For this month and next month, Dr Christy Russell and I will be covering some of the data from this year’s American Society of Clinical Oncology^® (ASCO) meeting. In this edition, I will review for you a number of the presentations and posters concerning hematologic malignancies, gastrointestinal (GI) cancers, lung cancer and head & neck cancers. In August, Dr Russell will cover breast cancer, genitourinary (GU) cancers, and other areas.

Presentations from the GI Malignancies Sessions at The Annual Oncology Meeting

There were 4 presentations in this section that I believe are worth reviewing.

Abstract 4503: Gemcitabine with or without cisplatin in patients (pts) with advanced or metastatic biliary tract cancer (ABC): Results of a multicenter, randomized phase III trial (the UK ABC-02 trial) by Dr Juan W. Valle, et al

Dr Juan W. Valle reported the results of a randomized phase III trial from the UK in biliary tract cancers. There is no standard of care for this aggressive malignancy when it presents in the advanced stages. Five-year survival for all cases, including surgical cases, is only 5% to 10%. The incidence of biliary tract cancers are increasing worldwide. Most studies in the past have been phase II or small phase III trials. The ABC-01 trial was presented at the 2006 Gastrointestinal Cancers Symposium. This was a phase II study with 86 patients randomized to gemcitabine or gemcitabine-cisplatin. Gemcitabine alone was given 3 out of 4 weeks. In the combined arms, gemcitabine 1000 mg/m² and cisplatin 25 mg/m² were given days 1 and 8 of a 21 day cycle. ABC-02 is an expansion of the ABC-01 trial to include an additional 324 patients. Overall survival was the primary endpoint. The authors presented the December 2008 interim analysis at which point 263 deaths had occurred. A total of 410 patients were randomized in a 1:1 ratio. Seventy-five percent had metastatic disease. Forty-four percent required biliary stenting. The median age was 63. No prior systemic therapy was allowed. Twelve percent were ECOG performance status 2. There were no significant differences in the adverse event profiles. Approximately 64% of patients in each arm experienced a grade 3-4 adverse event. Overall response rates were 16% for gemcitabine alone and 25.7% for gemcitabine-cisplatin. Stable disease was seen in approximately 55% of patients in each arm. Median duration of treatment was 19.7 weeks versus 13 weeks with P = .007. The main reasons for stopping treatment were completion of planned therapy (gemcitabine-cisplatin 77 vs gemcitabine 53) or disease progression (gemcitabine-cisplatin 26 vs gemcitabine 49) or death (gemcitabine-cisplatin 17 vs gemcitabine 26). Progression-free survival was 8.4 months versus 6.5 months with P = .003. Overall survival, the primary endpoint, was 11.7 months versus 8.3 months with P = .002 and a HR = 0.70.

The authors concluded that gemcitabine-cisplatin significantly improved the OS and PFS and recommended that it be considered the standard of care for advanced biliary tract cancers.

Abstract LBA4509: Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC) by Dr Eric Van Cutsem, et al

There is no widely accepted standard of care for advanced gastric cancer. Although fluoropyrimidines, platinum agents and anthracyclines have all been used in various combinations with some degree of efficacy, there remains an unmet need in the management of advanced gastric cancer. The investigators screened 3807 advanced gastric or GE junction cancers. Eight hundred ten or 22% were HER2 over-expressers by IHC. Five hundred eighty-four patients were then randomized to 5-FU or capecitabine plus cisplatin with (PF+T) or without (PF) trastuzumab. Eighty-seven percent received capecitabine, and 13% recieved infusional 5-FU. The primary endpoint was OS. Secondary endpoints included PFS, ORR, time-to-progression (TTP), clinical benefit, duration of response, and safety. Eighty percent had gastric cancer, and 20% had GE junction cancer. Overall survival, the primary endpoint, was 13.8 months for PF+T versus 11.1 months for PF with a HR = 0.74 and P = .0046. Progression-free survival was also significantly longer at 6.7 months for PF+T versus 5.5 months for PF. The ORR was 47.3% for PF+T and 34.5% for PF with P = .0017. Examination of IHC and FISH results demonstrated by forest plot that those patients whose tumors were IHC 2+/FISH-positive or IHC 3+ derived the most benefit from the addition of trastuzumab with OS of 16.0 months with PF+T versus 11.8 months with PF alone. Patients whose tumors were IHC 0-1+/FISH-positive did not show benefit from the addition of trastuzumab. Post-study systemic therapy was received by about 45% of patients with no significant differences in the agents received. Only a very small percentage of patients continued on HER2-targeted therapy. Adverse event profiles for grade 3-4 events were very similar in the 2 treatment arms. There were no significant cardiac events in either arm, although asymptomatic drops in left ventricular ejection fraction (LVEF) were more common in the PF+T arm, but these were still only in the 5% to 6% range.

