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Monday, July 28, 2014
BY SARAH DIGIULIO
Screening for hepatocellular carcinoma (HCC) is associated with significant improvement in early tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis, according to a meta-analysis published in Public Library of Science Medicine (DOI: 10.1371/journal.pmed.1001624).
“There is consistent data that shows a strong association between HCC surveillance and improved outcomes --i.e., detecting cancer at an earlier stage and increased survival -- among at-risk patients, including those with cirrhosis,” said the first author, Amit Singal, MD, MS, Assistant Professor of Medicine and Medical Director of the Liver Tumor Program at the University of Texas Southwestern.
HCC, the most common form of primary liver cancer, is the third leading cause of cancer-related death worldwide, and a leading cause of death among patients with cirrhosis, the researchers noted.
For this analysis, Singal and his coauthors -- Anjana Pillai, MD, and Jasmin Tiro, PhD -- identified 47 studies conducted between 1989 and January 2014 that assessed the impact of HCC surveillance on at least one of the following outcomes:
· The proportion of patients diagnosed with early-stage HCC (as defined by the Milan criteria—i.e., one tumor less than 5 cm in maximum diameter or two to three lesions, each no larger than 3 cm in diameter);
· The proportion of patients with HCC who underwent curative therapy (including liver transplantation, surgical resection, radiofrequency ablation, or percutaneous ethanol injection); or
· Overall survival.
Of a total of 15,158 patients with cirrhosis who had been screened, HCC was detected by surveillance in 6,284 patients (41.4%) and by symptomatic presentation or incidentally outside of a surveillance protocol in 8,874 patients (58.6%).
The key findings were that:
· Of the 38 studies that included data on tumor stage stratified by receipt of HCC surveillance, the rate of patients diagnosed with early-stage disease was significantly higher in patients undergoing surveillance compared with patients whose tumor presented symptomatically or incidentally (the pooled rates being 70.9% vs. 29.9%);
· Of the 34 studies that assessed the association of HCC surveillance and receipt of curative therapy, patients diagnosed with HCC by surveillance were significantly more likely to undergo curative therapy (the pooled rates being 51.6% of patients vs. 23.7%);
· There was a moderately strong positive correlation between early detection rates and curative treatment rates between studies (which the authors note suggest the association between surveillance and receipt of curative treatment is mediated by improved early tumor detection rates); and
· Of the 36 studies that included data on survival stratified by HCC surveillance, HCC surveillance was significantly associated with increased survival (with a pooled three-year survival rate of 50.8 percent among patients who underwent HCC surveillance compared with 27.9 percent of patients without prior surveillance).
“Our study highlighted that current data consistently demonstrate a strong association between HCC surveillance and improved outcomes -- i.e., early tumor detection, receipt of curative therapy, and improved survival,” Singal said via email. “Although we should strive to better evaluate the benefits and harms of HCC surveillance in well-conducted prospective studies, it is important for providers to be aware of currently available data supporting HCC surveillance.”
Guidelines Currently Inconsistent
Current guidelines from the National Comprehensive Cancer Network, the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver recommend regular liver cancer screening for individuals at high risk for the disease—including patients with cirrhosis. But, liver cancer surveillance is not included in recommendations from the U.S. Preventive Services Task Force for patients with cirrhosis.
“Given the lack of consistency between guideline recommendations, HCC surveillance is currently underused in the U.S.,” Singal said. Prior research by his team found that fewer than 20 percent of at-risk patients receive HCC surveillance—and most often the reason for not screening patients is that health care providers are not ordering the testing.
“The preponderance of data showing that HCC surveillance in patients with cirrhosis is associated with improved outcomes should provide sufficient rationale for providers to recommend HCC surveillance in at-risk patients, even in the absence of a randomized trial,” Singal said.
Monday, July 28, 2014
BY ROBERT H. CARLSON
BARCELONA, Spain – Two new entries in the treatment of metastatic colorectal cancer were discussed here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer, each showing promise in a heavily pretreated population.
The placebo-controlled, randomized, Phase III trials were for regorafenib (CONCUR) and TAS-102 (RECOURSE).
“The good news is, both of these drugs are active, said Richard M. Goldberg, MD, Professor and Physician-in-Chief at Ohio State University James Cancer Hospital and Comprehensive Cancer Center, who was the Discussant for both trials.
