Personalizing cancer care was the theme of the American Society of Clinical Oncology (ASCO) 45th Annual Meeting held May 29-June 2, 2009 in Orlando, Florida. This annual symposium brought together leading experts to present and discuss new research on cancer prevention, screening, and treatment. The data presented revealed significant steps towards the improvement of outcomes for patients with varying types of cancers. As seen during the past few years, attention has turned towards individualizing patient care through targeted therapies, optimizing patient selection for specific therapies, as well as a focus on quality of life and survivorship issues. Of particular interest at this year’s ASCO was the undisputed understanding that the integration of genetics in everyday practice is rapidly becoming a reality for oncology patients, providing the ability to individualize therapy. The role of genetics in selecting patient therapy is crucial and will undoubtedly change the way in which oncology patients are managed.

The presentations related to colorectal cancer concentrated on the role of anti-angiogenic therapy in the adjuvant setting, data on a genetic signature associated with recurrence in stage II colon cancer, the role of combination chemotherapy with radiation in rectal cancer, research on the role and timing of surgery for patients who are diagnosed with advanced disease, how to optimally sequence the various treatment options for patients with advanced colorectal cancer, and how to manage the side effects of the treatments. Fortunately, because newer therapies have significantly extended the lives of patients with advanced colorectal cancer, quality of life has become extremely important to both patients and doctors. The conference also served as a platform to introduce new targets in the treatment of colorectal cancer. This summary will highlight some of the abstracts presented during the colorectal cancer sessions of the conference.

Bevacizumab in Early-stage Colon Cancer

In contrast to the significant effect seen in metastatic colon cancer, the addition of bevacizumab (Avastin®) to chemotherapy for adjuvant treatment of earlier stage disease is not beneficial. These data come from a large phase 3 trial, known as NSABP CO-8, presented in the plenary session at the American Society of Clinical Oncology 45th Annual Meeting. The trial was conducted in 2672 patients with stage II or stage III colon cancer who had undergone surgery. All of the patients received 6 months of adjuvant treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin), and half of the patients also received 12 months of bevacizumab. After a median follow-up of 3 years, there was no difference in the disease-free survival between those who received bevacizumab and those who did not. Overall, CO-8 found no difference in the proportion of patients who were still alive and free from disease between the control group and the bevacizumab group (75.5% vs. 77.4%). This amounted to an 11% risk reduction (hazard ratio, 0.89; P = .15).

Lead author Norman Wolmark, MD, mentioned one positive result of the trial. There was a significant improvement in disease-free survival after 12 months of bevacizumab administration, although this benefit subsequently diminished and had disappeared by the time the trial ended. Dr. Wolmark highlighted the fact that there was a benefit from bevacizumab after 12 months (throughout the 6 months of chemotherapy and for 6 months afterward). At this time point, there was a 40% risk reduction (hazard ratio, 0.60; P = .0004). The difference in disease-free survival between the 2 groups remained significant at 1.5 and 2 years, was just significant at 2.5 years (P = .05), but was not significant at 3 years.

"Our overall conclusion is that bevacizumab is not effective as adjuvant treatment for early-stage colon cancer," Dr. Wolmark said. However, Dr. Wolmark suggested that the "transient benefit we saw in patients who received bevacizumab illustrates that we have more to learn about how this reagent works, and we need to design more clinical trials to determine how it can be used more effectively."
A companion study, known as AVANT, is about 6 to 12 months behind, Dr. Wolmark noted. The AVANT study was conducted in 3450 patients with early colon cancer, is similar to CO-8, but has an extra group — bevacizumab added to the XELOX (capecitabine and oxaliplatin) regimen. "We suspect that AVANT will confirm the CO-8 trial results and that it will show only a transient benefit for as long as bevacizumab is being administered," Dr. Wolmark commented.

