New research into the treatment of gastrointestinal cancers – and novel ways to predict recurrence and response were highlighted at the American Society of Clinical Oncology’s annual Gastrointestinal Cancers Symposium (January 20-22, 2011, San Francisco).

Intense radiation – as good as conventional therapy, but with fewer adverse effects

US researchers outlined data from a phase II clinical trial, demonstrating the benefit of treating anal cancer with intensity-modulated radiation therapy (IMRT).

It was reported that IMRT has fewer significant skin and gastrointestinal (GI) side-effects, which can limit anal cancer treatment. IMRT is specifically designed to focus on the tumour only, sparing surrounding healthy tissue.

This Radiation Therapy Oncology Group (RTOG) investigation showed that after two years of follow-up, combining chemotherapy with IMRT is not only as effective in treating anal cancer as chemotherapy and conventionally delivered radiation therapy, but has fewer significant side effects.

“Radiation therapy with concurrent 5-fluorouracil and mitomycin-C chemotherapy serves as the standard of care for patients with non-metastatic squamous cell cancer of the anal canal in the United States,” explained Dr Lisa Kachnic (Chair of radiation oncology, University of Boston, Massachusetts).

“This treatment results in long-term disease-free survival, but is associated with significant acute toxicity due in part to the large radiation fields used. The use of IMRT may address this problem.”

In contrast to two- or three-dimensional conventional radiation fields, which indiscriminately treat normal organs, IMRT is a novel technology that conforms or “paints” the radiation dose to the tumour and lymph node regions, while sparing healthy surrounding tissues.

Improvements in treatment-related toxicity have already been described in patients with breast, head and neck and prostate cancers treated with IMRT, as compared to conventionally-delivered radiation therapy.

In the current study, Dr. Kachnic and the RTOG analysed the outcome of 52 stage II and stage III patients with anal cancer treated with IMRT and 5-fluorouracil/mitomycin-C chemotherapy.

After a median follow-up of 26.7 months, 2-year disease-free survival (DFS) was 77%, and overall survival (OS) was 86%. These results were very similar to the 325-patient, 5-fluorouracil/mitomycin-C arm of the RTOG 9811 trial, which used conventionally delivered radiation: 75% DFS and 91% OS at two years.

However, the use of IMRT in this trial (RTOG 0529) was associated with less skin and gastrointestinal acute toxicity.

“Based on these new data,” said Dr. Kachnic, “IMRT will now serve as the standard radiation technique in future RTOG anal cancer trials assessing novel agents in combination with radiation.”

TK inhibition with sorafenib – another step forward for GIST patients?

Treatment with a targeted tyrosine kinase inhibitor (TKI), sorafenib, may be an effective alternative for patients with advanced gastrointestinal stromal tumours (GIST) that are resistant to standard therapies.

It was reported by Dr Nicholas Campbell (Oncology fellow, University of Chicago, Illinois) that while more than 80% of patients can be treated effectively with imatinib, resistance frequently develops, and other treatments are needed.

In the new data he presented, sorafenib halted disease progression in more than two-thirds of patients, some for as long as three years.

Patients with GIST, a soft tissue sarcoma that occurs in the stomach, small bowel, or other sites in the GI tract, usually have a mutation in the KIT or PDGFRA gene. Imatinib, also a TKI, targets these overactive genes, and is effective in more than 80% of patients with advanced GIST.

However, as Dr Campbell explained, most eventually develop resistance, and the disease progresses. Yet another TKI, sunitinib, is approved in the US for treating patients in whom imatinib is ineffective.

“There is an urgent need for additional agents to treat patients with imatinib- and sunitinib-refractory GIST, since there are no FDA-approved options for these patients other than resumption of imatinib,” said Dr Campbell.

In this phase II prospective trial, researchers at six centres examined the effectiveness of sorafenib in 38 GIST patients whose disease continued to worsen, despite treatment with imatinib and sunitinib.

Dr Campbell reported that sorafenib inhibits a wide range of TK mutations, including many of the secondary mutations that develop in patients who become resistant to imatinib and sunitinib.

Among the 38 patients investigated, six were resistant to imatinib and 32 were resistant to both imatinib and sunitinib.

Dr Campbell and his colleagues found that sorafenib controlled tumours in 68% of the patients recruited to this study. Tumours shrank in 13% of patients (partial response) and the disease did not progress in an additional 55% of patients (stable disease). One- and 2-year overall survival (OS) rates were 44% and 21%, respectively.

Side-effects from sorafenib included hypertension, fatigue and hand-foot syndrome (HFS). As a result, approximately 63% of the patients required dose reductions, though the drug was still effective at lower doses. Dr Campbell said that side-effects from imatinib tend to be relatively modest, while those associated with sunitinib – especially fatigue – can be worse than imatinib.

Dr Hedy Lee Kindler (Associate professor of medicine, University of Chicago) commented: “Most of these patients had received two lines of therapy and had nothing left to try.

