Salvage Abdominoperineal Resection for Squamous Cell Anal Cancer: A 30-Year Single-Institution Experience

Salvage Abdominoperineal Resection for Squamous Cell Anal Cancer: A 30-Year Single-Institution... Ann Surg Oncol (2018) 25:1970–1979 https://doi.org/10.1245/s10434-018-6483-9 OR IGINAL ARTIC L E – COLORECTAL CANCER Salvage Abdominoperineal Resection for Squamous Cell Anal Cancer: A 30-Year Single-Institution Experience 1 2 2 3 J. A. W. Hagemans, MD , S. E. Blinde, MD , J. J. Nuyttens, MD, PhD , W. G. Morshuis, MD , M. A. M. Mureau, 4 1 1 1 MD, PhD , J. Rothbarth, MD, PhD , C. Verhoef, MD, PhD , and J. W. A. Burger, MD, PhD Department of Surgical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Radiation Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Anesthesiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Plastic and Reconstructive Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands ABSTRACT repeat salvage surgery and 4 months (95% CI 2.8–5.1 Background. Failure of chemoradiotherapy (CRT) for months) following palliative treatment (p = 0.055). anal squamous cell carcinoma (SCC) results in persistent or Conclusions. Salvage APR for anal SCC after failed CRT recurrent anal SCC. Treatment with salvage resulted in adequate survival, with 5-year survival of abdominoperineal resection (APR) can potentially achieve 41.6%. Negative prognostic factors for survival were cure. The aims of this study are to analyze oncological and increased tumor size, lymph node involvement, and irrad- surgical outcomes of our 30-year experience with salvage ical resection. Patients with recurrent anal SCC after APR for anal SCC after failed CRT and identify prognostic salvage APR had poor prognosis, irrespective of perfor- factors for overall survival (OS). mance of repeat salvage surgery, which never resulted in Methods. All consecutive patients who underwent salvage cure. APR between 1990 and 2016 for histologically confirmed persistent or recurrent anal SCC after failed CRT were Squamous cell carcinoma (SCC) of the anal canal is a retrospectively analyzed. Results. Forty-seven patients underwent salvage APR for relatively rare malignancy, but its incidence has increased over the last few years. Currently, chemoradiotherapy either persistent (n = 24) or recurrent SCC (n = 23). Median OS was 47 months [95% confidence interval (CI) (CRT) is standard of care for anal cancer, resulting in superior local control compared with radiotherapy alone 10.0–84.0 months] and 5-year survival was 41.6%, which 2–8 with 5-year survival rates of 60–80%. CRT leads to did not differ significantly between persistent or recurrent disease (p = 0.551). Increased pathological tumor size (p\ preservation of the anal sphincter by avoiding surgery. Unfortunately, CRT fails in 20–30% of patients, resulting 0.001) and lymph node involvement (p = 0.014) were associated with impaired hazard for OS on multivariable in persistent (10–15%) or local recurrent disease 2–7,9 (10–15%). analysis, and irradical resection only (p = 0.001) on uni- variable analysis. Twenty-one patients developed local Salvage abdominoperineal resection (APR) is often the only option for patients with persistent or recurrent anal recurrence after salvage APR, of whom 8 underwent repeat salvage surgery and 13 received palliative treatment. SCC to achieve durable local control and survival. Several institutes have reported case series on this topic. However, Median OS was 9 months (95% CI 7.2–10.8 months) after due to heterogeneity in treatment protocols, results on 10–20 patient outcomes vary widely. Our institute has a well- established protocol for treatment of anal SCC, which has The Author(s) 2018 changed little in the last three decades. The aims of the First Received: 13 September 2017; present study are to analyze the results of a 30-year Published Online: 24 April 2018 experience with salvage APR for recurrent and persistent J. A. W. Hagemans, MD anal SCC after failed CRT in a large single-center cohort e-mail: j.hagemans@erasmusmc.nl Salvage Surgery for Anal Cancer 1971 and to identify prognostic factors for overall survival. In and abdomen were used to confirm absence of metastatic addition, outcomes of patients treated for local recurrence disease prior to surgery. developed after primary salvage APR for persistent or