Cetuximab Combined With Induction Oxaliplatin and Capecitabine, Followed by Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer: SWOG 0713.

BACKGROUND: Neoadjuvant chemoradiation (NCRT) is standard treatment for locally advanced rectal cancer. Pathologic complete response (pCR) has associated with improved survival. In modern phase III trials of NCRT, pCR ranges from 10% to 20%. Cetuximab improves response in KRAS (KRAS proto-oncogene) wild type (wt) metastatic colorectal cancer. S0713 was designed to assess improvement in pCR with additional use of cetuximab with induction chemotherapy and NCRT for locally advanced, KRAS-wt rectal cancer. PATIENTS AND METHODS: Patient eligibility: stage II to III biopsy-proven, KRAS-wt rectal adenocarcinoma; no bowel obstruction; adequate hematologic, hepatic and renal function; performance status of 0 to 2. Target enrollment: 80 patients. TREATMENT: induction chemotherapy with wCAPOX (weekly capecitabine and oxaliplatin) and cetuximab followed by the same regimen concurrent with radiation (omitting day 15 oxaliplatin). If fewer than 7 pCRs were observed at planned interim analysis after 40 patients received all therapy, the study would close. Eighty eligible patients would provide 90% power given a true pCR rate > 35% at a significance of 0.04. The regimen would lack future interest if pCR probability was ≤ 20%. RESULTS: Between February 2009 and April 2013, 83 patients registered. Four were ineligible and 4 not treated, leaving 75 evaluable for clinical outcomes and toxicity, of whom 65 had surgery. Of 75 patients, 20 had pCR (27%; 95% confidence interval [CI], 17%-38%); 19 (25%) had microscopic cancer; 36 (48%) had minor/no response (including 10 without surgery). Three-year disease-free survival was 73% (95% CI, 63%-83%). CONCLUSION: Our trial did not meet the pCR target of 35%. Toxicity was generally acceptable. This regimen cannot be recommended outside the clinical trial setting.

Randomized phase II trial of a toll-like receptor 9 agonist oligodeoxynucleotide, PF-3512676, in combination with first-line taxane plus platinum chemotherapy for advanced-stage non-small-cell lung cancer.

PURPOSE: This study assessed the efficacy of the combination of standard taxane plus platinum chemotherapy with the synthetic Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB to IV NSCLC were randomly assigned (one to two ratio) to receive four to six cycles of taxane/platinum chemotherapy alone or with 0.2 mg/kg of subcutaneous PF-3512676 on days 8 and 15 of each 3-week cycle. The primary end point was objective response rate (ORR). RESULTS: Baseline demographics were similar between treatment arms, although significantly more patients in the PF-3512676 arm had stage IV disease (85% compared with 62% in the chemotherapy-alone arm). The modified intent-to-treat analysis (n = 111) demonstrated a 38% ORR (confirmed and unconfirmed) in the PF-3512676 arm (n = 74) and 19% in the chemotherapy-alone arm (n = 37) by investigator evaluation. Blinded, independent radiologic review for 90 patients showed a similar trend in confirmed response rate (19% and 11%, respectively). Median survival was 12.3 months in the PF-3512676 arm and 6.8 months in the chemotherapy-alone arm, and 1-year survival was 50% and 33%, respectively. Mild to moderate local injection site reactions and flu-like symptoms were the most common PF-3512676-related adverse events, but grade 3/4 neutropenia, thrombocytopenia, and anemia were all reported more commonly for patients in the PF-3512676 arm. CONCLUSION: The addition of PF-3512676 to taxane plus platinum chemotherapy for first-line treatment of NSCLC improves objective response and may improve survival. Confirmatory phase III trials are ongoing.

Adjuvant therapy for colon cancer 2005: new options in the twenty-first century.

