Adjuvant Oxaliplatin Research Articles

Adjuvant capecitabine and oxaliplatin for gastric cancer: Results of the phase III CLASSIC trial.

LBA4002 Background: Surgical resection is a recommended treatment for operable gastric cancer (GC) in general, despite high recurrence rates (40%–80%). Adjuvant chemotherapy aims to reduce recurrences; however, there is currently no universally accepted adjuvant regimen for GC. Methods: CLASSIC is a randomized, open-label, multicenter, international (South Korea, China, and Taiwan) study of XELOX (capecitabine 1000mg/m2 bid, d1–14, q3w and oxaliplatin 130mg/m2, d1, q3w x 8 cycles) vs observation, following D2 gastrectomy. Eligible patients were chemotherapy- and radiotherapy-naive, with stage II (T2N1, T1N2, T3N0), IIIa (T3N1, T2N2, T4N0), or IIIb (T3N2) GC resected within 6 weeks prior to randomization. The primary endpoint is 3-year disease-free survival (DFS). A sample size of 512 patients per arm was planned to observe the 385 DFS events required to provide 80% power at a 5% significance level for the hypothesized treatment effect (hazard ratio [HR] 0.75). The Independent Data Monitoring Committee recommended full evaluation and reporting of results following a positive pre-planned interim analysis at 266 events. Results: The XELOX and observation arms (ITT populations of 520 and 515 patients, respectively) were well balanced for baseline characteristics. The median duration of follow-up was 34.4 (16–51) months. XELOX-related grade 3/4 adverse events (AEs) occurred in 244/496 patients (49%) of the safety population. Neutropenia was the only AE observed in >10% of patients (21%, n=106/496). Serious XELOX-related grade 3/4 AEs occurred in 34/496 patients (7%). There were 62/496 (13%) and 80/476 (17%) deaths on study in the safety populations of XELOX and observation arms, respectively, mostly due to disease progression. Efficacy results in the ITT population are summarized below. Conclusions: This study demonstrates the superior efficacy of adjuvant XELOX vs observation alone following D2 gastrectomy. Although OS data are still immature, there is a trend towards superiority of XELOX. These data support the use of adjuvant XELOX for GC. [Table: see text]

Failure of bevacizumab in early-stage colon cancer

A randomized phase III trial of patients with stage II and III colon cancer showed no benefit of adding bevacizumab to standard adjuvant oxaliplatin plus fluorouracil and leucovorin. Despite suggestive evidence of a short-term benefit, these data and other similar findings dictate that adjuvant bevacizumab should not be used in colon cancer.

Adjuvant oxaliplatin- or irinotecan-containing chemotherapy improves overall survival following resection of metachronous colorectal liver metastases

PurposeAdjuvant systemic 5-fluorouracil (5-FU)-based chemotherapy improves survival after resection of synchronous colorectal liver metastases (CLMs), but not metachronous. We retrospectively examined if adjuvant chemotherapy with new regimen containing oxaliplatin or irinotecan improved survivals after resection of metachronous CLMs.MethodsBetween 2000 and 2007, 52 patients having undertaken resection of metachronous CLMs with curative intent were identified from Taipei Veterans General Hospital hospitalization registry. One patient with perioperative mortality and another being lost to follow-up within 3 months after metastasectomy were excluded. Thirty-one patients experienced six to 12 cycles of FOLFOX or FOLFIRI chemotherapy while 19 patients with 5-FU/leucovorin (LV)-based chemotherapy following CLM resection. The primary end point was disease-free survival (DFS) and secondary end point, overall survival (OS).ResultsBy the univariate analysis, median DFS was 34.3 months in the FOLFOX/FOLFIRI group vs 14.2 months in the 5-FU/LV group (P = 0.022). The median OS and 5-year survival rates were longer than 57.7 months (not reached, with median follow-up of 35.5 months) and 54.0%, respectively, in the FOLFOX/FOLFIRI group compared to 49 months and 34.6% in the 5-FU/LV group (P = 0.027). FOLFOX/FOLFIRI chemotherapy was shown by multivariate analyses to be an independent factor predicting a better DFS (hazard ratio [HR] = 0.37; 95% CI: 0.15–0.94; P = 0.036) and a better OS (HR = 0.27; 95% CI: 0.083–0.86, P = 0.026) than 5-FU/LV-based.ConclusionsAdjuvant FOLFOX/FOLFIRI chemotherapy following resection of metachronous CLMs is demonstrated to have better DFS and OS than 5-FU/LV chemotherapy.

