Just In... Meeting News
Key news updates from recent oncology and hematology meetings.
Thursday, November 27, 2014
BY ED SUSMAN
BOSTON--Elderly patients diagnosed with hepatocellular cancer should be treated aggressively because their response appears to depend upon their condition and not their age, researchers suggested here at the American Association for the Study of Liver Diseases Annual Meeting.
More important than chronological age was the severity of liver cirrhosis at the time of diagnosis and the tumor characteristics of the hepatocellular carcinoma, reported Elena Dionigi, MD, a hepatologist in the Gastroenterology Unit at Azienda Ospedaliera in Melegnano, Italy.
In the retrospective study, she and her colleagues stratified patients into younger and older—defined here as younger than age 70, and age 70 and older. The median survival for both groups was about 35 months (34.89 vs. 34.35 months, respectively, a nonsignificant difference.
In analyzing the cumulative survival, the researchers observed that 60 percent of the younger patients survived one year following treatment compared with 42 percent of the older patients; at three years, 59 percent of the younger patients were alive, compared with 34 percent of the older group of patients.
“This study demonstrates that cumulative survival was mostly dependent on the underlining severity of cirrhosis and hepatocellular carcinoma profile at presentation, rather than on age,” Dionigi said. “Noteworthy, treatment per se emerged as the most important independent predictor of better outcome. These data should therefore discourage a nihilistic attitude of hepatologists towards the under-treatment of difficult-to-manage patients.”
Asked his opinion for this article, another liver cancer expert not involved with the study but who was looking at the poster at the same time as this reporter, Ashutosh Barve, MBBS, PhD, Head of the Liver Clinic at the Louisville VA Medical Center and Assistant Professor of Gastroenterology/Hepatology Medicine at the University of Louisville, said that in his practice he would definitely go ahead and treat these patients. “If a patient has good performance status and has small, isolated tumors, I would definitely treat them. I think this presentation indicates that these patients do quite well.”
Mean Age Progressively Increasing
The researchers reported in their poster presentation that the mean age in cirrhotic patients with hepatocellular carcinoma is progressively increasing, and with an aging population more liver cancer is being diagnosed. “Information on hepatocellular carcinoma management and outcome in elderly are still limited and are heterogeneous,” the team said.
“International guideline recommendations on hepatocellular carcinoma derive from cohorts including younger patients, and thus are inadequate to depict the real magnitude of the problem.”
Hence, the investigators sought information on how age might impact hepatocellular carcinoma characteristics at presentation; the type of therapeutic approach taken; and the efficacy of that treatment, as well as overall outcomes in a large series of newly diagnosed patients recruited in clinical practice.
Included in the multicenter study were cirrhotic patients with newly diagnosed hepatocellular carcinoma, who were consecutively enrolled in 31 Italian centers, starting in September 2008, as part of a national ongoing project of AIGO, the Italian Association of Hospital Gastroenterologists. The study did not include centers for transplantation or centers for specialized hepato-biliary surgery.
Also excluded were cases of HIV co-infection and patients who did not have evidence of liver cirrhosis. There were no fixed protocols for treatment, giving each institution free rein in determining therapy.
At the time of analysis in September 2013, the researchers identified 922 patients with data on therapy and survival, ranging in age from 26 to 92, and the group was divided by the 70-year milestone.
In general, the researchers said, “older patients displayed a well-compensated cirrhosis and a tumor profile that does not differ significantly from the younger cohort, and although the rate of treatment was similar in younger and older patients, the latter less frequently underwent surgical resection.”
The median age of the younger cohort of 422 patients was 61, versus 76 for the older patients. About 83 percent of the younger group were men vs. 64 percent of the older group.
The younger group was more likely to have Hepatitis B virus as the etiology of hepatocellular carcinoma (17.5%) compared with the older patients (7.4%), which was also significant. Among the elderly group, 61 percent had infection with Hepatitis C virus as the cause of the cancer, compared with 47.6 percent of the younger patients. Alcohol as a cause of cirrhosis and cancer was observed in 26 and 20 percent of the patients, respectively.
As would be expected, the older population had more moderate to severe co-morbidities (33%) compared with the younger patients (23%), and 62 percent of the younger patients fell into Child-Pugh Class I chronic liver disease compared with 69 percent of the older patients.
There was no difference in the rate of treatment according to age, with about 77 percent of patients treated in both groups. Surgical resection was performed in 12 percent of the younger patients and seven percent of the older patients, but other forms of treatment were not statistically different between the groups. The major other forms of treatment included ablation procedures, transcatheter arterial chemoembolization, and treatment with sorafenib. About 22 percent of patients in each group did not have any treatment.