Goldberg congratulated the researchers for well-designed trials in appropriate populations that showed significant survival and response benefit for each drug. But toxicities for regorafenib were too high, he said, recommending dose reductions or changes in dosing strategy.
CONCUR: Regorafenib Active in Asian Patients
In the CONCUR trial of 204 patients, reported by Jin Li, MD, Professor and Director of the Department of Medical Oncology at Fudan University Shanghai Cancer Center, use of regorafenib -- an oral multikinase inhibitor that targets pathways involved in tumor growth and progression -- was associated with a 45 percent reduction in the risk of death in Asian patients with metastatic colorectal cancer who had disease progression after standard therapy compared with placebo. And approximately half of treated patients experienced a clinical response or stable disease.
CONCUR, which was sponsored by Bayer HealthCare Pharmaceuticals, met its response goals but not the toxicity goals. “Regorafenib needs dose and schedule refinement,” Goldberg said in his discussion of the trial, suggesting dose reductions or a one-week-on one-week-off strategy.
With a median of 10.6 weeks under treatment, about 26 percent of patients had dose reductions and 66 percent had dose interruptions. “The biggest challenge for regorafenib researchers is to find a better way to give this drug so we can exploit its benefit, because there was a relatively high rate of grade 3 and 4 toxicity,” he said. “For those of us who use regorafenib in the clinic, treatment tolerance is the biggest issue we face.”
Median overall survival was 8.8 months for regorafenib (136 patients) versus 6.3 months for patients on placebo (68 patients). Progression-free survival was 3.2 versus 1.7 months, respectively, and the disease-control rates (including complete response [CR], partial response [PR], and stable disease [SD]) were 52.0 percent versus 7.0 percent, respectively.
Li noted that CONCUR is now the second Phase III trial showing that regorafenib monotherapy improves survival in patients with metastatic colorectal cancer who have disease progression after standard therapy. The Phase III CORRECT trial (Grothey et al: Lancet 2013;381:303-312) showed that regorafenib improves overall survival in patients with metastatic colorectal cancer who have disease progression after standard therapies. Those authors said regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer that has progressed after all standard therapies.
But only 15 percent of patients enrolled in CORRECT were Asian -- mostly from Japan -- while all patients in CONCUR were from mainland China, Hong Kong, Taiwan, the Republic of Korea, and Vietnam.
Patients who had disease progression after at least two prior lines of standard therapy were randomly assigned to receive oral regorafenib (136 patients) or placebo (68 patients) for the first three weeks of a four-week cycle. Prior anti-VEGF or anti-EGFR was allowed but not required.
The most frequent treatment-emergent adverse effects were hand-foot skin reaction (16% of patients), hypertension (12%), hyperbilirubinemia (12%), elevated liver enzymes (AST 10%, ALT 8%), hypophosphatemia (9%), anemia (7%), and hyperlipasemia (7%). There were no reports of liver failure or pancreatitis.
“What is important [regarding serious adverse events] is that the rate with regorafenib was similar to that of placebo -- 31.3 percent and 26.5 percent, respectively,” Li said.
RECOURSE: TAS-102 Improves Overall Survival
In the RECOURSE trial of 800 patients with metastatic colorectal cancer, TAS-102 treatment was associated with a significant improvement in overall survival and progression-free survival compared with placebo.
The lead author, Takayuki Yoshino, MD, a medical oncologist at National Cancer Center Hospital East in Chiba, Japan, explained that the global trial was conducted in 13 countries. Median overall survival was 7.1 months for patients receiving TAS-102 (534 patients) versus 5.3 months for those on placebo (266 patients), at a median follow-up of 8.4 months.
Median progression-free survival was 2.0 versus 1.7 months, overall response rates were 1.6 percent versus 0.4 percent, and disease-control rates (CR, PR, SD) were 44.0 percent versus 16.3 percent.
This was a heavily pretreated population, he noted, as patients had at least two prior lines of standard chemotherapy and had been resistant or refractory to fluorourpyrimidines, irinotecan, oxaliplatin, bevacizumab, and cetuximab or panitumumab for patients with KRAS wild-type tumors.
Neutropenia was the major adverse event, seen in 34.9 percent of patients receiving TAS-102 and none of the placebo patients. Other adverse events included leukopenia (12.8% vs. none for placebo); anemia (16.5% vs. 2.6 %); and febrile neutropenia (3.8% vs. none).
