SUMMARY: The American Cancer Society's estimates 40,000 new cases of rectal cancer in the United States for 2014. Rectal cancer diagnosed at an early stage such as Stage II (T3-T4, N0) or Stage III (Node positive disease without distant metastases) is potentially curable with a combination of neoadjuvant (preoperative) chemoradiation, surgery and postoperative chemotherapy. Unlike colon cancer, the risk of locoregional recurrence is high in rectal cancer due to its close proximity to the surrounding pelvic organs and difficulty in obtaining a clear surgical margins. Further, there is no serosal tissue surrounding the rectum. For all these reasons, preoperative Radiation Therapy (RT) with concurrent fluoropyrimidine based chemotherapy as a radiosensitizer followed by postoperative chemotherapy (total of 6 months of perioperative chemotherapy) has been the standard intervention. Infusional 5 Fluorouracil (5-FU) is often incorporated with concurrent radiation. This however is cumbersome and inconvenient for the patients. The NSABP protocol R-04 trial is a four arm phase III trial in which 1608 patients with clinical stage II or III rectal cancer undergoing preoperative RT were randomly assigned to one of four chemotherapy regimens – Continuous Infusion (CI) 5-FU 225mg/m2 over 24 hours, 5 days a week x 5 weeks (N=477), CI 5-FU with IV Oxaliplatin (ELOXATIN®) 50mg/m2 /wk x 5 weeks (N=329), Capecitabine (XELODA®) 825 mg/m2 PO BID 5 days/wk x 5 weeks (N=472) or XELODA® with ELOXATIN®, x 5 weeks (N=330). Radiation therapy consisted of 4,500cGy in 25 fractions over 5 wks plus a boost. The primary goals of this study were to compare preoperative XELODA® and CI 5-FU given along with concurrent pelvic RT and also determine whether ELOXATIN® would be of additional benefit. The primary endpoint of local-regional tumor control included locoregional tumor recurrence, less than complete surgical resection and no surgery. When combined with RT, this study showed no significant differences in local-regional tumor control, Disease Free Survival or Overall Survival between infusional 5-FU and XELODA® given alone or in combination with ELOXATIN®. The addition of ELOXATIN® was however associated with significantly more grade 3-4 diarrhea (P<0.0001). The authors concluded that outcomes and toxicities are similar with CI 5-FU or oral XELODA® when combined with RT. The addition of ELOXATIN® did not improve outcomes but resulted in significant toxicity. Oral XELODA® therefore obviates the need for central venous access and ambulatory infusion pumps and makes it more convenient for the patients without compromising efficacy. Allegra CJ, Yothers G, O'Connell MJ, et al. J Clin Oncol 32, 2014 (suppl 3; abstr 390)
Tag: Rectal Cancer
Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC) The phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG)
SUMMARY: Treatment of metastatic colorectal cancer with a combination of chemotherapy given along with AVASTIN® is well established. However the duration of therapy remains unclear and it is common to give drug holidays to patients. The outcome in patients who are given these drug holidays remains unclear. The CAIRO3 study is a phase III trial in which patients with previously untreated, unresectable metastatic colorectal cancer received induction treatment with six cycles of Capecitabine (XELODA®)/Oxaliplatin (ELOXATIN®) plus Bevacizumab (AVASTIN®) – CAPOX-B. Patients who had not progressed during induction and had reponses or had stable disease (N=558) were then randomized to receive either XELODA® at 625 mg/m2 twice daily along with AVASTIN® at 7.5 mg/kg every 3 weeks or be observed. Upon first progression, patients in both treatment groups were treated with CAPOX-B until second progression and this was considered the primary endpoint for this study. Secondary endpoints included Overall Survival (OS). Median follow up was 40 months. The median time to second progression from randomization was 19.8 months in the maintenance group and 15 months in the observation group (HR=0.63; P<0.001) The time to first progression in the maintenance treatment group was 8.5 months versus 4.1 months in the observation group (HR 0.41; P<0.001). The time to second progression following treatment with CAPOX-B was 11.8 months in the maintenance group versus 10.5 months for the observation group (HR 0.77; P=0.007), representing a 23% reduction in the risk of progression. The adjusted median OS was 21.7 months with maintenance treatment and 18.2 months in the observation group (HR=0.80; P=0.035). Treatment was well tolerated with slight increase in hand-foot syndrome and neurotoxicity in the maintenance group. Based on this data, the authors recommended maintenance treatment with XELODA® and AVASTIN® until progression or unacceptable toxicity, following 6 cycles of efficacious treatment with CAPOX-B. It is important to note that in the SAKK 41/06 trial conducted by the Swiss Group, observation alone was non-inferior to single agent maintenance AVASTIN® following initial chemotherapy, suggesting that the addition of fluoropyrimidine (XELODA®) chemotherapy to AVASTIN® as maintenance treatment, improves time to progression and median OS in patients with metastatic colorectal cancer. Koopman M, Simkens LH, Ten Tije, AJ et al. J Clin Oncol 31, 2013 (suppl; abstr 3502)
AVASTIN® (Bevacizumab)
The FDA on January 23, 2013 approved AVASTIN® for use in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy, for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first-line AVASTIN® – containing regimen. The FDA initially approved AVASTIN® in 2004 for the first-line treatment of patients with metastatic carcinoma of the colon and rectum (in combination with intravenous 5-fluorouracil-based chemotherapy). AVASTIN® is a product of Genentech U.S., Inc.
