|Ahead of print publication
Long-term oncologic and complication outcomes in anal cancer patients treated with radiation therapy
Ji Hyeon Joo1, Jin-hong Park2, Sang Min Yoon2, Jin Cheon Kim3, Chang Sik Yu3, Tae Won Kim4, Jong Hoon Kim2
1 Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul; Department of Radiation Oncology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
2 Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
3 Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
4 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Jong Hoon Kim,
Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505
Source of Support: None, Conflict of Interest: None
Aim: The aim of the study is to analyze prognostic factors for tumor control, survival, and late toxicity in patients with anal cancer treated with chemoradiation.
Materials and Methods: Anal cancer patients treated between 1996 and 2010 were analyzed. Patients received radiotherapy and concurrent 5-fluorouracil and mitomycin-C.
Results: Data from 70 patients were analyzed. With a median follow-up of 6.4 years, 5-year overall survival and progression-free survival were 88% and 84%, respectively. Female gender and total radiation dose (≥54 Gy) were significantly associated with better local control. For survival, female gender, patient age, and tumor size were significant prognostic factors. The most common late toxicity was lymphedema. Possible prognosticators were examined, and only radiation dose to the inguinal area was significant.
Conclusion: Despite moderately high radiation doses, local recurrence, and late complications were problems in treating anal cancer. In the intensity-modulated radiotherapy era, consensus on accurate target volume based on the pattern of failure analysis is required.
Keywords: Adverse effects, anus neoplasms, local, lymphedema, neoplasm recurrence, radiotherapy
|How to cite this URL:|
Joo JH, Park Jh, Yoon SM, Kim JC, Yu CS, Kim TW, Kim JH. Long-term oncologic and complication outcomes in anal cancer patients treated with radiation therapy. J Can Res Ther [Epub ahead of print] [cited 2019 Aug 17]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=263530
| > Introduction|| |
In anal cancer, the treatment paradigm has shifted from surgery to combined chemoradiation therapy (CRT). With this shift, the function of the anus could be preserved. After the 1970s, when Nigro et al. reported the treatment results of concurrent 5-fluorouracil (5-FU) and mitomycin-C (MMC) with radiation therapy (RT), it became the standard regimen. Since then, several efforts have been made to improve oncological outcomes and decrease toxicity. A multi-institutional intergroup trial showed that the addition of MMC significantly increased local control and colostomy-free and disease-free survival compared to the RT + 5-FU only group. After cisplatin had shown radiosensitizing effects in the treatment of squamous cell carcinoma of other sites, cisplatin was substituted for MMC. However, cisplatin-based therapy failed to improve disease-free survival and resulted in a significantly worse colostomy rate., After several randomized trials of induction chemotherapy, maintenance chemotherapy, and planned treatment breaks, the combination of MMC, 5-FU, and RT, without induction or maintenance chemotherapy or treatment breaks, remains the standard of care.,,
There is increasing interest in the use of conformal techniques, such as intensity-modulated RT (IMRT), to reduce toxicity while maintaining tumor control, and early reports are encouraging. For an IMRT treatment plan, accurate knowledge of patterns of failure is very important to decrease the possibility of marginal recurrence. To date, however, data on anal cancer failure are scarce.
In our institution, patients with anal squamous cell carcinoma have been treated with a combination of RT and cytotoxic drugs without planned treatment breaks since the 1990s. The chemotherapeutic agents, RT dose, and RT techniques have changed over time. Although it has not been compared in a randomized trial, the result of treatment that has been developed sequentially and modified according to experience nevertheless provides an opportunity to explore long-term treatment outcomes of anal cancer. The aim of this retrospective study was to analyze prognostic factors for tumor control, survival, and late toxicity in patients with anal squamous cell carcinoma treated with definitive chemoradiation.
| > Materials and Methods|| |
With Institutional Review Board approval, we included all consecutive patients who commenced definitive CRT between 1996 and 2010. Histology was confirmed in all patients. Pretreatment evaluation included history, physical examinations, laboratory evaluation, and imaging include computed tomography (CT) scans, or magnetic resonance imaging (MRI) of the abdomen/pelvis, and colonoscopy or sigmoidoscopy.
