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ORIGINAL ARTICLE
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Intensity modulated radiotherapy in anal canal squamous cell carcinoma: Implementation and outcomes


 Department of Radiation Oncology, Tata Medical Center, Kolkata, West Bengal, India

Correspondence Address:
Indranil Mallick,
Department of Radiation Oncology, Tata Medical Center, 14 MAR (EW), Newtown, Kolkata - 700 156, West Bengal
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_212_19

 > Abstract 


Objective: Concurrent chemoradiotherapy (CCRT) is the standard curative treatment option for nonmetastatic anal squamous cell carcinoma (SCC). Intensity modulated radiotherapy (IMRT) can reduce doses delivered to bowel and skin and reduce toxicities associated with conventional fields. Here, we present our institutional data on dosimetry, toxicity, and clinical outcomes with IMRT for anal cancer.
Materials and Methods: We analyzed 23 patients of anal SCC treated with curative-intent CCRT/radiation therapy alone, utilizing IMRT, between August 2011 and December 2016. The standard prescription dose was 54 Gy/27Fr/5.5 weeks, delivered in two phases, and concurrent chemotherapy with 5-fluorouracil and mitomycin-C. Acute and late toxicities and dosimetric data were compiled and analyzed.
Results: The median age was 65 years. Fourteen (60.7%) patients had Stage IIIC disease. Eighteen patients received concurrent chemotherapy. No patient had any treatment breaks. Grade 3 acute perianal dermatitis was recorded in 11 (47.8%) patients. Proctitis, diarrhea, and cystitis were limited to Grade 1 in 73.9%, 47.8%, and 8.6% patients, respectively. The only late Grade 2+ toxicities were gastrointestinal toxicities in 4 (17.4%) patients. Twenty (87%) patients had complete response at 6 months. The 3-year local control, nodal control, and distant metastases-free survival were 85.9%, 86.6%, 84.7%, respectively, with 3-year disease-free survival and overall survival of 63.4% and 81%, respectively.
Conclusion: In this report on IMRT in anal cancer from India, treatment was well tolerated with lower acute toxicity than reported in other prospective studies. Long-term results are at par with other published studies.

Keywords: Anal canal carcinoma, IMRT, clinical outcomes



How to cite this URL:
Das A, Arunsingh M, Bhattacharyya T, Prasath S S, Balakrishnan A, Mallick I. Intensity modulated radiotherapy in anal canal squamous cell carcinoma: Implementation and outcomes. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 4]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=298862




 > Introduction Top


Historically, abdominoperineal resection (APR) was the proposed line of treatment for anal squamous cell carcinoma (SCC), resulting in permanent colostomy.[1] Excellent pathological response rates after preoperative chemoradiotherapy (CCRT)[2] paved the way for further trials, eliminating the need for surgery or opting as a salvage measure. Addition of chemotherapy to radiation, resulted in commendable local control rates, but at the cost of significant acute toxicity rates[3],[4] and treatment breaks, which correlated to poorer locoregional control.[5] Concurrent chemoradiotherapy with mitomycin-C and 5-fluorouracil (5FU) has become the internationally accepted standard of care for the management of anal SCC, based on the results of various Phase III randomized trials,[6],[7],[8],[9] with superior locoregional control at longer follow-up.[10],[11] However, all these landmark trials used conventional radiotherapy portals to cover gross disease and elective nodal areas, resulting in high rates of acute gastrointestinal (GI), hematological, dermatological, and genitourinary (GU) toxicities.

Intensity-modulated radiation therapy (IMRT) has been a major advance in the field of oncology in the late 90s, which has been helping to conform radiation delivery to the desired target while reducing doses to the surrounding critical structures. Dosimetric studies incorporating IMRT in treating anal SCCs had achieved reduction in organs at risk (OAR) doses while maintaining adequate tumor coverage.[12],[13] Various retrospective series have presented the use of CCRT using IMRT, which reported reduced acute toxicity rates compared to historical standards while maintaining encouraging disease outcomes.[14],[15],[16] The prospective Phase II Radiation Therapy Oncology Group (RTOG) 05–29 trial demonstrated IMRT as an acceptable standard for treating anal SCC,[17] but have not reported clinically meaningful reduction in acute toxicity.

