Elective Inguinal Node Irradiation in Early-Stage T2N0 Anal Cancer: Prognostic Impact on Locoregional Control

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation: Gastrointestinal Cancer

Elective Inguinal Node Irradiation in Early-Stage T2N0 Anal Cancer: Prognostic Impact on Locoregional Control Thomas Zilli, MD,* Michael Betz, MD,*,x Sabine Bieri, MD,* Frederic Ris, MD,y Bruno Roche, MD,y Arnaud D. Roth, MD,z and Abdelkarim S. Allal, MD*,jj Departments of *Radiation Oncology, ySurgery, and zOncosurgery Unit, Geneva University Hospital, Geneva, Switzerland; x Radiation Oncology Institute, Hirslanden Lausanne, Lausanne, Switzerland; and jjDepartment of Radiation Oncology,Hoˆpital Fribourgeois, Fribourg, Switzerland Received Oct 25, 2012, and in revised form Mar 4, 2013. Accepted for publication Mar 6, 2013

Summary In patients with nodenegative stage T2 anal cancer, inguinal relapse rates remain low. The omission of elective coverage of inguinal nodes remains a controversial issue, especially in patients with favorable T2N0 disease. The role of inguinal node radiation therapy in the treatment of early-stage anal carcinoma needs to be investigated in future prospective trials.

Purpose: To evaluate the influence of elective inguinal node radiation therapy (INRT) on locoregional control (LRC) in patients with early-stage T2N0 anal cancer treated conservatively with primary RT. Methods and Materials: Between 1976 and 2008, 116 patients with T2 node-negative anal cancer were treated curatively with RT alone (nZ48) or by combined chemoradiation therapy (CRT) (nZ68) incorporating mitomycin C and 5-fluorouracil. Sixty-four percent of the patients (nZ74) received elective INRT. Results: Over a median follow-up of 69 months (range, 4-243 months), 97 (84%) and 95 patients (82%) were locally and locoregionally controlled, respectively. Rates for 5-year actuarial local control, LRC, cancer-specific, and overall survival for the entire population were 81.7%  3.8%, 79.2%  4.1%, 91.1%  3.0%, and 72.1%  4.5%, respectively. The overall 5-year inguinal relapse-free survival was 92.3%  2.9%. Isolated inguinal recurrence occurred in 2 patients (4.7%) treated without INRT, whereas no groin relapse was observed in those treated with INRT. The 5-year LRC rates for patients treated with and without INRT and with RT alone versus combined CRT were 80.1%  5.0% versus 77.8%  7.0% (PZ.967) and 71.0%  7.2% versus 85.4%  4.5% (PZ.147), respectively. A trend toward a higher rate of grade 3 acute toxicity was observed in patients treated with INRT (53% vs 31%, PZ.076). Conclusions: In cases of node-negative T2 anal cancer, the inguinal relapse rate remains relatively low with or without INRT. The role of INRT in the treatment of early-stage anal carcinoma needs to be investigated in future prospective trials. Ó 2013 Elsevier Inc.

Introduction Based on the results of large randomized phase 3 trials, a sphincter-sparing treatment approach with radiation therapy (RT) and concomitant chemotherapy is considered the Reprint requests to: Dr Thomas Zilli, MD, Radiation Oncology Department, Geneva University Hospital, CH-1211 Geneva 14, Switzerland. Tel: (41) 22 38 27 090; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 87, No. 1, pp. 60e66, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.03.008

standard of care for patients presenting with anal carcinoma (1-3). While for locally advanced (T3-T4) tumors the combination of elective lymph node irradiation along with concomitant chemotherapy has been demonstrated to improve locoregional control Conflict of interest: none.