In commenting on the study, Barve said, “All of the patients were receiving treatments that are available in most clinics in the United States. The tolerance for these treatments in this study seems pretty good, too. The point the authors are trying to make is that survival between the older and younger patients in this study was not different. I don’t see any reason not to treat these older patients. I am glad to see that treating the older patients does make a difference in outcome.”
In the study, patients who accepted any form of treatment achieved a median survival of about 40 months; while patients who were not treated had a median survival of about 12 months. Among patients who were treated with curative intent, 52 percent were in the younger group. At 48 months, 62 percent of these younger patients were alive compared with 44 percent of the older patients.
Barve suggested that hepatologists, at least in the United States, might be more aggressive in treating older persons than oncologists. He said he agreed with the Italian researchers that “we should treat these patients on the basis of their condition, not their age.”
Wednesday, November 26, 2014
BY ROBERT H. CARLSON
NEW YORK--Going beyond single-agent gemcitabine for first-line metastatic pancreatic cancer treatment, oncologists can choose between at least two combination regimens: FOLFIRINOX (folinic acid [leucovorin], fluorouracil [5-FU], irinotecan, and oxaliplatin), and gemcitabine-Abraxane (gemcitabine and nab-paclitaxel).
After years of negative clinical studies in pancreatic cancer, the two regimens are considered major treatment advances.
Two experts offered divergent views on which should be the preferred regimen, in a presentation here at the Chemotherapy Foundation Symposium, sponsored by the Mount Sinai School of Medicine. But with overall survival time in metastatic pancreatic cancer still so short, neither speaker thought either regimen was a “winner.”
“We are nowhere near 'winning' anything in this disease,” said Jordan D. Berlin, MD, Professor of Cancer Research and Medicine and Clinical Director of the GI Oncology Program at Vanderbilt-Ingram Cancer Center. “If we are going to sit here and concede that either one is a winner we're wrong--both regimens are losers. One might be a slightly better loser than the other, but the bottom line is that we're still not where we want to be.”
‘Superior Survival with FOLFIRINOX’
Within that context, though, Howard S. Hochster, MD, Associate Director of Yale Cancer Center and Professor of Medicine at Yale School of Medicine, advocated the use FOLFIRINOX: “The survival and response achieved with FOLFIRINOX are unprecedented and appear better than gemcitabine-Abraxane,” he said.
He cited the French PRODIGE trial, sponsored by the French Ministry of Health, with 342 patients with metastatic pancreatic cancer, which showed almost a doubling in progression-free survival for FOLFIRINOX compared with single-agent gemcitabine (6.4 months versus 3.3 months) and improved median survival (11 versus 8.5 months). Objective response rates were 31.6 percent versus 9.4 percent. (Conroy et al: NEJM 2011;19:1817-1825).
“So for everything we can see, FOLFIRINOX really is superior,” Hochster said.
He noted, though, that many U.S. oncologists were hesitant at first about FOLFIRINOX because of the toxicity profile. “We knew FOLFOX isn't that bad, and FOLFIRI isn't that bad, but giving three [chemotherapy] drugs might be a big problem. But in the meantime, people have become a lot more comfortable with FOLFIRINOX.”
The regimen does have a relative disadvantage in toxicities, he said, including diarrhea and febrile neutropenia—“but despite substantial toxicities, patients feel better longer on FOLFIRINOX,” Hochster said, calling it “the standard of care for 'fit patients' with advanced pancreatic cancer.”
“Fit” is not as restrictive a term as it might seem, he added.
“In our experience at Yale, with our modified FOLFIRINOX, we have been able to treat patients with performance status of 1 and even 2, and even some people in their 70s and 80s.” Hochster said a study at Yale used a modified regimen, reducing the 5-FU bolus and the irinotecan by 25 percent, and added pegfilgrastim to make the regimen more tolerable.
“For good performance-status patients FOLFIRINOX is the better option, and even for people who are borderline, it is doable with some modifications.”
Hochster concluded his talk saying the real question for him is what will be the best platform for combining new drugs and biologics: “We don't have enough data to know that, but I don't believe in my experience that gemcitabine-Abraxane is that much more tolerated. It may vary, though, and for a biologic that has a lot of side effects like diarrhea, [combining with] a drug like FORLFIRINOX would be less preferable.”
Berlin was tasked with arguing the relative merits of gemcitabine-nabpaclitaxel, but he that said until the last minute he thought he was to take the side of FOLFIRINOX, because he has a potential conflict of interest, related to a relationship with Abraxane’s manufacturer, Celgene.
“I take boatloads of money from Celgene and I enjoy it,” he said jocularly. “Let's face it, I might have a conflict here.”
