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. 2025 Nov 9;11(2):101952. doi: 10.1016/j.adro.2025.101952

Can Patients With Recurrent or Primary Squamous Cell Carcinoma of the Anus in a Previously Irradiated Pelvis Receive Definitive Reirradiation?

Jordan McDonald a,1, Ethan P Damron a,1, Prajnan Das a, Eugene J Koay a, Ethan B Ludmir a, Bruce D Minsky a, Sonal S Noticewala a, Grace L Smith a, Craig Messick b, Van K Morris c, Emma B Holliday a,⁎
PMCID: PMC12918202  PMID: 41726003

Abstract

Purpose

Although salvage surgery is the standard of care for locoregionally recurrent anal cancer, few local options exist for inoperable pelvic recurrences. Newly diagnosed anal cancer arising in a previously irradiated field also provides a unique treatment challenge, as delivery of standard doses would result in unsafe cumulative dose to pelvic structures. We aimed to evaluate efficacy and toxicity of a hyperfractionated accelerated reirradiation (reRT) regimen for such patients.

Methods and Materials

Patients treated with hyperfractionated accelerated reRT at a single institution between 2005 and 2024 for nonmetastatic inoperable locoregionally recurrent anal cancer or primary anal cancer in a previously irradiated field were included. The reRT regimen consisted of 1.5 Gy in twice daily fractions separated by 6 hours to a median (range) of 39 (30-51) Gy. Complete clinical response rates, recurrence rates, and toxicities were reported.

Results

The median (IQR) follow-up was 13.4 (7.5-42.2) months. Twenty-six (74.3%) patients were treated with reRT for recurrent anal cancer, and 9 (25.7%) patients were treated with reRT for a new squamous cell carcinoma of the anus (SCCA) primary after prior pelvic radiation. The complete clinical response rate was 46.2% among patients with recurrent anal cancer and 77.8% among patients with a new SCCA primary after prior pelvic radiation. Two-year locoregional recurrence rate was 64.0% among patients with recurrent anal cancer and 22.0% among patients treated with reRT for a new SCCA primary after prior pelvic radiation. Eight patients (22.9%) developed acute grade 3 toxicity and 10 (28.6%) developed late grade 3-4 toxicity.

Conclusions

Hyperfractionated accelerated reRT results in promising complete clinical response rates that appear to translate into durable pelvic control for patients with recurrent anal cancer or a new SCCA primary after prior pelvic radiation. Acute toxicity appears similar to initial standard chemoradiation, but limiting reRT doses to 39 Gy may reduce the risk of serious late toxicity.

Introduction

Chemoradiation therapy (CRT) results in excellent local control (LC) for the majority of patients with squamous cell carcinoma of the anus (SCCA).1 For patients who have persistent disease or who develop a local recurrence after initial CRT, abdominoperineal resection (APR) is the recommended salvage treatment.2 However, surgical salvage only results in approximately 50% pelvic control for patients with recurrent or persistent disease.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26

Treatment of a second recurrence post-APR is challenging. Repeat operation is often not possible and systemic therapy options will not often be curative. Additionally, not all patients with recurrent or persistent disease after initial CRT are candidates for surgery either due to the extensive infiltration of disease or because of medical comorbidities. Finally, patients with a history of pelvic radiation for a different pelvic malignancy prior to their SCCA diagnosis pose a special clinical challenge. Standard doses of definitive chemoradiation are risky due to high composite doses to the anorectum, bowel, bladder and other surrounding pelvic structures. For these 3 challenging clinical scenarios, a reirradiation (reRT) regimen is desirable to provide LC and overall survival (OS) for these patients.

At our institution, we have used a hyperfractionated accelerated regimen for pelvic reRT consisting of 1.5 Gy per fraction delivered twice daily separated by at least 6 hours to a total of 30 to 45 Gy. This regimen has been used to treat patients with recurrent gastrointestinal malignancies, mostly rectal adenocarcinoma, in several small series.25,27, 28, 29 However, it is unclear whether this reRT regimen would successfully treat patients with SCCA either in the recurrent setting or in the newly diagnosed setting in with a history of prior pelvic RT for a different pelvic malignancy. We aimed to report rates of LC and OS post-reRT as well as rates of radiation toxicity or functional problems among patients undergoing reRT for nonmetastatic inoperable locoregionally recurrent anal cancer or primary anal cancer in a previously irradiated field.