CT simulation was performed with intravenous contrast to allow better visualization of the bowel, iliac, and inguinal vessels. A radiopaque wire was used to outline the caudad extent of the anal tumor. Patients were scanned in a supine, frog-legged position using custom immobilization. The gross target volume (GTV) included the primary anal lesion and metastatic lymph nodes evidenced on physical examination, imaging, and endoscopy. The clinical target volume (CTV) included the gross visible tumor and the entire anal canal from the anorectal junction to the anal verge, including the internal and external anal sphincters. Elective nodal CTV included the mesorectal, presacral, and ischiorectal spaces, the bilateral inguinal, the obturator, and the internal and external iliac lymph nodes. All CTV expansions were modified to respect anatomical boundaries. The planning target volume was made with a 7 mm expansion to the CTV except to avoid overlap with the skin.
Three-dimensional (3D) planning was used with anterior-posterior and both lateral beams. The treatments were delivered once daily with a dose/fraction of 1.8 Gy. Boosts were sequential. The total dose to clinically negative nodal regions was 30.6 Gy/17 fx except for the pelvic nodal stations, which received 45 Gy/25 fx if clinically negative. In addition, boosts of 1.8 Gy per fraction were given to bring clinically positive nodes and the primary tumor to a total of 54 Gy. From 2006, IMRT was used for RT in anal cancer. On adopting IMRT, the prescription dose has changed and varies according to tumor stage. The IMRT doses are summarized in [Table 1]. All treatments were delivered at 1.8–2.0 Gy per fraction, once daily, five fractions per week. Boosts were sequential.
The most commonly used regimen was two cycles of 5-FU and MMC (infused 5-FU 1000 mg/m 2 daily on D1-4 and D29-32+ MMC 10 mg/m 2 on D1 and D29), in 33 (47%) patients. Nine (13%) received oral capecitabine (825 mg/m 2 administered twice daily) and MMC. Seven (10%) patients received 5-FU and cisplatin, 11 (16%) received capecitabine + cisplatin. Capecitabine alone was used in 9 (13%) patients, and one patient was treated with RT alone. Acute toxicities were assessed per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 weekly during treatment and follow-up. The incidence of the worst grade toxicity sustained up to 90 days from RT was recorded as an acute toxicity event.
Response evaluation and follow-up
The response evaluation included physical examination, imaging, and endoscopy with pathology. The physical or imaging examination was based on response evaluation criteria in solid tumors criteria. The biopsy was performed in 1–4 directions of the anus. Excision was performed when there was a suspicious lesion after chemoradiation. When the complete response was achieved, the patients were followed up every 6 months. Patients with the persistent disease were considered to have local failure on that day.
The SPSS software package (version 21.0; SPSS Inc., Chicago, IL, USA) was used for all statistical computations. The Kaplan–Meier method was used to estimate rates of local and regional recurrence, distant metastasis-free survival, progression-free survival (PFS), and overall survival (OS). To assess the level of statistical significance between prognostic factors and Cox regression models were used. For prognostic factor assessment for late complications, log-regression analysis was used.
