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Salvage Surgery for Locoregional Failure in Anal Squamous Cell Carcinoma

Guerra, Glen, R., M.B.B.S., F.R.A.C.S.1,2,4,5; Kong, Joseph, C., M.S., F.R.A.C.S.1,2,4,5; Bernardi, Maria-Pia, M.B.B.S., F.R.A.C.S.1,4; Ramsay, Robert, G., Ph.D.2,4; Phillips, Wayne, A., Ph.D.1,2,4,5; Warrier, Satish, K., M.S., F.R.A.C.S.1; Lynch, A., Craig, M.S., F.R.A.C.S.1,4; Ngan, Samuel, Y., M.B.B.S., F.R.A.N.Z.C.R.3,4; Heriot, Alexander, G., M.D., M.B.A., F.R.A.C.S.1,4

doi: 10.1097/DCR.0000000000001010
Original Contributions: Colorectal Cancer
Denotes Associated Video Abstract
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BACKGROUND: Anal squamous cell carcinoma is a rare cancer with a high cure rate, making research into the treatment of locoregional failure difficult.

OBJECTIVE: The purpose of this study was to examine factors related to local treatment failure and determine the outcomes of patients undergoing local salvage resection.

DESIGN: This was a retrospective cohort study.

SETTING: This study was conducted at a quaternary referral center.

PATIENTS: Patients with anal squamous cell carcinoma treated with chemoradiotherapy between January 1983 and December 2015 were included.

MAIN OUTCOME MEASURES: The influence of patient-, tumor-, and treatment-related factors on the primary outcome measures of locoregional failure, overall survival, and disease-free survival were investigated.

RESULTS: Of 467 patients with anal squamous cell carcinoma, 63 experienced locoregional failure with 41 undergoing salvage resection. Twenty-seven patients (38%) had persistent disease and 36 (62%) developed locoregional recurrence. Multivariate analysis identified tumor stage (HR, 3.16; p < 0.002) as an independent predictor of locoregional failure. Thirty abdominoperineal resections and 11 pelvic exenterations were undertaken with no surgical mortality. At a median follow-up of 20 months (range, 4–150 months), 5-year overall and disease-free survival for the salvage cohort was 51% and 47%. Margin positivity was an independent predictor for relapse post-salvage surgery on multivariate analysis (HR, 20.1; p = 0.027). Nineteen patients (48%) developed further relapse, which included all 10 patients with a positive resection margin, 3 of whom underwent re-resection. Of the 19 patients with relapse, 3 remain alive and 2 have persistent disease.

LIMITATIONS: Limitations include the retrospective nature of the database, the prolonged time period of the study, and episodes of incomplete data.

CONCLUSIONS: Advanced T stage is an independent predictor of local failure in anal squamous cell carcinoma. Most patients can be salvaged, with a positive resection margin being a strong predictor of further relapse and poor outcome. See Video Abstract at

1 Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

2 Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

3 Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

4 Sir Peter MacCallum Department of Oncology, University of Melbourne, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

5 Department of Surgery, University of Melbourne, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

6 Department of Pathology, University of Melbourne, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Funding/Support: Dr Guerra was supported by Royal Australasian College of Surgeons (RACS) Foundation for Surgery, ANZ Journal of Surgery and Tour de Cure Scholarships; Cancer Therapeutics CRC Top-Up Scholarship and NHMRC Postgraduate Research Scholarship (PGS). Dr Kong was supported by RACS Raelene Boyle, Paul MacKay Bolton, and John Loewenthal scholarships and a NHMRC PGS.

Financial Disclosure: None reported.

Glen R. Guerra and Joseph C. Kong are co-first authors and have contributed equally to this study.

Podium presentation at the meeting of The American Society of Colon and Rectal Surgeons, Seattle, WA, June 10 to 15, 2017.

Correspondence: Glen R. Guerra, M.B.B.S., F.R.A.C.S., Division of Cancer Surgery, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, Victoria, 3000, Australia. E-mail:

Anal cancer is a rare disease accounting for 2.5% of all GI cancers with squamous cell carcinoma (SCC) the most common histological subtype.1 , 2 Definitive chemoradiotherapy remains the primary management, following the seminal work of Norman Nigro in the 1970s.3 Subsequent phase III randomized controlled trials confirmed oncological equivalence of this regimen, relegating surgery to a salvage role. With sequential modifications over the ensuing 4 decades, this regimen offers 5-year survival rates of 65% to 90% with local control in 70% to 90%.4–10

