Roxanne Nelson, BSN, RN; Brandon G. Smaglo, MD; Aiwu R. He, MD, PhD; Michael J. Pishvaian, MD, PhD; John L. Marshall, MD


December 18, 2014

Editor's Note: The Ruesch Center for the Cure of Gastrointestinal Cancers held its annual symposium, "Fighting a Smarter War Against Cancer," on December 4-6. As part of the symposium, the Ruesch team presented highlights of 2014 advances in gastrointestinal (GI) cancer. Four of the presenters spoke with Roxanne Nelson, for Medscape, to provide a high-level overview of the year in upper GI, pancreatic, hepatocellular, and colorectal cancers.

Brandon G. Smaglo, MD, assistant professor in the Division of Hematology-Oncology and associate director of the Fellowship Program at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, highlighted upper GI and gastrointestinal stromal tumors (GISTs).

A Ruth He, MD, PhD, associate professor at Georgetown University and staff physician, Georgetown University Hospital, Washington, DC, reviewed advances in hepatocellular carcinoma (HCC).

Michael J. Pishvaian, MD, PhD, assistant professor in the Division of Hematology-Oncology at Lombardi Comprehensive Cancer Center, summarized advances in pancreatic cancer.

John L. Marshall, MD, director of the Ruesch Center for the Cure of Gastrointestinal Cancers, chief of the Division of Hematology-Oncology at Georgetown University Hospital, and associate director for clinical research at the Lombardi Comprehensive Cancer Center, highlighted advances in colorectal cancer.

New Drug for Gastric Cancer

The big news in gastric cancer is that a new drug has come on the market, noted Dr Smaglo. The US Food and Drug Administration (FDA) has approved the angiogenesis inhibitor ramucirumab (Cyramza®) for the treatment of advanced stomach cancer or gastroesophageal junction adenocarcinoma in patients with unresectable or metastatic disease after therapy with a fluoropyrimidine- or platinum-containing regimen.

Brandon Smaglo, MD

"This is the first antiangiogenic agent that has been approved for gastric cancer," said Dr Smaglo. "In colon cancer and other non-GI malignancies, the antiangiogenic agents bevacizumab and aflibercept are available and approved, but this is the first time we have been able to bring this to gastric cancer."

Ramucirumab is also the only biologic that has universal eligibility in gastric cancers. Trastuzumab (Herceptin®) has an indication for gastric cancer, but it is only useful for patients who overexpress human epidermal growth factor receptor 2 (HER2), and they comprise a small minority.

"What is also unique about this drug is its single-agent utility," explained Dr Smaglo. "Trastuzumab in gastric cancer needs to be combined with other therapies, as do bevacizumab and aflibercept in colon cancer."

The FDA initially approved ramucirumab as a monotherapy in April, on the basis of the REGARD trial, which showed superior survival benefits compared with placebo.[1] Median overall survival was 5.2 months in patients in the ramucirumab group and 3.8 months in those in the placebo group (hazard ratio, 0.776; P = .047). The survival benefit remained unchanged after multivariable adjustment for other prognostic factors (P = .042).

In November, the FDA granted additional approval for use of ramucirumab in combination with paclitaxel for the treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma, on the basis of the results of another phase 3 study.

The RAINBOW trial[2] found that the addition of ramucirumab resulted in a statistically significant prolongation of overall survival: 9.6 and 7.4 months in the ramucirumab plus paclitaxel arm, compared with placebo plus paclitaxel, respectively (P = .017). Progression-free survival was also significantly longer for those in the combination therapy arm (4.4 vs 2.86 months; P < .001).

Gastric cancer is the second leading cause of cancer mortality worldwide, although the burden in the United States is much lower. It remains difficult to cure in Western countries, primarily because most patients present with advanced disease. Improved diagnostics are needed so that it can be detected at an earlier stage, but for now, it is exciting to have another option to offer patients, said Dr Smaglo. "These biologic agents usually don't bring with them a significant burden of toxicity. There are associated side effects, but their safety profile is different from that of cytotoxic chemotherapy."

The reduced toxicity is important in this setting because these patients are often quite debilitated, having already undergone partial or total gastrectomy and are now experiencing disease recurrence. This is a group that should be getting single and double chemotherapy, but they just may not be able to tolerate it, Dr Smaglo noted.

However, the addition of ramucirumab to the treatment armamentarium will allow patients to receive one chemotherapy agent plus a relatively benign agent, or even to use the biologic as monotherapy. The burden of toxicity will be reduced while still providing benefit to the patient.