Comparative effectiveness of adjuvant oxaliplatin and irinotecan-based chemotherapy regimens among elderly stage III colon cancer patients completing 12 cycles.

e14069 Background: Randomized controlled trials and real world comparative effectiveness studies have suggested survival benefits with adjuvant oxaliplatin (OX)-based regimen in stage III colon cancer patients. However, patients in routine clinical practice may experience early discontinuation of therapy due to adverse events or other reasons. Our aim was to compare survival among colon cancer patients on OX and irinotecan (IRI)-based regimens who received at least 12 cycles of chemotherapy. Methods: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify stage III colon cancer patients older than 65 who were diagnosed between 2002 and 2005, with follow-up through 2007. Patients who received at least 12 cycles of OX (n = 439) or IRI-based regimen (n = 142) after surgery were included. The primary outcomes were survival time from initiation of chemotherapies to all-cause death, colon cancer-specific death, and non-colon cancer death. Cox proportional hazards models, adjusting for patient and clinical characteristics, were used to comparing the survival benefit between OX and IRI- based combination therapy. Results: The crude event rates for all-cause death per 100 person years were 6.7 and 15.2 among OX and IRI-based regimen users, respectively. The crude event rates for colon cancer-specific death per 100 person years were 0.5 among OX- based and 8.4 among IRI-based regimen users. The adjusted overall survival and non-colon cancer survival between OX-based and IRI-based regimen in stage III colon cancer patients who received at least 12 cycles of chemotherapies were comparable. However, the point estimate suggests that OX-based regimen (HR, 0.31; 95% CI, 0.10-1.00; p = 0.049) had more favorable colon cancer-specific survival benefit than IRI-based regimen. Conclusions: There appears to be a comparative effectiveness benefit of OX-based versus IRI-based regimens among elderly stage III colon cancer patients who receive chemotherapy at least 12 times. The survival benefit reflects a wide range of possible magnitudes and is impacted by a variety of patient and treatment-related characteristics. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis Amgen, Bayer, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, sanofi-aventis sanofi-aventis Pfizer, sanofi-aventis GlaxoSmithKline, Novartis, Pfizer, sanofi-aventis

Treatment of colorectal cancer – ASCO 2009

Colorectal cancer is a curable disease in stage II and stage III with higher cure rates if adjuvant chemotherapy is administered and that in most cases is treated with palliative intention in stage IV. Addition of bevacizumab, a vascular endothelial growth factor (VEGF) antibody, prolongs progression-free survival in stage IV when added to chemotherapy. Results of the NSABP study C-08 show that bevacizumab does not improve outcome when added to adjuvant chemotherapy in stage II and stage III colon cancer. Oxaliplatin led to a prolongation of progression-free survival and to improved response rates when added to 5-FU in stage IV colorectal cancer. In contrast, addition of oxaliplatin to 5-FU-based radiotherapy in neoadjuvant treated locally advanced rectal cancer did not improve the response rate. Survival results with adjuvant oxaliplatin in rectal cancer need to be awaited. Th e addition of oxaliplatin to 5-FU-based adjuvant chemotherapy in stage II (high risk) and stage III colon cancer became a standard of care after results of two randomized studies had been published. Current results suggest that the benefi t of adding oxaliplatin in patients >70 years is vanishing and 5-FU/folonic acid alone should be considered the standard of care in the adjuvant treatment of elderly patients. Cetuximab and panitumumab are two epidermal growth factor receptor (EGFR) directed monoclonal antibodies with proven activity in stage IV colorectal cancer. K-Ras mutations indicate resistance to anti-EGFR-directed antibodies. New molecular markers like the expression of the EGFR ligands epiregulin and amphiregulin, the expression of insulin-like growth factor-1 (IGF-1) and mutations of b-RAF and n-RAS may complement the panel of markers for the selection of patients who benefi t from anti-EGFR treatment.

