Chemotherapy in the treatment of anal canal carcinoma

Digestive and Liver Disease 44 (2012) 803–811

Contents lists available at SciVerse ScienceDirect

Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld

Review Article

Chemotherapy in the treatment of anal canal carcinoma Wulfran Cacheux a , Astrid Lievre a , Anne De La Rochefordiere b , Barbara Dieumegard a , Frédérique Cvitkovic a , Alain Labib b , Emmanuel Mitry a , Bruno Buecher a,∗ a b

Department of Medical Oncology, Groupe Hospitalier, Institut Curie, 26 rue d’Ulm, 75248 Paris Cédex 5, France Department of Radiotherapy, Groupe Hospitalier, Institut Curie, 26 rue d’Ulm, 75248 Paris Cédex 5, France

a r t i c l e

i n f o

Article history: Received 20 March 2012 Accepted 18 April 2012 Available online 30 May 2012 Keywords: Anal canal Cancer Chemotherapy

a b s t r a c t Squamous cell carcinomas of the anal canal are generally diagnosed at a localized or locally advanced stage and only 5% are metastatic at the time of diagnosis. Advanced forms are therefore much rarer than localized forms and usually correspond to metachronous metastases of initially localized disease. Systemic chemotherapy is indicated for the treatment of both localized disease, in combination with radiotherapy, and metastatic disease. The purpose of this article is to define the current indications and modalities of chemotherapy in the treatment of these cancers based on a review of the published data and in the light of available guidelines. © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Squamous cell carcinomas of the anal canal are generally diagnosed at a localized or locally advanced stage. Only 5% are metastatic at the time of diagnosis. Advanced forms are therefore much rarer than localized forms and usually correspond to metachronous metastases of initially localized disease. Systemic chemotherapy has a place in the treatment of both localized disease, in combination with radiotherapy, and metastatic disease. The purpose of this article is to define the current indications and modalities of chemotherapy in the treatment of these cancers based on a review of the published data and in the light of available guidelines. This review will be confined to squamous cell carcinomas and the treatment of localized disease and metastatic disease will be considered successively. 1. Chemotherapy in the treatment of localized carcinomas of the anal canal Radiotherapy plays a key role in the treatment of squamous cell carcinomas of the anal canal due to the particular sensitivity of these tumours to ionizing radiation. The superiority of concomitant chemoradiation over radiotherapy alone was demonstrated about fifteen years ago and this modality now constitutes the standard treatment for localized or locally advanced disease at the time of diagnosis (clinical stages T2/3 N0/3; Table 1), corresponding to the great majority of cases. In parallel with the evaluation of new modalities of radiation therapy, clinical research is also devoted to identify the most effective chemotherapy regimens. The role of

∗ Corresponding author. Tel.: +33 1 44 32 46 95; fax: +33 1 53 10 26 48. E-mail address: [email protected] (B. Buecher).

neoadjuvant or adjuvant chemotherapy and the value of cetuximab administered in association with radiotherapy and chemotherapy have also been evaluated. 1.1. Superiority of concomitant chemoradiation over radiotherapy alone Two randomized trials published in 1996 and 1997 established the superiority of radiotherapy combined with chemotherapy (combined modality therapy, CMT) over radiotherapy (RT) alone in this setting. The design of these trials is summarized in Table 2. The British multicentre ACT I trial (Anal Cancer Trial I) compared RT alone to RT combined with chemotherapy comprising 5-fluorouracil (5-FU) and mitomycin C (MMC) in patients with various stages of squamous cell carcinomas of the anal canal or anal margin (74.7% and 23.2% of the sample size, respectively) [1]. Thirteen percent of patients with anal canal cancer were stage I on the UICC 1985 classification. A significant reduction of the risk of locoregional failure or locoregional recurrence (primary outcome measure) was observed in patients treated with CMT (HR = 0.54; 95% CI: 0.42–0.69; p < 0.0001; 3-year local control rate: 61% versus 39%). Similarly, CMT was associated with a significant reduction of the risk of death from anal canal/anal margin cancer (HR = 0.71; 95% CI: 0.53–0.95; p < 0.0001). No significant difference was observed between the 2 arms in terms of overall survival. The results of a new analysis of the data of this trial were recently published [2]. This analysis confirmed the superiority of CMT over RT alone in terms of reduction of the risk of locoregional recurrence (HR = 0.46; 95% CI: 0.35–0.60; p < 0.001; 25.3% absolute reduction at 12 years in the CMT arm), improvement of recurrence-free survival (HR = 0.70; 95% CI: 0.58–0.84; p < 0.00; 12% absolute reduction

1590-8658/$36.00 © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dld.2012.04.013

804

W. Cacheux et al. / Digestive and Liver Disease 44 (2012) 803–811

Table 1 TNM staging classification of anal canal carcinomas. Primary tumour (T) Primary tumour cannot be assessed • TX No evidence of primary tumour • T0 Carcinoma in situ • Tis Primary tumour 2 cm or less in greatest dimension • T1 Primary tumour more than 2 cm but not more than 5 cm in greatest • T2 dimension Primary tumour more than 5 cm in greatest dimension • T3 • T4 Primary tumour of any size invading adjacent organ(s), e.g. vagina, urethra, bladder (direct invasion of rectal wall, perianal skin, subcutaneous tissue or the sphincter muscle alone is not classified as T4) Lymph node (N) Regional lymph nodes cannot be assessed • Nx No regional lymph node metastasis • N0 Metastasis in perirectal lymph node(s) • N1 • N2 Metastasis in unilateral internal iliac and/or inguinal lymph node(s) • N3 Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes Distant metastasis (M) Presence of distant metastasis cannot be assessed • Mx • M0 No distant metastasis • M1 Distant metastasis

at 12 years in the CMT arm) and colostomy-free survival (HR = 0.76; 95% CI: 0.63–0.91; p < 0.001; 9.5% absolute reduction at 12 years in the CMT arm). The absence of significant difference for overall survival between the 2 arms can be explained by an increased number of second cancers (especially lung cancers) observed during the 10 years following treatment in patients treated with CMT. No significant difference was observed between the patients of the 2 arms in terms of late complication rate: ulcers/radiation necrosis, anorectal, genitourinary or skin-related morbidity.