recurrent SCC were also analyzed. To the best of the Surgery authors’ knowledge, results of repeat surgery for treatment of local recurrence after salvage APR have never been All patients deemed eligible for complete, curative previously studied. resection underwent salvage APR. Multivisceral resection was performed if necessary. If possible, omentoplasty was PATIENTS AND METHODS performed to fill the pelvis. Primary closure of the perineal defect was routinely performed up to 1999, and if this was not feasible, the open wound was packed for healing by Data of all consecutive patients who underwent salvage APR with curative intent for histologically confirmed secondary intention. From 2000 onwards, the perineal defect was reconstructed with either a vertical rectus persistent or recurrent anal SCC between 1990 and 2016 at the Erasmus MC Cancer Institute, a tertiary referral center abdominis myocutaneous (VRAM) or gracilis muscle 21,22 flap. Inguinal lymph node dissection was performed in in The Netherlands, were retrospectively analyzed. Patient demographics, perioperative variables, tumor characteris- case of biopsy-proven positive lymph nodes. Postoperative tics, neoadjuvant therapy, short- and long-term outcomes, complications were graded according to the Dindo–Clavien and postoperative mortality and morbidity were collected classification. Local recurrence after salvage APR was from medical records, the municipality register, and gen- defined as any local recurrence after salvage APR, eral practitioners. All patients were followed up by our regardless of whether the indication for salvage APR was institute; last update of follow-up was 22 January 2018. for persistent or recurrent anal SCC. The present study was approved by the Erasmus MC local medical ethics committee (registration number MEC-2017- Statistics 448). Survival analysis was performed by Kaplan–Meier Primary Treatment method, and comparisons were made using log-rank tests. Survival was calculated from day of APR until data of All primary malignancies were initially treated with death or last follow-up. Survival rates for recurrence after radiotherapy, and the majority (78.7%) also received con- salvage APR were calculated from date of diagnosis of comitant chemotherapy. Radiotherapy was administered recurrent anal SCC until death or last follow-up. Cox with median dose of 60 Gy [interquartile range (IQR) proportional-hazard models were constructed to identify 60–60 Gy], and chemotherapy was administered in the first prognostic factors in univariable and multivariable analy- sis. Mann–Whitney U and chi-squared test were performed four days of the first week [5-fluorouracil (1000 mg/m ) and mitomycin C (10 mg/m )]. Patients with histologically as appropriate. Covariables with a trend towards signifi- cance (p\ 0.100) were selected for multivariable analysis, proven anal SCC within 6 months after the last day of radiotherapy, or patients with incomplete response, were with a maximum of three considering the number of classified as having persistent disease. Initial complete events. Two-sided p-values \ 0.05 were considered sta- responders to (chemo)radiotherapy, who were diagnosed tistically significant. Statistical analysis was performed with biopsy-proven recurrent anal SCC, after 6 months or using IBM SPSS Statistics version 24.0.0 for Windows more since the last day of radiotherapy, were classified as (IBM Corp, Armonk, New York, USA). having recurrent disease. RESULTS Staging Forty-seven consecutive patients underwent salvage Tumor stage was assessed by physical examination and APR for anal SCC between 1990 and 2016. Patient char- radiologic imaging according to the American Joint Com- acteristics are depicted in Table 1. mittee on Cancer (AJCC) tumor–node–metastasis (TNM) staging system (7th edition) for cancer of the anal canal. Surgical Results Nodal stage was assessed by pelvic magnetic resonance imaging (MRI), and suspicious inguinal lymph nodes were Indications for surgery were either persistent (n = 24; biopsied. Computed tomography (CT) scans of the chest 48.9%) or recurrent disease (n = 23; 51.1%). Median time between the last day of (chemo)radiotherapy and date of 1972 J. A. W. Hagemans et al. TABLE 1 Patient and tumor characteristics before and after TABLE 1 continued abdominoperineal