GI Cancer: Research Roundup of Selected Poster Studies

Figure: No Caption Available.ORLANDO, FL—The following are highlights from selected gastrointestinal cancer poster studies reported at the ASCO Annual Meeting here. For Early Rectal Cancer, Survival for Local Excision Found Same as for Abdominoperineal Resection. Patients with early-stage rectal cancer who underwent conservative surgery plus radiotherapy had survival times similar to those treated with radical resection. Angela H. Wortham, MD, a radiation oncologist with State University of New York Downstate Medical Center in Brooklyn presented her group's analysis from the Surveillance, Epidemiology and End-Results (SEER) registry in a poster discussion session (Abstract 4032). The data came from 2,144 patients treated for T1N0 or T2N0 rectal cancer—with tumors up to 4 cm— between 1988 and 2003, of whom 1,203 had abdominoperineal resection (APR) while 744 had local excision (LE) alone, with another 197 receiving radiotherapy as well.Figure: ANGELA H. WORTHAM, MD, said the results of her group's findings support the growing popularity of using local excision for T1 and T2 rectal cancers, and reinforce the practice of including radiation in selected patients. “You avoid colostomy completely with local excision, so that's why it's a very important alternative to have,” she said.“Within the entire cohort the survival was basically equivalent,” Dr. Wortham said. “Among patients who had T-2 lesions, LE alone was inferior, but we found that if you added radiation, survival was equivalent to undergoing an APR.” The investigators concluded that, despite the lack of details in the SEER data about other modalities of treatment that may have been used in these patients—such as chemotherapy—the findings support the growing popularity of using local excision for T1 and T2 rectal cancers, and reinforce the practice of including radiation in selected patients. “You avoid colostomy completely with local excision, so that's why it's a very important alternative to have—you avoid a lot of the morbidity associated with APR,” Dr. Wortham explained in an interview. This study along with additional retrospective and prospective studies provides more data to enable patients to have a viable alternative to radical resection. Already Standard in Europe Cornelis J.H. van de Velde, MD, PhD, Professor of Surgery at Leiden University Medical Center and President of the European Society of Surgical Oncology, said he agreed with Dr. Wortham's conclusions, giving a “cautious green light” to wider adoption of sphincter-preserving conservative therapy, which is already standard for T1 tumors in Europe, and has also proved curative in T2 tumors downstaged by chemoradiotherapy, he noted. The SEER analysis concurs with European experience using the sphincter-preserving technique of trans-anal endoscopic microsurgery (TEM) excision, which became standard in Europe because of the very encouraging findings from recent studies. “There are several series on TEM excision in T1 tumors with excellent results based on ultrasound staging without radiotherapy, and several studies on down-staged tumors after chemoradiotherapy— used in order to avoid AP resections and even to avoid surgery at all, such as in the series from Habr Gama [Angelita Habr-Gama, MD, Professor of Surgery at the University of São Paulo and President of the Brazilian College of Digestive Surgery].” Dr. van de Vende said his group's policy in Leiden was consistent with the New York team's findings from SEER, and the next step will be to refine ways to select patients for conservative therapy because of the 18% risk of recurrence in these tumors after TEM, especially since they are sometimes unresectable.Figure: RALF D. HOFHEINZ, MD: “Given the observed safety profile and the trend in improved downstaging in neoadjuvant stratum, capecitabine exhibits a potential to replace 5-FU as perioperative treatment of locally advanced rectal cancer. Efficacy results on the primary endpoint are expected for 2010.”His group is now identifying molecular markers such as caspase-3 to help predict lymph node metastases, he said. “You need to be careful in selection and ask if the cancers have potential to metastasize to lymph nodes.” Dr. Wortham and her colleagues cautioned that selected patients with T2N0 tumors should have additional radiation, predicting that the outlook for patients with T2 tumors should continue to improve thanks to better imaging using MRI and endorectal ultasound and by downstaging tumors with neoadjuvant therapy. Neoadjuvant Capecitabine in Locally Advanced Rectal Cancer In the setting of locally advanced, rectal cancer, however, another presentation at the same poster discussion session concluded that capecitabine has advantages when used in neoadjuvant chemoradiotherapy over fluorouracil (5-FU) (Abstract 4014). An improvement in nodal status has emerged after three years of study following preoperative (neoadjuvant) capecitabine as compared with neoadjuvant 5-FU in the randomized Phase III trial reported by Ralf D. Hofheinz, MD, of the University of Heidelberg in Manheim, Germany.Figure: NIALL C. TEBBUTT, MD: “Capecitabine plus bevacizumab with or without mitomycin C is an active, low-toxicity regimen that may be considered as a treatment option for patients with metastatic colorectal cancer.”Although final data on overall survival are not due until sometime next year, the trial has reported that patients receiving capecitabine had more hand-foot skin reactions, fatigue, and a higher rate of diarrhea during