Organ-preserving treatment for cancer of the anal canal can now be achieved in the majority of patients with a combination of radiotherapy and chemotherapy (chemoradiation). This treatment approach is well reviewed by Stafford and Martenson.
Not only has chemoradiation changed the management of this cancer from organ mutilation to organ preservation, but also it has achieved better survival compared to historical surgical controls. Based on recent phase II/III chemoradiation trials, colostomy-free survival is achieved in about 75% of patients. Also, the overall survival rate at 5 years with chemoradiation is between 70% and 75%, which is somewhat higher than the 62% 5-year survival rate from a large surgical series reported prior to the widespread acceptance of chemoradiation.
Double Chemotherapy Plus Irradiation
One useful perspective gleaned from two decades of chemoradiation results is that double chemotherapy (fluorouracil [5-FU] plus mitomycin(Drug information on mitomycin) [Mutamycin]) and irradiation (FUMIR) appears to be better than single-agent 5-FU plus irradiation (FUIR). Local control, colostomy-free survival, and disease-free survival all seem to be better when both agents are given. In the Radiation Oncology Therapy Group (RTOG) randomized trial, radiation sensitization with both 5-FU and mitomycin (FUMIR) was most effective in stage T3 and T4 anal cancers and in those with histologically proven inguinal lymph node involvement.
These observations are also supported by clinical radiobiologic studies, which demonstrate the importance of the dose-response relationship with respect to the degree of tumor burden. In this regard, the use of radiation doses of 45 to 54 Gy with chemotherapy is necessary to eradicate disease in the majority of patients. The new RTOG/intergroup study will test whether higher radiation doses can achieve even better local control. The randomized European Organization for Research and Treatment of Cancer (EORTC) trial also supports the use of high radiation doses (60 Gy), although the treatment approaches used in the European and American studies differ markedly.
The successful treatment of anal cancer by double chemoradiation has been associated with higher rates of acute and late complications than are seen with single-agent chemoradiation. For example, in the RTOG trial, a 23% rate of grade 4 toxicity occurred in those receiving FUMIR, as compared with only a 7% rate in those who were treated with FUIR.
One way to reduce toxicity would be to select only patients with larger tumors for double chemoradiation since the benefit from the use of mitomycin was seen mainly in these patients. Alternatively, a less toxic radiosenstizer could be used. In the new RTOG/intergroup study, for example, cisplatin(Drug information on cisplatin) will be used instead of mitomycin. Preliminary data suggest that 5-FU infusional chemoradiation plus cisplatin may be less toxic.
Yet another method to ameliorate toxicity may be to alter the method of administering radiosensitzing chemotherapy. It has long been understood that the dose per day (or dose per fraction in radiation oncology parlance) is one of the main determinants (along with the total dose) of the late effects of irradiation. Indeed, radiation therapy, as practiced today, is limited by the total dose and the volume of normal tissues that can be irradiated without producing a major late complication (eg, myelitis, fibrosis, necrosis). In the treatment of cancer of the anal canal, radiosensitizing chemotherapy given as a protracted infusion (ie, in low daily doses) appears to avoid late-occurring damage to normal tissues, as compared with studies using the typical Nigro treatment schedule (Table 1). In other words, a sparing effect occurs when both irradiation and radiosensitizing chemotherapy are fractionated.
Evidence supporting this hypothesis for a sparing of late effects in the lower gastrointestinal tract also comes from the results of protracted infusional chemoradiation in the recently reported rectal adjuvant therapy trial. These findings should be kept in mind not only in the design of newer chemoradiation trials for patients with anal canal cancer but also possibly in the implementation of chemoradiation trials at other sites where this hypothesis could be explored further.