Radiol Oncol 1997; 31: 199-201.
Treatment of epidermoid anal canal carcinoma
Richard Pötter and W. Dobrowsky
University of Vienna, Department of Radiotherapy and. Radiobiology, Allgemeines Krankenhaus
der Stadt Wien, Wien, Austria
During the last two decades, the role of surgery in anal cancer treatment has been changing continuously. Nowadays, surgery is applied only in treatment of (recurrent) radio-and chemoresistant disease. At present, anal function-conserving radiation therapy (45-60 Gy) and concomitant chemotherapy with 5-FU and MMC are considered to be standard therapy methods applied in locally advanced tumours, whether NO or N+. In small tumours (T1N0), chemotherapy can be omitted without jeopardizing the outcome. In future, the role of induction chemotherapy will have to be evaluated in order to see whether some other drug would contribute better to the improvement of the already favourable results.
Key words: rectal neoplasms; combined modality treatment
Introduction
Epidermoid cancer of the anus is a rare disease comprising 1-4% of malignant colorectal cancers, though 30% of all ano-rectal cancers are anal cancers. About 75% of anal cancers are anal canal cancers and are more common in women than in men (ratio 3:2 - 5:1) (Quan 1978, Beahrs 1979, Eschwege et al. 1985). Histologically, most cancers are of the squamous cell type of different keratini-zation. The lymphatic spread is mainly in three directions. The anal margin drains in the inguinal superficial region, anal canal tumours primarily in lymph nodes along the great vessels (A. mesenteri-ca inferior, A. iliaca) and perirectal/anal lymph nodes.
Treatment of anal canal cancers is mainly a loco-regional problem, distant metastases being uncommon. The age of patients has a wide range from 25 to 80 years, with a median age of about 60 years. About 75% patients have uncharacteristic symptoms with haemorrhoids, fistulas, pruritus or leuco-plakia which may delay the correct diagnosis.
Correspondence to: Univ. Prof. Dr. Richard Potter, Univer-sitaetsklinik fuer Strahlentherapie, und Strahlenbiologie, Waehringer Guertel 18-20, A-1090 Wien, Austria.
UDC: 616.351-006.6-08
Treatment
The role of surgery as primary treatment modality has gradually decreased during the last 30 years and has now been abandoned by most centres. Only very small tumours could be treated by conservative, sphincter saving surgery, and the local recurrence rate was high in these cases. Major abdominoperineal resection and permanent colostomy was the option for most patients undergoing surgery. In spite of major surgery, the survival results were far from acceptable. Tables 1 and 2 show the results of surgery for anal canal cancer.
In Europe, radiation therapy has always played a more important role in the therapy of these tumours, compared with North America where surgery was often preferred as initial therapy. Radiotherapy was abandoned in some centres during the early decades of this century because of severe side effects. With the introduction of modern, high voltage machinery, improved brachytherapy methods and more knowledge about the natural history of this disease, the treatment results of irradiation of anal tumours gradually improved. Table 3. shows the results of primary radiation therapy for anal canal cancers.
Following the introduction of combined radiotherapy and concomitant administration of chemotherapy
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(Mitomycin C and 5-Fluorouracil) by Nigro et al. 1974, this combination was widely adopted as the primary treatment of choice for anal cancers. This combined treatment was first used as preoperative treatment and resulted in over 60% tumour-free cases after a radiation dose of only 30 Gy (Nigro et al. 1981, Wanebo et al. 1981, Meeker et al. 1986). Following these encouraging results, surgery was gradually replaced by an increased radiation dose. The increased toxic effect of Mitomycin C (MMC) on hypoxic cells and on extracellular acidic environment is a clear benefit in large squamous cell cancers with considerable hypoxic regions being less sensitive to radiation (Rauth et al. 1983 Rockwell 1982, Dobrowsky & Dobrowsky 1995). 5-Fluorouracil (5-FU) was attributed a role of a radiosensitizing agent when administered after irradiation for longer time periods and was reported to be interacting in a supraadditive way with MMC in vitro (Byfield et al. 1982, Nakajima et al. 1979, Dobrowsky et al. 1992). It has been used in the clinic for many years in combination with radiation therapy. Table 4 shows some results from chemoradi-ation with MMC and 5-FU.