1.1.1. The European trial EORTC 22861 The design of this trial was almost identical to that of the British trial (Table 2), but the patient sample size was smaller and tumours were predominantly stage T3-4N0 or T3-4 N1-3 (46.6% and 35.9% of the sample size, respectively) [3]. Once again, the superiority of CMT over RT alone resulted in a significant improvement of the 5-year locoregional tumour control rate (68% versus 50%; p = 0.02) associated with a significant reduction of the colostomy rate (40% versus 72%; p = 0.002) in patients receiving the combined modality therapy. Combined modality therapy was also associated with a significant improvement of event-free survival (tumour recurrence; colostomy; severe late complications or death) (p = 0.03) and progression-free survival (p = 0.05), but no impact was observed on overall survival (56% 5-year overall survival for the total sample size; median survival not reached). On multivariate analysis, factors associated with improvement of tumour control were absence of lymph node invasion, absence of skin ulceration and combined modality therapy (CMT). Female gender was associated with a tendency to a better locoregional tumour control rate. Overall, the concordant results of these two trials confirm that administration of systemic 5-FU and MMC combination chemotherapy concomitantly with external beam radiotherapy significantly improves locoregional tumour control and decreases the risk of colostomy. This benefit was obtained at the price of an acceptable increase of acute toxicity, particularly haematological, with no marked increase of late toxicity, although this parameter was imprecisely and inadequately evaluated in these trials.

1.2. What chemotherapy should be used in combination with radiotherapy to treat localized anal canal carcinomas? 1.2.1. Value of the MMC–5-FU combination The RTOG 87-04/ECOG 1289 cooperative trial was designed to demonstrate the superiority of the 5-FU + MMC combination versus single-agent 5-FU chemotherapy administered concomitantly with RT [4,5]. Biopsies were performed 4–6 weeks after the “induction” sequence corresponding to radiotherapy delivered with 5-FU alone or in combination with MMC. In the 2 arms, patients with positive biopsies received an additional boost of RT in combination with chemotherapy comprising 5-FU and cisplatin (CDDP) (Table 2). Surgery was performed in patients with residual tumour 4 weeks after completion of this second treatment sequence. The superiority of the 5-FU + MMC combination was reflected by a significant reduction of the 4-year colostomy rate (9% versus 23%; p = 0.002) and a significant improvement of the 4-year recurrence-free survival (73% versus 51%; p = 0.0003) and of the 4-year colostomy-free survival (71% versus 59%; p = 0.014). The benefit of 5-FU + MMC was greater for stage T3–T4 tumours than for stage T1–T2 tumours, as reduction of the colostomy rate associated with administration of MMC was significant only for T3–T4 tumours. A tendency to improvement of overall survival was also observed with a smaller number of deaths due to disease progression among patients treated with 5-FU + MMC (15 versus 24). Haematological toxicity was significantly more severe in patients treated with 5-FU + MMC. No statistically significant difference was observed between the 2 arms for other acute toxicities or late toxicities. This trial confirmed the value of the 5-FU + MMC combination for CMT of localized carcinomas of the anal canal. The results of this trial are consistent with those of previously published nonrandomized trials [6] and support those of the British ACT I and EORTC trials, which established this regimen as standard therapy in this indication. 1.2.2. Comparison of the 5-FU + CDDP and the 5-FU + MMC combinations administered concomitantly with radiotherapy The encouraging results of phase II trials evaluating the combination of 5-FU + CDDP delivered concomitantly with radiotherapy for the treatment of anal canal carcinoma [7–9] led to the comparison of this combination with the standard combination (5FU + MMC) in two vast randomized trials also addressing the issue of the value of neoadjuvant chemotherapy in the RTOG trial [10,11] and the value of adjuvant chemotherapy in the British ACT II trial [12]. Standard treatment in the RTOG 98-11 trial consisted of CMT comprising 5-FU + MMC according to identical modalities to those of the RTOG 87-04/ECOG 1289 trial [10,11] (Table 2). In the experimental arm, chemotherapy delivered concomitantly with RT corresponded to the 5-FU + CDDP combination and CMT was preceded by administration of neoadjuvant chemotherapy corresponding to 2 cycles of the same 5-FU + CDDP combination. The primary outcome measure of this trial was progression-free survival, which was not significantly different between the 2 arms. The 5-year progression-free survival was estimated to be 60% (95% CI: 53–67%) for patients treated with 5-FU + MMC and 54% (95% CI: 46–60%) for patients treated with 5-FU + CDDP (p = 0.17). Similarly, no significant difference was observed for time to progression or for 5-year overall survival between the 2 arms (75% versus 70% for patients treated with 5-FU + MMC and 5-FU + CDDP, respectively; p = 0.10). On multivariate analysis, male gender, presence of clinically palpable lymph node metastases and tumour diameter > 5 cm were identified as factors of poor prognosis associated with shorter recurrence-free survival and shorter overall survival. In contrast, the treatment modality had no impact on survival. The

W. Cacheux et al. / Digestive and Liver Disease 44 (2012) 803–811

805

Table 2 Main randomized trials in localized carcinomas of the anus (mainly carcinomas of the anal canal). Author

Trial

Sample size

Study design

UKCCCR Anal Cancer Trial Working Party [1] Northover et al. [2]

ACT I

n = 585

• Standard arm: RT alone 2 Sequences separated by an interval of 6 weeks: (i) 45 Gy/20 or 25 fractions, then (ii) boost: 15 Gy external beam RT or 25 Gy brachytherapy • Experimental arm: CMT RT: idem standard arm 5-FU: 1000 mg/m2 /day from D1 to D4 or 750 mg/m2 from D1 to D5 1st and last week of the first RT sequence Mitomycin C: a single IV injection at the dose of 12 mg/m2 on the first day of 5-FU chemotherapy

Bartelink et al. [3]

EORTC 22861

n = 110

• Standard arm: RT alone 2 Sequences separated by an interval of 6 weeks: (i) 45 Gy/25 fractions, then (ii) boost: 15 Gy (complete response at 6 weeks); 20 Gy (partial response at 6 weeks) by external beam RT or brachytherapy • Experimental arm: CMT RT: idem standard arm 5-FU: 750 mg/m2 /day from D1 to D5 1st and last week of the first RT sequence MMC: a single IV injection at the dose of 15 mg/m2 on the first day of 5-FU chemotherapy

Flam et al. [4]