Nevertheless, Berlin said there is evidence from two clinical studies of synergy between gemcitabine and nab-paclitaxel, although they point to two different mechanisms.
To support the regimen's efficacy, he cited the Phase III MPACT trial, sponsored by Celgene, with 863 patients, comparing gemcitabine plus nab-paclitaxel versus gemcitabine alone. The study showed superior overall survival, progression-free survival, and response with the combination regimen, although the rates of peripheral neuropathy and myelosuppression were increased (Von Hoff et al: NEJM 2013;18:1691-1703).
Berlin pointed out that the gemcitabine-nab-paclitaxel response rate of 29 percent by investigator review in MPACT was very close to the 31 percent response rate by investigator review for FOLFIRINOX in the PRODIGE study. The two studies are comparable, he said, as there were many similarities between the patient cohorts, including median age, gender, and stage, and all patients had stage IV disease.
There were also differences: MPACT allowed performance scores of 2, although that was less than 10 percent of the study; allowed patients over age 75; and was worldwide, while PRODIGE was conducted only in France.
But there was no clear difference in toxicities, Berlin said. “People have this mythological belief that there’s a difference in the toxicity favoring gemcitabine-nabpaclitaxel and that therefore it’s easier to combine, and we automatically think it’s easier to give three drugs than four. But just as modifications in FOLFIRINOX can happen, modifications in gemcitabine-nabpaclitaxel might have to happen.”
Berlin lamented the fact that researchers tend to rationalize decisions about combination regimens made in advance rather than actually using the science: “They'll say 'this drug synergizes with platinum, and therefore we should use it with FOLFIRINOX,' or, 'this drug synergizes with irinotecan, so therefore we should use it.'
“That's what happened in the past,” Berlin explained in a follow-up interview. “Everybody just combined their drugs with gemcitabine, with or without data, and we did a lot of 'gemcitabine-plus-your drug here' studies that were negative. And this includes me.”
Researchers need to be cautious about picking the best chemotherapy platform when moving forward into combination regimens with targeted drugs and biologicals, he said. “We’ve actually not done the justification that we need to do for these randomized trials. We should be talking to our basic scientists working in the lab. They can explain things--for example, they might know more about negative trials that were presented but never got published.”
Berlin concluded by admitting that he could have taken either side in this debate. “It could be that FOLFIRINOX is a better regimen--certainly numerically it looks better, and honestly, I use FOLFIRINOX fairly regularly, a modified regimen FOLFIRINOX that’s used by the Intergroup as standard in clinical trials in the U.S. and Europe.”
But if the patient's performance score is poor, he said, he would use gemcitabine-nabpaclitaxel, and it is questionable whether FOLFIRINOX should be used in patients over age 75 while there are no safety or efficacy data.
State-of-the-Art Health Care versus Not So Much
Berlin went out on a limb in his presentation talking about the relative merits of clinical trials held in countries where medical care is top notch versus those in countries where the standard of care is not as good. Patients in PRODIGE were all treated in France, he said, while MPACT patients were from North American, several countries in Europe, Australia, and--to make his point--Russian and the Ukraine.
“Russia contributed a large number of patients, and we know they don’t have the same level of supportive care infrastructure that we’ve got in this country, or that France has. France is a modern country with an outstanding health care system and a ready availability of all supportive measures, while Russia is still developing. This is not an indictment of Russian physicians, but their resources are more limited and there's less availability of some of the supportive care measures, including growth factors that would allow you to not modify doses.”
He said after his presentation that the theoretical consequence in a trial of a drug with a higher toxicity profile could be that patients need more supportive measures, such as growth factors. And if that supportive care were not readily available more patients could go off study, more dose modifications could mean less drug exposure, and that could have an impact on outcomes.
On the other hand, a drug with a low-toxicity profile such as gemcitabine would require fewer supportive measures and there might be no effect or limited effect between countries, he said, cautioning: “There is no data to support what I just said. This is theoretical.”
Tuesday, November 25, 2014
BY ROBERT H. CARLSON
NEW YORK--Somatic mutations of DNA in cancer cells can be very effective biomarkers, largely because of their specificity. Two promising tests to detect tumor DNA were described here at the Chemotherapy Foundation Symposium, sponsored by Mount Sinai School of Medicine.
“We will see an evolution of mutations as diagnostic markers, and not just as predictive and prognostic markers,” said Luis A. Diaz, MD, Associate Professor of Oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, speaking here at the Chemotherapy Foundation Symposium, sponsored by Mount Sinai School of Medicine. “It's an evolving field but we'll be seeing its impact on cancer in the very near future.” His overall topic was on the use of serum tumor DNA for “liquid biopsies.”