chemoradiotherapy while leukopenia was more common among patients treated with 5-FU. But a significantly lower rate of N-positive tumors was seen with capecitabine. Dr. Hofheinz said this could be confirmation of a radiosensitizing effect of capecitabine similar to that seen in an earlier Phase I investigation (Dunst et al: JCO 2002;19:3983–3991): “If we have fewer nodal-positive tumors in the capecitabine arm, this might also translate into improved three-year disease-free survival, but we have to wait for this.” When he was asked at his poster whether preliminary data showing a three-year disease-free survival rate of 76% compared with 64.5% among patients treated with 5-FU were anything to get excited about, he said: “We have to wait one or two years more when we have the data.” Capecitabine Monotherapy for Metastatic Colorectal Cancer The effectiveness of first-line capecitabine monotherapy was confirmed for patients with metastatic colorectal cancer who were considered not fit enough to receive oxaliplatin- or irinotecan-based therapy in the Phase III randomized AGITG (Australian Gastro-Intestinal Trials Group) MAX three-arm study, which was conducted in Australia, New Zealand, and Great Britain. But neither adding the vascular endothelial growth factor inhibitor bevacizumab, nor bevacizumab plus mitomycin C extended overall survival, although bevacizumab did extend median progression-free survival— from 5.7 to 8.5 months (Abstract 4023). When lead investigator Niall C. Tebbutt, MD, a consultant medical oncologist with Austin Health in Melbourne, Australia, was asked during the poster session where the results were reported if the small benefit of just a few weeks justified the additional toxicity, he replied that the secondary endpoints of toxicity, response rate, and quality of life were not significantly changed. As for the vascular toxicity with bevacizumab, Dr. Tebbutt said: “We're not seeing high rates of vascular toxicity. It's important to bear in mind that we had the common bevacizumab exclusion criteria, so we didn't enroll people with a history of myocardial infarction or CVA [cerebral vascular accident] within a year of study enrollment. But we did have people who had a history of vascular disease. “I think this is an effective, well-tolerated treatment that is an option for many patients with colorectal cancer,” he said. Epiregulin May Be Marker for Cetuximab Sensitivity Patients with advanced colorectal cancer whose tumors have low expression of the epidermal growth factor receptor (EGFR) ligand epiregulin did not benefit from cetuximab after other therapies had failed, even though the patients had the wild-type K-ras gene, which until now has generally been regarded as the main indicator for potential benefit from this targeted therapy.Figure: CHRIS J. O'CALLAGHAN, MD: “What doctors should take home from these developments is that the field of targeted therapies based on biomarkers is moving forward very rapidly and that exploratory results such as ours suggest that there are opportunities for further refining therapy.”This is according to a subset analysis of findings released at a poster discussion session by Derek J. Jonker, MD, of the University of Ottawa and Chris J. O'Callaghan, MD, of Queens University in Kingston, Ontario, from the National Cancer Institute of Canada (NCIC) CTG CO.17 Phase III trial with 572 patients randomized to receive cetuximab or best supportive care (Abstract 4016). Dr. Callaghan is also Project Coordinator for the NCIC Clinical Trials Group. Since epiregulin is involved with the EGFR pathway it has been hypothesized that high expression would make patients more susceptible to targeting the EGFR pathway with cetuximab. This was questioned, however, by Robert Pirker, MD, Professor of Internal Medicine at Medical University of Vienna, who pointed out that high expression of epiregulin could turn out to have the opposite effect because it increases the expression of the growth factor being blocked by cetuximab. In the field of lung cancer such molecular markers for sensitivity to cetuximab are proving difficult to identify, he said. In the Canadian study, however, only the patients who had K-ras wild-type gene and also high expression of epiregulin (the “combimarker”) derived benefit from cetuximab. Those with K-ras wild-type and low epiregulin expression derived no benefit, and neither did patients who had mutant K-ras, irrespective of epiregulin expression. Response rate, progression-free survival, and overall survival were superior for patients who tested positive for the combimarker as compared with those who were negative—the response rate was 17% vs 0%, respectively; progression-free survival time was 5.4 vs 1.9 months; and overall survival was 9.8 vs 5.1 months. Dr. Pirker cautioned that it was important not to start using such a marker too soon, however, and that it was still too early to conclude anything from the results. Asked for his response, Dr. O'Callaghan said he agreed and was also cautious, and said that the main value of the study was as a proof of principle—that therapy could in the future be targeted more appropriately by checking prospectively for combinations of biomarkers, such as K-ras and epiregulin and probably others. “What doctors should take home from these developments is that the field of targeted therapies based on biomarkers is moving forward very rapidly and that exploratory results such as ours suggest that there are opportunities for further refining therapy,” he said.

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