Reference: Wolmark et al. A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08.J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4)

Genomic Test to Predict Recurrence in Stage II Colon Cancer

Dr. David Kerr presented data on a genetic signature associated with tumor recurrence in stage II colon cancer. The first genomic test to predict whether or not stage II colon cancer will recur has been developed and validated in a large number of tumor tissue samples from patients in the United States and the United Kingdom. The 12-gene assay can reliably predict whether an individual patient has a low, intermediate, or high risk of cancer recurrence. However, the study was not able to link recurrence scores with benefits from 5-FU and leucovorin chemotherapy.

Researchers from the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Cleveland Clinic analyzed tumor samples saved from 1,850 patients enrolled in clinical trials for 761 different genes. They found 18 that were likely to predict whether or not cancer would recur or whether the patient would benefit from 5-FU chemotherapy. The 18-gene assay was then validated by testing tumor tissue from more than 1,400 patients who participated in the QUASAR (Quick And Simple And Reliable) clinical trial. QUASAR had randomized patients to either receive chemotherapy with 5-FU and leucovorin or further treatment surgery.

The QUASAR validation showed that recurrence scores could accurately predict who had a low, intermediate, or high risk of recurrence. The score also reliably predicted disease-free and overall survival. Scores were ranked from 0 to 100 with the lowest scores having an 8 to 10 percent risk of recurring and the highest scores a 20 to 25 percent chance of recurrence.

About 25 to 30 percent of patients with colon cancer are diagnosed with stage II cancer where the tumor has gone to the outermost layers of the colon (T3) or through the colon wall (T4) but has not yet spread to nearby lymph nodes. Chemotherapy has only a modest benefit for stage II patients, reducing the absolute risk of recurrence for the whole group by approximately 3 percent. Two clinical factors — T4 stage and DNA mismatch repair status — remained independent predictors of recurrence. In the QUASAR study T4 tumors had a poor prognosis with a near doubling of the risk of recurrence. On the other hand, patients whose tumors showed deficient DNA mismatch repairormicrosatellite instability (MSI)had a 70 percent reduction in the risk of their cancer recurrence. T4 tumors and those with deficient mismatch repair genes account for only about 25 percent of stage II colon cancers.

A challenging dilemma for both doctors and patients is to accurately predict which patients will have cancer recurrence and/or metastases, and which patients might benefit from adjuvant chemotherapy. These data show that a reliable test for predicting recurrence in Stage II colorectal cancer may soon be available, however, the clinical significance of this test is still unknown and remains to be tested and validated in relation to which patients would precisely benefit from receiving adjuvant chemotherapy.

Reference: Kerr et al. A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study, J Clin Oncol 27:15s, 2009 (suppl; abstr 4000)

The Role of Oxaliplatin in Neoadjuvant Treatment of Rectal Cancer

Carlo Aschele, MD, PhD and colleagues presented the results of Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: Pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial. Adding oxaliplatin to standard preoperative chemoradiotherapy in patients with locally advanced rectal cancer does not improve tumor shrinkage. In the trial, 747 patients with locally advanced rectal cancer were randomized to receive standard preoperative chemoradiotherapy or the standard plus oxaliplatin. Patients were randomized to a regimen of infused FU (225 mg/m2 per day) concomitant to external-beam pelvic radiation (50.4 Gy in 28 daily fractions), or to the same regimen plus weekly oxaliplatin (60 mg/m2 × 6). Surgery was scheduled 6 to 8 weeks after initial therapy was completed. There was no significant difference between the 2 groups in terms of preoperative tumor reduction; 16% of patients in both groups had no tumor present at the time of surgery, and 29% in the oxaliplatin group had mildly invasive tumors (T1 or T2) without nodal involvement (vs. 30% in the control group). There was also no significant difference in the number of patients who had cancer in the lymph nodes (27% in the oxaliplatin group and 25% in the control group).