Methods and Materials

We obtained a waiver of consent and approval from our institutional review board for this study. Patients were included if they received reRT either for a new anal SCCA after previously receiving pelvic RT for another malignancy or for locally recurrent SCCA after intensity modulated radiation therapy (IMRT)-based CRT at our institution between January 1, 2005 until January 1, 2024. All patients were evaluated by a multidisciplinary team prior to treatment initiation and were deemed to be surgical inoperable by a colorectal surgeon. Patient information was obtained retrospectively from the medical record including disease characteristics, dates of treatment, total radiation dose and number of fractions, response to reRT, recurrence and survival information. Additionally, toxicity information as reported by the treating physician was obtained. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 (v4). Acute toxicities were assessed twice weekly during hyperfractionated accelerated reRT by the attending physician. Toxicities documented up to 12 wk postcompletion of reRT were recorded as acute toxicities. After treatment, patients were seen in follow-up every 3 to 6 months for 5 years. Toxicities reported thereafter were recorded as late toxicities if they were deemed to be potentially attributable to reRT.

reRT details

Patients received reRT as previously described.25 All reRT described in this series is type 1 reRT, which is defined by the European Society for Radiotherapy and Oncology and the European Organization for Research and Treatment of Cancer as delivering reRT to a site that partially or fully overlaps with previously irradiated volumes.30,31 Hyperfractionated accelerated reRT was delivered using 1.5-Gy fractions given twice daily with an interfraction interval of ≥6 hours. The most common reRT regimen was 39 Gy in 26 twice daily fractions but ranged from 30 to 51 Gy depending on extent of field overlap, prior dose delivered and reRT interval. All patients were treated with IMRT-based reRT. For patients with primary anal cancer arising in a previously radiated field, we typically included the gross tumor volume plus full elective nodal coverage of the pelvis and groins. For recurrent anal cancer, we typically only included the gross disease plus set up margin rather than treating the full elective volume a second time. Concurrent chemotherapy was given at the discretion of the treating medical oncologist. Complete clinical response (cCR) was assessed at approximately 3 months post-reRT and was defined by no evidence of disease on digital rectal exam, endoscopic exam and cross-sectional imaging.

Statistical analysis

Baseline characteristics, oncologic outcomes, and toxicities were reported using descriptive statistics. Locoregional recurrence was defined as a local or regional nodal recurrence of disease or persistence of disease after reRT. Cumulative incidence of locoregional failure curves were generated for pelvic failure after reRT. Kaplan-Meier curves were generated for OS after reRT. Software used for analysis was JMP, Version 18. SAS Institute Inc.

Results

We identified 35 patients who were treated with hyperfractionated accelerated reRT for SCCA. Median (IQR) follow-up from reRT was 13.4 (7.5-42.2) months. The majority of patients (N = 26, 74.3%) were treated with reRT for locoregionally recurrent SCCA a median (IQR) of 2.9 (2.1-4.8) years after initial CRT. Of those, 15 (57.7%) were treated for their first recurrence and 11 (42.3%) were treated for their second recurrence after salvage APR. Four (15.4%) had T1 SCCA at initial presentation while 13 (50%) had T2, 3 (11.5%) had T3, 4 (11.5%) had T4, and the T-stage was unknown for 3 (11.5%). Thirteen patients (50%) had node negative disease at initial presentation while 10 (38.5%) had node positive disease, and the N-stage was unknown for 3 (11.5%). Nine patients (25.7%) were treated with reRT for a new SCCA diagnosis after previously being treated with pelvic radiation for a different malignancy. Of the 9 patients whose first course of radiation was for a prior pelvic malignancy, 4 were treated with external beam radiation for prostate cancer in the range of 70 to 72 Gy, 2 were treated with low-dose-rate brachytherapy monotherapy for prostate cancer with an iodine implant to 145 Gy, 1 was treated with external beam radiation for endometrial cancer to a total dose of 60 Gy, 1 patient was treated with combined external beam and pulsed dose rate brachytherapy for cervical cancer to a total dose of 85 Gy equivalent dose in 2 gray fractions, and the final patient was treated with external beam radiation for ovarian dysgerminoma to a total dose of 40 Gy in 20 fractions. Patient and treatment characteristics are given in Table 1.