TAS-102 is a combination of the novel oral nucleoside trifluridine and tipiracil hydrochloride, the latter an inhibitor of thymidine phosphorylase which is seen in high levels in aggressive disease, Yoshino explained.
The agent is effective against human colorectal cancer cell lines that are resistant to fluorouracil (5-FU), and a randomized Phase II study showed a significant survival advantage for TAS-102 over placebo in refractory metastatic disease (Yoshino et al: Lancet Oncology 2012;13:993-1001).
He noted that trifluridine is activated by thymidine kinase, which does not have a role in activation of 5-FU, and trifluridine is incorporated into DNA, resulting in long-lasting DNA damage, both of which may explain why it is active in tumors refractory to 5-FU.
The DNA damage may also contribute to the toxicities, however.
Commenting in a news release, ESMO spokesperson Jean Yves Douillard, MD, Professor of Medical Oncology at the Institut de Cancérologie de l’Ouest René Gauducheau in France, said, “It is good to know that the magnitude of benefit shown in the smaller Phase II trial is confirmed in the larger Phase III trial and that the results apply to Asians and Caucasians alike.”
Douillard said he would probably move this drug into an earlier line of treatment and would also combine it with either irinotecan or oxaliplatin.
The trial was sponsored by Taiho Pharmaceutical Co.
“Is TAS-102 just another 5-FU?” Goldberg asked rhetorically in his discussion. “The answer is clearly no, it is a cytotoxic antimetabolite but it also has a potential antiangiogenic effect.”
Importantly, TAS-102 is active in KRAS-mutant tumors, but Goldberg noted that it was not as active in overall survival in patients with KRAS-mutant tumors as it had appeared to be in the Phase II trial.
He said the next step for TAS-102 – “besides giving it a name” – is regulatory approval in the U.S., which he said may be a challenge because it is a combination drug and the FDA looks at that differently.
He said trials combining each of these drugs with standard agents are underway.
Sunday, July 27, 2014
BY ROBERT H. CARLSON
BARCELONA, Spain -- The limited effectiveness of anti-EGFR agents such as cetuximab is a concern not only in patients with KRAS-mutant tumors, but also potentially for patients with any RAS mutation, including NRAS. Extended analysis of clinical trials in metastatic colorectal cancer have established that in the first-line setting, patients with metastatic colorectal cancer harboring any activating RAS mutation, not only KRAS, are unlikely to benefit from the addition of cetuximab to FOLFOX or to FOLFIRI.
As Eric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven and Head of the Digestive Oncology Unit at University Hospital Gasthuisberg in Belgium, explained in an interview here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer, classic KRAS exon-2 testing finds the mutation in approximately 40 percent of these patients, but extended RAS analysis finds another 10 to 15 percent.
“We should do not only KRAS testing anymore, but also RAS testing,” he said. “Today we know that we have to look at RAS and other so-called rarer RAS mutations, which are on KRAS exon 3, KRAS exon 4, and NRAS.
“The group identified by extended RAS testing, compared with KRAS testing, is 10 to 15 percent, but that's added to the 40 percent of patients with a KRAS mutation exon 2,” said Van Cutsem, Chair of the Congress. “That brings us to around 50 percent of patients with metastatic colorectal cancer.”
Patients with a RAS mutation should not be treated with an anti-EGFR antibody, he said. “In Europe we have changed the label already for that, but in the U.S., although the data are strong, the FDA has not yet changed the label. In Europe we are a bit more dynamic on that and have followed the scientific evolutions more rapidly.”
Introduce All-RAS Analysis in Clinics
There is no doubt that there is a benefit to selecting patients with metastatic colorectal cancer by RAS status, said Congress Vice-Chair Josep Tabernero, MD, PhD, Head of Medical Oncology and Director of Clinical Research at Vall d'Hebron University Hospital and Institute of Oncology in Barcelona.
In a separate interview at the meeting, Tabernero recommended that all-RAS analysis should be introduced in the clinic to make the best treatment decision at the time of diagnosis of stage IV colorectal cancer, to decide the most appropriate first-line therapy as well as the sequence of treatments. He said there may also be benefit in analyzing BRAF status.