resection (N = 47) N % N % Wound closure and/or reconstruction Gender Primary closure 10 21.3 Male 27 57.4 Wound left open 1 2.1 Female 20 42.6 VRAM-flap 31 66.0 Age Gracilis flap 3 6.4 At time of diagnosis primary 53 (46–66)* Pudendus flap 1 2.1 At time of operation 56 (48–66)* Gluteal flap 1 2.1 Clinical tumor stage Operating time T1 8 17.0 Minutes 378.6 ± 129.9** T2 20 42.6 Pathological tumor size T3 13 27.7 Maximum diameter (millimeter) 30.0 (20.0–48.3)* T4 6 12.8 Pathological nodal stage Clinical nodal stage N0/Nx 41 87.2 N0/Nx 40 85.1 N1 2 4.3 N1 5 10.6 N2 4 8.5 N2 2 4.3 Pathological metastases stage Clinical Metastasis stage M0/Mx 43 91.5 M0 45 95.7 M1 4 8.5 M? 2 4.3 Vasoinvasion Histology Yes 11 23.3 Squamous cell carcinoma 47 100 No 18 38.3 Pretreatment Unknown 18 38.3 Radiotherapy 47 100 Perineural growth Mean dose Gy 60 (60–60)* Yes 14 29.8 Concomitant chemotherapy No 15 31.3 5-FU Mitomycin C 36 76.6 Unknown 18 38.3 5-FU only 1 2.1 Pathological resection margins No chemotherapy 10 21.3 R0 38 80.9 Indication for surgery R1 8 17.0 Persistent disease 24 48.9 R2 1 2.1 Recurrent disease 23 51.1 *Median and interquartile range, **Mean and standard deviation Time interval radiotherapy and surgery (in APR abdominoperineal resection, IORT intra-operative radiotherapy, months) VRAM vertical rectus abdominus muscle, ILND Inguinal lymph node Persistent disease 5 (4–7)* dissection, 5-FU 5-fluorouracil Recurrent disease 15.0 (9.5–37.5)* Surgical procedure APR 35 74.5 APR and posterior vaginal wall 4 8.5 surgery was 5 months (IQR 4–7 months) for patients with Posterior exenteration 4 8.5 persistent disease and 15 months (IQR 9.5–37.5 months) Total pelvic exenteration 2 4.3 for patients with recurrent disease. APR without additional Posterior exenteration and vulvectomie 2 44.3 resections was performed in 35 patients, APR with poste- Additional procedures rior vaginal wall resection in 4 patients, posterior Partial sacrectomy 2 4.3 exenteration in 6 patients (including vulvectomy in 2 Synchronous ILND 2 4.3 patients), and total pelvic exenteration in 2 patients. Other Omentoplasty 33 70.2 additional procedures were partial sacrectomy (n = 2), IORT 2 4.3 synchronous inguinal lymph node dissection (n = 2), and intraoperative radiotherapy (IORT, n = 2). Omentoplasty was performed in 33 patients. One patient had two lesions Salvage Surgery for Anal Cancer 1973 in the liver suspicious for metastases, which were TABLE 2 Mortality, morbidity, and perineal wound complications histopathologically confirmed by frozen section. Salvage N % APR was performed, but the liver metastases were not resected. Until 1999, primary perineal closure was per- Mortality formed in seven patients, one open wound was packed for \ 30 days after surgery 0 0 secondary healing, and one gluteal transposition flap was During hospital admission 1 2.1 performed for reconstruction. In 38 patients treated from Dindo-Clavien 2000 onwards, primary perineal closure was performed None 17 36.2 three times, while a locoregional flap for perineal closure Dindo 1 6 12.8 was used 35 times [VRAM flap (n = 31), gracilis muscle Dindo 2 10 21.3 flap (n = 3), and bilateral pudendal flap (n = 1)]. Surgical Dindo 3A 1 2.1 characteristics are presented in Table 1. Radical resection Dindo 3B 10 21.3 (R0) was achieved in 38 patients (80.9%), microscopically Dindo 4 3 6.4 irradical resection (R1) in 8 patients (17.0%), and macro- Dindo 5 0 0 scopically irradical resection (R2) in 1 patient (2.1%). One Major complications patient had liver metastases, and three patients had inguinal Pulmonary embolism 1 2.1 lymph node metastases. Tumor characteristics are listed in Aspiration pneumonia 2 4 Table 1. Gastric ulcer bleeding 1 2.1 Major complications requiring surgery Mortality and Morbidity Stoma necrosis 1 2.1 Abdominal wound necrosis 1 2.1 None of the patients died within 30 days of surgery. Fascia dehiscence 1 2.1 Within 2 months, there was one case of euthanasia due to Perineal wound complications MFR No MFR unbearable suffering from severe wound infection and no (N = 36) (N = 11) perspective of cure considering confirmed liver metastases. The majority of patients (n = 33; 70.3%) experienced no or Additional muscle flap reconstruction 1 1 minor complications (Dindo–Clavien B 2), and 14 patients Vacuum assisted therapy 3 2 (29.7%) developed major complications (Dindo–Clavien Wound complication treated conservative 4 3 C 3). Mortality and morbidity are displayed in Table 2. Six Wound complication requiring debridement 2 0 out of 10 patients with primary closure of the perineal Perineal hernia 1 1 defect and 9 out of 36 patients with muscle flap recon- MFR muscle flap reconstruction struction (MFR) experienced perineal wound complications. Nine patients required surgery for perineal respectively; p = 0.551). Survival curves are shown in wound complications. The latter were treated with Fig. 1. On both univariable and multivariable analysis, debridement with (n = 5) or without vacuum-assisted clo- increased pathological tumor size (p\ 0.001) and positive sure therapy (n = 2) and muscle flap necrosectomy lymph nodes (p = 0.014) were significantly associated with followed by repeat reconstruction (n = 2). Median time worse OS. Irradical resection was only significantly asso- between last day of radiotherapy and surgery did not sig- ciated on univariable analysis (p = 0.001) but not on nificantly influence perineal wound complications (p = multivariable analysis (p = 0.087). Analyses are presented 0.909). The proportion of patients with perineal wound in Table 3, and the influence on survival in Fig. 2. complications was lower in patients treated with MFR (25%; 9/36) compared with patients treated without MFR Recurrence after Salvage APR (54.5%; 6/11), however this was not significant (p = 0.066). The overall rate of disease recurrence after salvage APR Survival was 55.3%. Twenty-one patients (44.7%) developed local recurrence after salvage APR, including 13 patients with Median follow-up time was 80 months (95% CI simultaneous locoregional recurrence or distant metastases 68.6–91.4 months). At last follow-up, 19 patients (40.4%) [inguinal lymph node (n = 7), liver (n = 2), adrenal gland were alive. Median overall survival (OS) was 47 months (n = 1), retroperitoneal lymph nodes (n = 1), peritoneal (95% CI 10.0–84.0 months), and the estimated 5-year carcinomatosis (n = 1), and cervical lymph node ? liver survival rate was 41.6%. Survival curves did not differ metastasis (n = 1)]. Five patients developed distant significantly between patients with persistent versus metastases or locoregional recurrence only [inguinal lymph recurrent disease (5-year survival rate 40.4 vs. 41.7%, 1974 J. A. W. Hagemans et al. FIG. 1 a Overall survival a b 100 100 (OS). b Local recurrence-free LRES OS survival (LRFS). c OS for 80 80 persistent versus recurrent 60 60 disease. d OS for local recurrence after salvage APR; 40 40 repeat salvage surgery versus palliative treatment 20 20 0 0 0 1224364860 0 12 24 36 48 60 Months Months No. at risk 47 34 24 22 19 14 No. at risk 47 27 23 21 17 14 Repeat salvage surgery c d Recurrent Palliative treatment Persistent p=0.055 p=0.551 60 60 40 40 20 20 0 0 0 12 24 36 48 60 0 12 24 36 48 60 Months Months No. at risk No. at risk Recurrent 23 19 12 10 8 7 Salvage surgery 8 4 0 0 0 0 Persistent 24 16 12 12 11 8 Palliative treatment 13 2 0 0 0 0 Tumor size >30 mm a b c 100 R0 100 N+ 100 Tumor size <30 mm R1/R2 N- p=0.000 80 80 80 p=0.000 p=0.009 60 60 60 40 40 20 20 0 0 0 0 12 36 48 60 0 12 24 36 48 60 0 12 24 4 36 8 60 24 Months Months Months No. at risk No. at risk No. at risk R1/R2 9 4 2 2 1 0 N+ 6 4 1 0 0 0 Tumor size >30 mm 17 7 4 4 2 2 R0 38 31 23 21 18 14 N- 41 31 23 22 19 14 Tumor size <30 mm 33 32 27 25 23 18 FIG. 2 Overall survival curves (prognostic factors): a resection margin, b nodal stage, and c pathological tumor size (diameter in millimeters with median as cutoff value) node (n = 2), retroperitoneal lymph nodes (n = 1), hilar Eight patients with local recurrence after salvage APR lymph nodes (n = 1), liver metastases (n = 1)]. Median OS underwent repeat salvage surgery by extensive local exci- for patients with local recurrence and/or distant metastases sion, including additional inguinal lymph node dissection after salvage APR was 12 months (95% CI 8.3–15.7 (n = 2), liver metastases resection (n = 1), and cervical months). Median local-recurrence-free survival after sal- lymph node dissection (n = 1). vage APR (LRFS) was not reached. The estimated 5-year Thirteen patients underwent palliative treatment for LRFS after salvage APR was 51.1%. None of the patients local