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Treatment Advances Reported for Gastrointestinal Cancers

By Caroline Helwick

Prior to the 10th annual Gastrointestinal Cancers Symposium, being held January 24-26, 2013 in San Francisco, CA, a January 22 press cast featured studies related to

  • S-1 chemotherapy for pancreatic cancer,
  • A new molecular classification system for colorectal cancer,
  • The benefit of surgery after imatinib in gastrointestinal stromal tumors (GIST),
  • Gene expression profiling of circulating tumor cells as a prognostic strategy in pancreatic cancer, and
  • Second-line docetaxel in esophageal and gastric cancers.

The symposium is jointly sponsored by American Society of Clinical Oncology, American Gastroenterological Association, American Society for Radiation Oncology, and Society of Surgical Oncology.

S-1 Treatment Out-Performed Gemcitabine in Pancreatic Cancer

Preliminary results from a Phase 3 trial conducted in Japan showed that pancreatic patients who received adjuvant chemotherapy with the oral drug S-1, an oral fluoropyrimide currently used in Asia (and to some extent Europe) but not approved in the United States, had a 44% lower risk of dying, compared with standard treatment with gemcitabine (Abstract 145).

“Our survival data were much stronger than expected,” said Katsuhiko Uesaka, MD, PhD, of Shizuoka Cancer Center Hospital. “Our interim analysis showed S-1 to be superior to gemcitabine in overall survival, and therefore it may be considered as a new standard treatment for resected pancreatic cancer patients in Japan.”

While the study was designed as a non-inferiority trial, the data found S-1 to be superior to gemcitabine. For this reason, Dr. Uesaka said the independent data monitoring committee recommended that the interim results be presented at this time.

The study included 385 patients with stage I-III pancreatic cancer who received post-operative treatment with gemcitabine or S-1. The interim analysis found an overall survival benefit for the experimental arm, with S-1 associated with a 44% reduction in mortality. The 2-year survival rates were 70% with S-1 versus 53% for gemcitabine (P<0.0001 for non-inferiority; P<0.0001 for superiority). The 2-year relapse-free survival rates were 40% and 29%, respectively.

S-1 was well tolerated in the Asian population, with more than 70% of this Asian population able to complete treatment.

Due to differences in toxicity according to ethnicity—probably a result of differences in how the drug is metabolized—the findings are not immediately applicable to non-Asian populations. Previous studies have shown that Caucasians have considerably more diarrhea as a side effect. However, Dr. Uesaka maintained that with dose adjustments, “I expect S-1 may be applicable to all patients with pancreatic cancer,” although at this time the use of the drug in the U.S. remains uncertain. A Phase 3 trial in the United States is currently exploring the drug for the treatment of stomach cancer.

Three Molecular Subtypes of CRC Identified

Similar to what has been done in breast cancer, tumor gene expression patterns can now classify colorectal patients into three distinct molecular subtypes, an international research team is reporting. The tumor subtypes are associated with different prognoses and responses to adjuvant chemotherapy, said Joseph Tabernero, MD, of Vall d’Hebron Institute of Oncology in Barcelona, Spain (Abstract 333).

“This study clearly shows that there are different subtypes in colorectal cancer with completely different biological and clinical characteristics,” he said. In the future, this classification system might be used to identify patients who require aggressive treatment and to predict which drugs will be most benefit in an individual patient.

This may be especially helpful in stage II patients, since clinical and pathological factors do not reliably indicate which of those patients are at greatest risk of relapse. Recent genomic classifiers—in particular, Oncotype® and ColoPrint®—can help in this regard, but current guidelines do not outline which should receive additional treatment. Current tests are also not helpful after relapse.

In the current study, gene expression data from 188 colorectal cancer patients (stage I-IV) were used to develop a molecular subtype classification system. The system was subsequently validated in tumor samples from 543 stage II and III patients. Investigators determined that 21.5% of the samples could be classified as subtype A, 62% as subtype B, and 16.5% as subtype C.

The three intrinsic subtypes differed in three biological hallmarks of colorectal tumors:

  • Epithelial-to-mesenchymal transition (associated with aggressive tumors),
  • Deficiency in mismatch repair genes (associated with genetic alterations), and
  • Rate of cell proliferation.

