Improved oncological treatment of anal cancer

Background: Squamous cell cancer of the anus (SCCA) is a rare malignancy, but the incidence is increasing. It is
associated with humman papilloma virus infection. The standard treatment is radiotherapy (RT) combined with
chemotherapy, usually 5-fluorouracil (5FU)/Mitomycin C (MMC). This treatment is relatively effective, but
recurrence still represents a problem especially in locally advanced SCCA.
The overall aim of this thesis was to improve the treatment of SCCA by analysing a large Nordic population-based
cohort and to explore a new treatment strategy in a prospective phase I study, NOAC 8.
Methods: Studies I-III were based on a retrospective cohort comprising 1266 patients with SCCA treated
according to Nordic guidelines between 2000 and 2007 (cohort 1), with definitive RT, alone or combined with
chemotherapy (CRT), stratified by tumor stage.The second cohort included 13 patients with locally advanced
SCCA enrolled in the NOAC 8 trial, investigating RT combined with cetuximab and 5FU/MMC, a combination that
had not been tested before. The primary aim was to determine the maximum tolerated dose (MTD) of
chemotherapy using a pre-defined dose escalation scheme.
Results: High age, male gender, large primary tumor, lymph node metastases, distant metastases, poor
performance status and non-inclusion into a protocol were all independent factors associated with worse
outcome.The treatment results were good, well in accordance with published randomized trials. A high incidence
(11%) of inguinal lymph nodes recurrence was observed in patients with small tumors where adjuvant lymph
irradiation was omitted. Surgery alone of early SCCA was associated with a high locoregional recurrence rate and
poor survival, which were significantly improved with postoperative RT/CRT.The outcome in patients with
metastatic SCCA was poor, but it was significantly better in patients receiving active treatment. Male gender,
metachronous disease and multiple metastatic sites were identified as prognostic factors associated with worse
prognosis.
The MTD of 5FU/MMC in combination with cetuximab and RT was determined.Dose limiting toxicity were
diarrhoea, febrile neutropenia and thrombocytopenia.
Conclusions: Good treatment results were obtained with widely implemented Nordic guidelines. We recommend
prophylactic inguinal lymph node irradiation also for small tumors. Postoperative RT/CRT is effective after primary
surgery for early SCCA. The addition of cetuximab to 5FU/MMC in combination with RT was a rather toxic
regimen but the side-effects were manageable.