recurrence after salvage APR, including fistula developed local recurrence after 42 months from salvage resection (n = 2), radiotherapy in combination with APR. Three patients received postoperative chemotherapy hyperthermia (n = 2), and chemotherapy for metastatic for metastatic disease, and none of the patients received disease (n = 2), while seven patients received best sup- standard adjuvant chemotherapy. portive care only. Median OS for all patients with local recurrence after salvage APR, calculated from date of Percent survival Percent survival Percent survival Percent survival Percent survival Percent survival Percent survival Salvage Surgery for Anal Cancer 1975 TABLE 3 Univariable and multivariable survival analysis for overall survival of squamous cell carcinoma Univariable P value Multivariable P value Hazard ratio [95% CI] Hazard ratio [95% CI] Male versus female 1.150 [0.536–2.466] 0.720 – – Age at time of operation 1.021 [0.986–1.058] 0.239 – – CTxRTx versus RTx 0.884 [0.332–2.351] 0.805 – – Recurrent disease versus persistent disease 0.794 [0.794–1.709] 0.556 – – Multivisceral resection 1.169 [0.524–2.608] 0.704 – – Irradical resection (R1/R2) 4.056 [1.746–9.423] 0.001 2.786 [0.862–9.005] 0.087 Node positive (N1/N2) 3.228 [1.255–8.302] 0.015 4.445 [1.356–14.563] 0.014 Metastasis positive (M1) 2.603 [0.878–7.712] 0.084 – – Vasoinvasion 2.081 [0.795–5.679] 0.144 – – Perineural growth 2.702 [0.973–7.504] 0.056 – – Pathological tumor size (maximum diameter in mm) 1.039 [1.023–1.055] \ 0.001 1.036 [1.018–1.054] \ 0.001 CTxRTx chemoradiotherapy, RTx radiotherapy diagnosis of local recurrence, was 7 months (95% CI eight patients received the standard protocol of 60 Gy. This 1.0–13.0 months). The 1-year survival rate was 19.0%, and in contrast to some other published series where the study all patients died within 15 months except for one patient, population was treated with a wide range of radiation 9–11,16 who had undergone repeat salvage surgery and was still doses. alive at last follow-up of 22 months. The percentages of radical resection and 30-day postop- 9,13,24–27 There was no significant difference (p = 0.055) in sur- erative mortality are comparable to previous studies. vival of patients with local recurrence after salvage APR Outcome measures of complications after salvage APR varied treated with repeat salvage surgery, with median OS of 9 widely in other studies, preventing adequate comparison. months (95% CI 7.2–10.8 months), compared with patients However, in the current study, surgical reinterventions were with palliative treatment, with median OS of 4 months slightly more common (25.5%) than the range reported by 13,24–26 (95% CI 2.8–5.1 months). others (12–20%). In this study, 31.9% of patients experienced perineal complications, while others reported perineal complications in 22–50% of patients, regardless of DISCUSSION 9,13,16,25,27 use of muscle flap reconstruction. We could not identify a group prone to perineal complications based on time The present study describes the results of salvage APR for SCC of the anal canal after failure of initial primary between radiotherapy and surgery or use of muscle flap reconstruction, possibly due to small numbers. therapy in 47 patients. Overall estimated 5-year survival was 41.6%. Negative prognostic factors were increased The 5-year OS in this study of 41.6% lies within the pathological tumor size and lymph node involvement on range of 23–69% reported by other authors. Survival of multivariable analysis, and positive resection margin only patients with persistent disease did not differ significantly on univariable analysis. Type of local failure did not affect from that of patients with recurrent disease, which is also in survival. The overall local recurrence rate after salvage agreement with results published previ- 10,11,14,15,17,19,28 APR was 44.7%. None of the patients who developed local ously, although some studies did report poorer survival rates in patients with persistent compared recurrence after salvage APR could be cured, and all had 10,16 poor prognosis. with recurrent disease. This could be explained by more aggressive behavior of tumor cells in persistent dis- Although surgery has been replaced by CRT for primary treatment of SCC of the anal canal, salvage APR has ease or fast