The need for all-RAS analysis can be seen, he said, in the PICCOLO study (Seymour et al: Lancet Oncology 2013;14:749-759), which showed that in patients with fluorouracil-resistant advanced colorectal cancer, the addition of panitumumab to irinotecan did not improve overall survival in the subgroup of patients with wild-type KRAS tumors. But the patients who had the worst overall survival were those with mutations in BRAF, NRAS, and PIK3A.
Not all RAS mutations are the same, Tabernero noted. In a pooled analysis of patients from seven clinical trials who were treated with chemotherapy-cetuximab versus chemotherapy alone, patients with KRAS (codon 12) G12V-mutated tumors treated with the cetuximab-containing regimen had inferior progression-free and overall survival and response rates compared with use of chemotherapy alone, as would be expected (De Roock et al: JAMA 2010;304:1812-1822). But patients with KRAS (codon 13) G13D-mutated tumors treated with chemotherapy-cetuximab had longer overall and progression-free survival than those treated with chemotherapy alone.
RAS analysis is also complicated because several different technologies are being used. The CRYSTAL and OPUS studies both used BEAMing technology from Sysmex Inostics; FIRE-3 used PyroMark (Qiagen) TheraScreenPyro Kits; and PRIME and PEAK used dideoxy sequencing with the WAVE MicroChip Electrophoresis System.
Adding further to the puzzle, sensitivity for RAS mutation detection with these systems ranges from 0.01 percent to 10 percent, Tabernero said.
Tabernero outlined a “switch” strategy to select the best candidates for first-line anti-EGFR therapy: patients with metastatic colorectal cancer would first be tested for KRAS exon-2 wild-type tumors, and those falling into this category would then be tested for all-RAS wild-type tumors. “This constitutes the first important step for stratified, personalized medicine in this setting,” he said. “The advantage in overall survival would be huge.”
OPUS Update: Any RAS Mutation Cancels Cetuximab Benefit
Updates with RAS analysis were presented here on two clinical trials, OPUS and CRYSTAL, highlighting the significance of expanded RAS analysis.
Researchers reported that an extended analysis of data on RAS mutation from the randomized Phase II OPUS trial (Bokemeyer et al: Ann Oncol 2011;22:1535-1546) shows that metastatic colorectal cancer patients harboring not just KRAS but any activating RAS tumor mutation are unlikely to benefit from the addition of cetuximab.
The original OPUS report showed that the addition of cetuximab to FOLFOX4 significantly increased response and progression-free survival in the first-line treatment of patients with KRAS exon-2 wild-type metastatic colorectal cancer. But patients with KRAS exon-2 tumor mutations showed no such benefit from cetuximab, with worse outcomes in patients in the FOLFOX4-cetuximab arm compared with FOLFOX4 alone. Those authors also concluded that KRAS mutation status is an effective predictive biomarker.
“Restricting administration of FOLFOX4-cetuximab to patients with RAS wild-type tumors enables further tailoring of therapy to maximize patient benefit and prevent harm,” said Sabine Tejpar, MD, PhD, Associate Professor of Medicine at University Hospital Gasthuisberg, who presented the extended analysis data at the World GI Congress.
And a retrospective subgroup analysis of data from the randomized, Phase III CRYSTAL trial (Van Cutsem E et al. N Engl J Med 2009; 360:1408-1417) showed no benefit from cetuximab in patients with RAS mutations. Those researchers initially reported that the addition of cetuximab to FOLFIRI significantly increased progression-free survival, overall survival, and response in the first-line treatment of patients with KRAS exon 2 (codon12/13) wild-type metastatic colorectal cancer, while patients with KRAS exon-2 tumor mutations showed no cetuximab treatment benefit.
The new data were presented here by Fortunato Ciardiello, MD, PhD, Professor and Head of the Division of Medical Oncology at Second University of Naples in Italy, who said they were consistent with less than five percent mutant sequences being a clinically appropriate cutoff to use in determining eligibility for first-line FOLFIRI-cetuximab.
“Molecular testing of tumors for all activating mutations of KRAS and NRAS are essential in selecting the most appropriate first-line treatment for patients with metastatic colorectal cancer,” he said.