Learning from the radiotherapy doses and results of the conventional standard treatment and IMRT results, we developed our own clinical treatment protocol in 2011, aiming to reduce the overall treatment time (OTT) without increasing the acute toxicity. Here, we present our institutional data on dosimetry, toxicity, and clinical outcomes.


 > Materials and Methods Top


Records of patients diagnosed with anal SCC, between August 2011 and December 2016, were retrieved from our prospectively maintained institutional electronic database. Patients treated with curative-intent CCRT/radiation therapy alone, utilizing IMRT, were included in this analysis.

Tumor diagnosis and local extent were ascertained with colonoscopy and biopsy. All patients were staged using contrast-enhanced magnetic resonance imaging (CEMRI) pelvis and contrast-enhanced computed tomography (CT) of the abdomen and thorax.

Patients were simulated on a General Electric (GE) Lightspeed 16-Slice unit, with intravenous contrast, following a standard bladder filling protocol of 500 mL of water and ½ h waiting period. All patients were scanned in the supine position. No immobilization devices were used. The leg position and the distance between the patellae were recorded and reproduced.

Treatment was planned into two phases, to a total dose of 54 Gy/27 Fr/5.5 weeks, without any planned treatment breaks. In the first phase, a dose of 36 Gy/18 Fr/3.5 weeks was delivered to a clinical target volume (CTV36), comprising the entire anal canal, adjacent rectum and mesorectum, plus all draining nodal areas (mesorectal, iliac, presacral nodes from L5-S1 junction, and inguinal nodes till 2 cm caudal to saphenofemoral junction). Gross disease was enlarged by a minimum margin of 1.5 cm. The gross primary and nodal disease were boosted in the second phase (CTV-P54 and CTV-N54) to 18 Gy/9 Fr in patients receiving concurrent chemotherapy, or to 24 Gy/12 Fr in those treated with radiotherapy alone. CTV-P54 (boost CTV) included gross pretreatment primary tumor with 1.5 cm margin and CTV-N54 comprised the gross pretreatment involved nodes with 1 cm margin.

The goal was to limit the elective dose and deliver treatment in 2 Gy/Fr without planned treatment breaks, limiting the OTT. Planning target volume (PTV) margins of 7 mm were used in all axes for primary and boost CTVs. All patients were treated with helical tomotherapy incorporating daily volumetric image guidance with megavoltage fan-beam CT.

Concurrent chemotherapy was prescribed with injection mitomycin 10 mg/m2 on day 1 and 29, and concurrent 5FU 1000 mg/m2 on days 1–4 and days 29–32. Complete and differential blood counts, renal function test, and liver function tests were done before commencing chemotherapy on days 1 and 28. Acute and late toxicities were assessed using RTOG acute and late radiation morbidity scoring criteria. For each symptom, the maximal recorded grade was defined as the grade of late toxicity. Dosimetric data were compiled and analyzed.

OAR dose constraints were based on departmental protocol. The relative volume of bladder receiving an absolute dose of 54 Gy and 36 Gy was kept <10% and 50%, respectively. Absolute volume of bowel bag receiving 45 Gy was kept below 196cc, and the relative volume of femoral heads receiving 45 Gy was kept below 5%. No perineal skin dose constraints were given.

Postradiotherapy, patients were followed up clinically at 6 weeks and 3 months, with digital rectal examination and palpation of inguinal nodes. CEMRI pelvis was done at 3 months. Patients having less than the complete response on imaging/clinical examination underwent repeat imaging at 6-month posttreatment. Persistent or residual tumor at 6-month postchemoradiation was subjected to biopsy and were referred for salvage surgery after pathological confirmation of disease. Patients in complete remission at 3 months were being followed up at 3–6 months interval till first 2 years, then at 6–12 months interval up to 5 years.

Overall survival was defined from the date of registration to date of death from any cause. Local control, nodal, and distant metastases-free survival were calculated from the date of registration to local recurrence, or appearance of new nodal or distant metastases, respectively. Survival was computed using the Kaplan–Meier statistics using the SPSS version 23 statistical software (©IBM Corporation, Armonk, New York, United States).