At the same session, Steven Itzkowitz, MD, Professor of Medicine and Oncological Services at the Icahn School of Medicine at Mount Sinai, discussed a diagnostic test for colon cancer that uses DNA found in stool.
Session co-moderator Jordan D. Berlin, MD, Professor of Cancer Research and Medicine and Clinical Director of the GI Oncology Program at Vanderbilt-Ingram Cancer Center, commenting on the multi-targeted stool DNA as screening tests for patients, said “This is real-time stuff that can be applied to practice.”
And he said he found the circulating DNA test “particularly cool.”
While neither test is ready for the clinic, both are worthy of being put in multiple clinical trials, he said.
Circulating Tumor DNA for Liquid Biopsy
Malignant tumors have an abundance of mutations – rearrangements, amplifications, translocation, deletions, etc. – that are released by the tumor into the circulation, Diaz said. “Cells are constantly turning over--very few tumors just sit there indolently. And when they undergo apoptosis or necrosis they release DNA into the circulation, and that's what we're trying to measure.”
Importantly, circulating DNA levels correlate with survival as a measure of tumor burden, tumor staging, and prognosis, he said.
Cell-free DNA testing made the news earlier this year when a study showed that fetal DNA circulating freely in the maternal blood stream could detect Down syndrome with an estimated false-positive rate of 0.3 percent and a positive predictive value of 45 percent (Bianchi et al: NEJM 2014; 370:799-808).
In oncology, Diaz said “mutations are beautiful biomarkers. They're incredibly specific, and unlike PSA, which is released by normal cells, they're discovered in both in tumors and in precancerous tumors.”
He said circulating tumor DNA can be used for monitoring response, as in a recent Phase II study of GTX-C (gemcitabine, capecitabine, taxotere, and cisplatin) as first-line treatment in patients with metastatic pancreatic cancer, on which he was senior author--the study was presented in a poster at the most recent American Society of Clinical Oncology Annual Meeting (Dung et al: ASCO Abstract 213).
The researchers reported that GTX-C was highly active and well-tolerated in patients with metastatic pancreatic cancer, but they also measured KRAS mutations in the patients’ plasma.
Diaz told the audience here that the researchers saw circulating DNA levels spike when therapy started and the patient had a response--“Dynamic changes were identified much faster than with an antigen biomarker.”
He said that because the half-life of circulating tumor DNA is one to two hours, he foresees circulating tumor DNA levels being used like the infectious diseases model, where dynamic changes can be quickly monitored to predict responses. This would be particularly useful in treating cancer patients with targeted therapies, he said.
In other research, circulating cell-free tumor DNA was used to track resistance to EGFR blockade.
“We could watch the molecular resistance building and we could delineate the pathway involved,” Diaz said. “We found mutations along the whole side of the pathway, in the binding domain, the kinase domain, NRAS and KRAS, and BRAF occasionally… It's frightening to me that there is heterogeneity in mutations in the same patient. Then the question is: Do you prioritize targeted therapy by the dominant lesions? This will have to be answered.”
MRD by Cell-Free DNA
Cell-free tumor DNA has also been used to detect minimal residual disease (MRD). Diaz related one case in which a tumor resected for metastatic colon cancer was sequenced, and the exact location was probed in the plasma of that patient several weeks after surgery.
“One day after surgery, we found almost no mutations, but at day 42 there was a small increase in circulating tumor DNA while the CT scan was negative,” Diaz said. “And then at day 244 the CT scan was positive for recurrence and there was a large amount of circulating tumor DNA.”
Early detection is where Diaz thinks circulating tumor DNA will have the biggest impact.
“In pancreatic cancer we've looked for mutations in tumors all the way from premalignant lesions to stage 4,” he said. “In the patients with metastatic disease, we could detect about 90 percent of the tumors [using circulating tumor DNA] and for stages 1, 2, and 3, we could detect about half of the cancers. And all this is from 2 cc's of plasma.”
CRC--Time to Find a Better Mousetrap
Itzkowitz, in his presentation, explained that until now the only tests for colorectal cancer besides colonoscopy have been fecal immunochemical tests (FIT) that detect occult blood but have high rates of false positives.
There is a strong biological basis for a stool DNA test--namely the abundance of DNA from tumors that can be amplified and detected in the stool.
He described the recent DEEP-C study (DEtEction of colorectal advanced adenomatous Polyps and Cancer) of a multi-target colorectal cancer screening test (Imperiale et al: NEJM 2014;370:1287-1297).
DEEP-C used a noninvasive, multi-target stool DNA test that contained a simple adapter device that fits on the toilet for collection, a preservative buffer that allows the DNA to become stable for a week at room temperature, and a mailing box.