In an unplanned analysis, Dr. Aschele and researchers found that, at the time of surgical removal of the primary tumor, only 0.5% of the oxaliplatin group (2 patients) had distant metastases in the abdomen, compared with 3% in the control group (11 patients). This difference was indeed statistically significant. Adding oxaliplatin also resulted in significantly increased adverse effects. Overall, grade 3 or 4 toxicity rates in treated patients were 8% in the control group and 24% in the oxaliplatin group. Despite this significant difference in adverse events, 96% of patients in both groups eventually underwent surgery. The authors concluded that the data do not support the use of oxaliplatin with the goal of shrinking tumors, but that adding oxaliplatin might reduce the number of distant metastases and that further study on the drug’s effect on metastases is ongoing and worthwhile.

Reference: Aschele et al. Preoperative fluorouracil (FU)-based chemoradiation with and without weekly oxaliplatin in locally advanced rectal cancer: Pathologic response analysis of the Studio Terapia Adiuvante Retto (STAR)-01 randomized phase III trial. J Clin Oncol 27:18s, 2009 (suppl; abstr CRA4008)

Surgery to Remove the Primary Tumor in Metastatic Colorectal Cancer

Dr. Philip Paty and colleagues at Memorial Sloan Kettering, New York, presented findings came from a retrospective analysis of 233 patients who had metastatic colorectal cancer at diagnosis. The principal objective was to ascertain the benefits of upfront surgery to remove the primary tumor. All of the patients received a three-drug chemotherapy combination (FOLFOX, IFL, or FOLFIRI), with or without bevacizumab (Avastin) as primary treatment. During subsequent follow-up, 217 patients (93%) had no complications that necessitated subsequent surgery for the primary tumor. Of those 217 patients, 47 eventually had elective colon resection at the same time as surgery to remove metastatic lesions, and eight others opted to have colon resection when surgeons implanted a hepatic-artery infusion-pump. Ten patients had non-surgical interventions (stents and radiation therapy) to treat obstructions and perforations. The remaining 16 patients required emergent surgery for primary tumor obstruction or perforation. Dr. Paty said procedures were successful in 14 of the 16 cases, suggesting that the delay of surgery posed little risk to the patients. Two of the 16 patients who had emergent surgery died, resulting in an operative mortality of 0.8% for the entire cohort. The results compare favorably with historical data on upfront surgery showing a 1.5% operative mortality, Dr. Paty noted.

The definitive answer to the timing of surgery of the primary tumor will likely come from an ongoing, multicenter clinical trial conducted by National Surgical Adjuvant Breast and Bowel Project (NSABP). Researchers are comparing upfront surgery for the primary tumor versus none in patients who have synchronous asymptomatic metastases.

Reference: Poultsides GA, et al. Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment. J Clin Oncol 2009; 27 (15S): Abstract CRA4030.

Ginger for Chemotherapy-related Nausea in Cancer Patients

Julie Ryan, PhD, MPH, presented results of a randomized, double-blind, placebo-controlled clinical trial of 644 cancer patients: Ginger for chemotherapy-related nausea in cancer patients. Patients who got ginger(Zingiber Officinale) in capsules twice a day for three days before chemo and three days after reported significantly less nausea that those who were treated with placebo. All patients in the study also received standard anti-nausea therapy on the day of chemo. Despite the widespread use of antiemetics, post-chemotherapy nausea and vomiting continue to be reported by up to 70% of patients receiving chemotherapy. The goal of this trial was to determine if ginger was more effective than placebo in controlling chemotherapy-related nausea in participants given a 5-HT3 receptor antagonist antiemetic. A total of 644 patients were accrued. All doses of ginger significantly reduced nausea and the authors concluded that ginger supplementation at daily dose of 0.5g-1.0g significantly aids in reduction of nausea during the first day of chemotherapy.

Reference: Ryan et al. Ginger for chemotherapy-related nausea in cancer patients: A URCC CCOP randomized, double-blind, placebo-controlled clinical trial of 644 cancer patients. J Clin Oncol 27:15s, 2009 (suppl; abstr 9511).