Patient reported quality of life after helical IMRT based concurrent chemoradiation of locally advanced anal cancer

Radiotherapy and Oncology 120 (2016) 228–233

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QoL after anal cancer RT

Patient reported quality of life after helical IMRT based concurrent chemoradiation of locally advanced anal cancer Kurian Joseph a,⇑, Larissa J. Vos a, Heather Warkentin a, Kim Paulson a, Lee-anne Polkosnik a, Nawaid Usmani a, Keith Tankel a, Diane Severin a, Tirath Nijjar a, Dan Schiller b, Clarence Wong c, Sunita Ghosh a, Karen Mulder a, Colin Field a a Department of Oncology, University of Alberta & Cross Cancer Institute; b Department of Surgical Oncology, University of Alberta & Alberta Health Services; and c Department of Internal Gastroenterology, Royal Alexandra Hospital, Edmonton, Canada

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Article history: Received 8 April 2016 Received in revised form 14 June 2016 Accepted 27 June 2016 Available online 9 July 2016 Keywords: Anal cancer Helical Tomotherapy Intensity-modulated radiation therapy (IMRT) Quality of life

a b s t r a c t Background and purpose: Concurrent chemoradiation (CCRT) is the standard treatment for locally advanced anal canal carcinoma, although treatment-related side effects can affect patient quality of life (QOL). The purpose was to prospectively evaluate the effects of Tomotherapy (HT) based CCRT on patient reported QOL in locally advanced anal cancer. Patients and Methods: Fifty-four patients treated with HT and concurrent 5-fluorouracil/mitomycin-C underwent QOL evaluation at baseline, after treatment, and during follow-up with EORTC core (QLQC30) and colorectal (QLQ-CR29) questionnaires. The QOL scores at baseline and post-treatment were compared. Results: All C30 functional symptoms, except emotional and cognitive functioning, were impaired endof-treatment and recovered by 3 months follow-up. The majority of symptom scores were worse endof-treatment but recovered by 3 months except for fecal incontinence (FI), diarrhea, urinary incontinence (UI), and dyspareunia which persisted. FI returned to baseline at 12 months while diarrhea, UI, and dyspareunia persisted. Conclusions: Most impaired functions and symptoms following HT based CCRT were temporary and improved by 3 months post-therapy. Late complications affecting QOL were FI, sexual function, UI, and diarrhea. Our observations support routine use of IMRT and emphasize the significance of precise evaluation of sexual, urinary, and anorectal functions before starting CCRT and routine incorporation of QOL evaluations. Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 120 (2016) 228–233

Squamous cell carcinoma of the anal canal (ACC) is an uncommon malignancy (1–2% of all bowel cancers) [1]. Randomized phase III studies have confirmed that sphincter-sparing concurrent chemoradiation (CCRT) is the standard treatment for locally advanced SCC [2–5]. Patients undergoing CCRT with standard or 3-dimensional conformal radiotherapy (3D-CRT) may experience substantial treatment-related acute and late side effects that could adversely impact the patient’s functional outcome and quality of life (QOL) [2–4,6]. Impaired QOL affects patient work performance, social life, mood, or other daily activities and can result in a negative outlook of the future [7]. Single institutional retrospective series and prospective phase II studies have reported improvements in both disease outcome and treatment-related toxicities with intensity-modulated radiation ⇑ Corresponding author at: Department of Radiation Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada. E-mail address: [email protected] (K. Joseph). http://dx.doi.org/10.1016/j.radonc.2016.06.020 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.

therapy (IMRT) based CCRT [8–11]. IMRT provides conformal radiotherapy to the tumor with significant sparing of the organs at risk and hence reduction of acute normal tissue toxicities without compromising locoregional control. Although IMRT has become the standard radiotherapy technique with an improved toxicity profile, the knowledge about the IMRT effects on QOL in treated patients is limited. The QOL evaluation is significant since overall survivorship and duration of survival are increasing after treatment. The QOL assessment may provide improved understanding of how IMRT influences patient’s lives and functional outcome. We previously reported that incorporation of Tomotherapy (dynamic helical IMRT) in anal cancer treatment resulted in low incidence of treatment-related acute and late morbidity [10]. An additional objective of the study was prospective evaluation of the impact of IMRT on QOL during and post-treatment. We hypothesized that reduced toxicity from IMRT could translate into improved QOL.