The study, on which he was an author, compared the noninvasive, multi-target stool DNA test with a fecal immunochemical test in persons at average risk for colorectal cancer. The DNA test included quantitative molecular assays for seven KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a quantitative hemoglobin immunoassay--“This is basically a FIT test plus DNA; it is not a pure DNA test because it also measures hemoglobin,” he said.
In asymptomatic persons at average risk for colorectal cancer, the multi-target stool DNA testing detected significantly more cancers than did FIT, but it also had more false-positive results, he said.
Of the 9,989 participants evaluated, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring 1 cm or greater in the greatest dimension) on colonoscopy.
The sensitivity for detecting colorectal cancer was 92.3 percent with the multi-target DNA testing and 73.8 percent with FIT. The sensitivity for detecting advanced adenomas was 42.4 percent with the multi-target DNA test and 23.8 percent with FIT. Specificity was 86.6 percent for the multi-target DNA test and 94.9 percent for FIT.
“The test was as good in the proximal colon as in the distal colon,” he reported.
The test, named Cologuard, was approved by both the Food and Drug Administration and Center for Medicare and Medicaid Services on the same day this summer--August 11, 2014 (OT 9/10/14 issue)—and is available through Exact Sciences Corp. of Madison, Wisconsin.
Itzkowitz said the test is not affected by the site of the colorectal cancer; is operator independent (i.e., it is automated); is noninvasive; requires no cathartic preparation; and there are no diet or medication restrictions.
He said that he expected that new screening guidelines will recommend having the stool test every three years, and that people who have a positive stool DNA test will be advised to undergo colonoscopy.
He said that in practice, the stool DNA test would be used first; and if it is positive the patient would be referred for a colonoscopy. “And if it was positive the colonoscopist will likely pay very close attention to find adenomas.”
Asked if he would recommend the DNA test to patients over colonoscopy, Itzkowitz joked that “I make my living doing colonoscopies.” But seriously, he said, “I am seeing more people come in for colonoscopies who have eight comorbidities and are on three anticoagulants, and a lot of times I'm looking for ways not to do colonoscopies. You will have to individualize.”
Noting that one-third of people currently eligible for colonoscopy avoid it, he said “this is most important for the third of patients who are doing nothing, who hopefully will at least accept this and then a colonoscopy if necessary.”
Tuesday, November 25, 2014
BY PEGGY EASTMAN
WASHINGTON—This year, almost 300,000 Americans will be diagnosed with gastrointestinal cancers, and nearly 150,000 Americans are expected to die of GI cancers. But despite that high incidence, research on GI cancers remains underfunded. That was the consensus of speakers here at a symposium on the state of GI cancers, sponsored here by the Ruesch Center for the Cure of Gastrointestinal Cancers at Georgetown University’s Lombardi Comprehensive Cancer Center.
“We are, as we say, in last place” when it comes to a dedicated research funding stream, said John L. Marshall, MD, Director of the Ruesch Center. “This is a major public health problem, and yet we are in last place.” He decided to hold the symposium, he said, “because this is such a critical area.”
According to statistics presented at the symposium, in the United States colorectal cancer is the second leading cause of cancer death; stomach cancer will be diagnosed in more than 22,000 Americans in 2014; pancreatic cancer is the fourth leading cause of cancer death, and has a low survival rate; and liver cancer and intrahepatic bile duct cancer combined is the seventh leading cause of cancer death.
Asked by OT what he hoped the symposium might accomplish, Marshall said he hoped to raise awareness on the magnitude of the problem of GI cancers; draw attention to the need for public/private partnerships (including collaborations with patient advocacy groups) to advance scientific knowledge on GI cancers; and bring up-to-date U.S. therapies to patients in the rest of the world (stomach cancer is the second leading cause of cancer mortality worldwide).
Currently there are about 800 medicines and vaccines in development to treat cancer and some 200 in development to treat patients with GI cancers, said John J. Castellani, President and CEO of the Pharmaceutical Research and Manufacturers of America (PhRMA). “GI cancers are one of the great priorities that we have.” C
He said that realistically, the majority of medicines in development will fail--“but some will be spectacularly successful.”
GI Cancer Medicines in Development
According to PhRMA data, there are currently 46 medicines in development to treat colorectal cancers. One particularly promising therapy is a humanized monoclonal antibody that targets the cell surface protein endosialin, a protein expressed on cells that are part of the tumor blood vessel structure. In preclinical studies, researchers have found that blocking endosialin’s function inhibits the growth of cancerous tumors and metastases.