Sunday, July 27, 2014
BY ROBERT H. CARLSON
BARCELONA, Spain -- Operable gastric cancer has a poor prognosis, with most studies showing that 65 to 75 percent of patients who relapse after localized treatment have systemic disease, and that the majority of patients who relapse die within two years.
Speaking here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer, David Cunningham, MD, Head of the Gastrointestinal Unit and Co-Director of Research Integration at the Royal Marsden Hospital in the U.K., said neoadjuvant and/or adjuvant treatment can improve those outcomes.
But is this treatment appropriate for all patients? he asked. He noted that outcomes for all patients have improved for many reasons, and one is better preoperative staging: “Better staging allows us to select out patients who intrinsically have a better prognosis and who do better than those patients in whom we have failed to diagnose ostensibly a more advanced disease.
“Early-stage T1N0 tumors (1A) have excellent prognosis with surgery alone, and it is fair to say that these cases do not require adjuvant or neoadjuvant treatment. But only one in 100 western patients present with early-stage gastric cancer patients, and very few patients in western countries are suitable candidates for surgery alone.”
So what is the optimal treatment approach, and for whom? Cunningham said patients with esophageal-gastric junction cancer appear to have the greatest benefit from perioperative chemotherapy.
“Perioperative chemotherapy clearly improved outcomes in trials of perioperative chemotherapy for T2 esophageal and esophageal-gastric junction cancer,” with chemotherapy before or after surgery reducing the risk of death by about 25 percent at five years, he said.
Two Phase III trials, he noted, have established perioperative chemotherapy as an international standard in esophageal gastric cancer: MAGIC, for which he was first author (NEJM 2006;355:11-20) and FNCLCC-FFCD (JCO 2011;29:1715-1721).
In MAGIC, the five-year overall survival rates improved with perioperative chemotherapy -- 23 percent for surgery alone versus 36 percent for surgery plus perioperative chemotherapy; and in FNCLCC-FFCD the rates were 24 versus 38 percent, respectively.
Perioperative chemotherapy also reduced the risk of metastatic disease in both studies: from 37 to 24 percent in MAGIC, and from 38 to 30 percent in FNCLCC-FFCD.
Downstaging Improves Outcomes
Preoperative chemotherapy also led to tumor downstaging in those trials. The rates of curative resection (R0) in MAGIC were 79 percent for surgery-chemotherapy versus 70 percent for surgery alone, and 84 percent versus 73 percent, respectively, in FNCLCC-FFCD.
And downstaging tumors with chemotherapy does improve survival, Cunningham said. He cited unpublished data in press in the Journal of Clinical Oncology by Davies et al on a study of 600 patients with esophageal-gastric junction cancer. A graph from that data showed that patients downstaged from T3N+ to T2N- with chemotherapy had survival rates similar to those of patients with T2N- tumors who did not have chemotherapy -- approximately 70 percent and 60 percent, respectively, at 10 years.
But patients who started and ended chemotherapy with T3N+ tumors had a survival rate, of about 10 percent, at 10 years.
Use of trastuzumab has improved survival in HER2-positive metastatic gastric cancer, Cunningham said, moving to the question of whether there is also a benefit in the neoadjuvant/perioperative setting.
Although there is no direct evidence of benefit, there is an indicator of potential benefit in the Phase II non-randomized trial of perioperative HER-FLOT (trastuzumab plus fluorouracil-leucovorin-oxaliplatin-docetaxel) as reported by Ralf Hofheinz et al at this year’s ASCO Annual Meeting (Abstract 4073).
“What's most impressive is the 22.2 percent pathologic complete response rate” with the HER-FLOT regimen, Cunningham said. “There is a compelling need for the oncology community to address this very question, because 15-20 percent of gastric cancer patients--if esophageal-gastric cancer is included--are not routinely receiving trastuzumab because we don't have the evidence.”
East versus West
Adjuvant chemotherapy has been shown to benefit Asian patients, Cunningham said. For example, two Phase III trials of surgery with/without chemotherapy -- CLASSIC (Bang et al: Lancet 2012; 379:315-321) with capecitabine-oxaliplatin and a trial testing S-1 (Sasako et al: JCO 2011; 294387-493) -- both showed improvements in overall survival in Asian patients receiving perioperative chemotherapy, but S1 is poorly tolerated in western patients due to CYP2A6 polymorphisms, he said.