regrowth. However, other studies reported significantly worse survival in patients with recurrent dis- remained the gold standard for patients with persistent 29,30 disease or local recurrent disease after failed CRT. Due to ease, which could not be explained clearly. the relative rarity of the procedure for this indication, most We found that increased pathological tumor size, lymph published series consist of only a small number of patients node involvement, and positive resection margins treated over a long period of time, and are therefore prone adversely affected survival, which is in concordance with 9–11,13–15,17,24,25,28,30–32 to a certain degree of bias. We present herein a rather most other series (Appendix 1). homogeneous group of patients. All patients were treated Although not identified on multivariable analysis in the present study, positive resection margin seems to remain with an adequate radiation dose of [ 45 Gy, and all but 1976 J. A. W. Hagemans et al. the most common factor negatively affecting survival. these patients. Some patients with local recurrence after sal- These findings emphasize the importance of achieving vage APR also had distant metastases or locoregional negative resection margins, which can sometimes only be recurrence, and type of surgery was not protocolled as it is for achieved by aggressive multivisceral resection or multi- the primary salvage APR. On the other hand, our results disciplinary treatment. clearly show that recurrence after salvage APR has poor Recently, Hallemeier et al. reported a multidisci- prognosis, regardless of the treatment. Palliative surgery may plinary approach, including reirradiation with or without still be considered for some patients, especially those with concomitant chemotherapy and IORT, in a small group of pain. Cure, however, does not seem to be possible. patients with persistent or recurrent anal cancer. Only 21% This study is limited by its retrospective nature and the developed recurrence within the reirradiated area. The small number of patients collected over a long time period. 5-year OS was 23%, but they specifically treated patients Patients with persistent or recurrent disease have different with expected narrow or positive resection margins. In tumor biology, and mixing these cases could affect the the present study, only two patients received IORT, and outcomes of salvage APR. Advances in diagnostic imaging none received reirradiation prior to salvage surgery, and treatment were made during the study period and likely because of the high-dose radiotherapy used as primary contributed to heterogeneity in our study population and treatment. Wright et al. retrospectively analyzed 14 outcomes. patients with locoregional recurrent anal SCC who under- went salvage surgery and IORT. Addition of IORT was not CONCLUSIONS associated with locoregional control or survival benefit and did not compensate for positive surgical margins. Reir- The results of the present study show that salvage APR radiation and IORT could potentially decrease local for patients with SCC of the anal canal after failed CRT recurrence rate, but this remains unclear. provides adequate long-term survival and local control. Currently there is no role for standard adjuvant Prognostic factors for survival were advanced tumor stage, chemotherapy, however the combination of cisplatin and lymph node involvement, and positive resection margins. 5-fluorouracil (5-FU) is the gold standard in metastatic Patients with recurrent anal SCC after salvage APR had 34,35 disease, with an overall response rate of 60%. Eng poor prognosis irrespective of performance of repeat sal- et al. showed a prolonged OS for multidisciplinary vage surgery, which never resulted in cure. management with systemic chemotherapy and intervention compared with palliative chemotherapy only in patients OPEN ACCESS This article is distributed under the terms of the with unresectable and metastatic anal SCC. In the present Creative Commons Attribution 4.0 International License (http://crea study, three patients received postoperative chemotherapy tivecommons.org/licenses/by/4.0/), which permits unrestricted use, without additional intervention. Therefore, we could not distribution, and reproduction in any medium, provided you give clearly assess the effect on