There are 37 medicines in development for liver cancer, according to PhRMA; these include a small molecule kinase inhibitor designed to selectively block transforming growth factor-beta (TGF-beta) signaling. Overexpression of TGF-beta in cells may boost tumor growth and intensify the metastatic process.
PhRMA data also show that there are currently 24 medicines in development to treat stomach cancer; one of these is a monoclonal antibody being tested for stomach cancer with high mesenchymal-epithelial transition factor (MET) expression that is designed to inhibit hepatocyte growth factor (HGF)/scatter factor from binding to the c-MET receptor. The HGF-cMET signaling pathway is believed to play a role in tumor growth and metastases in many cancers, including stomach cancer.
As for pancreatic cancer, there are 39 therapies currently in development. One of these takes advantage of tumor hypoxia, which is associated with tumor progression, metastases, and resistance to chemotherapy and radiation. This investigational therapy is activated when it reaches the hypoxic region of the pancreatic tumor environment, where it eventually kills tumor cells in its vicinity.
'Epicenter of Research'
“We see that the U.S. is the epicenter of research,” said Castellani, adding that PhRMA companies regularly partner with academic institutions, the hospital system, and patient groups--“This is progress based on each patient incrementally.”
Asked how he counters critics who charge that many cancer treatments cost too much and add only a few months of survival, Castellani answered that medicine accounts for only about one percent of the cost of cancer care. As for months of survival, he said, “The nature of the science of the discovery process is hard. The discovery process is not a stop-start process; it’s a continuum. I dare anyone to say how long each patient will live when they start on a drug.”
Castellani noted that the fees pharmaceutical companies pay to the US Food and Drug Administration through the Prescription Drug User Fee Act (PDUFA) are invested in improving and speeding the regulatory process at the agency. “We believe it’s incumbent on us to make that process quicker and better,” he said.
Marshall added that from his clinical experience he has found that some cancer patients are outliers, and live well beyond an average survival time when they start on a drug--“We can learn from outliers,” he said.
Centralized Banking System for Tumor Samples
Allen Melemed, MD, Distinguished Medical Fellow at Eli Lilly & Company, decried the fact that so few adults participate in cancer clinical trials, as opposed to the situation for children with cancer. He said that in addition to enrolling more adults on clinical trials, it is vitally important to have a centralized banking system to gain access to tumor samples.
“We need to have a better way to identify those genes earlier,” he said of mutations. “Stage IV is very hard to cure; we need to get patients at earlier stages.”
Speakers at the symposium emphasized that Congress plays a key role in keeping funding for cancer research, including funding for GI cancers, strong. Funding for biomedical research “is as close to a non-partisan issue as there is,” said David Pugach, Director of Federal Relations for the American Cancer Society Cancer Action Network (ACS-CAN). But, he noted, cuts to the budget of the National Institutes of Health have been very damaging.
Cancer research is an ecosystem; what we’re seeing is a real disruption of the ecosystem,” he said.
Wade Ackerman, Senior Counsel of the U.S. Senate Committee on Health, Education, Labor & Pensions, noted that Senator Tom Harkin (D-Iowa), a longtime advocate of funding for biomedical research, is retiring and did not run in the recent November election.
“It’s hard to overstate his support for NIH funding,” said Ackerman of Harkin’s long commitment to boosting the NIH budget. But, said Ackerman, “I see the future being just like the past; we roll up our sleeves on an issue and get it done. With a new Congress comes new opportunity... I do think advocates for biomedical research will emerge in the new Congress. People are using the ebola crisis as a way of advocating for the public health infrastructure.”
In an era of flat funding for biomedical research, “We’re open to looking at places where we can reallocate monies in the federal budget to NIH,” he added.
Paul Edattel, who is on the professional staff of the U.S. House of Representatives Committee on Energy & Commerce, said, “We hope money will free up for NIH… You need bipartisanship to get things done.”
He noted that Rep. Fred Upton (R-Mich.), Chairman of the House Committee on Energy & Commerce, is a champion of NIH. Upton, who recently won reelection, launched the 21st Century Cures Initiative earlier this year with co-convener Rep. Diana DeGette (D-Colo.). That initiative seeks to modernize clinical trials; facilitate data collection and data sharing; provide incentives to pharmaceutical companies to pursue drug and device research for unmet needs; incorporate the patient perspective into the research and regulatory process; develop and support young emerging scientists; and develop a stable funding stream for U.S. biomedical research.
Voice of the Patient
The House committee has sought ideas and listened to stakeholders all across the United States, said Edattel. One message the committee has heard again and again from patient groups is that their voice, the voice of the patient, needs to be heard more consistently in the regulatory-approval process for drugs and devices, he noted.