“Despite this, more than two-thirds achieved stabilisation of their disease or better. Many were maintained on sorafenib for extended periods – up to three years – and did quite well. These results give us hope that we can find additional treatment options for these patients.”

PET prognosis data promises improved survival in oesophageal cancer

European investigators have claimed that using positron emission tomography (PET) imaging to detect responses to chemotherapy prior to surgery can help determine a patient’s prognosis in locally advanced adenocarcinoma of the oesophagogastric junction.

Dr Florian Lordick (Director of the Department of Haematology and Oncology, Klinikum Braunschweig, Brunswick, Germany) reported that those patients responding to chemotherapy had better median event-free and overall survival than non-responders.

He and his colleagues also found that those who did not respond to chemotherapy did not benefit from additional radiation.

Dr Lordick, outlining data from a prospective study, MUNICON II, commented: “We confirmed that PET testing after two weeks of chemotherapy is a very important prognostic tool.

“This approach can help a physician distinguish patients who are responding to chemotherapy from those who are not, and who can therefore be spared from the unnecessary toxicities of treatment that is unlikely to improve their outcome,” he added.

Dr Lordick reported that earlier studies had shown that using PET imaging with fluorodeoxyglucose (FDG) can help detect response to chemotherapy given prior to surgery to shrink tumours in patients with locally advanced adenocarcinoma of the oesophagogastric junction.

He continued: “Tumours accumulate glucose as a result of increased proliferation and glucose demand. FDG-PET can detect the glucose uptake in tumour tissue. When tumours are treated successfully with chemotherapy, a sharp decrease in glucose uptake in the tumour can be seen and measured by PET. If the tumour is not sensitive to chemotherapy and continues to grow, no change in PET imaging will be observed.

In the MUNICON II study, 56 patients with locally advanced oesophagogastric cancer were divided into responders and non-responders on the basis of PET results after two weeks of chemotherapy.

For patients who had a metabolic response, treatment continued for three additional months before surgery. For those without a PET response early during chemotherapy, therapy was changed and radiation was given before surgery to reduce the tumour size and increase the likelihood of completely removing the cancer.

A total of 33 patients responded to chemotherapy as measured by PET, while 23 did not. Of the 33 responders, 27 (82%) were able to undergo curative surgery compared to 16 (70%) of non-responders.

After a median follow-up time of 38 months, the median event-free survival and median overall survival of non-responders were 15.4 months and 18.3 months, respectively. The responders had yet to reach median event-free survival and median overall survival after 38 months.

While PET can be used to guide treatment in other cancers, such as lymphoma and lung cancer, Dr. Lordick believes this is the first attempt to implement treatment changes on the basis of early PET findings.

“What’s unfortunate is that the results of our study also indicate that for early metabolic non-responders, there is not yet an effective salvage treatment that could improve their poor prognosis. We’re continuing to look for more effective ways to treat this group of patients,” Dr. Lordick said.

Next, the German researchers plan to confirm the prognostic and predictive value of PET in a randomised, multi-centre, international trial called IMAGE. In addition, they will look for new treatment approaches for those patients who have poor prognoses based on the lack of early metabolic responses in chemotherapy.

Bevacizumab fails to impress in adjuvant colon cancer trial

Disappointing data from the AVANT study, showing that treatment with bevacizumab does not prolong disease-free survival (DFS) when added to either FOLFOX4 or XELOX in patients with stage III colon cancer, was reported by Dr Aimery de Gramont (Hôpital Saint-Antoine, Paris, France).

Bevacizumab, a humanised anti-VEGF (vascular endothelial growth factor) monoclonal antibody, has demonstrated clinical efficacy in combination with 5-FU-based regimens in patients with metastatic colorectal cancer.

The therapeutic impact of concurrent bevacizumab with either FOLFOX4 or XELOX chemotherapy in the adjuvant setting was evaluated in this international, controlled phase III trial.

Eligible patients had high-risk stage II or stage III colon cancer and had undergone surgical resection. They were then randomly assigned to one of three treatment groups:

-         Arm A: FOLFOX4 on weeks 1-24

-         Arm B: FOLFOX4 + bevacizumab on weeks 1-24, then bevacizumab alone on weeks 25-48

-         Arm C: XELOX + bevacizumab on weeks 1-24, then bevacizumab alone on weeks 25-48

The primary endpoint was DFS for patients with stage III colon cancer, with follow-up assessments performed every six months after randomisation for four years, then annually until recurrence or death.

A total of 3,451 (2,867 stage III) patients (median age 58-59 years) were enrolled between December 2004 and June 2007. Median duration of follow-up was 48 months.

However, Dr de Gramont reported that bevacizumab did not prolong DFS or overall survival (OS) when added to either FOLFOX4 or XELOX in patients with stage III colon cancer based on the final efficacy analysis conducted in September 2010.

