UK Trial Establishes Standard of Care for Advanced Anal Cancer

Liam Davenport

October 26, 2018

MUNICH — Patients with locally recurrent or metastatic anal cancer should be treated with a chemotherapy combination of carboplatin and paclitaxel, say UK researchers in the first ever randomised clinical trial to be reported in these patients.

The study, which was presented at the European Society of Medical Oncology 2018 annual meeting, involved 91 patients who were randomised to either carboplatin and paclitaxel or treatment with another chemotherapy regimen that paired cisplatin and 5-fluorouracil (5-FU).

While the study was unable to show a difference in objective response rates between the two chemotherapy regimens, the carboplatin paclitaxel combination was associated with a lower rate of serious adverse events and a doubling of overall survival over the cisplatin 5-fluorouracil combination.

'New Kids on the Block'

Dr Sheela Rao, GI Unit, Royal Marsden NHS Foundation Trust, London, told the audience that, despite the lack of difference in the objective response rate, "carboplatin paclitaxel demonstrated less toxicity and this is declared the winner by this study design."

"In addition, carboplatin and paclitaxel demonstrated improved overall survival and can now be considered a new standard of care for patients with treatment-naïve advanced anal cancer."

In findings that lay the foundation for the assessment of more novel treatments, such as immunotherapy, Rao added: "Carboplatin and paclitaxel should be the cytotoxic platform for future combination trials."

Dr Claus-Henning Köhne, University Clinic Oncology and Haematology, North West German Cancer Centre, who was the invited discussant for the study, said that he "would choose this kind of regimen if I have the next patient with metastatic disease".

He urged the researchers to "please continue this fantastic, multinational effort," and predicted that the "new kids on the block", such as immunotherapy, "will be added to the new drug trials" in anal cancer.

Anal Cancers

Rao began by noting that anal cancer accounts for 3% of digestive system cancers, over 90% of which are associated with human papillomavirus (HPV), and the incidence of squamous cell carcinoma of the anus is increasing by 2.9% per year.


Moreover, 20% of patients develop metastatic disease, a rate that is also increasing year on year and is associated with a median survival of just 15–20 months.


Treatment choice for these patients is, however, hampered by no prospective randomised controlled trials having been carried out in advanced anal cancer.

"There are a lot of single arm series and a lot of our treatments are based on these single arm series," Rao observed, "but there's no established standard of care and this really is an area of strong unmet need."

The researchers therefore conducted the first international, multicentre, randomised phase 2 study, assigning advanced anal cancer patients to either a 21-day carboplatin and paclitaxel chemotherapy regimen (CP) or a 28-day cisplatin and 5-FU(C5) regimen.

The patients were stratified by ECOG performance status, HIV status, the extent of disease and the region in which they were recruited.

The aim was not only to assess objective response rates as the primary endpoint, but also the feasibility of conducting an international study in such a rare cancer, alongside toxicity and other outcomes.

Unusually, the team settled on a 'pick the winner' study design, in which the least toxic regimen would be selected as the 'winner' if no significant difference in objective response rate between treatment arms was detected.

"I want to highlight to you that this a rare cancer and, as such, we took a very pragmatic approach here as a group," Rao said.

"We decided to perform a randomised, phase 2 pick the winner design, and the reason for this is that we wanted to establish a chemotherapy backbone in order to be able to look at some more interesting phase 3 work with novel agents or immunotherapy."

Of note, they also analysed a modified intention to treat population, involving only those patients who were randomised, eligible, had received at least one cycle of treatment and were assessable for response.

In all, 91 patients with locally recurrent inoperable or metastatic squamous cell carcinoma of the anus from 60 sites in North America, Europe and Australia were randomised CP (n=45) or C5 (n=46).

The average age of the patients was 60 years, and approximately 67% were female. The majority (~88%) had metastatic disease, and 93% had an ECOG performance status of 0–1.

Only approximately 5% of patients were HIV positive. To be considered eligible for the trial HIV positive patients had to have a CD4 count of ≥200, or if the CD4 count was lower to be receiving HAART therapy.

Patients in the CP arm received a median of six treatment cycles, while those in the C5 arm received 4.5 cycles.

The overall rate of grade ≥3 adverse events was similar between patients receiving CP and those given C5, at 71% and 76%, respectively.

However, CP was associated with a far lower rate of serious adverse events, at 36% versus 62% among those treated with C5.

In terms of individual grade ≥3 adverse events, rates of fatigue, febrile neutropenia, mucositis, nausea, and thromboembolism were far lower with the CP regimen than that seen with C5.

Rao reported that, among the 39 CP patients and 35 C5 patients evaluable for response, the objective response rate was similar, at 59% and 57%, respectively (p=0.873).

Over a median follow-up of 25.3 months, progression-free survival was also not significantly different between the CP and C5 arms, at 8.1 months versus 5.7 months (p=0.375).

However, median overall survival was longer with the CP regimen versus C5, at a median of 20.0 months versus 12.3 months (p=0.014).

Patients treated initially with CP were less likely to receive a subsequent treatment during the study period, at 38% versus 54% among those in the 5FU arm.

Concluding, Rao said: "We accept that we used a pragmatic design but we have successfully demonstrated the feasibility of international collaboration in a rare cancer."

The study was supported by National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research. Additional funding by Cancer Research UK (CRUK).

Rao declares advisory roles with Shire, Servier, Amgen and Celgene.

Köhne reports personal honoraria from Amgen, Bayer, Merck, Roche, Servier, BMS, Lilly; and advisory roles at the EMA, haliodx, BMS, Amgen, Merck.

 ESMO 2018 Congress: Abstract LBA21. Presented 22 October.


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