Colon cancer and the elderly: From screening to treatment in management of GI disease in the elderly

Colorectal cancer is one of the commonest tumours in the Westernized world affecting mainly the elderly. This neoplasm in older individuals occurs more often in the right colon and grows more rapidly than in the young, often shows a mucinous histology and mismatch repair gene changes. Effective screening permits discovery of colorectal cancer at an early highly treatable stage and allows for detection and removal of premalignant colorectal adenomas. Screening methods that focus on cancer detection use fecal assays for the presence of blood or altered DNA, those for detection of adenomas (and early cancer) use endoscopic or computerised radiologic techniques. Broad use of screening methods has lowered colorectal cancer development by about 50%. In addition, prevention of the earliest stage of colon carcinogenesis has been shown to be effective in small prospective studies and epidemiologic surveys but have not been employed in the general population. Since 1996 the chemotherapeutic armamentarium for metastatic colorectal cancer has grown beyond 5-fluorouracil to include an oral 5-fluorouracil prodrug, capecitabine as well as irinotecan and oxaliplatin. Three targeted monoclonal antibodies (Moabs), bevacizumab (an anti-vascular endothelial growth factor Moab) and cetuximab/panitumumab, both anti-epidermal growth factor receptor inhibitors, have also earned regulatory approval. Most stage IV patients are treated with all of these drugs over 2 or 3 sequential lines of palliative chemotherapy and attain median survivals approaching 24 months. Lastly, adjuvant oxaliplatin plus 5-fluorouracil for high risk resected stage II and stage III colon cancer patient has led to substantial improvement in cure rates. With appropriate care of age associated comorbidities these treatment modalities are feasible and effective in the geriatric population.

Bevacizumab and Postoperative Complications After Hepatic Surgery for Colorectal Metastases

TO THE EDITOR: I congratulate Kesmodel et al from The University of Texas M. D. Anderson Cancer Center concerning their recent article in Journal of Clinical Oncology proposing that preoperative bevacizumab does not significantly increase postoperative complications in patients undergoing liver surgery for colorectal cancer metastases. The congratulations are not due to the superiority of their data, but importantly to their self-criticism of the data. The authors concluded that neither the use of bevacizumab nor the timing of bevacizumab administration increases surgical complication rates. However, they qualify their statement by relating that confirmatory prospective studies are required. This is important because in the discussion section of their article, they indeed relate that because their study is retrospective from a single institution with a small number of patients (81 patients in the chemotherapy-plus-bevacizumab group and 44 patients in the chemotherapy-alone group), definitive conclusions about the safety of neoadjuvant bevacizumab and its timing of discontinuation cannot be made. Since the type of chemotherapy, the decision to use bevacizumab, and the duration of chemotherapy and bevacizumab administration, along with the timing of surgical consultation, are at the discretion of the treating physician, the conclusion of their manuscript is preliminary and, as they have stated, must be confirmed prospectively. This group of investigators has a significant experience with hepatic resection of colorectal metastases and continues to recommend waiting at least 6 weeks from discontinuation of bevacizumab before hepatic resection is performed. We certainly can learn from retrospective series, but to the credit of these authors, the self-criticism of their data is laudable. Unfortunately, this is not the case with many retrospective series that appear in the literature, whereupon readers will take the conclusions as definitive. Many of the issues discussed by the authors of this article will be part of the aims of an NCI phase III clinical trial to evaluate neoadjuvant versus adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab in patients with potentially resectable hepatic colorectal metastases. The concept of this trial was developed by the Gastrointestinal Leadership of the National Surgical Adjuvant Breast and Bowel Project, American College of Surgeons Oncology Group, and the North Central Cancer Treatment Group. This trial has received approval by the National Cancer Institute Colon Task Force and will soon be presented to the National Cancer Institute Gastrointestinal Steering Committee for discussion. The trial will randomly assign patients with resectable colorectal hepatic metastases to FOLFOX plus bevacizumab before resection followed by the same combination postoperatively versus hepatic resection first followed by postoperative FOLFOX plus bevacizumab. Although the primary end point will be progression-free survival, many secondary end points will be evaluated, including perioperative morbidity related to the agents utilized. I congratulate the authors for discussing the shortcomings of their retrospective review, which should be an example for other authors.