Patient groups were on the agenda and well represented at the GI cancers symposium. For example, Michael Sapienza, President of the Chris4Life Colon Cancer Foundation, whose mother died of colon cancer and was a patient of Marshall’s, described being motivated to found an organization to honor her memory, help other colon cancer patients, and help to find a cure.
Beth Lambert, Board Chairman of No Stomach for Cancer, described what it is like to have a rare mutation that causes stomach cancer and runs in her family, to lose her brother to stomach cancer, and to opt to have a gastrectomy herself. “It’s very intimidating to get that news,” said Lambert. “We were lucky with our mutation that there was a solution.”
Sharon Brigner, RN, Deputy Vice President of PhRMA, also described having a gastrectomy due to a mutation. “My focus has radically changed,” she said. “When I was sitting in that hospital bed, I realized I needed to be working for innovative medicines. Hopefully this ends with me and my family.”
Elizabeth Hoffler, Senior Director of Policy and Advocacy for the Prevent Cancer Foundation, whose mother has a brain tumor, emphasized the power of a cancer patient’s story in advocating for cancer research. “The most important advocate is someone’s personal story,” she said.
Lambert agreed: “You have to tell your story, and that’s the best way to be an advocate.”
Tuesday, November 25, 2014
BY ROBERT H. CARLSON
NEW YORK--The bad news about human papillomavirus (HPV)-associated oropharyngeal squamous carcinomas is that the incidence has doubled in the past 15 years, it's increasing by about three percent a year, and patients are younger compared with the more commonly seen head and neck cancer associated with tobacco and alcohol use.
The good news, though, is that HPV-positive disease is very responsive to induction therapy, that patients are achieving good outcomes regardless of the therapy used, and treatment with EGFR-inhibitors is very effective.
“These patients are doing much better than the head and neck cancer patients we used to treat,” said Barbara Burtness MD, Professor of Medicine (Medical Oncology) at Yale School of Medicine, Clinical Research Leader for the Head and Neck Cancers Program at Yale Cancer Center, and Co-Director of the Developmental Therapeutics Research Program, speaking in a presentation here at the Chemotherapy Foundation Symposium, sponsored by Mount Sinai School of Medicine.
“Data just released of eight-year follow-up after chemoradiation show an overall survival of 81 percent and progression-free survival of 78 percent for good-risk patients,” she said, citing a recent paper that defined good-risk patients as those with T1-2N1-2b or T3N0-2b disease and who smoked no more than 10 packs of cigarettes a year (Nguyen-Tan et al: JCO doi: 10.1200/JCO.2014.55.3925).
Burtness said HPV-associated disease may have a more favorable natural history than tobacco-associated disease, and a more indolent course for metastatic/recurrent disease (Argiris et al: Ann Oncol 2014;25:1410-1415). And HPV positivity is a strong and independent predictor of overall survival after disease progression (Fakhry et al: JCO 2014;32:3365-3373 and OT 11/10/14 issue).
“These are two different diseases arising from different mechanisms, they have different molecular markers, and now we can see they have much different outcomes after treatment,” she said.
Besides the presence of HPV genome in the cell causing the cancer, these cancers do not have nearly as many mutations as tobacco-associated cancers. And very specifically, they do not have p53 mutation, a very common hallmark of HPV-negative cancers.
“These tend to have a slower natural history, they present with a low number of bulky, cystic neck nodes, and a small primary,” Burtness said. “Under the microscope they are poorly differentiated, and they don’t make as much keratin, so initially they were described as basaloid-type cancers.”
The response rate to induction chemotherapy is 82 percent instead of 55 percent as with tobacco-associated disease, and the cure rate with chemoradiation is 82 percent instead of 35 percent. And if resected, the finding of extracapsular extension of the lymph nodes is not as ominous.
If these tumor recur, their natural history is still longer, so the patient lives longer with recurrent disease, she noted. “So it’s really just a different cancer. It took us some time to figure that out, but now that we know, it’s imperative that we study it differently from HPV-negative cancer.”
Treatment De-intensification: Follow-up Looks Good
A recent study showed that HPV-associated resectable oropharyngeal squamous carcinoma is amenable to de-intensified radiotherapy after clinical complete response to induction chemotherapy. Burtness was senior author for that study, ECOG 1308, a pilot trial for treatment de-intensification with reduced-dose intensity-modulated radiotherapy (IMRT).
The final report on ECOG 1308, presented at this year’s ASCO Annual Meeting, showed that induction chemotherapy plus cetuximab and reduced-dose IMRT produced high tumor control rates with minimal late toxicities (Cmelak A et al, Abstract LBA6006).