Local failure in anal squamous cell carcinoma (ASCC) remains a problem in 10% to 30% of patients, portending a poor prognosis and presenting a difficult management problem for symptoms of locally progressive disease. This cohort comprises both patients with persistent disease following chemoradiotherapy (CRT) and patients with recurrent disease after initially achieving a complete clinical response.11–17 Salvage surgery is appropriate in select patients with local failure in an attempt to provide durable local control and possible cure. Abdominoperineal resection (APR) is the traditional salvage operation for patients with local failure; however, as is the nature with other advanced perineal and pelvic tumors, extended resections and multivisceral exenterations with autologous flap reconstructions are often required. Overall survival for patients with local failure has ranged extensively on review of the literature, from 23% to 78%, with improved survival where management has included more radical surgical approaches.13 , 14 , 18–27 Consequently, prediction of success is foremost in the selection of appropriate patients for salvage surgery.

The aim of the study is to assess the long-term outcomes associated with local salvage surgery for ASCC, and the modified approaches used at a quaternary center. Predictive variables of local failure and the success of salvage surgery are examined to guide future patient selection and management decisions.

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Cohort Selection

A search of a retrospective anal cancer database was performed. This contains information on all patients with anal cancer treated at a single quaternary referral center over a 33-year period (January 1983 through December 2015). The database was interrogated for patients diagnosed with SCC of the anal canal or margin and treated with curative-intent radical CRT over this period with a standardized protocol. Patients with metastatic disease, those managed with radiotherapy alone, and patients without adequate follow-up were excluded. Although the radiotherapy technique (2-D radiotherapy, 3-D conformal radiotherapy, intensity-modulated radiotherapy) has evolved over time, 90% of patients received a total dose of 50.4 to 54 Gy in conjunction with chemotherapy in the form of 5-fluorouracil and mitomycin C. Data collection and extraction was approved by the Peter MacCallum Human Research Ethics Committee.

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Patient Evaluation

Pertinent demographic and clinical data were extracted. Tumor staging was undertaken in accordance with the American Joint Committee on Cancer 2010 TNM staging system for anal cancer, involving a combination of clinical, radiological, and histological means.28 Response to primary treatment was confirmed in a similar manner. In the earlier years of this cohort, patients were predominantly assessed by clinical (digital ano-rectal and nodal basin examination) and histological means in conjunction with a CT scan for exclusion of distant disease. More recently, this compares with where patients are assessed on clinical and radiological grounds given the improved adjuncts of PET/CT and MRI for regional and distant disease staging. Nonetheless, histological confirmation has remained the mainstay of clarifying equivocal clinical or radiological findings.

Assessment of response was undertaken in the period of 6 weeks to 6 months after the completion of primary therapy. Patients were then followed up clinically every 3 months for the first 3 years, every 6 months out to five years, and annually thereafter. Digital ano-rectal and nodal examination was the mainstay of assessment, with adjunctive scans performed at the clinician’s discretion once a complete clinical response had been confirmed to exclude locoregional relapse and distant disease. Time to disease relapse following completion of CRT was recorded from the date of response assessment, with patients with local relapse classified as harboring persistent or recurrent disease. Persistent disease was defined as an incomplete response to primary treatment. Recurrent disease was defined as evidence of tumor relapse at least 6 months following primary therapy and after achieving an initial complete response.

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Salvage Surgery

Surgical treatment details were recorded including the specifics of extended resections and the type of flap reconstruction when utilized. Tumor characteristics were recorded in addition to resection margin status. Postoperative patients were reviewed clinically within the first month, followed by every 3 months in the first year, and every 4 to 6 months subsequently. Imaging (PET/CT, MRI) was used to assist assessment and biopsies were taken as deemed appropriate. Time and site(s) of relapse were also recorded.

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End Points

The primary end points included overall survival (OS) and disease-free survival (DFS) measured from the date of diagnosis. Time to locoregional failure (LRF) and time to re-recurrence were also examined, from the date of response assessment to the last follow-up or event. Wound complication rates were examined in the salvage cohort.

