A sneak preview of four studies to be presented at the upcoming ASCO GI (American Society of Oncology Gastrointestinal cancer) meeting in San Francisco (January 20-22) shows that the era of personalized medicine has arrived. The studies, respectively, focused on intensity –modulated radiation therapy (IMRT) as a safer alternative to conventional radiotherapy for the treatment of anal cancer, sorafenib as a third-line treatment option for gastrointestinal stromal tumors (GIST) resistant to both imatinib and sunitinib, a new gene signature test to identify patients with colorectal cancer at high risk for recurrence, and early use of positron-emission tomography (PET) imaging to identify poor prognosis patients with a rare form of esophageal cancer.
A small phase II study of 52 patients with stage II and III anal cancer showed that chemotherapy combined with IMRT was as effective but much less toxic compared with the same chemotherapy combined with conventional radiation after 2 years of follow-up.
Conventional radiation plus concurrent 5-fluorouracil and mitomycin-C is the standard of care for non-metastatic anal cancer, but conventional radiotherapy leads to significant toxicity due in part to the large area of the body that is radiated. By contrast, IMRT targets the radiation dose directly to the tumor and lymph nodes affected with cancer but spares healthy adjacent tissues, explained lead author Lisa Kachnic, MD, Boston University. The conformal radiation IMRT delivers is also referred to as “dose painted IMRT.”
Safety and efficacy results of the phase II RTOG 0529 study were compared with historical results from another study by the same group of investigators: RTOG 9811. At a median follow-up of 26.7 months, 2-year disease-free survival (DFS) was 77% and overall survival (OS) was 86% in RTOG 0529 compared with 75% DFS and 91% OS in RTOG 9811. However, use of IMRT resulted in significantly less stage 3 or higher skin and GI toxicity; in fact, grade 3 or higher GI toxicity was 15% less, grade 3 or high skin toxicity was 50% less, and Grade 2 or h igher hematologic toxicity was about 13% less when IMRT was used compared with conventional radiation.
Because 85% of stage II and III patients with anal cancer are cured with radiotherapy plus chemotherapy, researchers have turned their attention to strategies to avoid toxicity, explained session moderator Jennifer Obel, MD. IMRT limits radiation to nearby tissues, which should improve quality of life. If results of this study are confirmed by future studies using IMRT as a treatment platform, “IMRT may emerge as a key treatment modality for anal cancer,” Dr. Obel predicted.
A separate phase II trial found that sorafenib was a valuable third-line strategy in 38 patients with GIST resistant to first-line imatinib and second-line sunitinib. Six patients were resistant to imatinib and 32 were resistant to both drugs. Sorafenib achieved tumor control (i.e., partial response or stable disease) in 68% of patients. One-year survival was 44%, and 2-year survival was 21%.
Sixty-one percent of patients required dose reductions of sorafenib, mainly for hand-foot syndrome and hypertension – two common side effects of this agent.
“Many of these patients whose tumors progressed or worsened on two lines of therapy had nothing left to try. Some of the patients in this study were treated with sorafenib for up to 3 years and did quite well. These results suggest that sorafenib is an additional option,” said lead author Nicholas P. Campbell, MD, University of Chicago, IL. Although sorafenib is not yet approved by FDA as third-line therapy for GIST, NCCN guidelines recommend sorafenib as a third-line option for GIST, and is typically covered by insurers, Dr. Campbell noted.
At the Presscast, Dr. Obel said: “Understanding the mechanisms involved in GIST has allowed great strides in treating this disease, with two new treatments over the past decade. This study suggests that sorafenib is now another option. Patients who progress on imatinib and sunitinib can consider sorafenib as well as enrolling in a clinical trial.”
ColoPrint — an 18-gene signature test — correctly identified patients with stage II colorectal cancer at high risk of progression. Of the 235 patients included in the study, ColoPrint identified 73% as low risk and 27% as high risk. At a median follow-up of 97 months, only 5%of those identified as low risk had a recurrence compared with 20% of those deemed high risk
ColoPrint’s results were independent of the predictive value of most traditional clinical factors associated with recurrence. “There was a clear discordance between ASCO risk factors [e.g, T4, high grade, performance status, <12 lymph nodes assessed) and ColoPrint results, although there was a small degree of overlap. ColoPrint was the only factor to predict distant metastasis in stage II patients,” said lead author Robert Rosenberg, MD, University Hospital, Technical University, Munich, Germany. . ColoPrint could potentially be used to determine which patients can be safely managed without chemotherapy, he noted.
An ongoing prospective, international, multicenter study called PARSC is comparing ColoPrint versus clinical risk factors to predict risk of recurrence in stage II colon cancer.
ColoPrint is investigational, and the price of the test remains to be determined. Another genetic test for stage II colorectal cancer called Oncotype DX is commercially available and costs about $3000. Both tests have the same intent, Dr. Rosenberg explained. A major difference between them is that the 18 genes used in ColoPrint were based on an unselected review of the genome, while Oncotype DX was developed using a candidate gene. ColoPrint is a binary test – identifying low versus high risk -- while Oncotype DX discriminates between low, intermediate, and high risk with a lesser degree of sensitivity.
Dr. Obel said, “Both tests help to identify patients at high risk for recurrence, but neither test tells us who will benefit from chemotherapy with 5FU and oxaliplatin. At this point, we know the tests differ based on the way genes and datasets were derived, and ColoPrint is performed on fresh tissue while Oncotype DX is performed on frozen tissue.”
The prospective MUNICON II study found that using positron-emission tomography (PET) imaging to assess response early in the course of chemotherapy is an important prognostic tool for patients with locally advanced cancer of the esophagogastric junction. In the study, 56 patients were treated with 2 courses of chemotherapy and then underwent PET assessment to categorize them as responders (n=33) or non-responders (n=23). Responders continued chemotherapy for 3 additional months before surgery, while non-responders were treated with radiotherapy in hopes of shrinking the tumor size prior to surgery.
Twenty-seven of 33 responders (82%) were able to undergo complete resection versus 16 of the 22 non-responders (70%). At a median follow-up of 38 months, median event-free survival and median OS had not yet been reached in responder, but rates were 15.4 months and 18.3 months, respectively, in non-responders.
PET-guided therapy has been used for other cancers, including lymphoma and lung. According to lead author Florian Lordick, MD, Klinikum Braunschweig, Brunswick, Germany, this is the first study to use early PET results to change treatment strategy in esophageal cancer.
“Unfortunately, our study showed that radiation was not an effective salvage treatment for non-responders. Prognosis in non-responders is still poor because of poor tumor biology,” he said.
The European Organization for Research and Treatment in Cancer (EORTC) plans to use early PET assessment to explore alternative treatment approaches for non-responders, Dr. Lordick said.
By Alice Goodman
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