RTOG 87-04/ ECOG 1289

n = 310

“Induction” treatment • Standard arm: RT + 5-FU RT: 45 Gy 5-FU: 1000 mg/m2 /day from D1 to D4 at the 1st and 5th weeks of RT (i.e. D1 to D4, then D29 to D32) • Experimental arm: RT + 5-FU + MMC RT: 45 Gy 5-FU: 1000 mg/m2 /day from D1 to D4 at the 1st and 5th weeks of RT (i.e. D1 to D4, then D29 to D32) MMC: 10 mg/m2 on the 1st day of the 1st and 5th weeks (i.e. D1 and D29) “Salvage” treatment • For both arms: 2nd sequence of CMT in patients with positive biopsies 4 to 6 weeks after the “induction” sequence RT: 9 Gy/5 fractions 5-FU: 1000 mg/m2 /day from D1 to D4 CDDP: 100 mg/m2 on D2

Ajani et al. [10]c Gunderson et al. [11]e

RTOG 98-11

n = 644

• “Standard” arm RT + 5-FU + MMC RT: 45 Gy ± boost of 10–14 Gya 5-FU: 1000 mg/m2 /day from D1 to D4 at the 1st and 5th weeks of RT (i.e. D1 to D4, then D29 to D32) MMC: 10 mg/m2 on the 1st day of the 1st and 5th weeks (i.e. D1 and D29) • “Experimental” arm Neoadjuvant chemotherapy, corresponding to 2 cycles of 5-FU + CDDP prior to CMT 5-FU: 1000 mg/m2 /day from D1 to D4 then from D29 to D32 CDDP: 75 mg/m2 on D1 and D29 then, after 3 weeks, RT + 5-FU + CDDP RT = 45 Gy ± boost of 10–14 Gya 5-FU: 1000 mg/m2 /day from D1 to D4 at the 1st and 5th weeks of RT (i.e. from D57 to D60, then from D85 to D88)b CDDP: 75 mg/m2 on the 1st day of the 1st and 5th weeks of RT (i.e. D57 and D85)b

James et al.d [12]e

ACT II

n = 940

2 × 2 factorial plan A – Concomitant chemoradiation Modality 1: RT + 5-FU + MMC RT: 50.4 Gy/28 fractions (continuous administration) 5-FU: 1000 mg/m2 /day from D1 to D4 at the 1st and 5th weeks of RT (i.e. D1 to D4, then D29 to D32) MMC: 12 mg/m2 on D1 Modality 2: RT + 5-FU + CDDP RT: 50.4 Gy/28 fractions (continuous administration) 5-FU: 1000 mg/m2 /day from D1 to D4 at the 1st and 5th weeks of RT (i.e. D1 to D4, then D29 to D32) CDDP: 60 mg/m2 on D1 and D29 B – Adjuvant chemotherapy (2 cycles of 5-FU + CDDP administered at an interval of 3 weeks, starting 4 weeks after completion of CMT): Yes versus No 5-FU: 1000 mg/m2 from D1 to D4 at weeks 11 and 14 CDDP: 60 mg/m2 on D1 of weeks 11 and 14

806

W. Cacheux et al. / Digestive and Liver Disease 44 (2012) 803–811

Table 2 (Continued) Author e

Conroy et al. [21]

Trial

Sample size

Study design

ACCORD 03

n = 307

2 × 2 factorial plan A – “Conventional” concomitant chemoradiation RT: 2 sequences at an interval of 3 weeks: (i) 45 Gy/25 fractions, then (ii) boost of 15 Gy 5-FU: 800 mg/m2 /day from D1 to D4 at the 1st and 5th weeks of RT (i.e. D1 to D4, then D29 to D32) CDDP: 80 mg/m2 on D1 and D29 B – Randomization no. 1: Neoadjuvant chemotherapy (2 cycles of 5-FU + CDDP), versus no neoadjuvant chemotherapy C – Randomization no. 2: Increased radiotherapy boost (25 Gy), versus “conventional” dose (15 Gy)

CDDP: cisplatin; RT: radiotherapy; RTOG: Radiation Therapy Oncology Group; Gy = Greys; CMT: combined modality therapy; 5-FU: 5-fluorouracil; MMC: mitomycin C; UKCCCR: United Kingdom Coordinating Committee on Cancer Research. a Boost administered to patients with initial stage T3/T4 and/or N+ and/or residual T2 after administration of 45 Gy. b Days D57 and D85 correspond to the first days of the first and fifth weeks of radiotherapy, respectively. c Randomized trial comparing 2 treatment strategies differing in terms of the type of chemotherapy administered concomitantly with external beam radiotherapy (5FU + MMC or 5-FU + CDDP) and administration of a first sequence of chemotherapy alone (so-called “induction” or neoadjuvant chemotherapy) for patients treated with CDDP. d Trial with double randomization and factorial plan comparing 2 modalities of concomitant chemoradiation (continuous external beam radiotherapy in combination with 5-FU + MMC or in combination with 5-FU + CDDD) and testing the value of adjuvant chemotherapy (2 cycles of 5-FU + CDDD). e Results only available in abstract form.

5-year locoregional recurrence rate was 25% in the 5-FU + MMC arm versus 33% in the 5-FU + CDDP arm; the 5-year metastatic recurrence rate was 15% and 19% in these 2 arms, respectively. The 3-year and 5-year colostomy rates were significantly higher in patients treated with 5-FU + CDDP (16% and 19%, respectively) than in patients treated with 5-FU + MMC (10% and 10%, respectively). These results are difficult to interpret, as the purpose of this trial was not only to evaluate two modalities of CMT but to compare two treatment strategies, one of which comprised induction chemotherapy. The British ACT II trial (Anal Cancer Trial II) also compared 2 modalities of CMT comprising either 5-FU + MMC or 5-FU + CDDP (Table 2). Radiotherapy was administered continuously at the dose of 50.4 Gy (28 fractions) in both arms. The modalities of concomitant chemotherapy were similar to those of the RTOG 98-11 trial, but with only one injection of MMC 12 mg/m2 and a unit dose of CDDP of 60 mg/m2 . This trial also addressed the issue of the value of adjuvant chemotherapy comprising 2 cycles of 5FU + CDDP by means of double randomization with a factorial plan. The results are only available in abstract form [12]. A high complete response rate was obtained after CMT with no significant difference between the 2 treatment modalities (94% for patients treated with MMC versus 95% for patients treated with CDDP; p = 0.53). This suggests the absence of superiority of 5-FU + CDDP compared to 5-FU + MMC. Data concerning recurrence-free survival and overall survival are only preliminary and difficult to interpret, as they essentially question the value of adjuvant chemotherapy. In these 2 trials, the haematological toxicity was significantly more severe in patients treated with 5-FU + MMC. Overall, the results of the RTOG 98-11 and ACT II trials conclude on the absence of superiority of 5-FU + CDDP compared to 5-FU + MMC administered concomitantly with radiotherapy for the treatment of localized anal canal carcinoma. Data of the ACT II trial (equivalence of the two modalities of CMT tested in terms of response rate) suggest that the significant increase of the colostomy rate observed in patients treated with RT-5-FU + CDDP in the RTOG 98-11 trial (as well as the tendency towards less favourable results of this combination for the other parameters evaluated in this trial) can be attributed to neoadjuvant chemotherapy, responsible for a longer treatment sequence and delayed initiation of CMT, rather than inferiority of the 5-FU + CDDP combination.