Postoperative Adjuvant Gemcitabine Plus Oxaliplatin (GemOx) Chemotherapy Followed by Chemoradiation in Patients with Pancreatic Adenocarcinoma: Final Results of a Single Arm Multicenter Phase II Study

Postoperative Adjuvant Gemcitabine Plus Oxaliplatin (GemOx) Chemotherapy Followed by Chemoradiation in Patients with Pancreatic Adenocarcinoma: Final Results of a Single Arm Multicenter Phase II Study

Oxaliplatin in combination with 5-fluorouracil (FU) in a 48-hour continuous infusion (CI) as first-line chemotherapy for elderly patients (pts) with metastatic colorectal cancer (mCRC). TTD phase II trial

4057 Background: We previously reported a 35% overall response rate (ORR) with 5-FU CI (TTD schedule without modulation) plus CPT-11 as first line therapy in elderly pts with mCRC (Sastre et al. J Clin Oncol 23; 3545–51, 2005). The present study was carried out also in elderly pts to determine the efficacy (ORR as primary endpoint) and safety of oxaliplatin in combination with the same 5-FU schedule. Methods: Pts >72 y. with histologically confirmed mCRC, measurable disease, ECOG < 0–2, no previous adjuvant oxaliplatin and no prior treatment for metastatic disease. Treatment: Oxaliplatin 85 mg/m2 plus 5-FU 3,000 mg/m2 as a 48-hour CI q2w until progressive disease, undesirable toxicity or consent withdrawal. Results: 134 pts were included and 129 (96%) were eligible. Median age: 76y (72–85), male/female: 63/37%, and ECOG 0/1/2: 42/53/5%. Main comorbidities were hypertension (44%), diabetes (17%) and EPOC (11%). Median No of metastatic locations was 1 (37% with > 2 sites) mainly located in liver (77%) and lung (29%). 21% of pts received previous adjuvant chemotherapy. Efficacy: On an ITT analysis of 129 pts, ORR and control disease (ORR+SD) were 52% and 80% respectively. With a median follow-up of 14 months, median progression free survival and overall survival were 9 and 16.2 months respectively. 48 pts (37%) received 2 or more lines of chemotherapy mainly based in CPT-11. Seven pts (5.4%) followed resection of liver metastasis, of which 5 were complete. Grades 3–4 toxicities included anemia (2%), asthenia (9%), neutropenia (17%), febrile neutropenia (2%), thrombocytopenia (5%), diarrhoea (11%), nausea/vomiting (5/4%) and neurotoxicity grade 3 (18%). There was one treatment related death (pneumonia). Conclusion: To our knowledge this is the largest phase II prospective study in elderly pts with mCRC. The schedule seems to be effective and compared favourably with those reported in the literature in this population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis

3540 POSTER Postoperative adjuvant gemcitabine plus oxaliplatin (GemOx) chemotherapy followed by chemoradiation in patients with pancreatic carcinoma: mature results of a multicenter phase II study

3540 POSTER Postoperative adjuvant gemcitabine plus oxaliplatin (GemOx) chemotherapy followed by chemoradiation in patients with pancreatic carcinoma: mature results of a multicenter phase II study

Postoperative adjuvant gemcitabine plus oxaliplatin (GemOx) chemotherapy followed by chemoradiation in patients with pancreatic carcinoma: A multicenter phase II study