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Statistical Analysis

Time-to-event analyses were undertaken for all patients with ASCC and the subsets of LRF and salvage surgery by Kaplan-Meier analysis. This included time to initial local recurrence, re-recurrence after salvage surgery, and DFS and OS for all cohorts. The log-rank test was used to assess the difference between groups. The cumulative incidence method was used to analyze patient, tumor, and treatment characteristics. Univariate analysis was performed to identify significant predictors of LRF in the entire cohort and of re-recurrence in the salvage surgery subset. Fisher exact or Pearson χ2 tests were performed for categorical data and a Student t test for continuous data. Multivariate analysis with a Cox proportional hazards model via stepwise selection was used to identify independent predictive factors for time-to-event outcomes. A p value of <0.05 was accepted to demonstrate statistical significance. Follow-up data were recorded through to December 2016. Statistical analysis was performed by using Graphpad Prism 7 (La Jolla, CA) and IBM SPSS Statistics for Windows software (IBM Corp, Version 23, Armonk, NY).

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Patient Characteristics

Four hundred eighty-three ASCC patients were identified, of which 467 received curative-intent CRT and were included for analysis. Baseline patient and tumor characteristics and subsequent treatment and outcomes are displayed in Table 1 and Figure 1. Follow-up data were available over a median of 5 years (range, 0–21 years). Eighty-eight patients were identified to have failed primary therapy, 25 with distant disease and 63 with LRF. Of those with LRF, 41 underwent local salvage surgery with curative intent. The rarity of HIV-positive patients in this cohort reflects the referral patterns in Melbourne, with a dedicated HIV service colocated with another radiation oncology center.





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Primary Treatment Characteristics

Curative-intent definitive CRT was administered to a median dose of 54 Gy including the inguinal nodal basins for those patients with involved nodes. From the mid-1990s onward, patients with T2-4N0 disease were managed with prophylactic irradiation (36 Gy) to the inguinal region. Twenty-four patients were unable to complete their radiotherapy treatment, with a further 36 having modification of their chemotherapy regimen. Median time to assessment of response after completion of CRT was 73 days (range, 27–235). Median survival of the entire cohort was 19 years, with a 5-year OS of 83% (95% CI, 78%–86%) and 5-year DFS of 80% (95% CI, 76%–83%).

Univariate analysis of the entire cohort identified that T stage, N stage, adjacent organ involvement, and incomplete primary treatment (but not treatment interruption) were predictors of LRF. Only T stage reached statistical significance as an independent predictor of local recurrence over time in a Cox proportional hazards model, with a HR of 3.15 (95% CI, 1.52–6.53; p = 0.002) (Table 1). The 5-year LRF-free rate for T3/4 patients was 72% (95% CI, 62%–79%) compared with 92% (95% CI, 88%–95%; p < 0.001) for T1/2 patients (Fig. 2).



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Locoregional Relapse and Salvage Surgery

At a median time to assessment of 83 days (range, 32–235), 27 patients were confirmed to have persistent disease, of which 19 underwent local salvage surgery. Thirty-six patients subsequently developed local recurrence at a median duration of 15 months (range, 6–111) following confirmation of a complete clinical response. Twenty-two of the patients with local recurrence subsequently underwent salvage surgery.

The outcome for patients that had persistent or recurrent disease who did not undergo salvage surgery is displayed in Figure 1. Reasons for exclusion included inoperable disease, unfitness for surgery, patient refusal, and the development of a second incurable cancer. Ten node-negative patients from the first decade of the cohort developed inguinal node-only relapse, which was managed with CRT (given the basins had not been treated prophylactically).

Of the 41 patients who underwent salvage, 18 were male and 23 were female; their median age was 60 years (range, 39–86). Thirty patients underwent an APR with or without a posterior vaginectomy (8 patients). Eleven patients underwent an extended resection or exenteration including sacrectomy (n = 6), vaginectomy (n = 5), lateral pelvic sidewall dissection (n = 4), hysterectomy and salpingo-oophorectomy (n = 4), cystoprostatectomy (n = 2), cystectomy (n = 1), inguinal node dissection (n = 1), vascular resection (n = 1), and intra-operative radiotherapy (n = 3). The majority of specimens demonstrated poor differentiation (66%) with lymphovascular or perineural invasion identified in 37%. Margins were clear in 71% of resections, and all specimens were found to be node negative. The location of the tumor and the exenterative procedure undertaken did not stratify for an increased likelihood of a positive margin, but the small numbers limit interpretation.

Of the patients undergoing salvage surgery, 5-year and median OS for the persistent cohort was 41% and 2.3 years, compared with 59% and 6.3 years for the recurrent group. This difference failed to reach statistical significance (p = 0.64). Median time to recurrence did not predict whether patients underwent salvage surgery, with a similar time to failure between patients who subsequently underwent salvage or not (1.4 vs 1.2 years; p = 0.32). Median time to recurrence was similar for patients who survived or died after salvage surgery (1.3 vs 1.8 years; p = 0.3). Furthermore, persistence did not predict for an involved surgical margin compared with recurrence (p = 0.83).