1.2.3. Evaluation of other modalities of concomitant chemotherapy and radiotherapy Various phase II trials have been published or are currently underway to evaluate new modalities of concomitant chemotherapy and radiotherapy. The main trials are listed in Table 3. 1.2.3.1. Modulation of the regimens evaluated in phase III trials. The phase II EORTC 22953 trial was designed to evaluate a new modality of administration of radiotherapy and 5-FU + MMC compared to the regimen tested in the EORTC 22861 trial described above [13]: reduction of the interval between the 2 radiotherapy sequences to 2 weeks; continuous IV infusion of 5-FU throughout the first and second radiotherapy sequences; IV injection of MMC on the first day of each radiotherapy sequence (Table 3). The results of this trial were superior to those of the previous study, in terms of both safety and efficacy (initial complete response rate: 90.7%; 3-year local tumour control rate and colostomy-free survival: 88% and 81%, respectively), so that this new modality of CMT is finally considered to be the standard therapy for the EORTC. Modification of the modalities of administration of the 5FU + CDDP combination is frequently performed in clinical practice by teams using this combination, especially consisting of fractionated administration of CDDP in the form of a daily injection at the dose of 20 mg/m2 on the 4 or 5 days of administration of 5-FU. 1.2.3.2. MMC + CDDP combination. The RT/MMC + CDDP combination was evaluated in parallel with the RT/5-FU + MMC combination in a phase II randomized EORTC trial (22011-40014), the modalities of which are summarized in Table 3 [14]. Haematological toxicity was more frequent in patients treated with MMC + CDDP. The primary outcome measure of this trial was the objective tumour response rate 8 weeks after completion of the treatment, which was higher in the MMC + CDDP arm than in the 5-FU + MMC arm: 91.9% (lower bound of the 95% CI: 82,8%) versus 79.5% (lower bound of the 95% CI: 68,8%), respectively. The complete response rate at 8 weeks was also higher in the MMC + CDDP arm (73% versus 59%). The MMC + CDDP combination therefore appears to be superior and probably deserves to be evaluated in the context of a phase III trial. 1.2.3.3. 5-FU + MMC + CDDP combination. The 5-FU + MMC + CDDP combination was tested in combination with RT in a British phase II trial [15]. It was associated with unacceptable toxicity, particularly haematological toxicity, leading to early termination.

W. Cacheux et al. / Digestive and Liver Disease 44 (2012) 803–811

807

Table 3 Phase II trials in localized carcinomas of the anus (mainly carcinomas of the anal canal). Author

Trial

Sample size

Treatment regimen

Bosset et al. [13]

EORTC 22861

n = 88

• RT: 2 sequences separated by an interval of 2 weeks: (i) 36 Gy/20 fractions (26 days), then (ii) 23,4 Gy/13 fractions (17 days) • CT: 5-FU: 200 mg/m2 /day by continuous IV infusion throughout RT (from D1 to D26, then from D1 to D17) MMC: 10 mg/m2 IV on the 1st day of each of the 2 RT sequences

Matzinger et al. [14]

EORTC 22011-40014 Phase II randomized trial

n = 88

Treatment modality 1 (identical to that of EORTC trial 22861) (n = 44) • RT: 2 Sequences separated by an interval of 2 weeks: (i) 36 Gy/20 fractions (26 days), then (ii) 23.4 Gy/13 fractions (17 days) • CT: 5-FU: 200 mg/m2 /day by continuous IV infusion throughout RT (D1 to D26, then from D1 to D17) MMC: 10 mg/m2 IV on the 1st day of each of the 2 RT sequences Treatment modality 2 (n = 44) • RT: 2 sequences separated by an interval of 2 weeks: (i) 36 Gy/20 fractions (26 days), then (ii) 23,4 Gy/13 fractions (17 days) • CT: CDDP: 25 mg/m2 /IV once weekly during the 2 RT sequences (i.e. total of 7 injections; cumulative dose: 175 mg/m2 ) MMC: 10 mg/m2 IV on the 1st day of each of the 2 RT sequences

Glynne-Jones et al. [19]

“EXTRA”

n = 31

• RT: Gy/28 fractions by continuous treatment (identical modality to that of the ACT II trial) • CT: Capecitabine: 825 mg/m2 twice daily (morning and evening) throughout RT MMC: 12 mg/m2 on D1 (single injection)

Eng et al. [20]d

n = 20

Initial treatment modalitya • RT: (variable total dose delivered according to tumour stage): 45 Gy/25 fractions for stage T1; 55 Gy/30 fractions for stage T2; 59 Gy/32 fractions for stage T3–T4 • CT: Capecitabine: 825 mg/m2 twice daily (morning and evening) throughout RT Oxaliplatin: 50 mg/m2 IV once weekly

Deutsch et al. [27]d

n = 16b

Initial treatment modalityc • RT: 2 sequences separated by an interval of 2 weeks, successively: (i) 40 Gy, then (ii) 20 Gy • Cetuximab: 400 mg/m2 (loading dose), 1 week before starting CMT (D-7), then 250 mg/m2 once weekly for the 5 weeks of CMT • CT: 5-FU: 800 mg/m2 /day by 4-day IV infusion at the 1st and 5th weeks of RT (i.e. D1 to D4, then D28 to D31) CDDP: 80 mg/m2 IV on the 1st day of the 1st and 5th weeks of RT (i.e. D1 and D28)

CDDP: cisplatin; CT: chemotherapy; EORTC: European Organization of Research and Treatment of Cancer; RT: radiotherapy; RTOG: Radiation Therapy Oncology Group; Gy: Greys; CMT: combined modality therapy; 5-FU: 5-fluorouracil; MMC: Mitomycin C. a Modification of the treatment regimen due to toxicity during the trial with suppression of chemotherapy during the 3rd and 6th weeks of radiotherapy. b Premature closure of the trial following the inclusion of 16 patients (instead of the 77 initially planned). c Modification of the treatment regimen due to toxicity after inclusion of 10 patients: reduction of the doses of 5-FU and CDDP. d Results only available in abstract form.