Volume 87  Number 1  2013

Inguinal RT for T2N0 anal cancer

(LRC) and colostomy-free survival rates compared to RT alone, the need for such an intensive treatment protocol remains controversial in patients with early-stage anal tumors (T1-T2) without nodal involvement (4-6). If the addition of chemotherapy to RT nevertheless seems to improve the outcome in this subgroup of patients (7), prophylactic inguinal-node RT (INRT) remains an open issue, especially when appropriate radiological staging is performed. Indeed, the potential reduction of the risk of isolated inguinal relapse with INRT needs to be balanced against increased normal tissue exposure and a higher risk of radiation-induced side effects. As shown in randomized phase 3 trials, conservative treatment using INRT is associated with a relatively high rate of severe toxicities ranging between 15.8% and 86% and 5% and 41% for acute and late side effects, respectively (1, 2). To assess this open issue, we retrospectively evaluated a selected population of patients with T2N0 anal carcinoma treated conservatively with curative intent by primary RT with or without concomitant chemotherapy in a single institution. The aim was to assess the role of INRT in this subgroup of patients with early-stage anal cancer.

Methods and Materials

61

were treated curatively with RT with or without concomitant chemotherapy. Tumor staging was based on the American Joint Commission on Cancer (AJCC) 6th Edition staging system, and all tumors were classified retrospectively until 1990 and prospectively thereafter. Median age at diagnosis for the population was 67 years old (range, 35-94 years old); 42% of the patients (nZ49) were older than 70 years of age, and the male-to-female ratio was 0.38. All patients had histologically confirmed squamous cell (keratinizing, basaloid, and transitional or undifferentiated) anal carcinoma involving the anal verge and the perianal skin in 28% of the patients (nZ32). The mean tumor size at diagnosis was 3.5  0.8 cm. Pretreatment workup consisted of detailed medical history, physical examination including digital rectal examination (DRE), and palpation of the groins; proctoscopy, abdominal ultrasonography, chest radiography, and routine blood tests. For patients treated later in the study period, radiological staging included abdominopelvic computed tomography (CT) and transrectal echoendoscopy. Equivocal inguinal nodes on palpation or imaging were routinely biopsied to exclude histopathological nodal involvement. After complete staging workup, all patients were considered free of nodal and distant metastasis. Patient demographics and tumor characteristics are summarized in Table 1.

Patients and tumor characteristics

Treatment

Between January 1976 and September 2008, a total of 116 patients with node-negative T2 anal carcinoma (2-5 cm, greatest dimension)

All patients were treated with a split-course RT schedule, using external beam RT (EBRT) or brachytherapy (BT) boost. RT

Table 1

Patient demographics and tumor characteristics stratified by treatment modality (nZ116) INRT Characteristic

No. patients Age (y) Median (range) Age (y) <70 70 Year of diagnosis <1986 1986 Sex Male Female Tumor size (cm) (nZ113) Mean  SD Tumor size (cm) (nZ113) 2.1-3 3.1-4 4.1-5 Anal verge/perianal skin involvement No Yes Tumor status at diagnosis Post incisional biopsy Post excisional biopsy Recurrence*

Yes n (%)

No n (%)

74 (64)

42 (36)

65 (36-87)

71 (35-94)

.124

67 (35-94)

49 (66) 25 (34)

18 (43) 24 (57)

.019

67 (58) 49 (42)

3 (4) 71 (96)

35 (83) 7 (17)

.0001

38 (33) 78 (67)

21 (28) 53 (72)

11 (26) 31(74)

.833

32 (28) 84 (72)

3.4  0.8

3.8  0.8

.012

3.5  0.8

38 (52) 22 (30) 13 (18)

15 (38) 14 (35.0) 11 (27)

.286

53 (47) 36 (32) 24 8(1)

57 (77) 17 (23)

27 (64) 15 (36)

.194

84 (72) 32 (28)

63 (85) 10 (14) 1 (1)

34 (81) 8 (19) -

.562

97 (84) 18 (15) 1 (1)

Abbreviations: INRT Z inguinal node radiation therapy; SD Z standard deviation. * After prior local excision.

P value

Total n (%) 116 (100)

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Zilli et al.