For all of these reasons, Dr Smaglo surmises that ramucirumab will prove to be very useful in gastric cancer, and that it will also be explored with other lines of therapy and in other cancer types.

In the next 5 years, however, Dr Smaglo foresees that immunotherapy will become an important part of the standard treatment of these cancers. "Immunotherapy is the hot kid on the block right now, and this is certainly true for gastric cancer," he said. "We're learning how universally applicable these therapies are to tumor type, and how they can be used in different types of cancer."

These therapies are showing great promise, and most of the companies that are exploring immunotherapy are examining its utility in many different types of cancer, including GI cancer.

"Gastric cancer is one of the types that is actively being investigated; some products are in trials right now, and others are accruing," he said. "There are no data yet, but we are looking forward to the forthcoming results."

Changes for GIST?

Adjuvant imatinib (Gleevec®), given for 3 years, has become a standard treatment in all patients with significant risk for recurrence after resection of primary GISTs. However, the role of adjuvant imatinib may need to be revisited in this setting, commented Dr Smaglo.

"New data suggest that we may not be saving lives, but just delaying when the tumor recurs," said Dr Smaglo. "Patients who receive this therapy may not really be doing any better than those who never got it all."

The original studies that generated this data have now begun to mature,[3] and in the longer term, the evidence is more ambiguous about the true benefit of adjuvant therapy. Dr Smaglo pointed out that this idea is controversial, but the tumor isn't common enough to amass a great deal of data. "A phase 2 trial that is maturing is looking at 5 years of adjuvant therapy and its effect on survival, but we still have to wait for those results."[4]

Stratification of GIST is done on the basis of several different characteristics, including the location and size of the tumor and the mitotic index. An algorithm is then drawn from these characteristics and used to pinpoint which patients might benefit from adjuvant therapy. But the evidence to date is more arbitrary than anything, according to Dr Smaglo. "Why give therapy for 3 years? Someone decided that it was a good idea, but there are no solid data for just stopping then."

Findings from earlier studies established the paradigm, he noted. "One paper looked at 1 year vs 3 years of therapy and found that longer therapy improved both overall and recurrence-free survival.[5] There were similar rates of toxicity, so that gave us more evidence to choose the most optimal protocol."

This might end up being practice-changing in some way, he added, when there are more long-term data and a better understanding of the role imatinib plays in preventing recurrence.

As for pinpointing a single pivotal event for this year, Dr Smaglo moved beyond the realm of GI cancers and pointed to the Affordable Care Act. He acknowledges that it's far from perfect, but at least it means that everyone gets coverage. "That, in turn, limits emergency department overcrowding and hopefully will translate into better screening and thus better early detection and control of cancer and other diseases," he said.

Hepatocellular Carcinoma: Disappointments, but Moving Forward

No new drugs have come on the market this year for HCC, yet 2014 has seen important findings, several disappointments, and continuing activity into new treatment regimens. Among the important findings are studies deepening the understanding of HCC pathophysiology.

One recent study, commented Dr He, elucidated a connection between high-fat diet and a risk for liver cancer.[6] The study found that firmicutes, a type of bacteria in the gut, increased the production of lipopolysaccharides and a type of bile acid that contribute to risk for liver cancer and progression.

Another provocative study had more to do with basic science, and the findings may not be of immediate interest in clinical oncologists, but it can serve as a foundation for future biomarkers and development, explained Dr He.

A. Ruth. He, MD, PhD

Transancestry substitution signatures were analyzed in 608 liver cancer cases, and unique mutational signatures were identified that predominantly contribute to cases found in Asian patients.[7] The work elucidates previously unexplored ancestry-associated mutational processes in HCC development.

"A lot of researchers are trying to tease this out to develop and design future trials, and this can be very instrumental in moving forward," she said.

Key factors: Treating hepatitis C, downstaging tumors. Moving to new clinical research, the need to treat hepatitis C infection was underscored in a recent meta-analysis.[8] Patients who achieve sustained virologic response after treatment have a lower risk for death (60%-84%), are less likely to develop HCC (68%-79%), and need fewer liver transplants (90%) than those without a sustained response.

Over the past few years, there have been major developments in hepatitis C treatment, and now it has become clear that successful eradication of the infection will lower mortality in cirrhosis and liver cancer. "So this goes beyond just cancer treatment," Dr He emphasized. "These data are very important to all providers—they are relevant not just for medical oncologists, but for the medical community. Anyone at risk for hepatitis C infection should be screened, and those with chronic infection should seek treatment."