Table 1. Local excision for anal canal cancer - 5-year survival and local relapse rate
Author	No. Survival	Local
	of patients	recurrence
		rate
Kuehneiat 1968	26 75%	8%
Stearns & Quan 1970	30 66%	63%
Beahrs 1979	21 85%	42%
Klotz et al. 1967	33 61%	33%
Boman et al. 1984	19 84%	11%
Frost et al. 1984	20 66%	60%
Table 2. Major surgery for anal cancer - 5-year survival		
Author	No. of patients	Survival
0 Brien etal. 1950	45	32%
Grinell 1954	13	46%
Klotz et al. mi	194	50%
Kuehn et al. 1964	83	47%
Greenall et al. 1985	103	55%
Boman et al. 1984	114	71%
Table 3. Radiation therapy for anal cancer		
Author	No. of Survival	Local
	patients	recurrence
Green et al. 1980	16 81%	25%
Cummingseia/. 1982	51 59%	. 43%
Eschwege etal. 1985	64 46%	19%
Papillon 1982	88 68%	14%
Dobrowsky 1987	14 79%	14%
Table 4. Chemoradiation with MMC and 5-FU for anal cancer
Author	Primary tumour control	Survival
Leichman et al. 1985	86%	80%
Sischy etal. 1989	71%	73%
Papillon & Montbarbon 1987	81%	
Cummings et al. 1991	87%	65%
Dobrowsky et al. 1996	95%	73%
Other groups tested the combination of bleomycin and radiation, but it was stated that the benefit of bleomycin administration was of questionable value (Glimelius & Pahlman 1987, Svensson et al. 1993).
Most reports have dealt with single institutional experiences and there have not been any randomized trials until recently. Three major trials tested the effect of different chemotherapy regimens administered simultaneously with radiation therapy. An intergroup study tested whether or not the addition of MMC to 5-FU chemotherapy administered with radiation therapy was of benefit (Flam et al. 1996). At 4 years, colostomy rates were lower (9% vs 22%; p=0.002), colostomy-free survival higher (73% vs 59%; p=0.014) and disease-free survival higher (73% vs 51%; p=0.0003) in the MMC arm. Overall survival was not significantly different in the two arms and the MMC arm showed significantly higher toxicity.
The British UKCCCR Study made a comparison between radiation therapy with radiation therapy and concomitant chemotherapy (MMC and 5-FU) in a randomized trial in which 856 patients were treated (UKCCCR 1996). The group found a 46% reduction in local recurrence (p<0.0001) for patients treated by combined therapy. The risk of death from anal cancer was significantly reduced, but overall survival was not significantly different in the two treatment groups.
The EORTC also tested the addition of chemotherapy to radiation therapy (Bartelink 1996). After randomization of 110 patients, a higher local tumour control was reported after chemoradiation (local recurrence 9 vs 15, local recurrence and distant relapse 9 vs 10 for rt+ct vs rt, respectively; significant improvement in local tumour control: p<0.02). Overall survival was not significantly different in the two groups.
Although combined modality therapy is accompanied by an increased local toxicity and moderate haematological toxicity, it is believed to be justi-
Treatment of epidermoid anal canal carcinoma
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fied by the excellent results obtained with regard to local tumour control and colostomy free survival.
In conclusion, the standard therapy for anal canal cancers consists of radiation therapy and concomitant chemotherapy with the use of 5-FU and MMC. This is the best treatment for advanced tumours, whether NO or N+. All cases, even unresectable should be considered for this regimen. In small tumours (T1N0) chemotherapy can be omitted without jeopardizing the outcome with regard to response rate and survival. The future will show if induction chemotherapy will keep its role, or if a change of chemotherapeutic drugs (cisplatin or car-boplatin and 5-FU) will further improve the already very favourable results obtained by the present therapy in this rare disease.
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