Table 2

Characteristics of radiation therapy stratified by treatment modality (nZ116) INRT Characteristic

Treatment modality (nZ116) RT alone CRT RT modality (nZ116) EBRT EBRT þ BT boost RT total dose (Gy) (nZ116) Median (range) First course EBRT total dose (Gy) (nZ116) Median (range) Second course EBRT total dose (Gy) (nZ50) Median (range) BT total dose (Gy) (nZ66) Median (range) OTT (days) (nZ116) Median (range) Gap between EBRT courses (days) (nZ50) Median (range) Gap between EBRT and BT boost (days) (nZ66) Median (range)

Total n (%)

No. of yes (%)

No. of no (%)

P value

48 (41) 68 (59)

13 (18) 61 (82)

35 (83) 7 (17)

.0001

50 (43) 66 (57)

45 (61) 29 (39)

5 (12) 37 (88)

.0001

51.4 (45-65)

.0001

59.6 (45-68)

60 (45-68)

36 (24-63) 24 (16-34.8) 20 (10-30) 65 (38-261)

60 (45-110)

71 (38-261)

.057

15 (5-47) 46 (18-157)

Abbreviations: BT Z brachytherapy; CRT Z chemoradiation therapy; EBRT Z external beam RT; INRT Z inguinal node RT; OTT Z overall treatment time; RT Z radiation therapy.

treatment details stratified based on the use of INRT are summarized in Table 2. In the early 1980s, the majority of patients (nZ34) were treated with a prescribed dose of 30 Gy in 10 or 15 fractions with 1.25 MV Rg from a 60Co machine, using an appositional perineal field with (nZ16) or without (nZ9) a posterior presacral field to provide a more homogeneous dose to pararectal nodes, based on Papillon’s technique (8). This treatment was generally followed with a BT boost. No INRT was delivered. After the mid-1980s, based on the results of randomized phase 3 trials, the first course of EBRT was delivered in most patients by using anterior–posterior/posterior–anterior (AP/PA) opposed pelvic fields with 6- or 18-MV photon energies from a linear accelerator to adequately cover the primary anal tumor and pelvic and inguinal nodes. Routine CT-based planning was introduced starting from 1998, while intensity modulated RT (IMRT) was only used in 5 patients treated in the last 2 years of this study. The median delivered dose of the first EBRT course was 36 Gy (range, 24-63 Gy), in 20 daily fractions over 4 weeks. BT consisted of interstitial 192Ir implants and was used 6-8 weeks (median, 46 days; range, 18-157 days) after the end of EBRT as a boost. A BT boost was delivered in a total of 66 (57%) patients with technically accessible tumors for implantation. Median delivered dose was 20 Gy (range, 10-30 Gy). After 1993, EBRT was preferred to BT as boost technique. A total of 50 patients (43%) were treated with an EBRT boost to the anal tumor with a margin, using different field arrangements of 6 or more MV photon energy levels, after a median gap of 15 days (range, 5-47 days). Median dose for the EBRT boost was 24 Gy in 12 fractions of 2 Gy each, for a total delivered dose to the tumor of 60 Gy. Sixty-eight patients (59%) received concomitant chemoradiation therapy (CRT), mostly (nZ59) after 1985, based on the results of randomized phase 3 studies. The standard

chemotherapy schedule consisted of 2 cycles of mitomycin C (MMC) at 10 mg/m2 delivered with an intravenous bolus on day 1 of the RT in association with a 5-day continuous infusion of 5-fluorouracil (5-FU) at 600-800 mg/m2. The second cycle of the chemotherapy was delivered on day 1 of the second RT course in 54% of the patients receiving the first course (nZ37), especially in those treated with an EBRT boost. Overall, 5 patients received MMC only, and 1 patient underwent therapy with cisplatin instead of 5-FU.

Follow-up and statistical analysis All patients were followed regularly in radiation, medical, and surgical oncology clinics for 2-3 years at 3- to 4-month intervals and every 6-12 months thereafter. A complete physical examination including DRE was performed at each follow-up visit, with anuscopic examinations at regular intervals. Acute and late toxicities were recorded at each visit according to the European Organization for Research and Treatment of Cancer and the Radiation Therapy Oncology Group (EORTC/RTOG) scale. CT scans of the abdomen and pelvis and chest radiographs were taken in cases of persistent or recurrent disease. Anal biopsies were performed only in cases of suspected recurrence or persistent disease at DRE, to avoid iatrogenic fistulas or further damage to the sphincter. Comparisons between treatment groups were tested using the chi-square and nonparametric tests for categorical and continuous variables, respectively. Actuarial 5-year local control (LC) and LRC rates, cancer-specific survival (CSS) and overall survival (OS) rates were estimated from the date of diagnosis by using the Kaplan-Meier method and differences between the groups compared with the log-rank test. Locoregional failure was defined

Volume 87  Number 1  2013 as histologically confirmed tumor persistence after treatment or a recurrence in the anorectal area, perineal skin, or pelvic-inguinal nodes. All statistical tests were 2-sided, and a P value of <.05 was considered statistically significant. Statistical analyses were performed using SPSS, version 17.0, statistic software (SPSS Inc, Chicago, IL).