Also in western patients, preoperative chemotherapy is better tolerated than postoperative chemotherapy, as seen in the MAGIC trial, in which 91 percent of patients completed preoperative chemotherapy but only 50 percent complete postoperative chemotherapy.
5 Ongoing Trials to Watch
Cunningham concluded by listing five ongoing trials to watch for further developments in the field:
· ST03: Phase II/III, 1140 patients, peri-operative chemotherapy with/without bevacizumab;
· CRITICS: Phase III, 788 patients, peri-operative chemotherapy vs. neoadjuvant chemotherapy plus postoperative chemoradiotherapy;
· ITACA-S2: Phase III, 1180 patients, peri-operative chemotherapy with/without postoperative chemoradiotherapy vs. postoperative chemotherapy with/without chemoradiotherapy;
· TOXAG: Phase III, 40 patients, adjuvant chemoradiotherapy with capecitabine, oxaliplatin and trastuzumab; and
· POTENT: Phase III, 724 patients, adjuvant S-1 vs. S-1 plus oxaliplatin.
Advantages and Disadvantages of the 4 Major Staging Modalities
Accurate staging depends on accurate imaging, and Cunningham listed the advantages and disadvantages of the four major modalities:
· CT imaging of the thorax, abdomen and pelvis has the advantage of detecting local and distant lymph adenopathy and distant metastases, but the primary tumor can be difficult to assess;
· Endoscopic ultrasound can provide an accurate assessment of tumor and node stages and determine proximal and distal tumor extent, but is less useful in antral tumors;
· PET scanning improves detection of involved lymph nodes and metastases, but it may be uninformative in mucinous tumors; and
· Laparoscopy can exclude metastatic disease involving the peritoneum and diaphragm, but it is invasive.
Saturday, July 26, 2014
BY ROBERT H. CARLSON
BARCELONA, Spain – In patients from Western countries, second-line treatment for advanced gastric and gastro-esophageal cancer with the combination of paclitaxel and the VEGF antagonist ramucirumab is safe and efficacious, significantly increasing overall and progression-free survival and response compared with use of paclitaxel alone.
The combination reduced the risk of death by 27 percent and increased survival from 5.9 to 8.6 months compared with paclitaxel alone, according to a subanalysis of 398 patients from Western countries in the randomized placebo-controlled RAINBOW trial who had disease progression on or after use of platinum and fluoropurimidine-containing chemotherapy.
The subanalysis data were presented here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer (the full analysis of all of RAINBOW's 665 patients was presented earlier this year at the Gastrointestinal Cancers Symposium (Wilke H et al. Abstract LBA7).
The subanalysis was awaited because some trials have shown significantly different outcomes between patients from Asian and Western countries. In an example cited by several speakers here, the AVAGAST study (Ohtsu et al: JCO 2011;29:3968-3976) of bevacizumab plus capecitabine-cisplatin as first-line treatment of patients with gastric cancer, the addition of bevacizumab provided no overall survival benefit for the Asian study population or the study population as a whole, but did improve survival rates in non-Asian patients with diffuse or distal tumors. (Van Cutsem et al: JCO 2012;30:2119-2127).
In this RAINBOW subanalysis reported at the ESMO meeting, the efficacy and safety of ramucirumab, a vascular endothelial growth factor receptor-2 antagonist, were consistent with the overall study population results, said Eric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven and Head of the Digestive Oncology Unit at University Hospital Gasthuisberg in Belgium, first author of this study and second author of the paper presented at the GI Cancers Symposium.
“Ramucirumab plus paclitaxel should be considered as a new standard in second-line treatment for advanced gastric cancer.”
Regional Differences at Baseline and in Outcome
He acknowledged that the goal of RAINBOW was not to formally compare Western versus Asian patients, but the subanalysis did show some small differences in patient outcomes between the entire RAINBOW cohort and patients in Region 1, comprising Europe (including Israel), Australia, and the United States.
Overall survival for all RAINBOW patients was a median of 9.6 months for the drug combination versus 7.4 months for paclitaxel alone, compared with 8.6 months versus 5.9 months, respectively, for the Western countries of Region 1.
And the objective response rates for all RAINBOW patients was 27.9 percent for the drug combination versus 16.1 percent for paclitaxel alone, compared with 26.8 percent versus 13.0 percent, respectively, for Region 1.