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Patients and methods Patient selection Anal cancer patients were treated with helical Tomotherapy (Accuray, Inc, Sunnyvale, CA) and concurrent 5-flurouracil/ mitomycin-C combination (5FU/MMC) as part of an in-house prospective phase II study [10]. All patients were biopsy confirmed, non-metastatic, and newly diagnosed. All patients were staged as per AJCC/UICC (2010) staging guidelines. The study was approved by the Regional Research Ethics board and written informed consent was obtained from all patients enrolled into the study. The trial was registered with Clinical Trials.gov (identifier: NCT00754078). Radiotherapy and chemotherapy Details of radiotherapy treatment including simulation, planning, and delivery have been described elsewhere [10]. Briefly, all patients were treated with HT, delivering a dose of 54 Gy to 95% of the PTV54 volume (primary tumor PTV) and simultaneously delivering 45 Gy to 95% of the PTV45 volume (region at risk of disease spread) in 30 fractions over six weeks at 1.8 Gy per fraction (1.5 Gy per fraction to PTV45). All patients underwent daily megavoltage CT image-guided verification before each treatment. Chemotherapy with 5FU/MMC consisting of 5-fluorouracil 1000 mg/ m2/day continuous infusion over 96 h starting on days 1 and 29, and mitomycin-C 10 mg/m2 intravenous bolus on days 1 and 29. Patients were reviewed for treatment-related toxicity on the first day of radiation and then weekly during radiotherapy, followed by every 6 weeks for 3 months, and then every 3–4 months for a total period of 5 years (reported in [10]). QOL assessment The QOL of all patients in the study was prospectively evaluated by using the English version of the European Organization for Research and Treatment of Cancer (EORTC) core (QLQ-C30) and colorectal (QLQ-CR29) questionnaires (with permission) [12,13]. QLQ-C30 and QLQ-CR29 are validated self-rating questionnaires comprised of 30 and 29 questions respectively. The EORTC QLQC30 questionnaire assesses functional and symptom aspects of health related QOL, whereas QLQ-CR29 assesses site specific (anorectal) QOL. The EORTC QLQ-CR29 module specifically addressing body image, urinary symptoms, pain, anorectal, and sexual functions. A scale from 1 to 4 is used to rate each question (1:not at all, 2:a little, 3:quite a bit, 4:very much) except for the Global Health scale which is 1 to 7 (very poor to excellent). Patients completed the QOL questionnaires by themselves and returned it to the research nurse at baseline (on the day of first radiation), end of treatment, 6 weeks post treatment, then every 3–4 months for a period up to 2 years and finally every 6 months for another 3 years (total of 5 years).

report clinical significance of QOL changes in the EORTC QLQ-C30 questionnaire as small, medium or large [16]. The difference between QOL scores at baseline and the posttreatment points was evaluated by calculating mean difference and paired difference based on recommendations by Osoba et al. and Cocks et al. [15,16]. A 2-sided paired t-test was used to calculate statistical significance with a P-value less than 0.01 was deemed significant after Bonferroni correction for multiple comparisons. Generalized estimating equations (GEE) were used to evaluate the impact of age, gender, tumor stage, and toxicity on QOL. GEE method was used for repeated measures data, as it provided parameter estimates accounting for within and between subject correlations. Multivariate analysis was performed and parameter estimates and standard errors reported. The statistical analysis was carried out using SAS 9.3 software (version 9.3, SAS Institute Inc., Cary, NC). P-value less than 0.05 was regarded as significant unless otherwise specified. Results Patients Patient characteristics are summarized in Table 1. Among 58 patients enrolled, there were 54 patients evaluable for this QOL analysis. The reasons for ineligibility were that 1 patient withdrew consent and did not have CCRT and 3 patients did not complete baseline QOL assessment. The median age was 57 years (37–83) and there were 36 females and 18 males. The median QOL follow-up was 26.6 months from treatment initiation (range 0–66.43 months). The median number of QOL questionnaires completed per patient was 9 (range 1–16). The compliance of patients for completing the questionnaires was satisfactory and all patients completed questionnaires without help. The majority of questions had 100% completion or were rarely missed but many patients answered the questions regarding sexual function and dyspareunia as not applicable or leaving blank. At baseline 91.2% of enrolled patients returned EORTC QLQ-C30 and QLQ-CR29 questionnaires and were evaluable. The compliance for returning the questionnaires at different time points ranged from 74.5–91.2% with 84.4% of eligible patients completing the 12 month QOL time point. QOL evaluation Supplementary Table 1 presents mean scores and paired differences for the QLQ-C30 and CR29 subscales and Supplementary Table 2 present the mean scores and mean differences for each of the QLQ-C30 questions. EORTC QLQ-C30 Global Health status showed large deterioration at the end of treatment (mean difference -19.3), but returned to baseline level Table 1 Patient and Tumor Characteristics.