| > Results|| |
Patient and treatment characteristics
Retrospective chart review identified 101 patients. Thirty-one were excluded for the following reasons: pathology other than squamous cell carcinoma (n = 16), distant metastatic disease on presentation (n = 11), abdominoperineal resection before chemoradiation (n = 2), and incomplete RT (n = 2). As a result, data from 70 patients were analyzed. Patient and tumor characteristics are listed in [Table 2]. The median overall duration of follow-up was 76.5 months (range, 4.9–192.1 months). The median age was 60 years (range, 30–87 years); 74% of the patients were female. The median anal tumor size was 3.2 cm (range, 1.0–10.0 cm). The stage of the disease was I, II, and III in 13%, 46%, and 41% of patients, respectively. MMC and 5-FU (or capecitabine) were the most frequently used chemotherapy regimen (60%). Cisplatin and 5-FU (or capecitabine) were used in 26% of patients. Fifty-six (80%) and 16 (20%) patients were treated using 3D-CRT and IMRT, respectively. For the 3D-CRT group, the median dose to the inguinal nodes, pelvic nodes, and GTV was 30 Gy (range, 30–50.4 Gy), 50 Gy (44–54 Gy), and 50 Gy (45–56 Gy), respectively. Treatment interruptions occurred in 21 patients, with two patients having interruptions unrelated to acute toxicities. For the IMRT group, the median dose to the inguinal nodes, pelvic nodes, and GTV was 45 Gy (30–55 Gy), 48 Gy (44–55 Gy), and 55 Gy (45–60.2 Gy), respectively. Treatment interruption was noted in three patients, with one interruption unrelated to treatment toxicity.
Acute treatment toxicity
Eighteen patients (26%) experienced Grade 3 skin toxicity and 4 (6%) patients had Grade 3 gastrointestinal toxicity. Grade 3+ hematologic toxicity was reported in 29 (41%) patients, with neutropenia among the most common. Neutropenia was noted in 50% of patients receiving MMC and in 29% of patients not receiving MMC (P = 0.06). Grade 3+ anemia and thrombocytopenia developed in 5 (7%) and 8 (11%) patients, respectively.
The treatment response was evaluated at a median 10.8 ± 2.8 weeks from the start of radiation. CT or MRI was performed in 54 (77%) patients, and pathologic examination was performed in 61 (87%) patients. Sixty-eight (97%) patients achieved CR. Two patients showed partial response (PR) at the primary site. They initially had T3N1 and T2N0 tumors, respectively and were treated with capecitabine + cisplatin and RT (total 50 Gy). They underwent abdominoperineal resection.
Of all the patients, 83% (n = 58) were without evidence of disease at the time of the last follow-up. Eight (11%) patients developed distant metastasis, with one occurring simultaneously with local recurrence. The metastatic sites included the para-aortic lymph nodes (n = 3), lung (n = 2), lung and mediastinum (n = 1), lung and peritoneal seeding (n = 1), and supraclavicular node, lung, and bone (n = 1). The median time to the development of distant metastasis was 17.4 months (range, 2.1–29.6 months). The 5-year distant metastasis-free survival rate was 88%. Pelvic lymph node recurrence was observed in one patient. There was no inguinal failure. Local recurrence developed in four patients, including two patients who showed PR after chemoradiation. The median time to the development of local recurrence was 6.1 months (range, 2.3–15 months). The 5-year local recurrence-free survival rate was 94%.
The 5-year OS and PFS were 88% and 84%, respectively [Figure 1]. On prognostic factor analysis, female gender and total radiation dose were significantly associated with better local control in both univariate and multivariate analysis [Table 3]. Local recurrence-free survival rates for tumors treated <50 Gy and ≥50 Gy were 67% and 97%, respectively [Figure 2]a. For OS, female gender (hazard ratio [HR] = 0.13; P < 0.01), patient age (HR = 1.10; P = 0.03), and tumor size (HR = 2.42; P = 0.01) were significant prognostic factors in multivariate analysis [Table 4].
|Figure 1: Overall survival (a) and progression-free survival (b) in patients with anal cancer who underwent definitive radiotherapy|
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|Table 3: Predictive factors influencing local recurrence and distant metastasis|
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|Figure 2: Local recurrence-free survival for tumors treated with <50 Gy and ≥50 Gy (a) and late complication free at 3 years for patients treated with <36 Gy inguinal dose and ≥36 Gy (b), who had anal cancer and underwent definitive radiotherapy|
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|Table 4: Predictive factors affecting progression-free and overall survival|
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The most common late toxicity was lymphedema (n = 11, 16%). Leg edema and genital edema were noted in nine and two patients, respectively. One genital edema was seen in a patient who had been treated with abdominoperineal resection after RT. The time of onset was 9.6 months after treatment. Other late toxicities included chronic dermatologic problem in two patients (3%) and neurogenic bladder in one patient (1%). The median time to the development of lymphedema was 31.4 months (range, 6.5–114.9 months). Only radiation dose to the inguinal area was a significant prognosticator for late complications (HR = 0.90, P = 0.05) [Table 5]. The late complication-free rate at 3 years was 91% for patients treated <36 Gy inguinal dose versus 80% treated ≥36 Gy [Figure 2]b.