4520 Background: Gemcitabine (Gem) is an active drug in metastatic pancreatic cancer and a very good radiosensitizer. We evaluated the safety and potential activity of adjuvant GemOx chemotherapy followed by concurrent Gem and irradiation (RT) after curative resection of pancreatic cancer. Methods: Fifty four patients were enrolled from October 2002 to January 2005 in this trial with potentially curative resection of pathologically confirmed adenocarcinoma of the pancreas with negative resection margins (R0). Gem 1000 mg/m2 (100 min) on d1 then Ox 100 mg/m2 (120 min) on d2 were given (q2w for 6 cycles) followed 4 weeks after by Gem 100 mg/m2 (30 min) combined with RT 50 Gy (2Gy fraction) for 5 weeks in patients with no residual toxicity nor recurrence. Results: The treated population (at least 2 induction cycles) included 49 patients (91%). Characteristics at baseline: median age: 59.2 yrs; Karnofsky performance status =80: 96%; stage TX: 10%, T1: 8%, T2: 41%, T3:39%; T4: 2% (TNM classification, 5th edition); lymph node positive: 43%; median time from surgery to inclusion was 43 days. Forty six patients (85%) received the 6 planned induction cycles and 41 patients (76%) completed chemoradiation. The recurrence free 1-year survival rate is 71% (N=49); (95% CI 0.581–0 845). Forty one patients (98% of the irradiated population) received the total 50 Gy radiation dose. The most common Gr 3/4 toxicities during induction chemotherapy (N=51) were: neutropenia 18%, thrombocytopenia 14%; nausea, vomiting, diarrhea:16%, neurotoxicity (Gr 3 only) 4%. Acute Gr 3/4 toxicities during chemoradiation (N=42): neutropenia 19%, thrombocytopenia 7.0%, neurotoxicity (Gr 3 only) 7%. No toxic death occurred on treatment. Conclusions: GemOX in adjuvant followed by Gem + Radiotherapy have a manageable toxicity profile with a promising 71% 1 year RFS. Data of OS will be communicated during the meeting. No significant financial relationships to disclose.

Anaphylactic Shock to Oxaliplatin in the Adjuvant Context

Objective: To report a case of anaphylactic shock in a patient receiving oxaliplatin treatment. Case Summary: A 60-year-old Chinese woman received adjuvant oxaliplatin in combination with fluorouracil and folinic acid for treatment of stage 3 colon cancer. Shortly after initiation of her 12th infusion, she developed anaphylactic shock. She has since fully recovered from the adverse drug event. She was not rechallenged with oxaliplatin. Discussion: Severe hypersensitivity reactions to oxaliplatin are rare. An objective causality assessment using the Naranjo probability scale revealed that an adverse drug reaction to oxaliplatin was highly probable. Based on the Common Terminology Criteria for Adverse Events version 3 for defining reaction severity, our patient had experienced a grade 4 reaction, or anaphylaxis. Conclusions: With more widespread use of oxaliplatin in the treatment of early stage as well as advanced disease, the potential for more instances of severe hypersensitivity reactions exists, although the percentage of grade 4 reactions will likely remain rare. The role of intradermal skin testing to predict oxaliplatin sensitivity and the implementation of oxaliplatin desensitization protocols in cases of severe hypersensitivity reactions to this drug in the adjuvant setting may be useful.

Is There a Role for Routine p53 Testing in Colorectal Cancer?

The availability of new and more effective chemotherapeutic and molecular targeted agents has resulted in improved treatment of regional and advanced colorectal cancer. However, thefinancial cost and the morbidity associated with the new treatments have increased as well, and to date no reliable marker capable of selecting patients who will benefit from a specific treatment has been identified. Individualizingtreatmentbasedonthemolecularprofileof the patient and the tumor could lead to considerable improvement in treatment cost and outcomes. Although all patients with colorectal cancer would benefit from better prognostic and predictive markers, risk-benefit is particularly important for candidates for adjuvant therapy, which may expose patients already cured by surgery to unnecessary risk or to a treatment that fails to maximize their chances of cure from micrometastasis. The use of adjuvant oxaliplatin regimens after resection of stage II or III colon cancer is a good example of this clinicalconundrum.Theadditionofoxaliplatintofluorouracil and leucovorin improves the 3-year disease-free survival rate, and has been approved for high-risk resected coloncancerbytheUSFoodandDrugAdministration,but it is clear that not all patients benefit equally from oxaliplatin. In fact, when patients already cured by surgery alone and patients who experience disease recurrence despite treatment are excluded, fewer than 30% of stage II and III patients actually benefit from the use of any adjuvant chemotherapy.Unfortunately,wecurrentlyhavenopracticalwayofidentifyingthosewhowillandthosewhowillnot benefit from the treatment. We still identify which patients should receive adjuvant chemotherapy by their pathologic staging, a tool that has changed little since originally proposed by Dukes more than 70 years ago. 1 The choice of the chemotherapy regimen to be used also lacks sophistication and the currently accepted regimens are applied to the entire patient population without consideration for individual tumor sensitivity or for the patient’s tolerance for