Results Patients receiving INRT were more likely to be treated with CRT rather than RT alone (82% vs 17%, PZ.0001), with EBRT alone rather than EBRT with a BT boost (61% vs 12%, PZ.0001), and after 1986 rather than before (96% vs 17%, PZ.0001). Moreover, patients treated with INRT presented with a younger age and smaller tumors at diagnosis than subjects treated without INRT (66% vs 43% of patients <70 years old, PZ.019, and 3.4  0.8 cm vs 3.8  0.8 cm, PZ.012, respectively). Comparisons between groups are illustrated in Tables 1 and 2. With a median follow-up of 69 months (range, 4-243 months), 97 (84%) and 95% (82%) of patients were locally and locoregionally controlled, respectively. The 5-year actuarial LC and LRC rates for the entire population were 81.7%  3.8% and 79.2%  4.1%, respectively. A total of 22 failures were observed after primary treatment, of which 13 (59%) were local alone, 2 (10%) were regional alone, 4 (18%) were both local and regional (3 in perirectal and 1 in inguinal nodes), and 2 (10%) were local or locoregional with synchronous distant metastasis. The 2 patients with regional relapse alone presented with inguinal node metastasis. Only 1 patient presented with an isolated distant metastasis without evidence of locoregional relapse. The 5-year LC and LRC rates were 80.1%  5.0% versus 84.5%  5.8% (PZ.540) and 80.1%  5.0% versus 77.8%  7.0% (PZ.967) for patients treated with and without INRT, respectively (Fig. 1). Patients treated with RT alone achieved a 5-year LRC rate of 71.0%  7.2% compared to 85.4%  4.5% when treated with CRT (PZ.147). Results of univariate analysis of different patients, tumors, and treatment factors influencing LRC are reported in Table 3.

Figure 1. Kaplan-Meier estimates for locoregional control (LRC) for patients with T2N0 anal carcinoma treated with or without inguinal node RT (INRT).

Inguinal RT for T2N0 anal cancer

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Overall, 7 patients (6%) experienced inguinal relapse during follow-up, with a median time to relapse of 16 months (range, 8-60 months). The overall 5-year actuarial inguinal relapse-free survival was 92.3%  2.9%. In 4 patients, inguinal recurrence occurred as a first relapse, isolated (nZ2) or associated with synchronous local and/or distant recurrences (nZ2). Among the 4 patients, INRT was delivered in only 1 (1.4%), while the other 3 patients (7.4%) did not receive inguinal RT. In an additional 3 patients treated with INRT, groin relapse occurred as a second relapse after a primary local recurrence, alone (nZ2) or combined with an involvement of perirectal nodes (nZ1), all cases were initially salvaged by abdominoperineal resection (APR). Considering all inguinal relapses, patients treated with or without INRT showed 5-year inguinal relapse-free survival rates of 93.3%  3.2% and 90.4%  5.4%, respectively (PZ.733). Isolated inguinal relapse was the first site of recurrence in 2 patients. Both patients were treated without INRT and concomitant chemotherapy (4.7% of this cohort of patients) using an appositional perineal field followed by a BT boost. In 1 patient, the nodal relapse occurred 60 months after diagnosis in the right inguinal nodes and was salvaged with nodal dissection and adjuvant RT. At the last follow-up, the patient was disease free. In the second patient, the inguinal relapse was bilateral and was associated with subcutaneous outfield nodules in the scrotal region.