1.2.3.4. Capecitabine + MMC combination. Demonstration of the equivalence of capecitabine and 5-FU administered by continuous intravenous infusion for the treatment of various tumours, particularly gastric and colonic [16–18] led to evaluation of the feasibility, safety and efficacy of capecitabine + MMC administered concomitantly with RT for the treatment of squamous cell carcinoma of the anal canal. In the phase II trial conducted by Glynne-Jones et al., the safety of this treatment was globally satisfactory (Table 3) [19]. After 4 weeks, a complete clinical response was obtained in 24 patients and a partial response was obtained in another 4 patients (77% and 16% of the sample size, respectively). At six months, tumour control was obtained in 28 patients, i.e. 90% of the sample size. The capecitabine + MMC combination therefore appears to provide encouraging results and could constitute an alternative to 5-FU + MMC.

1.2.3.5. Other cytotoxic combinations. Capecitabine was also evaluated in combination with oxaliplatin and RT in a phase II trial [20]. The encouraging results of this trial justify further evaluation of this combination. Carboplatin has also been evaluated in CMT regimens, but no published data are currently available. 1.3. Is there a place for neoadjuvant chemotherapy before combined modality therapy in the treatment of localized anal canal carcinomas? Early control of microscopic metastatic disease and reduction of the primary tumour volume before CMT constitute the two main theoretical objectives for evaluation of neoadjuvant chemotherapy. The French intergroup ACCORD 03 trial is a prospective trial with double randomization and a 2 × 2 factorial plan evaluating

808

W. Cacheux et al. / Digestive and Liver Disease 44 (2012) 803–811

administration of neoadjuvant chemotherapy (2 cycles of 5FU + CDDP) and/or RT dose intensification (25 Gy boost) compared to the “conventional” treatment regimen [21]. Patients included in this trial were therefore treated with neoadjuvant chemotherapy followed by “conventional” treatment (arm 1); neoadjuvant chemotherapy and RT dose intensification (arm 2); “conventional” treatment alone (arm 3) or RT dose intensification (arm 4). The primary outcome measure of this trial was the 3-year colostomyfree survival, which was 83%, 85%, 86% and 80% for arms 1, 2, 3 and 4, respectively. Neither neoadjuvant chemotherapy nor RT dose intensification had any impact on this parameter. Threeyear colostomy-free survival was 84% for patients treated with neoadjuvant chemotherapy (arms 1 and 2) and 83% for patients not receiving neoadjuvant chemotherapy (arms 3 and 4). No significant difference was observed between the patients of the 4 arms for the other parameters tested: local tumour control; tumour control; event-free survival; overall survival and specific survival. The RTOG 98-11 trial also aimed to assess the value of neoadjuvant chemotherapy [10,11]. As indicated above, the results of this evaluation were negative, as the colostomy rate was significantly higher in patients treated with neoadjuvant chemotherapy and as a negative trend was also observed for this treatment modality in terms of the other parameters evaluated (locoregional recurrence; recurrence-free survival and overall survival). A pooled analysis of RTOG trials 98-11 and 87-04 was performed and the results were recently published [22]. This analysis was designed to assess the impact of the total duration of treatment on the tumour control rate and patient survival. On multivariate analysis, the following parameters had a significant impact on the local failure rate: total treatment duration (>53 days versus 53 days); treatment modality (RT/5-FU versus RT/5-FU + MMC); age; performance status (Karnofsky index 60, 70, 80 versus 90, 100); tumour stage (T3/T4 versus T1/T2); lymph node status (Nx/N1/N2/N3 versus N0) and total dose of RT delivered to the tumour. In contrast, the duration and the “intensity” of radiotherapy (defined as the ratio of the total dose delivered to the primary tumour/duration of treatment) had no impact on the local control rate after adjustment for the other parameters. It should be noted that there was a correlation between the “total duration of treatment >53 days” and “RT/5-FU + CDDP treatment modality” parameters, as only patients treated according to this modality received neoadjuvant chemotherapy, resulting in a longer treatment sequence. Once again, it is unlikely that the decreased tumour control rate observed in this arm can be attributed to the type of chemotherapy, as the British ACT II trial suggested an equivalent efficacy of the two 5-FU + CDDP and 5-FU + MMC combinations [12]. The particularly high complete response rate after CMT reported in this trial could have been related to the continuous mode of administration of RT that prevented tumour repopulation observed in the interval between the two irradiation sequences delivered according to current conventional strategies. All of these findings argue in favour of evaluation of “short” and intensified CMT regimens integrating the new modalities of administration of RT (conformational static field intensity modulated radiotherapy; helicoidal tomotherapy; volumetric modulated arc therapy). Interestingly, the reduction of the locoregional tumour control rate with increasing duration of treatment has already been reported in other tumour sites, particularly for squamous cell carcinomas of the head and neck [23,24] and cervix [25,26]. In conclusion, there is no place for neoadjuvant chemotherapy prior to combined modality therapy in the treatment of localized carcinomas of the anal canal, as this approach is associated with a lower tumour control rate and an increased risk of colostomy due to the longer duration of treatment and delayed initiation of CMT.

1.4. Is there a place for adjuvant chemotherapy after combined modality therapy for the treatment of localized anal canal carcinomas? The already mentioned British ACT II trial is the only randomized trial to have evaluated the role of adjuvant chemotherapy in patients responding to CMT [12]. Patients responding to one or other of the 2 treatment modalities tested (RT/5-FU + MMC or RT/5-FU + CDDP) with a performance status compatible with administration of adjuvant chemotherapy were randomized to 2 arms: adjuvant chemotherapy (2 cycles of 5-FU + CDDP) or no additional treatment. The preliminary results of this trial indicate that there is no significant difference between patients of the 2 arms in terms of recurrence-free survival (HR: 0.89; 95% CI: 0.68–1.18; p = 0.42) and overall survival (HR: 0.79; 95% CI: 0.56–1.12; p = 0.19) and therefore suggest the absence of benefit of adjuvant chemotherapy. This result must be interpreted cautiously in view of the preliminary nature of the data communicated, the absence of published data and a possible confounding factor related to the two possible modalities of CMT. In any case, there are no arguments in favour of administration of adjuvant chemotherapy or maintenance treatment in patients responding to combined modality therapy.