These features are known to independently affect outcomes in patients with cancer; in fact, the study did show that response to treatment varied by subtype, noted Dr. Tabernero.

Follow-up of the patients at 10 years revealed that subtype C had the worst outcome of the three and did not benefit from adjuvant chemotherapy. Subtype A had a good prognosis regardless of whether chemotherapy was given. Subtype B had a significantly better outcome with chemotherapy, versus no chemotherapy.

“In subtype B the effect of chemotherapy is pronounced. To the contrary, type C patients who got adjuvant chemotherapy did not benefit from it,” reported Dr. Tabernero.

“We have developed a diagnostic single-sample predictor that allows the classification of colorectal cancer tumors of different intrinsic molecular subtypes. These subtypes are potentially clinically relevant, as they differ in their underlying biology and clinical outcomes and consequently require different treatment strategies,” he concluded.

Researchers are currently evaluating the molecular subtypes in stage IV colorectal cancer.

Surgery After Imatinib Improves Survival in GIST

Patients with GIST who had residual disease resected after treatment with imatinib lived longer than those who received only imatinib, in a retrospective study from South Korea (Abstract 62). While previous studies have suggested as much, design flaws prevented conclusions to be drawn.

Seong Joon Park, MD, of Asan Medical Center in Seoul, reported the results of a study involving 134 patients with metastatic or recurrent GIST who were treated with imatinib alone or imatinib plus surgery to remove residual tumor (followed by more imatinib).  Patients were eligible for the study if they responded to prior imatinib for at least 6 months.

Dr. Park reported that the median progression-free survival in the non-surgical group was 42.8 months, increasing to 87.7 months in patients who underwent surgery (P=0.001).  Median overall survival has not been reached in the surgery arm, and was 88.8 months in the imatinib-alone arm (P=0.001).

The addition of surgical management reduced the odds of dying five-fold, he added, noting that about one-third of patients can undergo a successful resection for residual disease, depending upon tumor and patient characteristics. In a multivariate analysis, low initial tumor burden was associated with longer overall survival and low initial tumor burden, female gender and a specific alteration in the KIT gene (KIT exon 11 mutation, which is associated with improved responses) were associated with delayed disease progression.

“Considering the retrospective design of this study, it is difficult to established treatment guidelines based on this, but it provides good evidence supporting a clinical practice that is already widely adopted,” said Dr. Park.

Gene Expression Profiling of CTCs in Pancreatic Cancer

Gene expression profiling (GEP) of circulating tumor cells (CTCs) may help to personalize chemotherapy for patients with pancreatic cancer, researchers suggested after showing that CTCs predict for response to standard chemotherapy regimens (Abstract 142).

CTCs, shed by the tumor and accessible in the blood, can determine the molecular makeup of a tumor less invasively than biopsy and can be used to monitor treatment response. Tests for CTCs are already applied in breast cancer and are well suited to pancreatic cancer, which is difficult to biopsy. The study employed pharmacogenomics modeling, which has been used in other cancers; this is the first study to use this method to examine genetic response to chemotherapy regimens.

“This research lays important groundwork for customizing treatments according to a patient’s genetic composition,” said Kenneth Yu, MD, of Memorial Sloan-Kettering Cancer Center, New York. “We’re seeing encouraging signs that this strategy can help us determine which patients will benefit most from chemotherapy and more quickly identify the development of treatment resistance, even before physical changes in the tumor appear.”

The study enrolled 50 patients with unresectable stage II-IV pancreatic adenocarcinoma, who received 12 different drug combinations per physician’s choice. Circulating tumor progenitor cells were collected prior to chemotherapy and upon disease progression with the Vita-Cap™ device (Vitatex, Inc); total RNA was extracted and gene expression analysis performed. A pharmacogenomics model for the 12 chemotherapy regimens was created by CellPath Therapeutics and applied to the gene expression profiles to predict sensitivity to chemotherapy. Investigators compared gene expression differences between patients who continued to respond to a drug regimen and those who progressed while on treatment, looking at the individual gene level and also the genetic pathway level.