The data in this meta-analysis were also generated from patients who were treated with traditional regimens. Now that protocols have improved, the benefits are likely to be even greater, Dr He added.

Another study demonstrated further evidence for downstaging patients with HCC before liver transplantation, and that it can lead to excellent 5-year recurrence-free and overall survival rates. Treatment with local-regional therapy allowed 119 of 187 patients with HCC to become eligible for liver transplantation, and 80% of patients who had a transplant lived at least 5 years after surgery.[9]

The Milan criteria are considered to be the gold standard for selecting patients with cirrhosis and HCC for transplantation. According to the criteria, patients with one lesion no larger than 5 cm or two or three lesions no larger than 3 cm can be considered eligible for the procedure.

Downstaging large tumors allowed patients to meet these criteria, Dr He explained. "This study also emphasizes the importance of multidisciplinary management of newly diagnosed HCC. Some patients are treated locally, but they really need to be evaluated by a team and a transplant program."

Disappointing data on new agents. As for bringing new therapeutic agents and protocols into the treatment paradigm, some recent results have been disappointing. The only systemic therapy currently approved for HCC is sorafenib (Nexavar), which was approved in 2007.[10]

"Over the years, new targeted therapies have been tested in the frontline setting, usually with sorafenib, which is the standard of care, or with placebo if disease has progressed on sorafenib," said Dr He. "But even though there have been promising early-phase studies, we haven't had anything show superiority in the phase 3 setting."

In 2014, there were several negative phase 3 studies; one was the STORM trial, which assessed sorafenib in the adjuvant setting.[11] "Patients were randomized after resection to sorafenib vs placebo, but there was no survival benefit," Dr He said. "This study has been ongoing for many years, so these results are disappointing."

One of the promising agents in treating HCC is tivantinib (ARQ 197), an oral inhibitor of c-MET protein. Patients with HCC who have an increased level of c-MET protein ("c-MET–high HCC") have poor clinical outcome and shorter survival compared with patients who have low levels ("c-MET–low HCC"). In a randomized phase 2 study, tivantinib treatment improved survival in patients with c-MET–high HCC but not in those with c-MET–low HCC.[12]This finding suggests that c-MET is not only a prognostic biomarker for HCC, but may also serve as a biomarker that selects patients for effective treatment. Tivantinib and the utility of c-MET as a biomarker for tivantinib treatment are being tested in an ongoing international randomized clinical trial.[13]

Casting a shadow over potential treatment options is the ever-growing concern about cost, which is perhaps the most significant issue that physicians are grappling with this year, explained Dr He. "There is more awareness of cost of care to insurance and to society," she said.

Pancreatic Cancer: Approaching Better Therapies, Step by Step

Advances in pancreatic cancer have lagged behind those of other GI cancers. Despite decades of effort, the 5-year survival rate has stubbornly remained at only ~5%, and breakthroughs have been few and far between. Slowly but surely, that is starting to change, according to Michael J. Pishvaian, MD, PhD.

"We are doing better in pancreatic cancer," he said. "We are doing better with frontline therapies and getting to the point where patients can go on second- or even third-line therapies—that was previously unheard of in pancreatic cancer."

Michael J. Pishvaian, MD, PhD

Before 2011, the only therapeutic agent was gemcitabine (Gemzar®), which led to a survival of about 6 months. "But that changed when something came in under the radar: a study that was presented by a French group at ASCO," he said. "They used a combination of drugs that were already on the market, and showed that we could increase survival."

The combination of 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) was considerably more toxic than gemcitabine, but it nearly doubled the survival time (11.1 vs 6.8 months).[14] After 1 year, 48.4% of patients who received the combination were still alive, compared with 20.6% of those who received gemcitabine alone.

"That taught us that we could make progress in pancreatic cancer," explained Dr Pishvaian. "It changed the paradigm."

Two years later, another study revealed that the addition of nanoparticle albumin-bound (nab)-paclitaxel (Abraxane®) to gemcitabine improved overall survival vs gemcitabine alone.[15] This combination also improved survival significantly, although not to the same degree as FOLFIRINOX. "But now, we had officially discarded the old protocol (gemcitabine alone), and we knew there were other options," Dr Pishvaian noted.