Table 1.

Treatment characteristics for patients treated with definitive reirradiation for anal squamous cell carcinoma

Recurrent SCCA (N = 26) New SCCA primary after prior pelvic radiation (N = 9)
Age at reRT in years; median (IQR) 58 (53-66) 72 (60-81)
Sex; N (%)
 Female
 Male
19 (73.1)
7 (26.95)
3 (33.3)
6 (66.7)
Human immunodeficiency virus status; N (%)
 Negative
 Positive
22 (84.6)
4 (15.4)
8 (88.9)
1 (11.1)
Dose of initial radiation in Gy; median (IQR) 54 (54-58) 70 (64.2-145)
Reirradiation interval in years; median (IQR) 2.9 (2.1-4.8) 7.4 (5.6-31.1)
Tumor size in cm; median (IQR) 4.6 (2.0-6.1) 4.0 (3.0-4.5)
Extent of infiltration; N (%)
 Invades pelvic organs
 Invades pelvic sidewall
 Invade both
 Invades neither
7 (26.9)
3 (11.5)
8 (30.8)
8 (30.8)
0 (0)
0 (0)
0 (0)
9 (100)
Reirradiation dose in gray; median (IQR) 39 (39-45) 42 (39-46.5)
Reirradiation volume; N (%)
 Anal tumor only
 Nodal recurrence only
 Anal tumor plus standard elective clinical target volume coverage
13 (50)
11 (42.3)
2 (7.7)
1 (11.1)
0 (0)
8 (88.9)
Induction chemotherapy prior to reRT; N (%)
 No
 Yes
10 (38.5)
16 (61.5)
7 (77.8)
2 (22.2)
Concurrent chemotherapy; N (%)
 None
 Cis/5FU
 5FU or cape
 Other
4 (15.4)
10 (38.5)
6 (23.1)
6 (23.1)
0 (0)
7 (77.8)
2 (22.2)
0 (0)
Complete clinical response after reRT
 Yes
 No
12 (46.2)
14 (53.8)
7 (77.8)
1 (22.2)
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Abbreviations: 5FU = 5-fluorouracil; reRT = reirradiation; SCCA = squamous cell carcinoma of the anus.

Among patients treated with reRT for recurrent SCCA, 12 (46.2%) attained a cCR at 3 months posttreatment. The cCR rate was higher among patients treated with reRT for a new SCCA primary after prior pelvic radiation (N = 7, 77.8%). Two-year locoregional recurrence rate was 64% among patients with recurrent anal cancer and 22% among patients treated with reRT for a new SCCA primary after prior pelvic radiation (log-rank P = .098) (Fig. 1).

Figure 1.

Figure 1 dummy alt text

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Incidence of local failure for patients treated with reirradiation for anal cancer.

Among patients treated with reRT for recurrent SCCA, 13 (50%) developed distant metastases, and 11 of those patients died with progressing metastatic disease. However, among patients with primary SCCA in a previously irradiated field, only 1 patient developed a solitary lung metastasis that was successfully treated with radiation. That patient remains without evidence of disease more than 5 years posttreatment. At the time of last follow-up, 17 (65.4%) patients treated with reRT for recurrent SCCA and 5 (55.6%) of patients treated with reRT for primary SCCA in a previously irradiated field had died (log-rank P = .900) (Fig. 2). All but 1 patient who died after reRT for recurrent SCCA died with progressing disease while only 1 patient who died after reRT for primary SCCA in a previously irradiated field died with progressing disease.