Abstract LBA4 of Plenary Session: A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08 by Dr Norman Wolmark

The Plenary Session at this year’s ASCO meeting included an extremely important clinical trial in colon cancer. The bottom line is that at 3 years follow-up, this is a negative trial which failed to meet its primary endpoint of disease-free survival (DFS). In this large multicenter trial, 2710 patients were randomized. Seventy-five percent had stage III disease and 25% had stage II. The results were the same in both stage II and III. All patients received adjuvant therapy with 12 cycles of mFOLFOX6. Half the patients also received bevacizumab with mFOLFOX6 and then continued bevacizumab every 3 weeks for an additional 6 months. The median duration of bevacizumab therapy was 11.5 months. At the 1-year interim analysis, the DFS was significantly in favor of the bevacizumab arm with a HR of 0.6 and a P = .0004. But at 2 years, the HR had risen to 0.81 with P = .02 and by 3 years the HR = 0.89 and the P value was .15, thereby losing statistical significance.

There was significant speculation as to why this occurred. Some thought that a more prolonged course of anti-VEGF therapy might have helped preserve the DFS difference, but most concluded that bevacizumab simply did not increase the cure rate for colon cancer and could not be recommended for the adjuvant therapy of resected stage II or III colon cancers.

Abstract 4000: A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study by Dr David Kerr, et al

A multi-national group of investigators developed this study. The investigators asked the question “Are there tools that can be developed to identify the 20% to 25% of stage II colon cancer patients who will not be cured by surgery alone?” They hoped to develop a genomic tool that would be both prognostic and predictive of therapeutic response to 5-FU based adjuvant therapy. They initially examined tissue samples from National Surgical Adjuvant Breast and Bowel Project (NSABP) C-01 and C-02 and a Cleveland Clinic population all treated with surgery alone. They then examined tissue from the NSABP C-04 and C-06 trials of patients treated with surgery plus 5-fluorouracil/leucovorin (5-FU/LV). They looked at 761 candidate genes, and honed that down to 48 recurrence and 66 treatment benefit genes before finally identifying an 18 gene profile that included 7 recurrence genes, 6 treatment benefit genes, and 5 reference genes. They then applied this 18 gene profile using reverse transcription polymerase chain reaction (RT-PCR) to patients who had participated in the stage II QUASAR adjuvant trial of surgery versus surgery plus 5-FU/LV. The final evaluable population included 1436 stage II patients out of the 3239 patients who had participated in QUASAR. From this data, they developed a recurrence score (RS) based on the likelihood of disease recurrence over 3 years following primary treatment for stage II colon cancer. They defined low-risk (43.7% of patients) as an RS <30 with a recurrence risk at 3 years of 12%, an intermediate-risk (30.7% of patients) RS of 31-40 with a recurrence risk at 3 years of 18%, and a high-risk (25.6% of patients) RS of >40 with a recurrence risk at 3 years of 22%. Comparison of high-risk versus low-risk had a HR of 1.47 with P = .046. By multivariate analysis of the QUASAR trial population, the recurrence score along with deficient mismatch repair (dMMR), T-stage, tumor grade, and the number of nodes examined had prognostic significance. The recurrence score also appeared to have statistically significant value in prediction of OS. Unfortunately, the RS did not have predictive value for benefit of 5-FU/LV therapy in stage II colon cancer.

Therefore, there was no significant difference in the proportional benefit from 5-FU/LV. The benefit was the same in the low-risk, intermediate-risk and high-risk groups. Dr Kerr went on to say that those QUASAR patients who were MMR deficient had a low RS and a recurrence risk that was very low while those who were T4 had high RS and a very high risk of recurrence. The large group of stage II patients (76%) who had T3 tumors with proficient MMR was the group for which the RS might have the greatest predictive value.