This has really been a major breakthrough for the treatment of pancreatic cancer. "We are entering the realm where we are designing second-line and even third-line trials," explained Dr Pishvaian. "We are pushing the envelope." Not only are patients living longer and getting better treatment, but they are "living better and in better shape" when their disease starts to progress, he added.

In many cases, the cancer has begun to spread, but the patients are not experiencing any additional symptoms. The combination therapies have also slowed down progression sufficiently enough to allow time to try out other treatments, according to Dr Pishvaian.

Although there weren't any major breakthroughs this year, small steps are ongoing, especially in the setting of second-line therapies. A combination of capecitabine and ruxolitinib (Jakafi®), a drug approved for myelofibrosis, was evaluated as a second-line therapy for patients with metastatic disease.[16] It was not a positive study, but there was a subset of patients who might derive a benefit: those with metastatic disease characterized by an elevated C-reactive protein (CRP) level, a well-established marker of inflammation. In this subgroup, 3- and 6-month survival were 48% and 42% with the combination therapy, compared with 29% and 11% with placebo.

Another new second-line therapy being investigated is MM-398 (nal-IRI), a novel encapsulation of irinotecan in a long-circulating nanoliposome. Patients receiving the combination of MM-398, 5-FU, and leucovorin achieved an overall survival of 6.1 months, which was a 1.9-month improvement over the 4.2-month survival observed in the control arm that received 5-FU and leucovorin.[17]

The other big area of research is adjuvant therapy. "When patients have what seems to be a successful surgery, the reality is that about 70%-80% of the time, they will have a recurrence," said Dr Pishvaian. "Survival at 5 years is less than 5% even for those who are eligible for surgical resection."

Studies have already demonstrated that postoperative chemotherapy and gemcitabine have improved outcomes, compared with no intervention.[18] Dr Pishvaian explained that research is now geared toward improving the regimen and survival.

"We are seeing the door open to better outcomes,[19,20] and it should be a call to action that this is where we want to focus our clinical trials," he said.

Biomarkers and immunotherapy are prominent areas of research in virtually all cancer types, and in pancreatic tumors, "we are seeing the light in the end of the tunnel," he said.

The first potential biomarkers are mutations in the BRCA2 gene, which have been implicated in pancreatic cancer. BRCA1 and BRCA2 mutations are more widely associated with an increased risk of developing breast and ovarian cancers, but these mutations occur in about 3%-5% of pancreatic cancers as well.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown clinical activity in patients with BRCA-associated breast and ovarian cancers, and Dr Pishvaian pointed out that they have also been used in patients with pancreatic cancer who harbor the mutation, with "fairly dramatic results."[21,22]

"We are thinking of PARPi as the first truly targeted therapy for a subpopulation of pancreatic cancer," he said. "It is opening a door."

Another area of interest is cell-cycle mutations. In pancreatic cancer, mutations in genes involved in cell-cycle control are very common, and a driving force of the cell cycle is the activation of cyclin-dependent kinases (CDKs). This work is in its early preclinical stages, but one recent study looked at targeting CDKs in combination with other therapies.[23]

These data are very early but provocative, Dr Pishvaian explained. "One of the hopes is that we can fine-tune that selective approach, and we are now doing more genetic and genomic analyses in the hope that we can find the right drugs for the right patients."

The Pancreatic Cancer Action Network has begun leading an effort to provide patients with pancreatic cancer and their primary oncologists with access to molecular information,[24] with the long-term goal of building a registry of outcomes data.

And when asked whether there is any role for immunotherapy, the short answer is yes, Dr Pishvaian said. "There is a growing body of evidence that the ability to fight pancreatic cancer by enhancing the immune system might be a very attractive option."

New classes of drugs targeting the PD-1 and PD-L1 pathways are showing promise,[25] he pointed out. At the 2014 Gastrointestinal Cancers Symposium, an innovative immunotherapy strategy using two different anticancer vaccines showed, for the first time in a randomized trial, that immunotherapy could be effective in pancreatic cancer.[26]

Was there a single significant event for the year? Dr Pishvaian remarked, "There are rarely 'single most significant events' for this cancer. We make incremental advances."

Colorectal Cancer: Molecular Profiling Needed

Colorectal cancer is the most prevalent GI malignancy in the Western world, but there wasn't one single event that stands out for this disease in 2014. "The most important and significant thing involving colorectal cancer this year, in my opinion, is further molecular profiling leading to better response rates and enrichment," said Dr Marshall. "Possibly the most negative is the continued rise in the cost of cancer drugs, despite the lack of innovation."