At the Chemotherapy Foundation Symposium, Burtness reported that no patients are failing after about 20 months, and that most recurrences appear to have happened already: “There had been concern that since it’s a slow-moving disease, is it going to be safe to mount follow-up studies now or wait until we have longer follow-up?”
The authors concluded that further studies of reduced-dose IMRT in chemoresponsive HPV-positive patients are indeed warranted, but the question now is what the best induction regimen is.
The induction regimen used in ECOG 1308 included cisplatin, and there were concerns about late, non-cancer morbidity from that.
That regimen lasted nine weeks, she explained.
“There is another regimen we’ve also studied in ECOG that’s only six weeks and uses carboplatin instead of cisplatin. We’re hopeful it will have about the same response rate, and if we use that as our induction regimen the overall package of care would be shorter for patients.”
Cetuximab Active Despite Low EGFR Levels
The value of EGRF inhibition in treating HPV-associated head and neck cancer has been an ongoing debate, Burtness said.
All head and neck cancers express EGFR, and it is clear that HPV-negative tumors are richer in EGFR than HPV-positive tumors are.
This led to the contention by some researchers that the EGFR inhibitor cetuximab would not be effective in the HPV-positive patients because of the lower EGFR expression and because they were less likely to have mutations. “But that just flew in the face of what people were seeing in the clinic, where cetuximab was quite active in these patients,” she said. “I think the misunderstanding came from an expectation that higher EGFR expression meant the cells were more EGFR dependent and so cetuximab would therefore be more active.
“Actually that’s not the case, as was shown in ECOG 5397, a randomized trial of platinum versus platinum-cetuximab, in which patients with the highest density of EGFR staining were more resistant to cetuximab
Burtness said the question has been laid to rest in head and neck cancer by data presented at the ASCO Annual Meeting from a group led by James Bonner (ASCO Abstract 6001).
“The researchers went back and looked at oropharynx cancer patients in the Phase III IMCL-9815 trial assessing the role of HPV status in locally advanced squamous cell head and neck cancer patients receiving radiotherapy plus cetuximab or radiotherapy alone, and measured p16 status,” she said. “They found that the addition of cetuximab to radiotherapy improved locoregional control, overall survival, and progression-free survival in both p16-positive and p16-negative patients.
“But for the p16-positive, or the HPV-associated patients, the effect was much more striking, so I think those data have hopefully settled this.”
A biological explanation might be that EGFR ligand binding exhibits “negative cooperativity,” Burtness continued.
In negativity cooperativity, EGFR tends to dimerize when it is ligand bound, so the first receptor binds its ligand leading to a conformational change and dimerization.
But the second receptor then has a lower affinity for binding ligands than the first one did -- “so the more EGFR you have, the less EGFR-dependent the cancer is,” she said. “That finding may explain why super-high EGFR expression has never been predictive of cetuximab sensitivity.”
Burtness said that in another trial, the recently completed RTOG-1016, of chemoradiation versus cetuximab-radiation confined to patients with HPV-associated cancer, there were many opportunities in that study to stop early if cetuximab wasn’t working with radiation but the trial went on to accrue a thousand patients.
“The take-home message is that cetuximab is active in HPV-associated cancer, and that we don’t need to be concerned about using it as a way of treatment de-intensification for these patients.”
Discussant: Reducing RT Dose a Good Idea
The discussant for the paper at the symposium, Krzysztof Misiukiewicz, MD, Assistant Professor of Medicine, Hematology and Medical Oncology and Assistant Professor of Otolaryngology at Icahn School of Medicine at Mount Sinai, said that reducing the radiation dose, as tested in ECOG 1308, is an excellent idea.
“But it's something we have to be very careful about, so it’s not going to be based just on HPV status in this very heterogeneous population. We have the heavy smokers in this [HPV-positive] group, so we’re going to have to be very cognitive in selecting those patients very carefully when offering the de-escalated treatment.”
Because the HPV-positive population is much younger than the typical oropharyngeal cancer patient, side effects and long-term quality-of-life are important as well as efficacy, he said.
Even though HPV-positive patients generally have a better prognosis than HPV-negative patients, Misiukiewicz pointed out that in ECOG1308, heavy smokers were among the patients who had the worst outcomes: “So obviously those are the patients who won’t have as favorable an outcome.”
In an interview, he speculated that changing lifestyles may be the reason for the fast rise in the prevalence of HPV-positive oropharyngeal cancer. “If patients have risky behavior and more sexual partners, that probably is contributing to the higher incidence,” Misiukiewicz said. “But we're probably going to see a peak for this. Since we now have the vaccinations, for boys as well as girls, down the line at some point we’re hoping to see a decline in the incidence.”