 > Results Top


A total of 25 patients were identified with anal SCC, who was treated with curative-intent radiotherapy/chemoradiation. Two patients defaulted to follow-up after their last treatment day (without any documented severe toxicity or disease-related concerns), and hence, we have included 23 patients in our final analysis. Patient characteristics and treatment details are mentioned in [Table 1]. The median age was 65 years. Three patients had Stage I (T1N0) disease and were treated with radiotherapy alone to doses of 54 Gy/27 Fr. Concurrent chemotherapy was omitted in two elderly patients due to borderline performance status, who was treated with radiotherapy alone to doses of 60 Gy/30 Fr. Eighteen (78.2%) patients were treated with CCRT to standard doses of 54 Gy/27 Fr. The median OTT was 37 days.
Table 1: Patient, disease and treatment characteristics

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The average bowel bag V15 and V45 was 872.83 cc and 28.01 cc, respectively. The average bladder V35 and V50 was 47.09% and 8.07%, respectively. No patient had any treatment breaks.

Toxicity profile is shown in [Table 2] and [Table 3]. Grade 3 acute perianal dermatitis was recorded in 12 (52.2%) patients. Proctitis and diarrhea were limited to Grade 2 in 3 (13%) patients, Grade 1 in 17 (73.9%) and 11 (47.8%) patients, respectively. None reported any acute Grade 3+ GI or GU toxicities. Only one patient had Grade 3 anemia, who received blood component transfusion in due course. There was no Grade 3+ neutropenia or thrombocytopenia recorded. Two patients did not receive the second cycle of mitomycin-C and 5FU due to Grade 2 thrombocytopenia and Grade 3 anemia. Late Grade 2 GI toxicities were found in 4 (17.4%) patients. None reported any Grade 3+ late GI and Grade 2+ late GU toxicities.
Table 2: Acute toxicity profile

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Table 3: Late toxicity profile

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Twenty (87%) patients had complete response at 6 months. After a median follow-up of 25 months, 3 (13%) patients had local failure, confirmed histopathologically. They were planned for salvage surgery in the form of APR. Only one patient was surgically salvaged, but developed distant metastases after 3 months and started on palliative chemotherapy. The remaining two patients did not return for salvage surgery. Two (8.7%) patients had nodal relapse with one patient having in-field nodal recurrence within 1 year, at the level of L5; the nodal mass being treated with chemoradiotherapy to doses of 54 Gy/27 Fr. The other patient had inguinal nodal metastases and was salvaged with bilateral inguinal nodal dissection. Three (13%) patients had distant metastases. One patient had out-of-field para-aortic nodal metastases and was managed with radical radiotherapy to 54 Gy/27 Fr. Summary of failures is shown in [Table 4].
Table 4: Outcome details

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The 3-year local control, nodal control, and distant metastases-free survival were 85.9%, 86.6%, and 84.7%, respectively, with 3-year disease-free survival and overall survival of 63.4% and 81%, respectively. The Kaplan–Meier curves have been depicted in [Figure 1], [Figure 2], [Figure 3], [Figure 4].
Figure 1: Kaplan–Meier curve illustrating nodal control rates

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Figure 2: Kaplan–Meier curve illustrating distant metastases-free survival

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Figure 3: Kaplan–Meier curve illustrating disease-free survival rate

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Figure 4: Kaplan–Meier curve illustrating local control rates

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 > Discussion Top


This audit reports the results of a standardized clinical protocol for IMRT for anal cancer in our institution. The protocol was developed after reviewing the literature available in 2011 on prescription doses and elective doses and volumes available from large cooperative trials. The goal of the protocol was to deliver the entire course of radiotherapy without a treatment break and deliver doses at 2 Gy/fraction to reduce the OTT.

Appropriate management of anal SCCs had been long validated by the results from the landmark trials, which have established CCRT with mitomycin-5FU as the primary treatment option. Moreover, even before treatment, proper staging of the local disease warrants adequate imaging measures, preferably in the form of magnetic resonance imaging (MRI) pelvis.[18] We have staged as well as assessed radiological response with MRI, which was not uniformly mandated in the randomized trials or several retrospective series.

The Phase II multi-institutional prospective trial, RTOG 0529 investigated IMRT in anal SCCs. Although it could not meet the primary objective of a 15% reduction in the rate of Grade 2+ acute GI/GU toxicities from the historical standard of RTOG 9811 trial,[11] the study showed significant reduction in Grade 3 acute GI (21 vs. 36%), cutaneous (23 vs. 49%) toxicities.[17]

A prospective study from India, compared three-dimensional conformal radiotherapy (3D-CRT) and bone marrow-sparing IMRT in 20 patients of anal canal SCC, prescribing 45 Gy/25 fractions with weekly cisplatin and 5FU, and reported decreased rates of acute GI and hematological toxicities in the IMRT arm.[19]

Our rates of acute GI, GU, or hematological toxicities are rather fewer compared to most published series on IMRT in anal SCC,[14],[17],[20],[21] with no Grade 3 or more GI/GU toxicities. Although the perianal Grade 3 dermatological toxicities were common in our series (47.8%) compared to the RTOG study, they were localized to the perianal region, with a relatively low incidence of severe dermatitis in the groin and perineum. None needed any treatment interruptions, and all recovered within 6–8 weeks with conservative management.