Statistical analysis The responses were scored as per recommendations by the EORTC QLQ-C30 scoring manual [14]. All QLQ-C30 and CR29 scores were linearly adjusted to range scores from 0 to 100. A high score on Global Health status/QOL and function scales indicates a higher level of functioning. However, a high score on symptom scale indicates a high degree of the symptom. Osoba et al. recommended that a change in QOL score of 5 points from baseline be considered clinically relevant, a change in score between 5 and 10 of moderate relevance, and a change in score of 10 or more is considered clinically significant [15]. Cocks et al. provided more specific criteria to

Characteristics

Number of patients (n = 54)

Median age in years (range) Gender Male Female Location Anal Perianal AJCC stage grouping II IIIA IIIB

57 (37–83) 18 36 49 5 26 9 19

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at 12 weeks and remained stable with small improvement at 6 months onwards. Similarly, large deteriorations in mean scores occurred at the end of treatment for the items in the functional scales, except for emotional and cognitive functioning (Fig. 1a). Emotional and cognitive functioning reported small deteriorations in scores only at the end of treatment and was improved to baseline level or small improvement occurred from 6 weeks posttreatment. The mean scores for all the items in the functional scales were returned to baseline level or showed small improvements in scores at 12 week post-treatment. Among the symptom scales, large deterioration of mean scores occurred for subclasses fatigue and pain whereas medium deterioration in scores has seen for nausea/vomiting, appetite loss and diarrhea, at the end of treatment (Fig. 1b). The scores were returned to initial levels at 12 weeks except for diarrhea which remained persistently impaired to the level of small deterioration up to the end of 12 months (mean difference 8.6). Based on the recommendation by Osoba et al. [15], the mean scores for Global Health status, physical and role, and social functioning were worsened to statistically and clinically significant level at the end of treatment (paired difference >10). Similarly,

A

the deterioration of mean scores was significant both clinically and statistically for items in the symptoms scale such as fatigue, nausea/vomiting, pain, dyspnea, and diarrhea at the end of treatment and scores returned to initial levels at 12 weeks except for diarrhea. Constipation and pain were improved significantly at 12 weeks, both clinically and statistically. EORTC QLQ-CR29 The CR29 gathered information on anxiety, body image, sexual function, urinary function, and anorectal function (summarized in Fig. 2 and Supplementary Table 1). Evaluation of data was done based on the recommendation by Osoba et al. [15]. Anxiety and body image scores were minimally altered during treatment and remained the same as baseline or at an improved level throughout the period of evaluation. Chemotherapy related side effects such as dry mouth and taste were impaired significantly after treatment although taste returned to baseline by 6 months post-treatment (Fig. 2b). Both female and male patients experienced a significant decrease in sexual function during or at the end of treatment (P < 0.001), with moderate improvement at 6 weeks. The mean

100

90

Mean QOL Scores

80

70

Global Health Status Physical functioning

60

Role functioning Emotional Functioning

50

Cognitive Functioning Social Functioning

40

30

B

70

60

Mean QoL Score

50 Fatigue 40

Constipation Diarrhea Dyspnea

30

Pain Appetite Loss

20

Insomnia Nausea/Vomiting

10

Financial Difficulties

0

Fig. 1. Mean scores of QLQ-C30 QOL factors. (A) The functional QOL factors, except emotional, were all significantly impaired at the end of treatment and recovered by 3 months post-treatment. (B) The majority of the symptom QOL factors were worse during and at the end of RT and recovered by 3 months post-treatment. Constipation improved during and after treatment.

