'Important Milestone' in Anal Cancer -- Later Assessment

Roxanne Nelson, BSN, RN

February 28, 2017

A later assessment following chemoradiotherapy in anal cancer may save some patients from undergoing unnecessary surgery.

Current guidelines for anal cancer recommend assessing response to chemoradiation 6 to 12 weeks after starting treatment and to then proceed with surgery if residual tumor remains.

However, new findings show that some patients who do not achieve a complete clinical response at 11 weeks do in fact respond by 26 weeks and will not need to undergo salvage surgery.

The new data were published online February 10 in the Lancet Oncology.

Lead author Robert Glynne-Jones, MBBS, a consultant clinical oncologist at Mount Vernon Hospital, Watford and Barnet General Hospitals, in London, United Kingdom, and colleagues advise careful monitoring after the completion of chemoradiotherapy in order to facilitate timely surgical salvage therapy for progressive disease.

However, they emphasize that it does seem "safe to observe a resolving tumor up to 26 weeks after the start of chemoradiotherapy, and some patients could thus avoid unnecessary surgery." They suggest that it may be time to revisit the guidelines.

"We propose guidelines should be revised, and that the assessment of response at 26 weeks be used in future trials and explored as a surrogate endpoint for overall survival and progression-free survival," they write.

It could be safe to extend evaluation even further, they add, because some data suggest that select patients may need more than 10 months for complete regression, although this would need to be confirmed in prospective studies.

Response Increases Over Time

The standard treatment for anal cancer is chemoradiotherapy with concurrent fluorouracil and mitomycin. Although guidelines recommend assessment of response at 6 to 12 weeks, there is discordance as to how often and when biopsies should be performed, and there is uncertainty over the optimum time to assess response, the authors write.

To determine the optimum timepoint for assessing tumor response after chemoradiotherapy, Dr Glynne-Jones and colleagues conducted a post hoc analysis of ACT II, a phase 3 randomized trial that included 940 patients with squamous cell carcinoma of the anus without metastatic disease. ACT III results were reported a few years ago (Lancet Oncol. 2013;14:516-24.)

Patients were randomly assigned to receive either intravenous mitomycin (one dose of 12 mg/m² on day 1) or intravenous cisplatin (one dose of 60 mg/m² on days 1 and 29), with intravenous fluorouracil (one dose of 1000 mg/m² per day on days 1-4 and 29-32) and radiotherapy (50.4 Gy in 28 daily fractions).

A second randomization was conducted after initial therapy in which patients received either maintenance chemotherapy (fluorouracil and cisplatin) or no maintenance chemotherapy.

The primary endpoint was complete clinical response, as well as overall and progression-free survival.

For their latest analysis, the authors analyzed complete clinical response at 3 timepoints after the start of chemotherapy: 11 weeks (assessment 1), 18 weeks (assessment 2), and 26 weeks (assessment 3). At each assessment, estimates were made of overall and progression-free survival for patients with complete clinical response or without complete clinical response.

Within the cohort, response data were available for a total of 691 patients for all three timepoints.

The authors note that the proportion of patients with complete clinical response increased over time. At assessment 1, 441 (64%) patients had a complete clinical response; at assessment 2, 556 (81%) had a complete clinical response; and at assessment 3, 590 (85%) had a complete response.

Of the 441 patients who achieved a complete clinical response at 11 weeks, that response was maintained until 18 weeks for 421 (95%) patients; 411 (93%) patients were still experiencing a complete clinical response at 26 weeks.

For the full cohort of 940 patients, a complete clinical response was achieved in 492 (52%) at 11 weeks, 665 (71%) at 18 weeks, and 730 (78%) at 26 weeks.

However, 151 (72%) of 209 patients who did not experience complete clinical response at 11 weeks did achieve this by 26 weeks. In addition, 115 (76%) of these 151 patients remained alive and disease free on last follow-up after treatment.

Therefore, those patients who eventually achieved a complete clinical response at 26 weeks could be considered slow responders, note the authors.

Important Milestone

"The observation that the ideal interval to assess tumor response is 26 weeks is remarkable and a leap forward in clinical practice for the management of these patients, especially considering that this interval was formerly only 8 weeks," comment experts in an accompanying editorial. The editorialists are Angelita Habr-Gama, MD, PhD, and colleagues at the University of São Paulo, in Brazil.

The observation...is remarkable and a leap forward in clinical practice for the management of these patients. Dr Angelita Habr-Gama and colleagues

Because the study was conducted at multiple institutions, they note that subjectivity of clinical response assessment and the variation in examiners and assessment of response could have accounted for some complete clinical responses being incorrectly labeled as incomplete clinical response in the early intervals.

Despite those limitations, the editorialists emphasize that the findings represent "an important milestone," and they are emphatic in their recommendation. These findings "must be implemented into clinical practice to the benefit of patients with anal cancer in the very near future," they write.

"Furthermore, these results and the kinetics of tumor regression after neoadjuvant chemoradiotherapy and the accuracy of clinical assessment might not be unique to anal carcinoma and might again apply, at least to some extent, to rectal adenocarcinoma after neoadjuvant chemoradiotherapy," they add.

The study was funded by Cancer Research UK. Dr Glynne-Jones has receivee grant funding and personal fees from Merck and Roche and personal fees from Eisai, Amgen, and Servier. Coauthor David Cunningham, MD, has received research funding from Amgen, AstraZeneca, Bayer, Celgene, Merrimack Medimmune, Merck, and Sanofi. The other study authors and the editorialists have disclosed no relevant financial relationships.

Lancet Oncol. Published online February 10, 2017. Full text, Editorial

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