The RTOG 0529 study investigated dose-painted IMRT (DP-IMRT), prescribing 42–45 Gy in 28–30 fractions to the elective nodal volumes and 50.4–54 Gy in 28–30 fractions to the anal tumor. This schedule was followed in several institutions, which treated the patients with volumetric arc therapy/helical tomotherapy, incorporating simultaneous integrated boost.[14],[16],[20],[21] The United Kingdom Coordinating Committee on Cancer Research Act I and EORTC 22861 trials used elective nodal irradiation (ENI) of 45 Gy/25 fractions/5 weeks, followed by a 6-week gap, before the sequential boost phase.[7],[8] The Phase II EORTC 22953 study used ENI doses of 36 Gy in 20 fractions, followed by boost of 23.4 Gy/13 fractions to gross disease after a 2 weeks gap and showed better local control and survival outcomes compared to EORTC 22861 study.[22] Limited ENI doses provided high rates of microscopic nodal control. Lépinoy et al. demonstrated the efficacy of 36 Gy ENI in a retrospective series of 142 patients treated with 3D-CRT, reporting similar local control rates as historical standards, and inguinal groin control rate of 98.5%.[23] Sequential boost using IMRT has been recently reported in a multi-centric retrospective series, treating the elective nodal volumes to 36 Gy/20 fractions, followed by 23.4 Gy/13 fractions to the gross disease with margins.[16]

We have treated the patients abiding our departmental protocol of sequential boost, prescribing ENI with 36 Gy/18 fractions, immediately followed by a boost of 18 Gy/9 fractions, with a median OTT of 37 days, which is much lesser than the published RCTs and the retrospective series utilizing sequential boost. Prolongation of OTT had been found to be adversely affecting disease-free survival.[24] The significantly lower rates of GI toxicity in our patients can be attributed to the limited ENI doses. Daily image guidance with online image verifications in all our patients allowed stringent PTV expansions, which further helped in reducing acute/late toxicities.

Our local and nodal control rates at 3 years are 86%, which is comparable with the major randomized studies[7],[10] and reported retrospective series utilizing DP-IMRT or sequential boost IMRT.[15],[16],[21]

A comparative description of the RTOG 0529 study and several studies employing IMRT in anal SCC is presented in [Table 5].
Table 5: Experience with IMRT in anal cancer

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Our study is a retrospective review, with limitations of inherent bias associated with any retrospective study. Moreover, the overall incidence of anal cancers is less all across the world, which is reflected as well in the small cohort of patients in our study.

Precision of local staging and posttreatment response assessment is of utmost importance to deliver accurate treatment and intelligently select patients for salvage on recurrence. MRI pelvis is the best imaging modality in this aspect but has not been mandated in most of the mentioned studies. We have routinely incorporated MRI in staging and response assessment of our patients and offered standardized treatment in our patients. Limited ENI doses resulted in lower hematological and GI toxicities while maintaining excellent nodal control rates. This is one of the first series reporting implementation and disease outcomes with IMRT in anal canal SCC in the Asian population, with standard doses of chemoradiotherapy, and the toxicities are much lower than other prospective studies, with similar encouraging outcomes.