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A

B

90

50 45

80

40

70

35

50

Anxiety (Health) Anxiety (Weight)

40

Body Image Male Sex Interest

30

Mean QoL Score

Mean QoL Score

60

Female Sex Interest

Hair loss

25

Abd Pain Bloating

20

Dry Mouth Taste

15

20

C

30

10

10

5

0

0

D

70

80

70

60

60

40 Urine Freq UI 30

Urine Pain Impotence

Mean QoL Score

Mean QoL Score

50 50 Rectal Pain 40

Dyspareunia

Sore Skin Bowel Freq

20

0

Flatulence Leakage

30

20

10

Blood/Mucous in Stool

Embaressment

10

0

Fig. 2. Mean scores of QLQ-CR29 QOL factors. (A) The functional QOL scores of anxiety and body image remained high through treatment and follow-up. Sexual interest decreased during treatment but recovered by 3 months post-treatment. (B) The symptom QOL factors related to chemotherapy were worst at the end of treatment or 6 weeks post treatment (hair loss) and then recovered between 3 and12 months post-treatment. (C) The genitourinary of urine frequency and pain were worse during treatment but recovered by 3 months post-treatment. Urinary incontinence and sexual function symptoms remained impaired at 6 months post-treatment. (D) The gastrointestinal and rectal symptoms from the QLQ-CR29 questionnaire were worse at the end of treatment and all had recovered to baseline levels by 12 months.

scores returned to baseline at 12 weeks. Dyspareunia was worse at 12 weeks and remained persistently elevated throughout the period of evaluation. Impotence scores were elevated after therapy but improved at 12 weeks post treatment (Fig. 2c). The majority of patients experienced an increase in urinary symptoms during or after treatment. Urinary frequency and dysuria returned to baseline at 12 weeks but urinary incontinence following treatment remained persistently elevated throughout the period of evaluation (P = 0.033 at 12 months). The disease symptoms of rectal pain, bloating, and blood or mucous in stool were improved with lower scores after completion of CCRT. Measures of anorectal function including flatulence, leakage, and bowel frequency were impaired after CCRT and returned to baseline at 12 months (Fig. 2d). Patients experienced a moderate increase (non-significant) in the level of embarrassment until 12 months post treatment. Ten patients in the study underwent abdominoperineal resection (APR) following CCRT due to local recurrence (6 patients), fecal incontinence/rectal pain (2 patients), and planned surgery (2 patients). Three patients (2 patients with planned surgery and one with local recurrence) declined follow up. Median time of QOL evaluation of the remaining 7 patients post-APR was 10 months. QOL evaluation showed significant intra-patient variability for various QLQ scores. However, QLQ scores showed overall improvement in Global Health status, rectal pain, and GI symptoms

post-APR, compared to pre-APR period. Body image, urinary incontinence, and social functioning scores were worse after APR. It was difficult to interpret the QLQ scores for cognitive, emotional, role, or physical functioning, embarrassment, or sexual function. Discussion Health related QOL has become an important outcome measure for anal cancer treatment, because of improved survival following CCRT. The sphincter-sparing CCRT approach can be influenced by function of the preserved sphincter or treatment-related factors [17]. QOL provides a better understanding of the impact of the disease and therapy on the patient. Currently there are limited published data on QOL evaluation in ACC patients treated with CCRT and the majority are retrospective and lack pre-treatment baseline data [8]. In general, most studies have reported that patients treated with CCRT have acceptable long term QOL (Supplementary Table 3) [18–23]. However, studies that used conventional radiotherapy techniques also reported increased late gastrointestinal (GI) and genitourinary (GU) toxicity as well as sexual dysfunction. We believe these specific functional limitations could have significant impact on a patient’s long term QOL. At present two studies have prospectively evaluated acute QOL changes of anal cancer patients treated with CCRT [8,17]. TournierRangeard et al. compared QOL of a sub-group of 119 patients at