Table 3 (nZ116)

Kaplan-Meier estimates for locoregional control Univariate analysis Variable (n/events)

Age (y) <70 (67/12) 70 (49/9) Sex Female (84/16) Male (32/5) INRT Yes (74/13) No (42/8) RT technique EBRT (50/7) EBRT þ BT (66/14) Treatment strategy RT (48/12) CRT (68/9) OTT (days) <65 (57/8) 65 (59/13) Treatment year <1986 (38/7) 1986 (78/14) Anal verge/perianal skin involvement Yes (32/6) No (84/15) Tumor size (cm) 3 (53/7) >3 (60/12)

5-y LRC

P value

79.3  5.4 79.0  6.3

.983

78.3  4.9 81.5  7.5

.818

80.1  5.0 77.8  7.0

.967

76.9  5.4 82.5  6.3

.508

71.0  7.2 85.4  4.5

.147

82.3  5.9 76.4  5.8

.460

78.5  7.3 79.7  4.9

.998

77.2  8.5 79.9  4.7

.902

85.7  5.0 77.3  5.8

.305

Abbreviations: BT Z brachytherapy; CRT Z chemoradiation therapy; EBRT Z external beam RT; INRT Z inguinal node RT; OTT Z overall treatment time; RT Z radiation therapy.

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The patient initially underwent salvage treatment with nodal dissection and adjuvant RT on the groin and scrotal region. He died 19 months later from metastatic disease. No isolated groin relapse was observed in those treated with INRT. The 5-year colostomy-free survival for the whole cohort was 79.4%  4.2%, with no significant differences between patients treated with RT alone and those treated with CRT (74.2%  7.1% vs 83.0%  4.9%, respectively, PZ.326). Thirteen patients underwent APR as salvage treatment for residual or recurrent disease. Sixty-seven patients (58%) were alive at last follow-up. Overall, 12 deaths were related to anal cancer. The estimated 5-year CSS and OS rates for the whole study cohort were 91.1%  3.0% and 72.1%  4.5%, respectively. Two patients experienced grade 4 acute toxicity consisting of acute bowel obstruction. Grade 3 toxicity was observed in 44 patients (38%). Acute erythema was the most common grade 3 acute toxicity (nZ39, 34%). Other grade 3 toxicity included either diarrhea (nZ9) or mucositis (nZ6) or both (nZ2) or abdominal pain (nZ1). A trend toward a higher rate of acute grade 3 or more acute toxicity was observed in patients treated with INRT compared to those treated without (53% vs 31%, PZ.076), while no difference was observed between patients treated with and those treated without concomitant chemotherapy (PZ.835). Grades 3 and 4 late toxicity were observed in 9 (8%) and 11 (10%) patients, respectively. Grade 4 side effects were perineal skin or mucosal ulceration of the anus in 8 patients and rectovaginal fistula, bowel adherences, and a pubic bone fracture in each of the other 3 patients. No significant differences in grades 3-4 late toxicities were observed between patients treated with or without INRT (21% vs 13%, respectively, PZ.315). Seven patients, all treated with a BT boost with (nZ3) or without INRT (nZ4), were colostomized between 1979 and 1992 for treatmentrelated toxicity.

Discussion Inguinal lymph nodes represent a common site of metastatic spread of anal cancer, and their involvement represents a major prognostic factor in the outcome after conservative treatment (9, 10). Published randomized prospective clinical trials have helped to establish treatment guidelines for patients with locoregionally advanced anal cancer, demonstrating definitive CRT to be superior to RT alone (1, 2). These studies, however, did not investigate the role of concomitant chemotherapy or inguinal irradiation in patients presenting with more limited disease. In the EORTC trial, T1 or T2 node-negative patients were excluded from randomization (2). Similarly, in the United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) trial more than 53% of patients had T3-T4 tumors, and close to 20% had palpable nodes (1). Therefore, if the optimal therapeutic approach to treat locoregionally advanced anal tumors seems nowadays to be well defined, it remains unclear if the addition of prophylactic INRT and concomitant chemotherapy is necessary to improve the outcome in patients with early-stage node negative disease. The aim of this study was to explore the role of prophylactic INRT in a large cohort of 116 patients with early-stage anal tumor treated at the same institution. We specifically sought to analyze the impact of groin irradiation in a population of patients with T2N0 disease, as this stage constitutes a “gray zone” between patients with stage I disease (T1N0) for whom an exclusive,