1.5. Is there a place for targeted therapies in the treatment of localized anal canal carcinomas? At the present time, only cetuximab has been evaluated or is currently under evaluation in combination with CMT for the treatment of localized carcinoma of the anal canal. The frequent overexpression of the EGF receptor and the rarity of KRAS and BRAF mutations in the tumour provide the rationale for evaluation of EGFR inhibitors in this indication. The results of the French phase II multicentre ACCORD 16 trial were presented at the 2011 ASCO congress and have been published in abstract form [27]. Cetuximab was administered in combination with 5-FU and CDDP concomitantly with RT (Table 3). The primary objective was to evaluate the objective tumour response (complete and partial) 8 weeks after completion of treatment. The induced toxicity led to premature closure of the trial, after the inclusion of 16 patients (instead of the planned 77 patients), despite modification of the treatment regimen with reduction of the doses of 5-FU and CDDP after inclusion of the first 10 patients. The main toxicities were haematological (lymphopenia; neutropenia and thrombocytopenia); cutaneous (radiation mucositis and acneiform rash), gastrointestinal (diarrhoea) and general (fatigue). After exclusion of 3 patients who dropped out of the trial, the median progression-free survival was 9 months and the one-year survival rate was 91%. Four patients failed to achieve locoregional tumour control and one presented metastatic progression. Colostomy was performed in 4 patients for locoregional relapse (n = 2) or fistula (n = 2). These results are similar to those of the study by Pfister et al. which tested the same combination in patients with head and neck cancer and which was also prematurely closed because of unacceptable toxicity [28]. However, these results should not exclude further evaluation of EGFR inhibitors, either in combination within other CMT regimens or for consolidation treatment after CMT. The french group FFCD (Fédération Francophone de Cancérologie Digestive) will soon launch a phase I–II trial (FFCD 0904) testing the combination of panitumumab with 5-FU and CDDP administered concomitantly with radiotherapy in the treatment of localized anal canal carcinomas (http://www.ffcd.fr). At the present time, there is no place for targeted therapies in the treatment of localized anal canal carcinomas.

W. Cacheux et al. / Digestive and Liver Disease 44 (2012) 803–811

2. Chemotherapy for advanced, metastatic at presentation or recurrent, forms 2.1. Introduction and general principles of management The initial mode of presentation of squamous cell carcinoma of the anal canal and the characteristics of its natural history explain why the majority of studies have been devoted to the treatment of localized forms. Data concerning the treatment of metastatic forms are much more limited and no phase III trial is available in this setting. The prognosis is very poor with an estimated 5-year overall survival rate of 18% based on data from the SEER cohort [29]. The choice of treatment strategy must take several parameters into account: performance status, comorbidities, symptomatic or asymptomatic nature (particularly in cases with pelvic involvement), as well as, for patients with recurrent disease: previous treatment modalities, initial response to treatment and interval between completion of treatment and relapse. Chemotherapy is the central element of treatment in all patients with a compatible performance status. Radiotherapy is generally not possible and is not indicated in patients with previous pelvic irradiation; it can be delivered concomitantly to chemotherapy in patients with metastatic disease at presentation when the primary tumour is symptomatic. Colostomy may also be indicated in this setting. 2.2. Which cytotoxic chemotherapy regimen should be used? Demonstration of the efficacy of 5-FU + MMC and 5-FU + CDDP combinations delivered concomitantly with RT for the treatment of localized anal canal carcinoma constitutes the rationale for administering these regimens in the advanced setting, by preferring the combination not initially administered. The 5-FU + CDDP combination therefore constitutes the chemotherapy recommended by guidelines in the metastatic setting (see below), particularly in patients previously treated with 5-FU + MMC. Administration of another course of the chemotherapy initially delivered, concomitantly with RT, may also be indicated in patients achieving a prolonged complete tumour response. In the retrospective series of 19 patients with metastatic disease reported by Faivre et al., the 5-FU + CDDP combination achieved a complete response in 1 patient and a partial response in another 11 patients, i.e. an objective response rate of 66% [30]. The median survival was 34.5 months and the 1- and 5-year actuarial survival rates were 62.2% and 32.3%, respectively. Two patients were in persistent complete response 4 and 5 years after stopping treatment. Metastases were exclusively nodal (pelvic and retroperitoneal) in both cases and chemotherapy was followed by surgical resection of residual tumour in one case and by boost RT in the other case. Other chemotherapy regimens have been evaluated in the context of very small patient series. The results of the high-dose vincristine, bleomycin and methotrexate combination were disappointing, as a partial response was obtained in only 3 out of 15 patients included in the series by Wilking et al. [31]. The mitomycin C, adriamycin and cisplatin combination achieved partial tumour response in 12 (60%) of the 20 patients included in the phase II study reported by Jhawer et al. [32]. Second-line chemotherapy with bleomycin and lomustine was administered to 2 non-responding patients. The median overall survival was 15 months and the median time to progression or death was 8 months. Haematological toxicity was significant. The paclitaxel, carboplatin and 5-FU combination was administered to 60 patients with metastatic squamous cell carcinoma (excluding carcinoma of the lung; only 4 cases of squamous cell carcinoma of the anal canal) as first-line (n = 12) or second-line (n = 48) treatment [33]. A tumour response was demonstrated in 65% of patients (all tumour types combined). A complete response was obtained in 15 patients (25% of the sample size),

809

including 2 patients with squamous cell carcinoma of the anal canal (the other two patients obtained a partial response). The results of the study by Pathak et al. presented at the ASCO GI congress in 2008, are only available in abstract form [34]. This study was based on retrospective evaluation of the results obtained in 40 patients with metastatic squamous cell carcinoma of the anal canal (metastases at presentation: n = 11; metachronous metastases: n = 29) treated heterogeneously in a single centre. The majority of patients (n = 23) received first-line platinum-based systemic chemotherapy: cisplatin (n = 13), carboplatin (n = 6) or oxaliplatin (n = 4). Time to progression after first-line chemotherapy was 19 weeks. Twenty patients (50% of the sample size) received more than 3 lines of chemotherapy. The median overall survival was 38 months. Chemotherapy was followed by CMT in 3 patients, one of whom achieved prolonged complete remission. Five patients responding to chemotherapy underwent secondary surgery for metastases and two of them are in prolonged complete remission. Overall, cytotoxic chemotherapy constitutes the central element of management of patients with advanced carcinoma of the anal canal. The 5-FU + CDDP combination is the generally preferred first-line option, particularly in patients relapsing after initial treatment comprising RT/5-FU + MMC. Other chemotherapy regimens have been evaluated in small series. Paclitaxel-based combinations could be useful. Successive administration of several lines of chemotherapy should be considered in patients with a good performance status. Similarly, the indications for radiotherapy targeting residual lesions, or even surgery should be systematically considered in patients with a favourable response to chemotherapy.