Figure 2.

Figure 2 dummy alt text

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Overall survival for patients treated with reirradiation for anal cancer.

In the total cohort, 8 patients (22.9%) developed acute grade 3 toxicity during or within 6 weeks of reRT; 5 (19.2%) among patients treated with reRT for recurrent SCCA and 3 (33.3%) among patients treated with reRT for primary SCCA in a previously irradiated field. Grade 3 acute toxicities included diarrhea (N = 2), anal canal pain (N = 5), dermatitis (N = 1). One patient (2.9%) required a 2-day treatment break due to a hospital admission for nausea and vomiting, thought to be related to concurrent chemotherapy, and 2 patients (5.7%) stopped treatment early. One patient elected to forgo her last 2 fractions due to pain; she finished 27 Gy of a planned 30 Gy. Another patient developed small bowel obstruction after receiving 7.5 Gy of a planned 39 Gy reRT and required urgent surgery; on surgical exploration, the small bowel obstruction was found to be related to peritoneal disease and was not a complication of reRT.

In the total cohort, 10 patients (286%) developed late grade 3+ toxicity; 6 (23.1%) among patients treated with reRT for recurrent SCCA and 4 (40%) among patients treated with reRT for primary SCCA in a previously irradiated field. Details of late toxicities can be found in Table 2. Most late toxicities were managed with medications and/or procedures, though 3 patients developed catastrophic complications potentially attributable to reRT. One patient treated with 42 Gy reRT after iodine brachytherapy for prostate cancer 15 years prior developed a rectourethral fistula 5 months after reRT and died from complications related to pelvic abscess 11 months after reRT. Another patient treated with 39 Gy reRT for recurrent SCCA 4.3 years after an initial 55.8 Gy course developed a rectovaginal 3 months after completing reRT; that patient was referred to hospice shortly thereafter and passed away from complications related to pelvic abscess. A final patient treated with 45 Gy reRT for recurrent SCCA after an initial 59 Gy course developed an enterocutaneous fistula 5 months after completing reRT. It was unclear whether the fistulas were a result of radiation toxicity and/or local disease progression. Numerically, more patients treated with reRT doses >39 Gy developed late G3+ toxicity (N = 6 of 14) compared with those treated with reRT doses ≤39 Gy (N = 4 of 21), but the difference was not significant (P = .127).

Table 2.