 > Conclusion Top


CCRT with this protocol implementing limited doses of ENI and sequential boost IMRT is very well tolerated in anal SCC. Acute toxicity is much lower than reported in other prospective studies, and all patients completed treatment without planned breaks. Long-term results are at par with other studies. This protocol for IMRT can be implemented in experienced centers in routine clinical practice.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Greenall MJ, Quan SH, Urmacher C, DeCosse JJ. Treatment of epidermoid carcinoma of the anal canal. Surg Gynecol Obstet 1985;161:509-17.  Back to cited text no. 1
    
2.
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Cummings B, Keane T, Thomas G, Harwood A, Rider W. Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy. Cancer 1984;54:2062-8.  Back to cited text no. 3
    
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Constantinou EC, Daly W, Fung CY, Willett CG, Kaufman DS, DeLaney TF. Time-dose considerations in the treatment of anal cancer. Int J Radiat Oncol Biol Phys 1997;39:651-7.  Back to cited text no. 4
    
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Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: Results of a phase III randomized intergroup study. J Clin Oncol 1996;14:2527-39.  Back to cited text no. 6
    
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Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, 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. J Clin Oncol 1997;15:2040-9.  Back to cited text no. 7
    
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Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr., et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: A randomized controlled trial. JAMA 2008;299:1914-21.  Back to cited text no. 9
    
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Northover J, Glynne-Jones R, Sebag-Montefiore D, James R, Meadows H, Wan S, et al. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR anal cancer trial (ACT I). Br J Cancer 2010;102:1123-8.  Back to cited text no. 10
    
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Gunderson LL, Winter KA, Ajani JA, Pedersen JE, Moughan J, Benson AB 3rd, et al. Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: Survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol 2012;30:4344-51.  Back to cited text no. 11
    
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Chen YJ, Liu A, Tsai PT, Vora NL, Pezner RD, Schultheiss TE, et al. Organ sparing by conformal avoidance intensity-modulated radiation therapy for anal cancer: Dosimetric evaluation of coverage of pelvis and inguinal/femoral nodes. Int J Radiat Oncol Biol Phys 2005;63:274-81.  Back to cited text no. 12
    
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Menkarios C, Azria D, Laliberté B, Moscardo CL, Gourgou S, Lemanski C, et al. Optimal organ-sparing intensity-modulated radiation therapy (IMRT) regimen for the treatment of locally advanced anal canal carcinoma: A comparison of conventional and IMRT plans. Radiat Oncol 2007;2:41.  Back to cited text no. 13
    
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Salama JK, Mell LK, Schomas DA, Miller RC, Devisetty K, Jani AB, et al. Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal cancer patients: A multicenter experience. J Clin Oncol 2007;25:4581-6.  Back to cited text no. 14
    
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Arcadipane F, Franco P, Ceccarelli M, Furfaro G, Rondi N, Trino E, et al. Image-guided IMRT with simultaneous integrated boost as per RTOG 0529 for the treatment of anal cancer. Asia Pac J Clin Oncol 2018;14:217-23.  Back to cited text no. 15
    
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De Bari B, Lestrade L, Franzetti-Pellanda A, Jumeau R, Biggiogero M, Kountouri M, et al. Modern intensity modulated radiotherapy with image guidance allows low toxicity rates and good local control in chemoradiotherapy for anal cancer patients. J Cancer Res Clin Oncol 2018;144:781-9.  Back to cited text no. 16
    
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Franco P, Arcadipane F, Ragona R, Mistrangelo M, Cassoni P, Munoz F, et al. Volumetric modulated arc therapy (VMAT) in the combined modality treatment of anal cancer patients. Br J Radiol 2016;89. Doi: 10.1259/bjr.20150832.  Back to cited text no. 20
    
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Mitra D, Hong TS, Horick N, Rose B, Drapek LN, Blaszkowsky LS, et al. Long-term outcomes and toxicities of a large cohort of anal cancer patients treated with dose-painted IMRT per RTOG 0529. Adv Radiat Oncol 2017;2:110-7.  Back to cited text no. 21
    
22.
Bosset JF, Roelofsen F, Morgan DA, Budach V, Coucke P, Jager JJ, 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. Eur J Cancer 2003;39:45-51.  Back to cited text no. 22
    
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Lépinoy A, Lescut N, Puyraveau M, Caubet M, Boustani J, Lakkis Z, et al. Evaluation of a 36 gy elective node irradiation dose in anal cancer. Radiother Oncol 2015;116:197-201.  Back to cited text no. 23
    
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Glynne-Jones R, Meadows HM, Lopes A, Adams RA, Sebag-Montefiore D. Compliance to chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance 5FU/CisP chemotherapy (CT) in squamous cell carcinoma of the anus (SCCA) according to radiotherapy (RT) dose, overall treatment time (OTT) and chemotherapy (CT) and their impact on long-term outcome: Results of ACT II. J Clin Orthod 2015;33:3518.  Back to cited text no. 24
    


    Figures

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