International Journal of Radiation Oncology  Biology  Physics involved-field RT might be a treatment option (6), and patients with T3-T4 disease and/or nodal involvement for whom concomitant CRT including INRT is standard. Our results showed that the rate of isolated inguinal relapse in patients with T2N0 tumors remains low when INRT is omitted, as we only observed 2 cases. However, these findings may have been biased by the lack of quality radiological imaging during the first period of this study, with as consequence a possible underestimation and delayed diagnosis of isolated failures occurring in the groins and other regional nodes. It should be underlined that any inguinal nodal recurrence, isolated or associated with other sites of failure, constitutes a challenging situation often difficult to manage. In this series, first inguinal failures were reduced by an absolute rate of 6% through the use of INRT. Among the 74 patients who received INRT, only 1 (1.4%) had any inguinal component to initial relapse. In contrast, in 7.1% (3 of 42) of the patients treated without INRT, inguinal nodal recurrence occurred as at least a component of the first failure. As previously described by other authors (11-13), we found that inguinal relapse was associated in 86% (6 of 7 patients) of cases with local or distant recurrence. We believe that a direct correlation exists between local and inguinal control in the outcome of anal cancer after conservative treatment. It seems to be essential to sterilize the primary anal tumor to achieve long-term LRC. The omission of prophylactic INRT in patients with T2N0 anal tumors remains controversial. Although different patient- and treatment-related factors may limit the comparability between series, the overall reported rate of inguinal relapse in studies including early-stage tumors remains relatively low, ranging between 0 and 8.6%, with isolated groin recurrences occurring in less than 5% of the cases (Table 4) (1,6,11-17). An exception is the high rate of inguinal recurrence (22.5%) observed by Matthews et al in a series of 40 patients with node-negative tumors 4 cm treated without INRT in a phase 2 study (13). It is possible that under-staging or the use of suboptimal CRT regimens (a single cycle of MMC at 10 mg/m2, a planned gap of 2 weeks, and a total RT dose to the tumor of only 50.4 Gy) may have contributed to these poor results. The management of patients with isolated inguinal relapse after curative treatment of a primary tumor remains difficult to standardize. In our series, in the patient with an isolated monolateral inguinal relapse, complete disease control was achieved after nodal dissection and further irradiation of the inguinal groin. Of note, Gerard et al (11) achieved control in the inguinal region with surgical dissection and adjuvant RT or RT alone in 68% of the patients presenting with a metachronous relapse at this level, with a 5-year OS rate of 41.4%. Any inguinal nodal failure can dramatically impact patient quality of life and decrease the overall chances of salvage. Therefore, any step that can reduce the likelihood of inguinal nodal relapse should be considered, provided the morbidity risk does not exceed the cancer risk. In our series, grade 3 or more toxicities compare favorably with previously published studies using elective inguinal node irradiation (1-3). Overall rates of severe toxicity were higher with INRT than without (53% vs 31% and 21% vs 13% for acute and late toxicity, respectively). However, the coverage of the mid to the upper pelvis in patients treated with INRT may have contributed together with the coverage of the groins to this higher rate of morbidities. It should be noted that recent improvements in RT delivery techniques have reduced the toxicities associated with INRT compared to classical

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Inguinal RT for T2N0 anal cancer

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Comparative series exploring inguinal relapse in early-stage anal cancer after conservative treatment

Study (ref)

n

Median FU (mo)

Matthews et al (13) Hatfield et al (16) Ortholan et al (12) Ortholan et al (6) Crowley et al (17) Gerard et al (11) Das et al (14) Ferrigno et al (15) Current series

40 21 208 69 30 243 124 26 116

44 42 61 66 41 72 42 42 69

T stage (% T2N0)

RT dose (Gy)

T1-2 N0 (4 cm) (67) 50.4 Microinv/T1-2 N0 (24) 30 T1-4 N1-3 (38) 60.5 Tis-1 N0-1 (0) 55-59 T1-3 N0 (53) 50 T1-4 N0 (66) 50 T1-4 N0-1 (w40) 55 T1-3 N0 55 T2 N0 (100) 59.6

CRT (%) Yes Yes Yes Yes Yes Yes Yes Yes Yes

(100) (100) (71) (10) (100) (58) (100) (w88) (59)

INRT (%)

LC (%)

Overall inguinal RFS (%)

