Clinical Cancer Advances 2013: Gastrointestinal Cancers
Specialty Editor: John Marshall, MD, Lombardi Cancer Center
"We have made progress in metastatic GI cancers, nearly tripling overall survival in CRC and rivaling results seen in some types of metastatic breast cancer. However, unlike so many others, we have yet to identify key drivers for our most common and most fatal cancers. Our future success lies in prospective tumor analysis and treatment assignments, replacing a one size fits all treatment pathway. Using our systemic treatments wisely, in innovative doses, schedules and indications should result in further improvements in outcome."
GI cancers include those of the esophagus, stomach, liver, pancreas, biliary tract, small bowel, appendix, colon, rectum, and anus. This year, researchers reported significant advances in some of the most difficult-to-treat GI cancers: neuroendocrine tumors, colorectal cancer, and pancreatic cancer.
One study reported that the hormonal drug octreotide improves survival for some patients with advanced midgut neuroendocrine tumors, a rare form of GI cancer. A landmark study in patients with advanced and inoperable colorectal cancer establishes capecitabine and bevacizumab as a new standard maintenance treatment. A retrospective analysis of genetic changes in tumors of patients with metastatic colorectal cancer identifies new mutations that predict lack of response to the targeted drug panitumumab. Finally, two large studies of patients with pancreatic cancer point to new, life-prolonging treatment options: nab-paclitaxel plus gemcitabine and S-1.
Octreotide LAR prolongs overall survival in some patients with a rare form of GI cancer.
Neuroendocrine tumors begin in the hormone-producing cells of the body’s neuroendocrine system. Neuroendocrine cells are found throughout the body, including the GI tract (stomach, intestine, appendix, colon, or rectum). They perform specific functions, such as controlling the speed at which food is moved through the GI tract. An estimated 8,000 people in the United States are diagnosed with a neuroendocrine tumor that starts in the GI tract each year. These patients often have significant disease burden and symptoms but few standard therapy options.
An earlier study showed that a drug called octreotide LAR substantially prolongs time to disease progression in patients with metastatic midgut neuroendocrine tumors. This year, researchers reported longer-term follow-up data from that same clinical trial, finding that octreotide LAR also extends overall survival in a subset of patients.1 Between 2001 and 2008, 85 patients were randomly assigned to receive octreotide LAR or placebo. Patients whose disease progressed while receiving placebo crossed over to octreotide. Poststudy treatment was at the discretion of the local investigator.
By January 2013, the median overall survival in the placebo arm was 84 months and was not reached in the octreotide LAR arm, meaning that overall survival in that arm will exceed 84 months, but longer follow-up is needed to determine the median overall survival in that arm. The drug was most beneficial for patients with a hepatic load (ie, percent of the liver that is replaced by cancer) less than or equal to 10%(ie, limitedtumorspread to the liver) at study entry. In that subset of 64 patients, the median overall survival was 80.5 months in the placebo arm and not reached in the octreotide arm. Octreotide LAR did not extend overall survival in the high–hepatic load subgroup.
The benefit of octreotide in patients with midgut neuroendocrine tumors has been debated for some time. These encouraging findings will motivate many physicians to start using octreotide LAR, particularly in patients with a low hepatic load.
Maintenance treatment with capecitabine and bevacizumab extends overall survival in patients with inoperable metastatic colorectal cancer.
Chemotherapy in combination with bevacizumab is a standard first-line therapy for patients with metastatic colorectal cancer. However, there has been great debate as to how best to use the agents to optimize both efficacy and toxicity.
To address this question, Dutch researchers conducted a phase III clinical trial comparing the efficacy of maintenance treatment with the chemotherapeutic drug capecitabine and bevacizumab versus observation in 558 previously untreated patients with inoperable metastatic colorectal cancer that had not worsened after six cycles of induction treatment with CAPOX-B (capecitabine, oxaliplatin, and bevacizumab).2 Compared with patients in the observation group, patients in the maintenance treatment group experienced a substantially longer time to first progression (7.1 v 4.1 months). On disease progression, patients in both groups received CAPOX-B, which temporarily stalled tumor growth. It took longer for the disease to progress again in the maintenance group than in the observation group (11.5 v 15.4 months). The median overall survival in the maintenance group was 21.7 months compared with 17.9 months in the observation group. Toxicity was minor with maintenance treatment. This study establishes capecitabine and bevacizumab as a standard maintenance therapy in colorectal cancer.
Patients with colorectal cancer harboring NRAS mutations are unlikely to benefit from panitumumab.
Panitumumab is an antibody drug that targets EGFR. It has been approved by the FDA for the treatment of metastatic colorectal cancers, but only in patients without mutations in the KRAS protein, because mutations in KRAS render the drug ineffective. Patients are routinely tested for KRAS mutations before deciding on panitumumab therapy.