A total of 21 patients in our salvage cohort underwent flap repair of the perineum with complications recorded in 8 (38%; vacuum-assisted closure n = 6, flap revision n = 2). In the nonflap salvage patients, 7 (35%) experienced wound breakdown with delayed healing. Two patients required a repair of a perineal hernia on follow-up, both with an autologous flap. There was no statistically significant difference identified in wound complications between the 2 groups (p = 0.84).

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Recurrence and Survival After Salvage Surgery

At a median follow-up of 20 months (range, 2–210 months) and no postoperative mortality, 5-year OS was 51% (95% CI, 33%–67%), DFS 47% (95% CI, 31%–64%), and local DFS 50% (95% CI, 32%–66%) (Fig. 3). One patient was lost to follow-up with no evidence of disease at the 2-month time point. There was no statistical difference in OS for the salvage patients based on the operation undertaken.



Nineteen patients developed relapse of disease post-salvage surgery, with 16 patients dying of their disease and 2 alive with disease at the conclusion of the study (5 and 15 months follow-up). The remaining patient with relapse underwent a partial hepatectomy for an isolated liver metastasis, and is currently alive and disease free at 2.5 years follow-up.

The patterns of re-recurrence are detailed in Figure 1. This group included all 10 patients with a positive resection margin. Three of these with local recurrence post-APR, underwent curative-intent pelvic exenterations, 2 of which received preoperative chemotherapy and reirradiation in addition to intraoperative radiation therapy. Despite the radical treatment, all 3 had a relapse and died of their disease.

To identify predictive variables, we analyzed the relapse rate of the 41 patients who underwent curative-intent salvage surgery. Univariate analysis identified tumor size and margin positivity with subsequent Cox proportional hazards testing identifying margin positivity alone as an independent predictor of further recurrence, with a HR of 20.38 (95% CI, 1.41–296) (Table 2). Kaplan-Meier analysis demonstrated a significant difference in 5-year OS of 66% (95% CI, 41%–80%) for R0 vs 7% (95% CI, 1%–32%) for R1/2 (Fig. 4).





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Definitive CRT offers a high rate of cure in ASCC. The rarity of this tumor and low failure rate after CRT make research into the treatment of LRF difficult. In our series of 467 patients, 63 patients experienced LRF, translating to a 5-year LRF rate of 14% (95% CI, 11%–19%). This is consistent with Radiation Therapy Oncology Group 98-11 results (5-year LRF rate of 20%).29 When patient and tumor factors of the entire pretreatment cohort were examined for prediction of LRF, only T stage reached statistical significance on multivariate analysis. This is in contrast to the results of the European Organisation for Research and Treatment of Cancer trial, which also demonstrated that nodal involvement was an independent predictor of local recurrence over time, irrelevant of the site or extent of nodal disease.9 Given that the majority of patients in our cohort are from the mid-1990s onward, our results may reflect improvements in the delivery of treatment compared with the period of time over which the European Organisation for Research and Treatment of Cancer study was undertaken.

For the cohort of patients who experience LRF, the majority can be salvaged with surgery offering an improved OS. In our cohort, 41 patients (65%) underwent curative-intent local salvage surgery with a 30-day mortality rate of zero, and a 5-year OS and DFS of 51% and 47%. The OS of our cohort sits midway within the range quoted in the literature of 23% to 78%.14 , 15 , 17 , 18 , 20–23 However, this approach often necessitates aggressive and complex surgery. Although APR +/– posterior vaginectomy was the most common operation until the early 2000s, more than 50% of our salvage patients underwent an extended resection in the second half of our study period. This has provided the ability to offer a further line of treatment with an aim of cure to patients who would otherwise face palliation.

Despite salvage surgery offering a curative second line of treatment, the magnitude of this form of surgery necessitates a patient who is medically fit to survive the taxing perioperative period. Consequently, patient selection and preoperative planning are of critical importance, but remain a challenge. On examining predictive factors of relapse post-salvage surgery, only the resection margin reached statistical significance on multivariate analysis. This is in keeping with the findings of previous studies and further emphasizes the importance of achieving an R0 resection given its impact on outcome.14–17 Our margin positivity rate of 29% is within the range reported in the literature of 5% to 41%.14 , 18 , 24 , 27 , 30