The most effective current regimen for adjuvant treatment of surgically resected stage III colon cancer is the FOLFOX regimen of oxaliplatin, 5-FU and LV for 12 weeks, with a proportional risk reduction of 45% compared with approximately 36% for 5-FU/LV regimens. Infusion regimens of 5-FU with and without LV have been shown to confer equivalent benefit to bolus regimens in reducing the risk of cancer recurrence, but with lesser toxicity profiles. Oral 5-FU prodrug regimens have similarly shown equivalent benefit to bolus regimens, and toxicity comparable to infusional regimens, but with the added convenience over 5-FU infusion therapy. The addition of irinotecan to 5-FU and LV regimens has not demonstrated an advantage compared with 5-FU/LV treatments in the adjuvant setting.

Definitive and neoadjuvant therapies for esophageal and gastroesophageal junction tumors: a look back and toward the future.

This article gives a brief discussion of "state-of-the-art" therapeutic strategies for esophageal and gastroesophageal junction tumors, with an emphasis on combined-modality therapy. In addition, we review the results of a multimodality trial conducted using a new agent against esophageal cancer, oxaliplatin. In this trial, the emphasis was on the efficacy and toxicity of oxaliplatin in combination with protracted infusion 5-fluorouracil and radiation. A secondary endpoint of the study was the relationship between efficacy and toxicity to specific intratumoral gene expressions within the primary esophageal tumor.

Regional chemotherapy is indicated after surgical resection of colorectal metastases to the liver: a debate.

Surgical resection for selected patients with hepatic metastases from colorectal cancer can cure approximately one-fourth of these patients. The addition of regional chemotherapy as an attempt to improve this statistic has been extensively investigated in clinical trials. As part of a multidisciplinary educational program, a series of debates on various topics in oncology are held at the Roswell Park Cancer Institute, Buffalo, New York, involving the medical, surgical, and radiation oncology departments. One such debate focused on the use of regional chemotherapy after potentially curative resection of hepatic metastases from colorectal cancer. The representative medical and surgical oncology fellows (N.I.K. and B.P.M.), with guidance from their respective mentors (C.G.L., J.F.G., and N.J.P.), presented concise reviews from the literature arguing for and against the use of regional chemotherapy in this setting. They appear as Parts 1 and 2 in this article. This exercise is purely educational and does not in any way reflect the opinion or the clinical practice of the authors. .

Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer.

PURPOSE: To identify a dose and schedule of oxaliplatin (OXP) to be safely administered in combination with protracted-infusion (PI) fluorouracil (5-FU) and external-beam radiation therapy (XRT) for patients with primary esophageal carcinoma (EC). PATIENTS AND METHODS: Eligibility included therapeutically naïve EC patients with clinical disease stages II, III, or IV. Initial doses and schedules for cycle 1 consisted of OXP 85 mg/m(2) on days 1, 15, and 29; PI 5-FU 180 mg/m(2) for 24 hours for 35 days; and XRT 1.8 Gy in 28 fractions starting on day 8. At completion of cycle 1, eligible patients could undergo an operation or begin cycle 2 without XRT. Postoperative patients were eligible for cycle 2. Stage IV patients were allowed three cycles in the absence of disease progression. OXP and 5-FU increases were based on dose-limiting toxicity (DLT) encountered in cohorts of three consecutive patients. RESULTS: Thirty-eight eligible patients received therapy: 22 noninvasively staged as IV and 16 noninvasively staged as II and III. Thirty-six patients completed cycle 1, 29 patients started cycle 2, and 24 patients completed cycle 2. The combined-modality therapy was well tolerated, but DLT prevented OXP and 5-FU escalation. No grade 4 hematologic toxicity was noted. Eleven grade 3 and two grade 4 clinical toxicities were noted in eight patients. After cycle 1, 29 patients (81%) had no cancer in the esophageal mucosa. Thirteen patients underwent an operation with intent to resect the esophagus; five patients (38%) exhibited pathologic complete responses. CONCLUSION: OXP 85 mg/m(2) on days 1, 15, and 29 administered with PI 5-FU and XRT is safe, tolerable, and seems effective against primary EC. The role of OXP in multimodality regimens against EC deserves further evaluation.