Van Cutsem said these differences were possibly due to differences in baseline characteristics. For example, more patients in the overall trial received doublet rather than triplet chemotherapy as first-line therapy -- 75 vs. 24.5 percent, while in Region 1 the mix was 62.1 vs. 37.2 percent.
Patients globally had shorter times to disease progression, 66.8 percent during first-line therapy versus 58.0 percent for Region 1; and more patients had gastric versus gastro-esophageal junction cancer globally -- 79.4 and 20.6 percent, while in Region 1 the mix was 69.3 and 30.7 percent, respectively.
Gastric cancer of all types is more common in Asian countries but the outcomes are typically better -- thought to be due to more extensive screening.
In April the U.S. Food and Drug Administration approved ramucirumab as a single agent for second-line treatment of metastatic gastric cancer and gastro-esophageal adenocarcinoma, following the outcome of the placebo-controlled Phase III REGARD trial of 355 patients (Fuchs et al: Lancet 2014;383:31-39). “We expect that the authorities will also approve the combination of paclitaxel plus ramucirumab, based on the RAINBOW study,” Van Cutsem said in an interview. “That’s an important breakthrough in second-line treatment.”
Era of New Targeted Therapies in GEJ Cancer
Another speaker here, Manish A. Shah, MD, Director of the Department of Gastrointestinal Cancer and Co-director of the Research Center for Advanced Digestive Care at Weill Cornell Medical College, called the RAINBOW study the most recent success story in GI cancer.
“We’re in an era of new therapies for gastric cancer and gastroesophageal junction adenocarcinoma,” he said in an interview. “Many new targets are available and validated, we're seeing positive results targeting antiangiogenesis and HER2, and new targets are being evaluated such as MET inhibition.”
He said that HER2 is now a validated target for first-line gastric cancer, and that targeting the angiogenesis pathway in gastric and gastroesophageal adenocarcinoma is also validated.
In his own presentation he expanded on data he has published recently, including that of tumor heterogeneity, discussed in a review paper he wrote in Nature Reviews Clinical Oncology (2014;11:10-11). “Historically all the different gastric diseases have been lumped together – proximal stomach cancer, distal stomach cancer, diffuse stomach cancer,” he said. “We put them all together, but their biology might be different and so they may not all respond to the same targets the same way -- which may explain why some of the previous studies didn’t work,” he said. “But we still need to learn who would benefit most from antiangiogenic therapy.”
On July 23, researchers from the Cancer Genome Atlas published results in Nature (doi:10.1038/nature13480) identifying four subtypes of gastric tumors based on shared mutations and other molecular abnormalities.
At the World Congress on GI Cancers, Shah said that researchers are beginning to understand the difference in outcomes between Western and Asian populations. Because Asians, particularly in Korea and Japan, have regular screening, they typically present with earlier disease -- “so most of the time when patients have metastatic disease, their stomach is already removed. Whereas in the West, patients present with metastatic disease with their primary tumor in place and so the disease burden is different and they need to get second-line and third-line therapy.”
Differences in molecular subtypes are also being found between geographic regions. The most exciting studies now are in inhibition of MET, the STAT-3 oncogene, and the immune checkpoint inhibitors PD1/PDL1 pathways.
History of the World Congress
The World Congress on Gastrointestinal Cancer began in 1999 as Perspectives in Colorectal Cancer, founded by Mario Dicato, MD, and Eric Van Cutsem, MD, PhD, along with Jacques Wils, MD, of Laurentius Hospital in The Netherlands, who retired as chair following the 2003 Congress. Dicato and Van Cutsem remain as Chairs, and Vice-Chair is Josep Tabernero, MD, PhD, of Vall d'Hebron University Hospital and the Institute of Oncology in Barcelona.
An agreement was reached in 2004 between the organizers and the European Society for Medical Oncology to collaborate on the development of the Congress with the goal of increasing the educational value, and expanding the reach to a wider audience.
The meeting originally focused only on colorectal cancer, but after partnering with ESMO the program was expanded to include sessions on gastric cancer, pancreatic cancer, esophageal, pancreas and bile duct, neuro-nephrotic and upper GI cancers, liver, and gastrointestinal stromal tumors.
“Knowing the right people, having good networking, and being on top of the science has helped the Congress evolve,” Van Cutsem said. This year it attracted 2,500 attendees.