| > Discussion|| |
This present analysis represents the long-term follow-up results of chemoradiation for the treatment of anal cancer treated with varying radiation doses. Our patient cohort consisted of 20% and 39% of patients with ≥T3 and node-positive disease, respectively. With a median follow-up time of 6.4 years, the 5-year rates of local control, distant control, PFS, and OS were 94%, 88%, 84%, and 88%, respectively. They compare favorably with those of previous large retrospective studies.,
Sex, age, smoking, HIV status, and stage are known prognostic factors for anal cancer. The dose-response relationship has been proven several times by retrospective studies. Local control rates of 77%–90% have been reported when administering doses between 50 and 55 Gy, and 34%–60% when administering lower doses.,, In a study by Rich et al., 58 patients were treated by RT with 5-FU ± cisplatin. The 2-year local control rate for patients treated with RT doses >60 Gy, 50–54 Gy, and <45 Gy was 83%, 73%, and 50%, respectively. Based on these findings, a randomized trial was designed to determine whether dose escalation leads to improved colostomy-free survival. By 2 × 2 factorial design, the ACCORD 03 trial tested the effect of induction chemotherapy and high dose RT (65–70 Gy compared to 60 Gy). However, high dose boost failed to show better local control or colostomy-free or OS compared to standard dose boost. The 5-year colostomy-free survival was 74% and 78% in the high-dose group and the standard dose group, respectively. Therefore, many centers prescribe RT doses of 50–60 Gy to the GTV, depending on T stage. Our institutional policy is 50.4 Gy to T2 tumors and 54 Gy to T3–4 tumors. In this study, a dose-response relationship for local control was seen with an HR of 0.56 (0.39–0.86, P = 0.01). The local control rate for tumors treated with <50 Gy and ≥50 Gy was 67% and 97%, respectively (P < 0.01 by log-rank test). We recommend that RT below 50 Gy should be avoided at any stage in anal carcinoma. Based on the experiences of other sites of squamous cell carcinoma, RT over 60 Gy might have benefit in some patients. However, at this point, a very cautious approach is needed. Our data also confirm the poorer local tumor control and survival outcomes in men. Although not reported in all series, this pattern has been observed in limited data from other studies.,, Behavioral confounders such as smoking could not be assessed in our analysis. However, there may be gender-related disparities in tumor biology that will become apparent with routine tissue banking in future clinical trials.
Tumor size was also a significant prognostic factor for PFS and OS, but not for local control. The failure to demonstrate differences in local control rates may be because of differential prescription doses according to T stage or an insufficient number of events. However, the size of the primary tumor is the most significant predictor for disease-free survival. In a Princess Margaret Hospital series, the local control rate was 94% versus 72% for patients with tumors ≤2 cm versus those with tumors >2 cm. In the RTOG 9811 study, tumor size >5 cm was an independent prognosticator for worse disease-free survival. Besides, the traditionally known factors such as TN category, some anal carcinomas express biomarkers of therapy resistance, such as Ki67, NF-κB, SHH, and Gli-1. Biomarker-based examination of the heterogeneous clinical biology of patients with anal carcinoma is becoming increasingly studied, and as more information becomes available, may help predict and improve prognosis.