Finally, in colorectal cancers, there were a number of other studies examining the value of biomarkers for prognostic and predictive value in early stage colon cancer. Investigators from EORTC and SAAK presented 2 abstracts 4001 and 4002, in which they examined the role of molecular markers in the PETACC3 adjuvant trial. This large negative trial randomized stage II-III patients to adjuvant chemotherapy consisting of infusional 5-FU/LV with or without irinotecan.

Abstract 4001: Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial) by Dr Sabine Tejpar, et al

The first presentation focused on the significance of microsatellite instability (MSI). They were able to evaluate tissue samples from 1564 out of 3278 trial participants. Outcomes used in the study included relapse-free survival (RFS) at 3 and 5 years as well as OS at 68 months follow-up. Microsatellite instability–high (MSI-H) is defined as the result of inactivation of the DNA mismatch repair (MMR) system. Microsatellite instability–high patients have a more favorable prognosis than MSI-low or microsatellite stable (MSS) patients. They examined the incidence of MSI-H in stage II and III colon cancer, the prognostic effect of MSI-H, whether there were any stage specific effects of MSI-H, and if MSI-H was predictive of any benefit from the addition of irinotecan to infusional FU/LV. Microsatellite instability-high was seen in 22% of stage II tumors, but only 12% of stage III tumors. They also noted that MSI-H has been reported to be present in only 3.5% of stage IV patients in the CAIRO study. Univariate analysis demonstrated that MSI-H is statistically more common in stage II, node negative, T3-4, grade 1-2, and right sided tumors as well as patients age ≤60 years. It is also found more commonly in BRAF mutated tumors and thymidylate synthetase (TS) intense tumors. It is less common in p53 abnormal tumors, tumors with complete loss of Smad4 and 18q loss of heterozygosity (18qLOH) tumors. It is somewhat less common is KRAS mutated tumors (P = .034). Microsatellite instability–high was a strong statistically significant predictor for RFS and OS in stage II colon carcinoma, but not in stage III. Patients who were MSI-H obtained much less benefit from infusional FU/LV compared to the MSS patients in the PETACC3 trial. Stage III patients benefited from FU/LV-irinotecan to the same proportion whether they were MSI-H or MSS. In addition, the RFS for all MSI-H patients was no different whether they received irinotecan or not. The authors concluded that MSI-H is a strong prognostic predictor for stage II and much less so for stage III suggesting possible stage specific biological effects of MSI.

Abstract 4002: Stage-specific prognostic value of molecular markers in colon cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial by Dr Arnaud Roth, et al

In the second abstract presentation, the PETACC3 investigators presented the results of an analysis of the presence of a variety of molecular markers among patient tumors in the PETACC3 study. These markers included p53, Smad4, TS and telomerase (hTERT) by IHC plus MSI, 18qLOH, KRAS, and BRAF by molecular analysis. Analysis was successful in 80% to 90% of tumor samples. There were very significant differences in the presence of these biological makers by colon cancer stage. Microsatellite instability and TS were much more frequent in stage II versus stage III, and p53 over-expression, Smad4 and 18qLOH were more common in stage III. Differences for hTERT, KRAS and BRAF were not significant. By univariate analysis, those markers with significant prognostic value in stage II included MSI-H, 18qLOH and TS-high. In stage III, the markers with significant prognostic value included any loss of Smad4, hTERT high, p53-high and TS-high. KRAS and BRAF did not have significant prognostic value in either stage. However, on multivariate analysis, only T-stage, age and MSI had significant prognostic value in stage II, whereas in stage III there was significant prognostic value for T-stage, nodal status, p53 expression and any loss of Smad4. 18qLOH lost its value as a prognostic marker in both stages. This raises some concern among investigators because the current US trial (E5202) for high-risk stage II colon cancers stratifies patients by both 18qLOH and MSI status. The authors concluded that stage II and III colon cancer express different prognostically significant biomarkers suggesting the possibility that stage II and III colon cancer are biologically different diseases rather than sequential evolutionary steps in the same pathological continuum. They suggested further that this consideration should be carefully evaluated in the future.

OncoFacts™ Editor:

James Epstein, MD

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