New results reported this year, however, indicate that mutations in a related protein, NRAS, also interfere with the efficacy of panitumumab.3 In a retrospective analysis of data from a phase III clinical trial comparing panitumumab plus FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) chemotherapy and FOLFOX alone, investigators assessed the impact of specific KRAS, NRAS, and BRAF gene mutations on overall survival in 641 patients with metastatic colorectal cancer. Among the 512 patients with no mutations in either NRAS or KRAS genes, the addition of panitumumab improved both median overall survival (26.0 v 20.2 months) and median progressionfree survival (10.1 v 7.9 months). However, there was no benefit with panitumumab for patients harboring mutations in KRAS or NRAS; in fact, patients with these mutations did worse with combination treatment than those treated with FOLFOX alone (overall survival: 15.6 months for panitumumab plus FOLFOX v 19.2 months for FOLFOX alone). In this analysis, BRAF gene mutations were not associated with patient survival. These findings suggest that patients should be tested for both KRAS and NRAS mutations before receiving panitumumab to avoid the adverse effects and costs of a potentially ineffective treatment. Approximately 40% of patients have KRAS mutations, and 10% have NRAS mutations.
Large phase III study establishes a new standard treatment option for patients with metastatic pancreatic cancer.
In the United States, pancreatic cancer is the fourth-leading cause of cancer-related death. More than half of patients are diagnosed at an advanced stage, for which the 5-year survival rate is less than 2%. Chemotherapy with gemcitabine is a standard treatment for advanced pancreatic cancer. Adding other drugs to gemcitabine, such as erlotinib or capecitabine, has been shown to help some patients live longer. Findings from a large international study published this year establish a new gemcitabine combination for this group of patients.4
In the study, 861 patients with pancreatic cancer that had spread to the liver were randomly assigned to receive nab-paclitaxel (paclitaxel protein-bound particles) plus gemcitabine or gemcitabine alone. Patients who received the combination treatment had a higher response rate (23% v 7%), longer median overall survival (8.5 v 6.7 months), and longer progression-free survival (5.5 v 3.7 months) compared with patients who received gemcitabine only. These results establish gemcitabine plus nab-paclitaxel as a new standard treatment option for patients with metastatic pancreatic cancer. In September, based on the findings of this study, the FDA approved nab-paclitaxel for treatment of patients with metastatic pancreatic cancer.5
Postoperative treatment with S-1 chemotherapy reduces relapses and extends survival in Asian patients with pancreatic cancer.
After surgery for advanced pancreatic cancer, patients typically receive gemcitabine, which has been shown to lengthen survival by several months compared with surgery alone. Interim results from a phase III clinical trial of 385 patients with stage I to III pancreatic adenocarcinoma reported this year suggest that another chemotherapy drug, S-1, substantially improves survival compared with gemcitabine in Asian patients.6
In the study, conducted in Japan, patients were randomly assigned to receive gemcitabine or S-1 after surgery. Patients who received S-1 had a 44% lower risk of dying compared with patients treated with gemcitabine. The 2-year survival rates were 70% and 53% for S-1 and gemcitabine, respectively. Relapse rates were also lower in the S-1 arm. The 2-year relapse-free survival rates were 49% and 29% for S-1 and gemcitabine, respectively.
These findings demonstrate that S-1 is superior to the current standard postoperative (adjuvant) therapy for advanced pancreatic cancer, warranting serious consideration of S-1 as a new standard of care for this population of patients.
In Japan and some other countries, S-1 has been approved to treat several cancers, including stomach, colorectal, pancreatic, biliary, head and neck, NSCLC, and metastatic breast cancers. Although S-1 is not yet FDA approved in the United States for any indication, it is being explored in several clinical trials. The active component of S-1, tegafur, is converted in the bloodstream to fluorouracil, which is FDA approved to treat pancreatic cancer. Previous studies have shown that S-1 is more toxic for patients of European descent, requiring use of lower doses.
- Arnold R, Wittenberg M, Rinke A, et al: Placebo controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): Results on long-term survival. J Clin Oncol 31, 2013 (suppl; abstr 4030)
- Koopman M, Simkens LHJ, Ten Tije AJ, et al: J Clin Oncol 31, 2013 (suppl; abstr 3502)
- Douillard J-Y, Oliner KS, Siena S, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369:1023-1334, 2013
- Von Hoff DD, Ervin TJ, Arena FP, et al: Results of a randomized phase III trial (MPACT) of weekly -paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA19-9 correlates. J Clin Oncol 31, 2013 (suppl; abstr 4005^)
- US Food and Drug Administration: FDA approves Abraxane for late-stage pancreatic cancer.
- Fukutomi A, Uesaka K, Boku N, et al: J Clin Oncol 31, 2013 (suppl; abstr 4008)