2.3. Is there a place for targeted therapies in the treatment of advanced diseases? Encouraging results have been obtained with cetuximab administered alone or in combination with irinotecan in several patients with metastatic squamous cell carcinoma of the anal canal, particularly in the absence of somatic KRAS mutation [35–37]. These results justify further evaluation of agents targeting the EGF receptor (EGF-R) in this indication. No data are currently available concerning anti-angiogenic agents, tyrosine kinase inhibitors or molecules targeting other intracellular signalling pathways (PI3K or mTOR inhibitors) in the treatment of advanced squamous cell carcinoma of the anal canal. Trials with these agents are currently underway, including cases of squamous cell carcinoma of the anal canal, but also other sites, particularly cervix, upper aerodigestive tract and oesophagus. In conclusion, the use of various targeted therapies is not currently recommended for the treatment of advanced carcinomas of the anal canal.

3. Guidelines 3.1. French guidelines French guidelines for the management of carcinoma of the anal canal are described in the Thésaurus National de Cancérologie Digestive (TNCD), the latest version of which was published in June 2010. It is available on-line from the TNCD web site (http://tncd.org) and from the Fédération Francophone de Cancérologie Digestive (http://www.ffcd.fr) and the Société Nationale Franc¸aise de GastroEntérologie (http://www.snfge.org) web sites. Modalities of management are based on the stage of disease at diagnosis, determined by a meticulous staging assessment. These guidelines do not provide any precise information concerning the modalities of radiotherapy.

810

W. Cacheux et al. / Digestive and Liver Disease 44 (2012) 803–811

3.1.1. Stage T1N0 tumours Standard therapy is RT alone for these small tumours with no lymph node metastasis. 3.1.2. Stage T2/3 N0/3 tumours The majority of tumours are classified T2 or T3 N0/3 at the time of diagnosis and should be treated by first-line concomitant CMT alone. The standard chemotherapy regimen is 5-FU + MMC. The modalities of RT (total dose delivered, irradiation fields, etc.) are determined by tumour stage. Surgery (abdominoperineal resection) is reserved for nonresponding patients. It is also indicated after a sequence of concomitant CMT when a functional sphincter cannot be preserved. Exclusive RT is another possible treatment option for T2N0 lowstage tumours (i.e. small, <3 cm, with no lymph node metastasis). 3.1.3. Stage T4 tumours The standard treatment for these tumours consists of neoadjuvant CMT followed, 6 weeks later, by abdominoperineal resection. Surgery can be avoided only in the rare patients who achieve an excellent response to treatment and who preserve a functional sphincter. 3.1.4. Metastatic disease at presentation The standard treatment in these settings is exclusive chemotherapy. Colostomy is sometimes indicated in the case of sphincter destruction with severe incontinence. 3.2. European guidelines (ESMO = European Society of Medical Oncology: http://www.esmo.org) [38] and US guidelines (NCCN = National Comprehensive Cancer Network; http://www.nccn.org) [39] The main difference with respect to French guidelines concerns the smallest tumours, classified T1N0, in which standard treatment is exclusive concomitant CMT, as for tumours diagnosed at a more advanced stage, although with different modalities of radiotherapy. As in the French guidelines, 5-FU + MMC is the standard chemotherapy in this setting, in combination with RT. Exclusive 5-FU + CDDP chemotherapy is the standard treatment for metastatic disease. It should be noted that although surgery alone is the first-line treatment recommended for well-differentiated T1N0 tumours of the anal margin, it does not constitute a treatment option in any of the clinical practice guidelines for the treatment of small squamous cell carcinoma of the anal canal. Conflict of interest statement No conflict of interest to declare. References [1] UKCCCR Anal Cancer Trial working party. Epidermoid anal cancer: results from the UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5fluorouracil, and mitomycin C. Lancet 1996;348:1049–54. [2] Northover J, Glynne-Jones R, Sebag-Montefiore D, et al. Chemotherapy for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomized UKCCCR anal cancer trial. British Journal of Cancer 2010;102:1123–8. [3] Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal cooperative groups. Journal of Clinical Oncology 1997;15:2040–9. [4] Flam M, John M, Pajak T, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive non surgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. Journal of Clinical Oncology 1996;14:2527–39.

