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Neoadjuvant Options Increase for Localized Rectal Cancer

Carlson, Robert H.

doi: 10.1097/01.COT.0000473101.41079.b7
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BARCELONA, Spain—New options for neoadjuvant treatment in rectal cancer are being tested in multiple ways—combining neoadjuvant chemoradiotherapy with adjuvant chemotherapy, treatment intensification, and even using neoadjuvant chemotherapy instead of chemoradiation.

Speaking here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer, David Sebag-Montefiore, MD, Professor of Clinical Oncology at the University of Leeds and St. James's Institute of Oncology in the U.K., said there is a strong rationale for adding neoadjuvant chemotherapy to standard treatment for rectal cancer.

Among the benefits, for example, neoadjuvant treatment:

  • Allows full-dose systemic chemotherapy to be given earlier;
  • Can be associated with reduced toxicity and better compliance;
  • Provides for future biomarker and novel therapies; and
  • Makes earlier reversal of a defunctioning stoma possible.

“The last point is not commonly recognized, but it is clearly important to the patient,” he said.

On the other hand, the disadvantages of neoadjuvant chemotherapy include difficulty in selecting appropriate patients, risk of over-treatment, delays to curative surgery, and that there is no Phase III trial evidence.

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Neoadjuvant Chemo and ChemoRT

Very encouraging pathological complete response rates are being seen using both neoadjuvant chemotherapy and chemoradiotherapy, Sebag-Montefiore said. For example, in MRI-defined high-risk rectal cancer, the PANEX pooled analysis of the two trials called EXPERT and EXPERT-C trials (Sclafani et al: ASCO 2014 Annual Meeting, Abstract 3575), using neoadjuvant capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, total mesorectal excision, and adjuvant CAPOX (with/without cetuximab), showed an encouraging pathological complete response rate of about 18 percent, a five-year local progression-free survival rate of 95 percent, and a five-year progression-free survival rate of 70 percent.

Sebag-Montefiore also cited the randomized Phase II Spanish GCR (Grupo Cancer de Recto)-3 study with 108 patients (Fernandez-Martos et al: JCO 2010;28:859-865) given concomitant chemoradiotherapy followed by surgery and adjuvant CAPOX or induction CAPOX followed by concomitant chemoradiotherapy. The results suggested that compared with conventional preoperative chemoradiation, the addition of chemotherapy before chemoradiation and surgery allows most patients to receive their planned treatment with a better toxicity profile without compromising the pathological complete response and complete resection rates.

The pathological complete response rates were similar for the two arms of the study: 14.3 percent for patients receiving neoadjuvant chemotherapy prior to adjuvant chemoradiation and 13.5 percent for whose having adjuvant chemoradiation.

“The advantage of neoadjuvant chemotherapy was a significant reduction of Grades 3 and 4 toxicity during neoadjuvant chemotherapy compared with postoperative adjuvant chemotherapy,” Sebag-Montefiore said.

He noted that even though a long-term follow-up of that trial published earlier this year (Fernandez-Martos et al: Ann Oncol 2015;26:1722-1728) showed very low local recurrence rates for the two arms, distant metastasis remains a problem, at 21 and 23 percent, respectively.

“Clearly in a study of this size [108 patients] it would be hard to see a clear signal in favor of neoadjuvant chemotherapy, but there are no signs of a deleterious outcome from that approach,” he said, adding that the ongoing Phase III RAPIDO trial and the proposed CREATE trial hopefully will answer the question of neoadjuvant chemotherapy's value in rectal cancer.

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Standards of Care

Sebag-Montefiore pointed out that the guidelines from ESMO and the UK's National Institute for Health and Care Excellence (NICE) for standard of care for patients with rectal cancer are similar in their approach of identifying risk stratification for patients selected for preoperative radiotherapy or chemoradiation. “Importantly, in early tumors they recommend avoiding radiotherapy or chemoradiotherapy prior to resection in good prognosis patients,” he said.

“It's very important to think about this, because there is a significant element of overtreatment in patients having resection of early stage tumors. I think this reflects high-quality staging.”

For intermediate-risk patients, he continued, both short-course radiotherapy and chemoradiation are recommended in the guidelines, and the results of those two appear fairly similar. The recommendation for intermediate-risk patients is 25 Gy in five fractions, with a delay to surgery as optional in frail patients who are unfit for chemoradiotherapy in the advanced group.

For high-risk patients, chemoradiation is the standard of care, with fluoropyrimidine (fluorouracil or capecitabine) plus varying doses of radiotherapy.

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Without Radiation?

Sebag-Montefiore said a number of randomized Phase II studies have reported encouraging outcomes with impressive pathological complete response rates using neoadjuvant chemotherapy without radiotherapy—“but clearly these are exploratory.”

