Reports

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31st Congress of the European Society of Medical Oncology

Istanbul, Turkey / September 29-October 3, 2006

Each year, 940,000 people worldwide develop colorectal cancer. Despite advances in the treatment of local disease, many patients will suffer relapses. In such patients, systemic chemotherapy is often the only treatment option, although outcomes are still not optimal. Combination chemotherapy regimens, including those with oxaliplatin and irinotecan, have shown encouraging results. Doses of cytotoxic chemotherapy, however, are often limited by toxicity, reducing the efficacy of the treatment.

The oral fluoropyrimidine prodrug capecitabine is preferentially converted to 5-fluoro-uracil (5-FU) in tumour tissue by exploiting the increased expression of thymidine phosphorylase. This should provide more targeted delivery to tumour cells, with the added advantage that patients tend to prefer oral treatment. The incorporation of biologic targeted therapies into the cytotoxic chemotherapy may further improve survival. For example, a number of treatments are being developed that target the epidermal growth factor receptor and the vascular endothelial growth factor receptor signalling pathways. Vascular endothelial growth factor is a key mediator in tumour angiogenesis, which in turn is essential for tumour growth. Recently, bevacizumab became the first anti-angiogenic agent to be approved as an anticancer therapy in first-line metastatic colorectal cancer.

Clinical Trial Results

Dr. James Cassidy, Professor of Oncology and Head, Department of Cancer Research, UK Department of Medical Oncology, University of Glasgow, Scotland, presented the results of the “largest trial in metastatic colorectal cancer to be conducted so far.” Initially, the study was designed to assess whether a regimen that included XELOX (capecitabine/oxaliplatin) was non-inferior to FOLFOX (5-FU/oxaliplatin/leucovorin), which was considered the standard for the treatment of metastatic colorectal cancer at the time. The XELOX regimen required one visit to the clinic every two weeks whereas the FOLFOX regimen required two nights in hospital every two weeks. According to Dr. Cassidy, the underlying aim was to answer the question: “Can we use a mainly oral chemotherapy with its advantages in terms of patient convenience as a substitute for an infusional regimen with the same outcome results and so change the standards of care?”

According to the protocol, approximately 1000 metastatic colorectal cancer patients were to be recruited and randomized to either XELOX or FOLFOX. But after approximately half of these had been recruited, evidence had accumulated that addition of bevacizumab was beneficial (Hurwitz et al. N Engl J Med 2004;350(23):2335-42), so the design was amended in order to maintain recruitment. In the new design, bevacizumab 7.5 mg/kg intravenous (i.v.) or placebo was added to either of the regimens (XELOX or FOLFOX) to yield a 2x2 partially blinded study. Patient recruitment was extended to give a total of approximately 1400. After the amended design, another primary objective was added, namely, to show that addition of bevacizumab to either of the chemotherapy regimens was more efficacious in terms of the main end point of the trial, which was progression-free survival. Dr. Cassidy limited his presentation to analysis of this end point because other end points were not yet ready for publication.

The baseline data were comparable across all groups except that baseline ECOG (Eastern Cooperative Oncology Group) performance status improved in the second part of the study compared to the first. Dr. Cassidy explained that this was probably because “our internal bias as clinicians meant that we were slightly more selective about putting patients in the second part of the trial because of our unfamiliarity with bevacizumab at the time and the potential for additional toxicity.”

The median progression-free survival was eight months for XELOX compared to 8.5 months for FOLFOX. The hazard ratio for the comparison of the XELOX and FOLFOX regimens was 1.04 (97.5% CI, 0.93-1.16). Given that the prespecified upper limit for non-inferiority was 1.23, this “provides compelling evidence that the two regimens are the same, the two values for progression-free survival statistically are identical.”

Progression-free survival for XELOX and FOLFOX was also analyzed according to a number of different predefined subgroups which might affect prognosis, such as ECOG score at baseline, number of sites of metastases, age, sex and ethnicity, but Dr. Cassidy stressed that none of the relative risk ratios gave any cause for concern.

Although the two regimens demonstrated the same efficacy, Dr. Cassidy remarked that they did differ in their toxicity profiles. Grade 3/4 diarrhea was reported in 20% of those in the XELOX group compared to 11% of those in the FOLFOX group. In contrast, neutropenia was reported in 43% of those in the FOLFOX group compared to just 7% in the XELOX cohort. Febrile neutropenia, which is the form that medical oncologists are particularly concerned about, was 4.8% for the FOLFOX group compared to 0.9% for XELOX. Dr. Cassidy commented, “There is no clear winner but rather a trade-off between diarrhea and neutropenia.”

Adding to Standard Chemotherapy Regimens

The other main question addressed by the study was the benefit of adding bevacizumab to chemotherapy regimens in the treatment of metastatic colorectal cancer. Median progression-free survival for bevacizumab added to FOLFOX or XELOX was 9.4 months compared to eight months for placebo plus the standard chemotherapy (P=0.0023). The primary end point was met and addition of bevacizumab was undoubtedly more efficacious than placebo but the benefit was not as great as might have been expected from comparison with the pivotal phase III trial with bevacizumab. In an effort to explain this finding, Dr. Cassidy presented some exploratory subgroup analyses, although he stressed that these were preliminary findings and work is still ongoing.