[5] John M, Flam M, Berkey B, et al. 5-Year results and analyses of a phase III randomized RTOG/ECOG chemoradiation protocol for anal cancer. In: Proc. ASCO. 1998. p. 989 [abstract]. [6] Cummings BJ, Keane TJ, O’Sullivan B, et al. Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-FU with and without mitomycin C. International Journal of Radiation Oncology, Biology, Physics 1991;21: 1115–25. [7] Rich TA, Ajani JA, Morrison WH, et al. Chemoradiation therapy for anal cancer: radiation plus continuous infusion of fluorouracil with or without cisplatin. Radiotherapy and Oncology 1993;27:209–15. [8] Gerard JP, Ayzac L, Hun D, et al. Treatment of anal carcinoma with highdose radiation and concomitant fluorouracil–cisplatin: long-term results in 95 patients. Radiotherapy and Oncology 1998;46:249–56. [9] Martenson JA, Lipsitz SR, Wagner Jr H, et al. Initial results of a phase II trial of high-dose radiation therapy, fluorouracil and cisplatin for patients with anal cancer (E4292): an Eastern Cooperative Group Study. International Journal of Radiation Oncology, Biology, Physics 1996;35:745–9. [10] Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs. fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal. A randomized controlled trial. Journal of the American Medical Association 2008;299:1914–21. [11] Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of U.S GI intergroup RTOG 98-11 phase III trial for anal carcinoma: disease-free and overall survival with RT + 5 FU-mitomycin versus RT + 5 FU-cisplatin. Journal of Clinical Oncology 2011;29(Suppl):4005 [abstract]. [12] James R, Wan S, Glynne-Jones R, et al. A randomized trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5 FU in squamous cell carcinoma of the anus (ACTII). Journal of Clinical Oncology 2009;27(Suppl.):4009 [abstract]. [13] Bosset JF, Roelofsen F, Morgan DAL, et al. Shortened irradiation scheme, continuous infusion of 5-fluorouracil and fractionation of mitomycin C in locally advanced anal carcinomas. Results of a phase II study of the European Organization for Research and Treatment of Cancer. Radiotherapy and Gastrointestinal Cooperative Groups. European Journal of Cancer 2003;39:45–51. [14] Matzinger O, Roelofsen F, Mineur L, et al. Mitomycin C with continuous fluorouracil or with cisplatin in combination with radiotherapy for locally advanced anal cancer (European Organisation for Research and Treatment of Cancer phase II study 22011-40014). European Journal of Cancer 2009;45: 2782–91. [15] James RD, David C, Neville D, et al. Chemoradiation and maintenance chemotherapy for patients with anal carcinoma: a phase II trial of the UKcoordinating committee for cancer research (UKCCCR) anal cancer trial working party. Journal of Clinical Oncology 2000;19:1045 [abstract]. [16] Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. New England Journal of Medicine 2008;358:36–46. [17] Reddy GK. Efficacy of adjuvant capecitabine compared with bolus 5fluorouracil/leucovorin regimen in Dukes C colon cancer: results from the X-ACT trial. Clinical Colorectal Cancer 2004;4:87–8. [18] Twelves C, Boyer M, Findlay M, et al. Capecitabine (Xeloda) improves medical resource use compared with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients with advanced colorectal carcinoma. European Journal of Cancer 2001;37:597–604. [19] Glynne-Jones R, Meadows H, Wan S, et al. EXTRA—a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. International Journal of Radiation Oncology, Biology, Physics 2008;72:119–26. [20] Eng C, Chang GJ, Das P, et al. Phase II study of capecitabine and oxaliplatin with concurrent radiation therapy (XELOX-RT) for squamous cell carcinoma of the anal canal. Journal of Clinical Oncology 2009;27(Suppl.):4116 [abstract]. [21] Conroy T, Ducreux M, Lemanski C, et al. Treatment intensification by induction chemotherapy (ICT) and radiation dose escalation in locally advanced squamous cell anal canal carcinoma (LAAC): definitive analysis of the ACCORD 03 trial. Journal of Clinical Oncology 2009;27(Suppl.):4033 [abstract]. [22] Ben-Josef E, Moughan J, Ajani JA, et al. Impact of overall treatment time on survival and local control in patients with anal cancer: a pooled data analysis of radiation therapy oncology group trials 87-04 and 98-11. Journal of Clinical Oncology 2010;28:5061–6. [23] Nguyen LN, Ang KK. Radiotherapy for cancer of the head and neck: altered fractionation regimens. Lancet Oncology 2002;2:693–701. [24] Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: A meta-analysis. Lancet 2006;368:843–54. [25] Girinsky T, Rey A, Roche B, et al. Overall treatment time in advanced cervical carcinomas: a critical parameter in treatment outcome. International Journal of Radiation Oncology, Biology, Physics 1993;27:1051–6. [26] Lanciano RM, Pajak TF, Martz K, et al. The influence of treatment time on outcome for squamous cell cancer of the uterine cervix treated with radiation: a patterns-of-care study. International Journal of Radiation Oncology, Biology, Physics 1993;25:391–7. [27] Deutsch E, Lemanski C, Paris E, et al. Cetuximab plus radiochemotherapy in locally advanced anal cancer: interim results of the French multicenter phase II trial ACCORD 16. Journal of Clinical Oncology 2011;29(Suppl.):4098 [abstract]. [28] Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin and concomitant boost radiotherapy for locally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined modality paradigm. Journal of Clinical Oncology 2006;24:1072–8.

W. Cacheux et al. / Digestive and Liver Disease 44 (2012) 803–811 [29] Johnson LG, Madeleine MM, Newcomer LM, et al. Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973–2000. Cancer 2004;101:281–8. [30] Faivre C, Rougier P, Ducreux M, et al. 5-Fluorouracile and cisplatinum combination chemotherapy for metastatic squamous-cell anal cancer. Bull Cancer 1999;86:861–5. [31] Wilking N, Petrelli N, Herrera L, et al. Phase II study of combination bleomycin, vincristine and high-dose methotrexate (BOM) with leucovorin rescue in advanced squamous cell carcinoma of the anal canal. Cancer Chemotherapy and Pharmacology 1985;15:300–2. [32] Jhawer M, Mani S, Lefkopoulou M, et al. Phase II study of mitomycin-C, adriamycin, cisplatin (MAP) and bleomycin-CCNU in patients with advanced cancer of the anal canal: an eastern cooperative oncology group study E7282. Investigational New Drugs 2006;24:447–54. [33] Hainsworth JD, Burris 3rd HA, Meluch AA, et al. Paclitaxel, carboplatin, and long-term continuous infusion of 5-fluorouracil in the treatment of advanced squamous and other selected carcinomas: results of a Phase II trial. Cancer 2001;92:642–9.

811

[34] Pathak P, King BT, Ohinata A, et al. The treatment of metastatic squamous cell carcinoma of the anal canal: a single institution experience. In: ASCO GI cancer symposium. 2008. p. 352 [abstract]. [35] Saif MW, Kontny E, Syrigos KN, et al. The role of EGFR inhibitors in the treatment of metastatic anal canal carcinoma: a case series. Journal of Oncology 2011 [Article ID 125467, 5 p.]. [36] Lukan N, Ströbel P, Willer A, et al. Cetuximab-based treatment of metastatic anal cancer: correlation of response with KRAS mutational status. Oncology 2009;77:293–9. [37] Phan LK, Hoff PM. Evidence of clinical activity for cetuximab combined with irinotecan in a patient with refractory anal canal squamous-cell carcinoma: report of a case. Diseases of the Colon and Rectum 2007;50:395–8. [38] Glynne-Jones R, Northover JM, Cervantes A, ESMO Guidelines Working Group. Anal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2010;21(Suppl. 5):v87–92. [39] Engstrom PF, Arnoletti JP, Benson 3rd AB, et al. NCCN clinical practice guidelines in oncology. Anal carcinoma. Journal of the National Comprehensive Cancer Network 2010;8:106–20.