For example, the authors of a recent review (Sclafani and Cunningham: Future Oncol 2014;10:2243-2257) concluded that “neoadjuvant chemotherapy without radiotherapy is an attractive therapeutic option that yields theoretical advantages. Moreover, if carefully selected, patients may be spared the effects of radiotherapy without compromising the oncology outcome.”

Sebag-Montefiore said a trial to watch is the ongoing Phase II/III PROSPECT trial, planned for 1,060 patients, comparing chemotherapy alone versus chemotherapy plus radiation therapy in treating patients with locally advanced rectal cancer undergoing surgery.

“Clearly, Phase III trial data is required to make major changes in the standard of care, both in the value of adding neoadjuvant chemotherapy to the standard of care and the more contentious—but also interesting—question of whether neoadjuvant chemotherapy is as good as neoadjuvant chemoradiotherapy,” he said.

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Dose Intensification

A bigger problem for patients than local recurrence, though, he said, is distant metastasis, as seen in the long-term follow-up of the German CAO/ARO/AIO-94 trial. That study showed a 30 percent rate of distant metastasis after chemoradiation, with local recurrence around 10 percent (Sauer et al: JCO 2012;30:1926-1933).

One approach to the problem is intensification of concurrent chemoradiotherapy, Sebag-Montefiore said, citing five Phase III trials that have tested dose intensification:

  • The German CAO/ARO/AIO-04 study (JCO 2012:30:1936-1933);
  • The National Surgical Adjuvant Breast and Bowel Project (NSABP) R04 study (ASCO 2011 Annual Meeting, Abstract 3503);
  • The ACCORD 12/ 0405 PRODIGE 2 study (JCO 2012;30:4558-4565);
  • The STAR-01 study (JCO 2011;29:2773-2780); and
  • The Pan-European Trials in Alimentary Tract Cancer (PETACC) 6 study (Ann Oncol 2013 suppl iv120).

“None of the five has led to a change in the standard of care, and we are awaiting published outcome data from the majority of these trials,” Sebag-Montefiore said.

Analyzing them in great detail is important, though, he said: to identify the true benefit of dose intensification in the long term and to identify subsets of patients more likely to benefit.

“Many of these trials are difficult to interpret because they lack high-quality pelvic MRI at the time of staging, and also because they differ in platforms, radiotherapy dose, and trial design, and there are also questions about toxicity and radiotherapy compliance,” he said.

He also noted that intensification with targeted therapies remains the subject of several Phase II tests, but that the results have been disappointing to date.

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Limit Targeted Therapies to Trials

Another speaker in the session on Multimodality Therapy for Rectal Cancer, David Cunningham, MD, Director of Clinical Research and the National Institute for Health Research Biomedical Research Centre at Royal Marsden Hospital in the U.K., said that targeted therapies in localized rectal cancer should be limited to clinical trials.

“I could probably give this talk in 30 seconds,” he said. “Preoperative fluoropyrimidine-based chemoradiotherapy followed by total mesorectal excision remains the standard treatment for locally advanced rectal cancer, and use of targeted therapies in this setting should be regarded as investigational. And you're not going to use investigational agents in patients with good prognosis, so you have to look elsewhere.”

Only small Phase II trial data are available to date, with limited data on survival outcome, he said. Pathological complete response rates range from five to 26 percent with cetuximab-based chemoradiotherapy, and 13 to 32 percent with bevacizumab-based chemoradiotherapy.

“Pathological complete response rates do not appear significantly different compared with those reported with standard fluoropyrimidine-based chemoradiotherapy,” Cunningham said. “And enhancement of tumor radiosensitivity by either cetuximab or bevacizumab may not be as relevant as suggested by preclinical studies.”

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Even so, using targeted therapies in combination with neoadjuvant systemic chemotherapy for locally advanced rectal cancer has potential advantages:

  • The combination may increase the chances of tumor response (especially with anti-EGFR monoclonal antibodies), which could translate into higher rates of tumor downstaging and R0 resection—this is particularly relevant for high-risk/bulky tumors;
  • Patient selection can be based on predictive biomarkers, such as RAS mutational status for anti-EGFR monoclonal antibodies;
  • There may be a reduced need for preoperative radiotherapy if sufficient tumor downsizing is achieved and the circumferential resection margin is safe, which would spare the patient from radiotherapy-related toxicity; and
  • Targeted therapies potentially improve survival outcomes.

Cunningham said rectal cancer is biologically similar to non-hypermutated colon cancer, and the clinical benefit from anti-EGFR agents in metastatic colorectal cancer is therefore independent of the site of the primary tumor.

He also said caution is needed when investigating anti-angiogenic therapies, and an adequate interval before surgery must be considered.

In addition, identification of prognostic biomarkers for risk stratification and predictive biomarkers for treatment selection is crucial.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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