Determining KRAS mutation status in all patients who are candidates for anti-epidermal growth factor receptor (EGFR) therapy has become standard practice, but it is time to expand upon that. "We recently learned that about 20% of patients have other RAS mutations,[27,28] and we are calling it 'extended RAS,'" he said.

John L. Marshall, MD

About 40% of patients have KRAS mutations, and not only is anti-EGFR not helpful in this population, but it can also be harmful. The same is true for those with extended RAS. "Now that we have narrowed who should be getting these drugs, we are seeing a steady increase in the benefit rate," explained Dr Marshall. "We are finding, if you will, a correct side of the haystack."[29]

The problem is that recognition of extended RAS is not widespread, especially in the United States. Another problem is that it has been difficult finding laboratories that can run these tests. "Before panitumumab or cetuximab is given, it is critical to know about extended RAS testing, and to do the testing," Dr Marshall emphasized.

Although this is not a problem for patients treated at large centers—Dr Marshall noted that it is standard at his institution—the situation is different for those receiving treatment in the community. "In the community, there are medical oncologists who are seeing cancer patients with all types of tumors, and they may not be aware of these changes," he said.

Adjuvant therapy: Teasing out the patients who benefit. Adjuvant treatment is another important area in need of further research, in order to tease out which patients can really benefit. "The way I like to couch this is that what we really need in adjuvant therapy—not just for colon cancer, but for all cancers—is a Harry Potter sorting hat," he said. "That was when the kids showed up at the Hogwarts School and a magical hat went on their head, and then they were told which house they should live in."

In a sense, the same holds true for adjuvant therapy in colorectal cancer. "If we had this for cancer, there would be four houses," he continued, using the Harry Potter theme. "One house is where the patient is actually cured by the surgery and doesn't need any chemotherapy; the second house is where they need a little 5-FU and that will cure them; the third house is where they need 5-FU and oxaliplatin, and then they are cured; and in the fourth house, they will still progress, with or without chemotherapy."

The problem is that because the sorting hat doesn't exist, nearly everyone ends up getting chemotherapy, and patients who don't need it and don't benefit are still being treated. "We are working hard to develop a molecular sorting hat, where we can take a tumor and test it and that will tell us which one of the four treatments best fits the patient," Dr Marshall said. "There is nothing more important in medical oncology than refining that. We have the Oncotype DX® (Genomic Health; Redwood City, California), but it really doesn't do that, although it's trying, and we are now working on the ColoPrint® assay, and that study is ongoing."

Developed by Agendia (Irvine, California), the ColoPrint microarray is an 18-gene expression signature for predicting the risk for distant recurrence of stage II colorectal cancer in patients who have undergone surgery.Study results initially found that it was superior to clinical factors in selecting high-risk patients with stage II disease, a group that includes patients with T4 tumors, perforation, fewer than 12 lymph nodes assessed, and high-grade histology.[30]

Maintenance therapy: Chemo lite. The other big topic is maintenance therapy, which is sometimes referred to as "chemo lite"—the idea being that patients who respond to their initial therapy may have difficulty with repeating it, because of the side effects, explained Dr Marshall.

"Many studies have shown that you can give a lighter dose or regimen, and the cancer can be controlled and patients' quality of life is better," he noted. "As a take-off on that, there is a question of doing maintenance therapy after resection for liver metastasis."

Patients with metastases are increasingly having surgery, but a standard protocol for postoperative treatment is lacking. "We don't really have any idea what we should do systemically, and many different approaches are being used," Dr Marshall pointed out. "Some are just doing maintenance therapy, with the idea that it isn't curative and the patients will just be treated until progression. We all feel like we need to do something, but we really don't have the data to guide us."

Thus, there is a great need for a study on managing patients who are at high risk for recurrence but who have no evidence of disease after surgery. "It would really help to have some strong evidence at hand," he said.

Although tremendous progress has been made overall in the management of GI cancers, there is always more work to be done. Looking at GI cancers collectively, they are the most common and fatal malignancies, Dr Marshall said. "If we look at research, investment, and understanding the biology of the disease and major successes, we still haven't gotten to the point where we want to be."

"The Ruesch Center's mission is to bring us all together under one tent, because we are more successful as a collective than as individual subgroups," summarized Dr Marshall. "The Ruesch Symposium is a partnership with our community oncologists, to get together, share, and update each other. Working together is the only way we are going to move the bar."


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