Hypersensitivity Reactions to Oxaliplatin in Two Asian Patients

To report 2 cases of hypersensitivity reactions associated with oxaliplatin treatment in Asian patients. A 33-year-old Chinese woman received adjuvant oxaliplatin in combination with fluorouracil and leucovorin. Shortly during her sixth infusion, she developed a severe hypersensitivity reaction. Despite prophylactic measures, she developed another reaction of similar severity during her subsequent infusion and was not further rechallenged with oxaliplatin. The second case involved a 45-year-old Malay woman who received oxaliplatin, fluorouracil, and leucovorin for metastatic colorectal cancer. Shortly during her ninth infusion, she developed a mild hypersensitivity reaction. With prophylactic measures, she developed less marked reactions with her subsequent 3 infusions. Hypersensitivity reactions to oxaliplatin have been reported to be between 12% and 16% in the Western population. As of April 20, 2005, there are only 2 previously published reports of hypersensitivity reactions to oxaliplatin in 6 Asian patients. The incidence rates of such reactions in different Asian ethnic groups could vary. The cumulative dose, time of exposure to oxaliplatin, and clinical features were variable and unpredictable in all of the reported Asian patients who developed hypersensitivity reactions. An objective causality assessment using the Naranjo probability scale revealed that oxaliplatin was the highly probable cause of hypersensitivity in the 2 Asian patients reported by our center. Patients who develop mild to moderate reactions can be rechallenged with the drug administered as a slow infusion with prophylactic measures. Desensitization may allow patients who experience severe hypersensitivity reactions to oxaliplatin to further receive effective therapy for their colorectal cancer.

Compliance to chemotherapy with oxaliplatin and 5 fluorouracil in patients with advanced rectal cancer who have received prior high-dose pelvic radiotherapy

3747 Background: Pelvic radiotherapy (RT) may compromise the compliance and effectiveness of future chemotherapy (CT). Patients and Methods: 20 patients (15 male, 5 female), mean age 69 yrs (range 51–75) were studied in a prospective, multicenter, phase II study. All patients had recurrent or metastatic diease. All had received previous pelvic RT: 45Gy 25 fx (15), 45 Gy 30 fx (3), 45 Gy 20 fx (2) and 25 Gy 5 fx (1) at a 16 months prior to this study. Most patients had received concurrent chemoradiation (CRT). Patients were treated with a schedule consisting of oxaliplatin 85 mg/m2 on day 1 and 5FU 400 mg/m2 iv bolus and 600 mg/m2 iv 22hour infusion with folinic acid on day 1 and 2. A maximum of eight cycles of CT were administered every two weeks. Results: A median number of 7 cycles of CT was given (range 3–8), with 132 cycles being given in total. There were 8 episodes of grade III neutropaenia (1 with sepsis). There were 4 episodes of grade III/IV diarrhoea, two of which required hospitalisation, but all resolved. In 18 evaluable patients patients the overall response rate was 33% (3 CR; 3 PR), with 2 patients having SD. Conclusion: This study shows that the combination of oxaliplatin, 5FU and folinic acid after high-dose pelvic RT is well tolerated and has comparable efficacy to that seen in other metastatic studies and a dose intensity equal to that achieved in adjuvant studies. Based on the results of this study, adjuvant oxaliplatin is being delivered in a randomised phase III study (CHRONICLE) following CRT. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; Sanofi