation of each of the cell lines was inhibited by interferon-γ. In all cases, removal of interferons from culture media resulted in resumption of the rate of cell growth after a variable delay of 6–10 days. If the antiproliferative effects of interferons predominate in mediating tumor regression, clinical response may depend upon the type of interferon to which the tumor is exposed.