ERBITUX® (Cetuximab)
The FDA on July 9, 2012 granted approval to ERBITUX® for use in combination with FOLFIRI (CAMPTOSAR® [Irinotecan], 5-fluorouracil, leucovorin) for first-line treatment of patients with K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use. ERBITUX® is a product of Eli Lilly and Co.
STIVARGA® (Regorafenib)
The FDA on September 27, 2012 approved STIVARGA® (Regorafenib) for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, ELOXATIN® (Oxaliplatin)-, and CAMPTOSAR® (Irinotecan)-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. STIVARGA® tablets are a product of Bayer HealthCare Pharmaceuticals, Inc.
ZALTRAP® (Ziv-aflibercept injection)
The FDA on August 3, 2012 approved ZALTRAP® (Ziv-aflibercept injection), for use in combination with 5-fluorouracil, leucovorin, CAMPTOSAR® (Irinotecan) (FOLFIRI) for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin containing regimen. ZALTRAP® is a product of Sanofi U.S., Inc.
ZALTRAP® for second line treatment of metastatic CRC
ZALTRAP® (Aflibercept) is a soluble fusion protein that is capable of binding with high affinity to pro-angiogenic factors such as all VEGF-A isoforms, VEGF-B, and PlGF. This is unlike bevacizumab, which is a monoclonal antibody that only targets all isoforms of VEGF-A. In the VELOUR trial, second-line chemotherapy in combination with ZALTRAP® (Aflibercept) demonstrated significant improvement in the progression-free survival as well as overall survival compared to chemotherapy alone. This benefit was seen irrespective of prior bevacizumab therapy. This data was presented at the 13th ESMO world congress.
Regorafenib improves survival in advanced CRC
The CORRECT trial is a randomized phase III study which demonstrated improved survival with Regorafenib, an oral multikinase inhibitor when compared to placebo, in individuals with advanced colorectal cancer, who had progressed on all available standard therapies. This important study gives a new option for individuals with advanced colorectal cancer. Additional data will be presented at ASCO 2012 meeting.
Oncoprescribe Blog To treat or not to treat Stage II colon cancer? – Molecular Markers to the rescue
As we understand the molecular biology of colon cancer, it is becoming clear that tumors with MisMatch Repair Deficiency (MMR-D) and high MicroSatellite Instability (MSI) tend to have a favorable prognosis and do not benefit from chemotherapy and on the contrary, 5-FU based chemotherapy may potentially result in a detrimental effect. The Oncotype DX colon cancer 12 gene assay is a valuable tool that can provide additional information in the decision making process.
Oncoprescribe Blog Will BRAF trump KRAS testing in Metastatic Colon Cancer?
Testing for KRAS mutations is presently the standard of care prior to treatment with anti EGFR monoclonal antibodies such as cetuximab and panitumumab, as KRAS mutant colorectal tumors do not respond to anti EGFR monoclonal antibodies. However it is becoming clear that BRAF which is involved in intracellular signaling and cell growth and a principal downstream mediator of KRAS, when mutated resulted in shorter progression free survival and overall survival regardless of KRAS status. Targeted therapy may be taking a turn for the better making treatment more personalized.