He added that efficacy results favoured the chemotherapy-alone control arm, and that numerically more relapses and deaths occurred in both the BEV arms compared to control.

The observed adverse events were consistent with those previously reported in pivotal trials of BEV across tumour types for approved indications.

Adjuvant chemo – no benefit reported in patients with rectal cancer

Patients with pathologic complete response (pCR) or ypT3-4 residual tumour after neoadjuvant chemoradiation (CRT) for rectal tumour do not seem to benefit from adjuvant chemotherapy.

This was the main finding of a large-scale analysis of patient data, details of which were reported by  Dr Geerard Beets (University Medical Centre, Maastricht, The Netherlands).

Dr Beets said these discouraging data might be due to the already good prognosis of patients with pCR and less responsiveness to 5-FU based chemotherapy in the poor responders (the ypT3-4 tumours).

He explained there was a possibility that adjuvant chemotherapy could be omitted or adapted for these patients – also that patients with ypT1-2N0 appear to benefit most from adjuvant chemotherapy.

Dr Beets added that CRT for rectal cancer increasingly results in pathologic response. It has been suggested that patients with different degrees of response might not have the same benefit of adjuvant chemotherapy.

The aim of this study was to determine whether patients with a pathologic complete response (pCR), ypT1-2 or ypT3-4 tumour after CRT for rectal cancer have different benefits of adjuvant chemotherapy for disease-free survival (DFS).

Authors from studies evaluating different degrees of response to CRT were contacted to share individual patient data, and the collected individual patient data were pooled into one dataset.

A total of 2,724 patients were included - 811 had pCR (28%), 863 had ypT1-2 (30%) and 1,050 had ypT3-4 (37%).

During a median follow-up of 50 months, 41% of patients underwent adjuvant chemotherapy, which consisted mostly of 5-FU based chemotherapy.

The hazard ratio (HR) for DFS for adjuvant chemotherapy was 0.94 for patients with pCR, 0.61 for patients with ypT1-2 tumours and 0.97 for patients with ypT3-4 tumours.

 Meanwhile, ypT1-2N0 patients benefited most from adjuvant chemotherapy (HR 0.45 vs 0.79 for patients with ypT1-2N+. For ypT3-4 patients pN-stage did not alter benefit of adjuvant chemotherapy.

Combination therapy for advanced neuroendocrine cancer – successful outcome in RADIANT-2

New data from the randomised, double-blind, placebo-controlled, multicenter phase III RADIANT-2 trial has revealed that combination therapy with a rapamycin-derived immunosuppressant, everolimus, and the somastatin analogue, octreotide LAR, lengthens median progression-free survival (PFS) in patients with advanced neuroendocrine tumours (NET).

Dr James Yao (Associate professor, Department of GI medical oncology, MD Anderson Cancer Centre, University of Texas, Houston, Texas) reported that patients who received the everolimus-octreotide LAR combination had a median PFS of 16.4 months versus 11.3 months in patients assigned to placebo plus octreotide LAR.

"Conventional chemotherapy has limited efficacy for patients with advanced neuroendocrine tumours, and there remains a significant unmet medical need in this population," he commented.

While the everolimus and octreotide LAR combination did not achieve its primary PFS endpoint, the 5.1- month extension in PFS represented a clinically meaningful improvement.

Importantly, analyses that adjusted for imbalances in baseline characteristics in the two treatment groups and inconsistencies in the review of radiology scans for disease progression showed that everolimus plus octreotide LAR significantly decreased the likelihood of disease progression.

A total of 429 patients with advanced low- or intermediate-grade neuroendrocine tumours and a history of symptoms attributed to carcinoid syndrome were randomised to treatment with oral everolimus (10 mg/day) plus octreotide LAR (30 mg administered by intramuscular injection every 28 days) or placebo plus octreotide LAR. Treatment continued until disease progression.

Dr Yao said that octreotide LAR has been the foundation of therapy for patients with NET. However, additional treatment options were needed. Everolimus, an oral inhibitor of mTOR, had demonstrated promising anti-tumour activity in patients with NET as a single agent and in combination with octreotide LAR in two phase II studies.

The difference in median PFS between the two arms of RADIANT-2 represented a 23% reduction in risk of progression (hazard ratio [HR] 0.77, p=0.026)

Correcting for the informative censoring bias, further analysis showed a significant 5.5-month improvement in median PFS with the combination (HR 0.60, p= 0.0014).

The benefit of the everolimus-octreotide LAR combination was seen across all patient sub-groups. Most frequent drug-related adverse events (AEs) were stomatitis, rash, fatigue, and diarrhoea; mostly grade 1-2. Grade 3-4 AEs reported in >5% were stomatitis, fatigue, diarrhoea, infections, and hyperglycaemia.

Dr Yao concluded: “In this large phase III trial, the combination of everolimus and octreotide LAR provided a 5.1-month clinically meaningful increase in median PFS – a benefit that was increased to 5.5 months after correcting for reporting bias.”