Several retrospective trials have reported reduced acute toxicity using IMRT for anal cancer, with varying results. A multicenter trial by Salama et al. including 53 patients treated with chemotherapy and IMRT, reported 15% gastrointestinal and 38% dermatological Grade 3 toxicities. DeFoe et al. reported early data on 78 patients with a median follow-up of 16 months. Gastrointestinal, hematological, and dermatological Grade 3 toxicity were experienced by 28%, 29%, and 43% of patients, respectively. One of the largest series is from the Massachusetts General Hospital. Mitra et al. reviewed 99 patients treated using dose-painted-IMRT according to RTOG 0529. They found that Grade 3+ gastrointestinal, skin and genitourinary toxicities were experienced by 10%, 13%, and 1% of patients, respectively. The dosimetric advantage over conventional radiotherapy was confirmed in the UK ACT II protocol, which revealed a significant reduction in the dose delivered to the external genitalia, small bowel, bladder, and femoral heads. In our institution, IMRT has been used since 2006, and 20% of patients were treated using IMRT in the present study. The rate of Grade 3 dermatitis (36%) in the IMRT cohort was comparable to that reported by Salama et al. and Defoe et al., but higher than that reported by Mitra et al. The rate of gastrointestinal toxicity in the IMRT group (7%) was one of the lowest among studies in this cohort. The interruption rate was 30%, which was also lower than that of other trials (40%–67%).,,
At present, we apply inguinal irradiation in all anal cancer patients, and the inguinal dose varies. Policies on elective inguinal irradiation are diverse, with some centers advocating universal use and others applying it only to selected patients with certain high-risk features such as advanced T-stage and node positivity. Elective treatment of the groin results in an inguinal failure rate of <5% but increases the treated volume and potential toxicity. A retrospective study by Tomaszewski et al., one of the largest retrospective studies with a long-term follow-up, revealed that, without elective irradiation, the inguinal failure rate in T1N0 disease was 1.9% compared with 12.5% in T2N0 patients. There were no failures in patients who received prophylactic inguinal irradiation. The authors recommended that most patients (≥T2N0) should receive prophylactic inguinal RT of 36 Gy. The risk of inguinal recurrence after definitive chemoradiation is very low. A retrospective analysis was performed at the MD Anderson Cancer Center to evaluate patterns of locoregional failure. When treated with 30.6 Gy in negative inguinal nodes and 55 Gy in positive nodes, only 2% of patients with inguinal nodal involvement at presentation developed inguinal recurrence. Among those with negative nodes at presentation, none developed recurrence.
The inherent limitations of this study are its retrospective nature, and that accurate grading was not reported. The anal cancer literature on late complications is sparse and only reports Grade 3+ toxicities. Tomaszewski et al. reported late toxicity over 25 years ≥ Grade 3, including overall (8%), vaginal (3%), anorectal (3%), insufficiency fractures (1.4%), urinary (1.4%), and others (1.8%). The definition of Grade 3 lymphedema in the NCI-CTCAE v. 4.02 is “severe symptoms; limiting self-care activities of daily living (ADL). Grade 3 edema limbs is >30% inter-limb discrepancy in volume, gross deviation from normal anatomic contour, limiting self-care ADL.” Late complications may persist and reduce the quality of life for a long period. Therefore, in contrast to acute toxicities, it is valuable to report mild symptoms. One observation of the current study is that lymphedema was directly related to inguinal radiation dose. Compared to conventional anterior-posterior-posterior-anterior, IMRT reduces the mean and threshold doses to the small bowel, bladder, and genitalia; however, lymphedema directly associated with pelvic or inguinal irradiation cannot be reduced. In the IMRT era, no consensus has been achieved on uninvolved nodal irradiation dose. To achieve this, it is important to identify failure patterns in anal cancer and determine the accurate target volume.
| > Conclusion|| |
Despite moderately high radiation doses, local recurrence and late complications were problems. New and novel treatment approaches are needed to improve the treatment ratios in these patients. In the IMRT era, consensus on accurate target volume based on patterns of failure analysis is required. The omission of elective inguinal irradiation or dose reduction might be considered in some patients.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]