The ACS recently updated Colorectal Cancer Screening Guideline using prevailing evidence as well as microsimulation modeling analyses. The new guideline does not prioritize among screening test options. This is because test preferences vary among individuals and the guidelines development committee emphasized that screening rates could be improved by endorsing the full range of tests without preference. Adults born around 1990 have twice the risk of colon cancer and four times the risk of rectal cancer compared with adults born around 1950, who have the lowest risk. In the updated guideline, screening is recommended earlier, starting at age 45 years and may be performed with either a high-sensitivity stool-based test or a structural (visual) exam, depending on patient preference and test availability.
Tag: Rectal Cancer
FDA Approves OPDIVO® for MSI-H or dMMR Metastatic Colorectal Cancer
The FDA on July 31, 2017, granted accelerated approval to OPDIVO® (Nivolumab) for the treatment of patients 12 years and older with MisMatch Repair deficient (dMMR) and MicroSatellite Instability-High (MSI-H) metastatic ColoRectal Cancer, that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Patients with metastatic ColoRectal Cancer who have dMMR or MSI-H tumors are less likely to respond to conventional chemotherapy and OPDIVO® demonstrated durable responses and disease control in this heavily pretreated patient group.
Three Months of Adjuvant Therapy Adequate for Stage III Colon Cancer
The IDEA Collaboration is a prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials, which included 12,834 patients from 12 countries. They concluded that a risk-based approach has to be taken when making adjuvant chemotherapy recommendations for patients with stage III colon cancer. Three months of adjuvant chemotherapy is adequate for patients with T1-3, N1 disease. This study data was presented at 2017 ASCO Annual Meeting.
Chemoradiation Alone without Surgery does not Compromise Survival in Selected Patients with Rectal Cancer
SUMMARY: The American Cancer Society estimates 39,910 new cases of Rectal Cancer will be diagnosed in the United States in 2017. 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 and often treated with a combination of neoadjuvant (preoperative) chemoradiation and 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, has been the standard intervention. Radiation consists of 45 Gy delivered in 25 fractions 5 days a week with a 5.4 Gy boost. Concurrent chemotherapy in the US has included 5-FU/Leucovorin, single agent 5-FU or single agent XELODA® (Capecitabine). Complete Response is seen in approximately 25% of the patients who receive chemoradiation. However, 15% to 25% of these patients develop local recurrence. Surgery following chemoradiation may result in long term complications and may necessitate temporary or permanent colostomy in addition to sexual and urinary dysfunction.
The International Watch & Wait Database Consortium was established in 2014 by EURECCA (the European Registration of Cancer Care) and the Champalimaud Foundation in Lisbon. This Consortium which includes 35 institutions in 11 countries was established mainly to collect all available data and expand knowledge on the benefits, risks and oncological safety of organ preserving strategies, in Rectal Cancer. This database as of August 2016 included 775 patients and majority of these patients had stage T2/3 disease (92%) with clinical N0/1 nodal status (75%). Ninety percent of these patients (N=679) had a clinical Complete Response following induction therapy with chemoradiation. These patients did not undergo surgery and were followed up for a median of 2.6 years.
It was noted that 25% of all patients had local recurrence and 84% of these occurred in the first 2 years of follow up. Local recurrence was endoluminal in 96% of the patients and in the loco-regional lymph nodes in 4%. Distant metastasis occurred in 7% of the patients. The 3-year Overall Survival rate was 91% among all patients, and was 87% for patients who experienced local recurrence. These findings are comparable to survival rates seen in patients with a Complete Response, who undergo standard surgery.
It was concluded that in this largest series of patients to date with Rectal Cancer, a “watch-and-wait” strategy to treating Rectal Cancer without surgery, following Complete Response to chemoradiation, resulted in outcomes comparable to historical controls. As more information is gathered, it is important that restaging be performed in all patients with Rectal Cancer who undergo chemoradiotherapy, to prevent unnecessary surgical procedures, and give patients the option for a watch-and-wait approach. The International Watch & Wait database (IWWD) for rectal cancer: An update. van der Valk M for the International Watch and Wait Database Consortium. J Clin Oncol 35, 2017 (suppl 4S; abstract 521)
Short Course Neoadjuvant Radiation Therapy Effective and Less Toxic in Advanced Rectal Cancer
SUMMARY: The American Cancer Society estimates 39,220 new cases of Rectal cancer will be diagnosed in the United States in 2016. 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, has been the standard intervention. Radiation consists of 45 Gy delivered in 25 fractions 5 days a week with a 5.4 Gy boost. Concurrent chemotherapy in the US has included 5-FU/Leucovorin, single agent 5-FU or single agent XELODA® (Capecitabine).
The authors in this study evaluated the efficacy of a short course of neoadjuvant radiation therapy for patients with unresectable cT3 or cT4 Rectal adenocarcinoma. The trial included 515 patients who were randomly assigned either to the control group (N=254), in which patients received RT at 50.4 Gy delivered in 28 fractions, given simultaneously with a regimen of 5-FU bolus, Leucovorin and ELOXATIN® (Oxaliplatin) or the experimental group (N=261) in which patients received a short Five day course of Radiotherapy at 5 Gy per day (Total 25 Gy), followed by three courses of FOLFOX4 delivered over 48 hours, during weeks 3, 5, and 7. Both treatment groups underwent surgery approximately 12 weeks after radiation was started and about 6 weeks following neoadjuvant treatment. ELOXATIN® inclusion in the chemotherapy regimen was at the discretion of the treating physician, due to increase in toxicity. Nonetheless, 70% of the patients had received ELOXATIN® at the end of the study. It should be noted that the NSABP protocol R-04 demonstrated that the addition of ELOXATIN® in the neoadjuvant chemotherapy regimen did not improve outcomes but resulted in significant toxicity. The median follow up was 35 months.
The primary endpoint of the rate of curative resection (R0) was 71% in the control group versus 77% in the experimental group. Pathological Complete Response rates were 11.5% in the control group and 16% in the experimental group. The 3 year Overall Survival rates for the control versus experimental group were 65% vs 73% and Disease Free Survival for the control versus experimental group were 52% vs 53%. These differences were not statistically significant. The local failure rates were similar in both treatment groups (22%).
The authors concluded that a short course of radiotherapy combined with three cycles of chemotherapy post radiation, can be more convenient with lower toxicity and this regimen would be an appealing option for patients with locally advanced Rectal cancer, with metastases in liver or lungs, for whom chemotherapy to control systemic disease can be started much earlier, following a short course of radiation therapy. Neoadjuvant chemoradiation for fixed cT3 or cT4 rectal cancer: Results of a Polish II multicentre phase III study. Bujko K, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 489)
Neoadjuvant therapy for rectal cancer Mature results from NSABP protocol R-04
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)
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.