According to the subgroup analysis, progression-free survival was significantly longer for bevacizumab vs. placebo only in the XELOX group. Furthermore, examination of the baseline characteristics of the FOLFOX group showed that more time had elapsed since adjuvant therapy in placebo patients. Dr. Cassidy added, “Those of us who work in this area of oncology suspect that patients who have a long time from adjuvant chemotherapy until relapse do somewhat better, that is, this is an indicator of good prognosis.” Therefore, placebo patients in the FOLFOX arm may have had better prognosis from the start, although he pointed out that this tentative explanation was derived from exploratory analysis. Dr. Alberto Sobrero, Professor of Medical Oncology, San Martino Hospital, Genoa, Italy, who discussed Dr. Cassidy’s presentation, also remarked, “In the pivotal phase III trial, bevacizumab was continued for 8.5 months, whereas in this study, everybody seems to stop at six months, so the message is maybe we should continue until real progression.”

It is also important to know how the toxicity profile changes on addition of bevacizumab. Events such as gastrointestinal perforation, bleeding, thrombotic events and hypertension have been associated with this agent, and indeed, an increase in the frequency of these events was seen on addition of bevacizumab. Nonetheless, according to Dr. Cassidy, “These percentages are actually quite small and in fact, they are smaller than previous comparative trials with bevacizumab.”

In his discussion, Dr. Sobrero was encouraged by the relatively benign toxicity profile of bevacizumab added to chemotherapy, in particular that only 3.7% of the patients experienced grade 3/4 hypertension. “We are all eager to pursue the ‘pile-on’ approach to the treatment of this disease, meaning combination chemotherapy plus bevacizumab,” noted Dr. Sobrero, who also underlined that these encouraging and reassuring safety results are the latest in a series of promising data and that the overall safety profile was in line with previous bevacizumab clinical trials.

Use in the Clinical Setting

Randomized clinical trials provide the most robust measure of the efficacy of a given treatment, but because the patient populations are well defined through a strict series of inclusion criteria, patients enrolled in such trials may differ from those who receive treatment in a clinical setting. Observational trials, although not able to answer detailed questions about the comparative effectiveness of treatments, nevertheless provide valuable information about treatment in day-to-day clinical practice.

Dr. Mark Kozloff, Clinical Associate of Medicine, Section of Hematology/Oncology, University of Chicago, Illinois, presented the results of the BRITE (Bevacizumab Regimens Investigation of Treatment Effects and Safety) registry. Inclusion criteria were minimized to ensure that the population was as representative as possible of patients with metastatic colorectal cancer. The study aimed to determine the progression-free survival of those patients who received bevacizumab in combination with a variety of chemotherapy regimens. Data were available for 1950 patients (median age 63.6 years) who were followed for a median of 12.9 months. The most commonly used chemotherapy regimens were FOLFOX (55.9%), infusional FOLFIRI (5-FU/leucovorin/irinotecan) (14.3%) and IFL (irinotecan/bolus 5-FU/leucovorin), the regimen used in the phase III confirmatory trial for approval of bevacizumab (9.7%). Median progression-free survival was 10.2 months (95% CI, 9.9-10.9 months) and showed little variation according to the chemotherapy used. As in the confirmatory trial, a common adverse event was hypertension requiring medication (16.4%). Dr. Kozloff concluded, “Despite the less-selected patient population enrolled in the BRITE registry as compared to the pivotal phase III trial, the estimated progression-free survival is comparable.”

The First BEAT (Bevacizumab Expanded Access Trial) aimed to evaluate the safety of bevacizumab when added to a variety of first-line chemotherapies in a broad patient population. Patients from 41 countries were enrolled with a median age of 59 years and 33% were over 65 years old. Oxaliplatin-containing chemotherapy regimens were received by 48% of the patients, whereas irinotecan-containing regimens were given to 33%. Serious adverse events (SAEs) were reported in 29.6% of the patients and 9.5% of the patients experienced bevacizumab-related SAEs according to the investigators’ assessment. The most common possibly-related SAE or common toxicity criteria grade 3-5 event was hypertension, followed by proteinuria. Gastrointestinal perforations were reported in 1.6% of the patients and such events were slightly more common in those with prior NSAID use and intact primary tumour. The researchers concluded, “This preliminary analysis shows that the safety profile of bevacizumab in clinical practice appears to be consistent with that observed in prospective clinical trials.”

In another study, the efficacy and safety of first-line bevacizumab plus FOLFIRI was evaluated in the treatment of metastatic colorectal cancer. Preliminary data yielded an estimated six-month progression-free survival of 82%, which exceeds that reported for the addition of bevacizumab to IFL in the phase III confirmatory trial.

Quality of Life

A recurring theme of the presentations during the scientific sessions was the potential gain in quality of life (QoL) with an oral chemotherapy agent. Dr. Carlos Beato, Hospital Amaral Carvalho, Jaú, Brazil, presented the results of a study that specifically addressed the question of QoL associated with capecitabine treatment. Responses from 1437 patients to the EORTC QLQ C-30 questionnaire (specially designed to assess the QoL of cancer patients) were analyzed. Approximately 60 to 85% of patients experienced improved or maintained QoL with capecitabine. According to Dr. Beato, “The QoL benefits of capecitabine are particularly important when choosing appropriate therapy for patients with incurable metastatic colorectal cancer.”

Summary

Surgery remains the mainstay option for colorectal cancer management. Systemic chemotherapy and additions to chemotherapy are becoming increasingly important, whether administered as adjuvant or neoadjuvant therapy. In relapsed patients, chemotherapy is often the only option. In such cases, outcomes are generally poor, but new chemotherapy regimens are extending survival.

Capecitabine, an oral prodrug that is metabolized to 5-FU, is a viable new development, in that it could make chemotherapy regimens more amenable to patients. Results presented here confirmed its efficacy in clinical trials with restrictive inclusion criteria and in the clinical practice setting. The combination of chemotherapy with biologic agents may also be beneficial. A large recent study has confirmed the efficacy of bevacizumab as first-line treatment in metastatic colorectal cancer.