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Table 2 Multivariate analysis of factors influencing QOL variance. Characteristic Gender (F vs M) Age (<58 vs >58 years old) T stage (stage 1 & 2 vs 3 & 4) Acute toxicity (6grade 2 vs Pgrade 2) Time point compared to baseline End of RT 6 weeks post 12 weeks post 6 months post 12 months post

b estimate

Standard error

2.204 0.776 2.777 0.977

3.748 3.582 3.527 3.584

19.138 7.924 1.518 6.826 9.952

4.131 4.833 4.393 4.391 3.741

2 months post-treatment with baseline as part of the ACCORD 03 trial in which radiotherapy was delivered by conventional techniques [17]. The study reported an overall improvement in QOL at two months post-treatment. Similarly, Han et al. reported that QOL scores including Global QOL were returned to baseline by 3 months after CCRT by using Linac based-IMRT [8]. Our results are in line with findings of these studies in that most of the impaired functions and symptoms caused by adverse treatment effects were temporary and improved back to baseline level by 3 month after therapy. Even though introduction of image guided radiotherapy has resulted in reduction of radiation induced side effects, we conclude that the impaired post-treatment Global QOL was uninfluenced by the treatment technique (conventional vs IMRT) and may be dominantly related to chemotherapy [8–10]. The QLQ-CR29 anorectal instrument has provided meaningful self-evaluation of body image, anxiety, bladder, bowel, and sexual functions of patients who have undergone CCRT. In general, the majority of QOL scores were returned to baseline by 12 weeks. Diarrhea, flatulence, and fecal incontinence (FI) are the commonly reported treatment-related late GI complications that may lead to significant limitations in daily life. Andreyev et al. reported that about 50% of patients have their QOL affected by GI symptoms following pelvic radiotherapy [24]. The studies from Das et al. and Bentzen et al. reported that 31% and 20% of study patients respectively continued to have difficulty with diarrhea at a median time of 60 months post-treatment [19,20]. In our study, only 16% of patients had significant diarrhea at 12 months; the lower incidence in our study compared to published data could be due to IMRT. The reported incidence of some form of fecal incontinence following CCRT varies from 22% to 44% and severe FI occurred in 6% of patients [19,20,23]. Vordermark et al. performed anorectal manometry to evaluate continence of 16 ACC patients treated with CCRT and the study reported that 56% were completely continent at a median follow-up time of 3.5 years post-treatment. However pre-treatment baseline data were not available for comparison [23]. In our data, 10% of patients had severe and 26% of patients had minimal FI before starting therapy. At the end of 12 months, 53% of patients were completely continent and there was no increase in the incidence (11%) of severe FI. However, the incidence of minimal FI increased by 10%. It is a common belief that radiotherapy is the most important risk factor for the occurrence of anorectal dysfunction posttherapy. Many studies have reported that the incidence of anorectal dysfunction is high when the anal canal region receives a dose higher than 40 Gy [25–27]. Curative anal cancer radiotherapy includes a total dose of 50.4–54 Gy with concurrent chemotherapy and the maximum dose is targeted to the anal canal itself. However, only about 50% of these patients are reported to develop any degree of anorectal dysfunction or FI [28]. Published data do not report on frequent confounders such as obstetric trauma, diabetes mellitus, chronic cough, or chronic constipation etc. We

95%CI 9.550–5.143 7.796–6.245 9.689–4.135 8.003–6.048 27.235 to 11.041 17.397–1.549 7.092–10.128 1.779–15.431 2.621–17.283