No 77 (4-y) 77 (4-y) No* 95.3y 100y Yes (36) NA 97 vs 88 (5-y)z,x Yes (21) 91y 100 No 87y 97y No 92y Yes (100) 92 (3-y) 100 Yes (w21) 72.3 (5-y) 100 vs 92y Yes (64) 81.7 (5-y) 93 vs 90 (5-y)z

Isolated inguinal relapse # (%)

Overall inguinal relapse # (%)

5 (12.5) 9 (22.5) 0 0 4 (1.9) 18 (8.6) 0 0 1 (3) 1 (3) NA 19 (7.8)jj 0 0 NA 2 (7.7) 2 (1.7/4.7{) 7 (6)

Abbreviations: CRT Z chemoradiation otherapy; FU Z follow-up; INRT Z inguinal node RT; LC Z local control; Microinv Z epithelial dysplasia with foci of microinvasion; RFS Z relapse-free survival; RT Z radiation therapy. * One patient was treated with INRT to an equivocal inguinal node on staging CT. y Crude value. z Rates of inguinal node control in patients treated with or without INRT. x Actuarial rates for T1-T2 N0-N3 patients. jj Of which 8 (3.3%) and 11 (4.5%) patients presented with T1-T2 N0 anal tumor with T3-T4 N0, respectively. { Overall risk for the whole population/for patients treated without INRT.

techniques using opposed AP/PA fields. Delivered doses to the normal structures (particularly small bowel, skin, femoral heads, bladder and external genitalia) have been significantly reduced with the use of intensity modulated RT, helical tomotherapy, or volumetric-modulated arc RT compared to 2-dimensional conventional or 3D conformal RT techniques (18-21). Limited toxicity rates and improvements in long-term functional and oncologic outcomes have been recently reported in the literature, using these high-precision RT techniques, although follow-up remains limited and long-term data are awaited (21-23). Some limitations of this study need to be addressed. First, given the retrospective nature of this study and the extended time period covered, the evolution of staging methods may have introduced some bias in the results of our analysis. We also acknowledge that the large heterogeneity of the RT techniques, including differences in the total delivered doses, field dimensions and BT use, may have influenced the outcome, as well as the toxicity rates. However, despite these limitations, we believe these data are a useful contribution to discussions of the best management strategy for early-stage anal cancer. New diagnostic approaches available for accurate staging of anal cancer, such as magnetic-resonance imaging, 18F-labeled fluorodeoxyglucose positron emission tomography/CT (24), or sentinel node biopsy (25), may help to select patients for whom elective INRT could be safely omitted. Overall, even if we were unable to identify a subgroup in our cohort deriving a significant LRC benefit from INRT, we acknowledge that T2N0 lesions are a heterogeneous tumor group. Patients with more aggressive tumor features (ie, tumors with a large size involving more than 2/3 of the anal circumference [12] and/or tethered tumors [9]) constitute a subgroup in whom it may be risky to omit inguinal node irradiation.

Conclusions In conclusion, the inguinal relapse rate remains relatively low in patients with node-negative T2 anal cancer, and the

omission of elective coverage of inguinal nodes remains a controversial issue, especially in patients with favorable disease. The use of elective INRT in patients with early-stage anal cancer needs to be investigated in the context of future prospective trials.

References 1. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UK Co-ordinating Committee on Cancer Research. Lancet 1996;348:1049-1054. 2. 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;15:2040-2049. 3. 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;299:1914-1921. 4. Deniaud-Alexandre E, Touboul E, Tiret E, et al. Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal. Int J Radiat Oncol Biol Phys 2003;56:1259-1273. 5. 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;14:2527-2539. 6. Ortholan C, Ramaioli A, Peiffert D, et al. Anal canal carcinoma: earlystage tumors < or Z10 mm (T1 or Tis): therapeutic options and original pattern of local failure after radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:479-485. 7. Zilli T, Schick U, Ozsahin M, et al. Node-negative T1-T2 anal cancer: radiotherapy alone or concomitant chemoradiotherapy? Radiother Oncol 2012;102:62-67. 8. Papillon J, Montbarbon JF. Epidermoid carcinoma of the anal canal. A series of 276 cases. Dis Colon Rectum 1987;30:324-333.

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