For those with relapse post-salvage surgery, the outcome is dismal, and, consequently for most patients, there is only once chance to perform an adequate salvage operation. The most important factors to consider when evaluating patients with LRF for salvage surgery are the exclusion of metastatic disease and determining the likelihood of a margin-negative resection. However, significant limitations still exist in identifying resectable patients, despite advances in imaging and exenterative surgery. The increased uptake of CT/PET and MRI as a modality for both pre- and posttreatment staging has significantly improved the ability to more accurately determine resectability. Nonetheless, inflammatory change, postradiotherapy scarring, and the desmoplastic effects of the tumor at differing time points can all confound the ability to accurately predict a negative resection margin. Despite performing exenterative surgery in 11 patients, over a third (4 patients) had a positive margin. Three of these 4 were treated with intraoperative radiotherapy at the time of the resection, given the suspicion of microscopic involvement or confirmation on frozen section. All 4 patients went on to have a relapse despite these measures. This is in keeping with previous results, where clear evidence of the benefit of intraoperative radiotherapy is lacking.16 , 31

There has been longstanding conjecture on what is the appropriate time period to wait before declaring a patient as having achieved a complete response or as having persistent disease. This is not dissimilar to determining a posttreatment response in rectal SCC or, more recently, in rectal adenocarcinoma, which has gained much attention since the advent of the novel watch-and-wait approach.32 , 33 In our series, median time to assessment was 87 days in the LRF group, with a range of 27 to 235 days posttreatment completion. A recent re-analysis of the ACTII trial identified that a number of ASCC patients do not attain a complete response to primary treatment until the 6-month mark.34 This delayed regression is of particular importance in ensuring that patients are not salvaged prematurely, given the radical surgical approach and significant morbidity that accompanies it. Furthermore, delaying the assessment of response in patients without clear progression also provides time for occult metastatic disease to become apparent, further reducing the incidence of futile surgery. Given that our median assessment period was significantly less than that currently recommended, it may have increased the incidence of patients with persistent disease undergoing salvage surgery, and spuriously improved the survival of that subset.

Perineal wound healing in a radiotherapy-affected field is often poor, with flaps utilized in more recent times in an attempt to improve healing and reduce morbidity. Rectus abdominis flaps dominated as the flap of choice at our institution until 2014. Subsequently, the inferior gluteal artery myocutaneous flap became the standard for reconstruction, because it preserves the anterior abdominal wall for stoma siting, and can be performed entirely following the resection in the prone position. However, despite the proposed benefits, of the 21 patients in our salvage cohort who underwent flap closure, 38% (8 patients) experienced a complication requiring a return to the operating theater, with 2 requiring a second flap. This is significantly higher than that reported previously, and similar to perineal wound complications in those with primary closure.18 , 20 , 35 However, the majority of these complications occurred early in the study period, with only 1 complication affecting the last 9 flaps performed, and none since instituting the inferior gluteal artery myocutaneous flap (n = 6).

Although the salvage cohort has not achieved the same level of survival as primary therapy, it is likely that failure of CRT reflects a more biologically aggressive tumor, rendering itself more difficult to salvage by any means. Human papillomavirus-positive tumors are traditionally more radiosensitive, a variable that was not captured in our data set.36 It would be of interest to identify whether p16-negative patients have a higher local failure rate and whether this may act as a marker of resistance.

There are several limitations to the conclusions that can be drawn from our results. Despite our institution being a major referral center for anal cancer treatment, the infrequency of patients precludes a large cohort size, particularly when examining the salvage group. Furthermore, the data collection is retrospective, in some cases incomplete, and over a prolonged time period, during which there have been some changes in practice. These factors have limited the degree to which the data can be statistically analyzed and interpretations made. Given the limited number of HIV patients in this cohort, inferences regarding the effectiveness of salvage surgery also cannot be generalized to this population. Nonetheless, this study has provided insight into the success of local salvage surgery in patients with relapsed ASCC, and reaffirmed it as the best currently available line of treatment for this patient group.

In the current era, patients who do not respond to definitive CRT continue to present a treatment challenge. With the advent of new treatment modalities, there is the possibility of improved treatment options and response. The role of these therapies, either in conjunction with neoadjuvant or as a second line of therapy, are yet to be explored in anal cancer, however. Consequently, at present, salvage surgery remains the most successful course of treatment, offering long-term survival in over half of those salvaged for local relapse. Appropriate patient selection along with careful preoperative planning and frequently extended resections are required to achieve a negative resection margin, which is critical to the success of this treatment pathway.

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Anal cancer; Chemoradiotherapy; Locoregional failure; Salvage surgery; Squamous cell carcinoma

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