“The clinical questions were whether the pharmacogenomics model would predict treatment response and resistance, and whether the pharmacogenomics profile would change when the cancer progressed,” said Dr. Yu.

Differences in outcomes were apparent according to the model, among the 20 patients who had progressed at the time of the current analysis. Six patients received treatment that the model predicted they would be sensitive to; 6 received a regimen predicted to elicit an “intermediate” response; and for 8 patients, the model predicted complete resistance.

“Patients receiving treatment predicted by our model to be more effective did better,” he reported. Dr. Yu emphasized that all patients received standard treatment. The preliminary analysis showed that patients for whom chemotherapy was predicted to be effective had a median time to progression of 7.3 months, compared with 5.3 months for the intermediate group and 3.7 months for the resistant group. Interestingly, changes in chemotherapy sensitivity patterns were evident at disease progression, reflecting the development of treatment resistance, he added.

“We also did a sophisticated analysis of the gene pathways and showed that disruption in pathway E2F1 predicted for longer treatment response and disruption in the NFkB pathway predicted for shorter duration of response,” he said. Upon disease progression, the phospholipase C and retinoblastoma 1 pathways were disrupted.“

Gene pathway analysis provides insights into pancreatic cancer prognosis and the development of drug resistance, he concluded. “Ultimately, we hope this strategy can be used to determine which drug cocktail would be most suitable for the patient and to monitor patients during the course of therapy, so treatments can be modified at the earliest molecular sign of disease worsening,” said Dr. Yu.

Neal Meropol, MD, Chief of Hematology/Oncology at University Hospitals Case Medical Center at Case Western Reserve University in Cleveland, OH who moderated the session, said the studies by Dr. Yu and Dr. Tabernero highlight the direction that the field of oncology is going, both for research and clinical practice, that is, the future categorization of tumors molecularly. “We are starting to use genetic makeup to make treatment decisions regarding which drugs work best against a patient’s tumor and which may not work at all,” he said.

Second-Line Docetaxel Improves Esophageal and Gastric Cancer Survival

A Phase 3 study from the United Kingdom showed that second-line treatment with docetaxel improved overall survival in advanced esophago-gastric cancer. The strategy has already been adopted, but the study is the first to show definitive evidence of a survival benefit with docetaxel given in the second-line setting, said Hugo Ford, MD, of Addenbrooke’s Hospital in Cambridge, UK (Abstract LBA4).

Patients with advanced disease who relapse after first-line chemotherapy have a median overall survival of only 3 months, without second-line treatment, noted Dr. Ford. “The current practice in the United States and much of Europe is to give second-line chemotherapy, even though the evidence isn’t as strong as we would like,” he said. This is the first trial to show second-line chemotherapy extends survival, without causing deterioration in quality of life.

The COUGAR-02 study enrolled 168 patients with locally advanced or metastatic esophago-gastric adenocarcinoma whose disease progressed within 6 months of first-line treatment. Patients were randomly assigned to receive docetaxel (75 mg/m2 every 3 weeks for up to 6 cycles) or active symptom control, which included radiotherapy, steroids and/or supportive care. The median overall survival with docetaxel was 5.2 months, versus 3.6 months for patients receiving only symptom control, a 33% reduction in mortality (P=0.01).

Partial responses to chemotherapy were observed in 7% and disease stabilization in 46%. Docetaxel was associated with grade 4 toxicity in 21% of patients.

The survival benefit was evident across all subgroups; the most benefit was seen in “very fit” patients with performance status of 0. Preliminary data on quality-of-life suggest docetaxel led to improvements in pain and no loss in global quality-of-life or function. “However, benefits were seen across all groups, with no cohort of patients seeming to fare worse with chemotherapy,” said Dr. Ford.

According to him, the study confirms docetaxel as a standard second-line therapy in the United Kingdom, and informs treatment choices for physicians in the United States.

Dr. Meropol commented that the study is “a model for providing an evidence base to help guide our treatment decisions at points in time when the goals are palliative and not curative, and a model for the type of study we would like to see more of…Treatment toward the end of life is an area where we have fallen a little short (regarding evidence) and we need to pay additional attention.”

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