P-Value 0.56 0.83 0.43 0.79 <0.001 0.10 0.73 0.12 0.008

believe the occurrence of FI is multifactorial and we strongly recommend a baseline anorectal functional evaluation or anorectal manometry, since many pre-existing conditions can predispose post-treatment FI and effective treatments such as bowel training, pelvic floor physical therapy, biofeedback, sacral nerve stimulation, or surgery are available that could improve or restore bowel control [29,30]. Previous studies have reported that about 50–65% of patients lost sexual interest following CCRT [18–20,22]. For men, 70% reported erectile dysfunction and 50% of female patients suffered from dyspareunia. Our data showed that 59% of men reported adequate sexual interest and 47% were potent before starting CCRT. Among women, 60% had sexual interest and 15% reported significant dyspareunia on baseline assessment. Sexual interest was impaired significantly, both clinically and statistically, at the end of treatment for both men and women however scores were improved to baseline level by 12 weeks. For women, despite improved sexual interest, dyspareunia increased by 10% at the end of the follow-up period which may lead to a negative impact on sexual life. The impotence scores were also impaired at the end of treatment but reached baseline level at 6 weeks with further non-significant improvement at 12 months. Although there was an overall improvement in sexual function at 12 months, testicular exposure to radiotherapy could lead to low testosterone level and sexual dysfunction on long term follow-up [31–33]. The results of our study and previously published reports indicate that more emphasis is needed to identify the prevalence and causes of baseline sexual dysfunction [20] and all patients undergoing CCRT should be instructed about the risk of sexual dysfunction and provided with appropriate management. Provencher et al. reported increased urinary frequency in 40% of patients, with 10% experiencing severe extent (#4 on scale) at a median period of 50 months post-treatment [22]. Similarly, Allal et al. and Jephcott et al. reported high urinary symptom scores among ACC patients 60 months post-CCRT [18,21]. The rate of late GU toxicity (>grade 2) in our study was 3.5% [10]. We found urinary symptoms such as frequency and dysuria were returned to baseline at 12 weeks but 8% of patients (3 women) had ‘‘quite a bit” (#3) of urinary incontinence (UI) at 12 months post treatment. Given the close proximity to the anal canal, the bladder and urethra are exposed to high doses of radiotherapy that could lead to laxity of the pelvic floor musculature [34]. Factors that could worsen UI over time include aging and lower estrogen level. Hence, it is of great importance to assess baseline urinary symptoms at pretreatment evaluation. Currently QOL assessment of anal cancer patients following CCRT is performed by either using EORTC QLQ-C30 with QLQ-CR29 questionnaires or the Functional Assessment of Cancer TherapyColorectal (FACT-C) questionnaire and these questionnaires are designed for QOL evaluation of colorectal patients. The treatment approaches and treatment related toxicities and complications of

K. Joseph et al. / Radiotherapy and Oncology 120 (2016) 228–233

anal cancer differ from rectal cancer. Hence, current QOL assessment tools for anal cancer may not be adequately addressing anal cancerspecific issues. Sodergren et al. conducted a systematic review on behalf of EORTC quality of life study group on the QOL issues associated with anal cancer treatment and identified the need for anal cancer specific QOL instrument to addresses all relevant and specific issues relating to anal cancer [35]. This study is the first prospective report on acute and long term QOL of anal cancer patients treated with dynamic helical IMRT. However, this study has limitations since it is a single institution, single arm study. The mean scores for the majority of the QOL functions and symptoms in our study were returned to baseline by 12 weeks and if persisting beyond 12 weeks were returned to baseline by 12 months, except for diarrhea, dyspareunia, and urinary incontinence. In the multivariate analysis, higher tumor stage was an independent risk factor for diarrhea, dyspareunia, and FI (Table 2). This could be due to the larger target volumes receiving higher doses of radiation delivered. Our observations support routine use of IMRT and emphasize the significance of precise evaluation of sexual, urinary, and anorectal functions before starting CCRT as well as routine incorporation of QOL evaluations. This approach would further improve the functional outcome of ACC patients following IMRT based CCRT. Funding This study was funded by the Alberta Cancer Board seed funding and Grant and Alberta Innovates Health Solutions (Grant: 2011-RES0008619.) The funding agencies had no role in study design, data analysis, or manuscript preparation. Conflict of interest statement The authors have no conflicts of interest to disclose. Acknowledgments The authors thank Juliette Jordan, Wanda Churchill, and Elizabeth Gaetz for help with patient enrolment and data collection. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2016.06. 020. References [1] Johnson LG, Madeleine MM, Newcomer LM, Schwartz SM, Daling JR. Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973–2000. Cancer 2004;101:281–8. [2] Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 1996;348:1049–54. [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. J Clin Oncol 1997;15:2040–9. [4] Flam M, John M, Pajak TF, 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. [5] Nigro ND, Vaitkevicius VK, Buroker T, Bradley GT, Considine B. Combined therapy for cancer of the anal canal. Dis Colon Rectum 1981;24:73–5. [6] 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. JAMA 2008;299:1914–21.

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