Patients with G3+ late toxicity after reirradiation

Initial radiation course HIV status Reirradiation interval Reirradiation dose and fractionation Radiation field Toxicity
External beam + brachytherapy for cervical cancer (36.23 Gy to the right parametria and 23.16 Gy to the left parametria + two 72 h brachytherapy implants) without concurrent chemo Negative 46 y 48 Gy in 32 twice daily fractions with concurrent 5FU Anal tumor plus full elective nodal volume 8 mo after reRT, developed grade 3 radiation-induced stricture of the distal ureter leading to hydronephrosis managed with ureteral stent placement.
Iodine brachytherapy for prostate cancer without concurrent chemo. Unknown prior radiation dose Positive 15 y 42 Gy in 28 twice daily fractions with concurrent cis/5FU Anal tumor plus full elective nodal volume 5 mo after reRT, developed grade 4 rectourethral fistula. Treated with diverting ostomy and palliative care.
70 Gy in 35 fractions salvage treatment for prostate cancer without concurrent chemo Negative 5 y 45 Gy in 30 twice daily fractions with cis/5FU Anal tumor plus full elective nodal volume 3 mo after reRT, developed grade 3 chronic pain requiring a nerve block and grade 3 fecal incontinence requiring use of daily pads.
40 Gy in 20 fractions for ovarian cancer Negative 47 y 42 Gy in 28 twice daily fractions with cis/5FU Anal tumor plus full elective nodal volume 4 mo after reRT, developed grade 3 chronic diarrhea and radiation proctitis with urgency and incontinence requiring use of daily pads.
58 Gy in 29 fractions for a T3N+ SCCA with 5FU/MMC Positive 2 y 39 Gy in 26 twice daily fractions with 5FU Anal tumor only 3 mo after reRT, developed grade 3 radiation proctitis with bleeding requiring transfusion and endoscopic intervention
50.4 Gy in 28 fractions for a T2N0 SCCA with 5FU/MMC Negative 6 y 39 Gy in 26 twice daily fractions with cis/5FU Anal tumor only 9 mo after reRT, developed grade 3 small bowel obstruction requiring hospitalization but resolved with conservative measures
30.6 Gy in 17 fractions for T2N1 SCCA with cis/5FU (treatment stopped early due to toxicities) Negative 3.3 y 51 Gy in 34 twice daily fractions with cis/5FU Anal tumor plus full elective nodal volume 6 mo after reRT, developed grade 3 urethral stricture requiring dilation
62 Gy in 32 fractions for T4N+ SCCA with 1 cycle of 5FU/MMC during radiation and a second one after treatment ended due to poor tolerance Negative 2 y 39 Gy in 26 twice daily fractions without concurrent chemo Anal tumor only 6 mo after reRT, developed grade 3 lymphedema treated with a compression garment and manual lymphatic drainage therapy.
55.8 Gy in 31 fractions for T3N+ SCCA with 5FU/MMC Negative 4.3 y 39 Gy in 26 twice daily fractions without concurrent chemo Anal tumor only 3 mo after reRT, developed grade 3 rectovaginal fistula with possible abscess. Patient was referred to hospice.
59 Gy in 30 fractions for T3N+ SCCA with 5FU/MMC Positive 12 y 45 Gy in 30 twice daily fractions with initial concurrent 5FU (discontinue due to neurologic changes) Anal tumor only 9 mo after reRT, developed grade 3 pain, with enterocutaneous fistula potentially related to necrotic tumor vs reRT toxicity. Patient was referred to hospice.
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Abbreviations: 5FU = 5-fluorouracil; MMC = mitomycin C; reRT = reirradiation; SCCA = squamous cell carcinoma of the anus.

There appeared to be a relationship between rates of late toxicity and the extent of the reRT field. Of the 11 patients treated focally to a nodal recurrence, 91% experienced no G2+ late toxicities and only 1 (9%) reported late G2 diarrhea after reRT. Of the 14 patients treated focally to an anal recurrence (N = 13) or new anal primary (N = 1), 7 (50%) experienced no G2+ late toxicities, 1 patient had G2 toxicity only, 5 had both G2 and G3+ toxicities and 1 could not be assessed for late toxicity due to development of tumor-related fistula on fraction 3 of reRT and requiring urgent laparoscopy and diversion at which time peritoneal disease was found. Of the 10 patients treated to full elective nodal volumes for recurrent disease (N = 2) or a new anal primary (N = 8), 5 (50%) experienced no G2+ toxicities, 1 patient had G2 toxicity, 3 patients had both G2 and G3+ toxicities, and 1 had G3+ toxicity only. Additionally, persons living with HIV seemed to develop late toxicities disproportionate to their representation within the cohort. While only 5 patients in this cohort (14.2%) were HIV positive, they made up 30% of those patients experiencing late G3+ toxicities.

Discussion

In this retrospective review, we describe oncologic outcomes and toxicities for 35 patients treated with a hyperfractionated accelerated reRT regimen consisting of 1.5 Gy per fraction, delivered twice daily with a 6-hour interfraction interval to a total of 30 to 51 Gy, but most commonly 39 Gy. We found reRT to result in cCR in 54% of patients with reasonable toxicities. There may be a correlation between higher reRT doses and increased risk of G3-4 toxicities, but the numbers were too small in our study to say with certainty.

Hyperfractionated accelerated pelvic reRT has been studied for salvage preoperative or definitive treatment in patients with recurrent rectal adenocarcinoma at our institution. In a study by Tao et al,32 patients were treated with a similar regimen to our cohort of patients using the same twice daily regimen used in our study. Among patients who were treated with definitive intent, 3-year freedom from local progression was 30% and 3-year OS was 20%. Modest reRT doses would be expected to have a better chance of control with SCCA compared with rectal adenocarcinoma given what we know about their relative radioresponsiveness.33 Indeed, Osborne et al25 showed 3-year freedom from local progression of 56% in a small series (n = 10) of patients treated with the same hyperfractionated accelerated reRT for recurrent SCCA at our institution between 2003 and 2012. However, the Osborne series included a mix of patients who received reRT with definitive and preoperative intent. In the current series, we restricted our analysis to patients who received definitive reRT without subsequent surgery and found over 50% of patients attained a cCR after reRT, but among patients with primary SCCA arising in a previously irradiated field, the cCR rate was even higher at 77.8%. Patients treated with reRT for recurrent SCCA had a lower cCR rate which is likely due to more aggressive biology, infiltrative nature of recurrent disease and potential radioresistance of recurrent tumors. Initial cCR rates appeared to be durable, with only 2 patients who had attained a cCR developing subsequent local recurrence. The patients with HIV in our cohort, however, did not achieve durable LC, suggesting more aggressive disease.

There are few other treatment options for patients with previously treated inoperable local recurrences from SCCA. Immunotherapy has promise, with NCI9673 showing a response rate in 9 patients (24%) with unresectable metastatic SCCA after treatment with nivolumab. Two of those patients developed cCR.34 Especially for patients with disease confined to the pelvis, however, local strategies are desirable. A small series describing interstitial brachytherapy to a dose of 120 Gy to the gross tumor volume for locally recurrent anorectal cancers included 3 patients with locally recurrent SCCA.35 One-year LC was 80% in this series, but numbers were small and this approach requires specialized technical expertise.

With regard to toxicity, we found 22.9% of patients developed acute grade 3 toxicity during or immediately after treatment and 28.6%% developed late grade 3-4 toxicity long term. Acute grade 3 toxicities were similar to what is seen with initial standard CRT for SCCA: diarrhea, pain, and dermatitis. Late toxicities included higher rates of fistula and stricture than are typically seen with initial standard CRT.1 However, only 14 patients (40%) were alive with more than 2 years of follow-up due to patients dying or electing to transfer follow up to a closer institution to their home. This limits our ability to outline true rates of toxicity or durability of control. Numerically, rates of these more serious late toxicities seemed to be higher with reRT doses in excess of 39 Gy, even with a prolonged reRT interval of >10 years. Numbers in this study were too small for reliable analysis, but our group has moved toward limiting reRT dose to 39 Gy for most situations, and even prescribing 30 Gy for cases with considerable overlap of the reRT field with prior delivered doses >54 Gy in the region of the anorectal wall, vagina, ureters, and urethra.

The main limitation of this study is its retrospective nature and relatively small sample size. However, our experience with hyperfractionated accelerated reRT for recurrent SCCA or newly diagnosed SCCA in a previously irradiated field suggests that this treatment approach may be considered for those with inoperable disease. Results were particularly encouraging for patients with new primary anal cancers arising in a previously irradiated field. To minimize risk of toxicity, our current practice is to limit reRT prescription dose to 39 Gy unless there is minimal overlap of the prior radiation field with the anorectal wall, vaginal, ureters, and urethra. We were not able to report cumulative dose metrics in this study as many patients received their initial and reRT courses at different institutions separated by many years, which made evaluation of true composite doses challenging. Innovations such as The Support Tool for Re-Irradiation Decisions guided by Radiobiology project may allow for improved standardized evaluation and reporting in the future.36

Disclosures

Emma B. Holliday receives grant funding from Genentech that is unrelated to this work.

Footnotes

Prior presentations: An earlier version of these data were presented in abstract form as a poster presentation at The American Society for Radiation Oncology in San Diego, CA, September 30–October 4, 2023. Outcomes were updated for this analysis.

Sources of support: This work was supported in part by the Cancer Center Support Grant (NCI Grant P30 CA016672).

Research data are stored in an institutional repository and will be shared on request to the corresponding author.

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