OS. Multidisciplinary treatment appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were for unresectable and metastatic anal SCC can potentially made. lead to prolonged OS. To our knowledge, this is the first study to present data on treatment of recurrent anal SCC after failed CRT for primary anal SCC and salvage APR for recurrent/persistent anal SCC. 27 24 Alamri et al. and Correa et al. only reported survival for Salvage Surgery for Anal Cancer 1977 APPENDIX 1: OVERVIEW OF CURRENT LITERATURE Ref. Year of publication No. of patients 5-Year OS (%) Prognostic factors for OS after salvage APR Zelnick et al. 1992 9 24 Not identified or not mentioned Ellenhorn et al. 1993 38 44 Nodal disease Tumor fixed to lateral pelvic wall Involvement of perirectal fat Longo et al. 1994 34 23–53 Stage Method of treatment Pocard et al. 1998 21 33 Not identified or not mentioned Allal et al. 1999 26 45 Not identified or not mentioned Smith et al. 2001 22 33 Not identified or not mentioned Van der Wal et al. 2001 17 47 Not identified or not mentioned Nilsson et al. 2002 35 52 Persistent disease Akbari et al. 2004 62 33 Tumor size [ 5cm Local extent Nodal disease Positive resection margins Ghouti et al. 2005 36 69 Not identified or not mentioned Ferenschild et al. 2005 18 30 Not identified or not mentioned Renehan et al. 2005 73 40 Positive resection margins Mullen et al. 2006 31 64 Nodal disease \ 55 Gy radiotherapy dose Stewart et al. 2007 22 24–48 Tumor differentiation Positive resection margins Schiller et al. 2007 40 39 Tumor size Sex (male) Mariani et al. 2008 83 57 Age [ 55 years Nodal disease T3–4 tumor Local extent Sunesen et al. 2009 49 61 Positive resection margins Eeson et al. 2011 51 29 Positive resection margins Correa et al. 2012 111 25 Nodal disease Positive resection margin Perineural and/or lymphovascular invasion Lefevre et al. 2012 105 61 T3–T4 status Positive resection margins Metastatic disease Hallemeier et al. 2014 32 23 Recurrent disease versus persistent disease Positive resection margins Viable disease in resection specimen Alamri et al. 2016 27 78 None identified Pesi et al. 2017 20 37 None published Present study 2017 47 41 Increased pathological tumor size (mm) – Nodal disease – Positive resection margins 1978 J. 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Salvage surgery after failed for squamous cell anal carcinoma: survival and risk factors for chemoradiation for anal canal cancer: should the paradigm be recurrence. Ann Surg Oncol. 2012;19(13):4186–92. changed for high-risk tumors? J Gastrointest Surg. 14. Mariani P, Ghanneme A, De la Rochefordiere A, Girodet J, 2007;11(12):1744–51. Falcou MC, Salmon RJ. Abdominoperineal resection for anal 32. Eeson G, Foo M, Harrow S, McGregor G, Hay J. Outcomes of cancer. Dis Colon Rectum. 2008;51(10):1495–501. salvage surgery for epidermoid carcinoma of the anus following 15. Mullen JT, Rodriguez-Bigas MA, Chang GJ, et al. Results of failed combined modality treatment. Am J Surg. surgical salvage after failed chemoradiation therapy for epider- 2011;201(5):628–33. moid carcinoma of the anal canal. Ann Surg Oncol. 33. Wright JL, Gollub MJ, Weiser MR, et al. Surgery and high-dose- 2007;14(2):478–83. rate intraoperative radiation therapy for recurrent squamous-cell 16. Nilsson PJ, Svensson C, Goldman S, Glimelius B. Salvage carcinoma of the anal canal. Dis Colon Rectum. abdominoperineal resection in anal epidermoid cancer. Br J Surg. 2011;54(9):1090–97. 2002;89(11):1425–29. 34. Faivre C, Rougier P, Ducreux M, et al. [5-Fluorouracil and cis- 17. Schiller DE, Cummings BJ, Rai S, et al. Outcomes of salvage platinum combination chemotherapy for metastatic squamous- surgery for squamous cell carcinoma of the anal canal. Ann Surg cell anal cancer] Carcinome e ´pidermoide me ´tastatique de l’anus: Oncol. 2007;14(10):2780–89. e ´tude re ´trospective de l’efficacite ´ de l’association de Salvage Surgery for Anal Cancer 1979 5-fluorouracile en perfusion continue et de cisplatine. Bull Can- 37. Pocard M, Tiret E, Nugent K, Dehni N, Parc R. Results of salvage cer. 1999;86(10):861–65. abdominoperineal resection for anal cancer after radiotherapy. 35. Jaiyesimi IA, Pazdur R. Cisplatin and 5-fluorouracil as salvage Dis Colon Rectum. 1998;41(12):1488–93. therapy for recurrent metastatic squamous cell carcinoma of the 38. Ferenschild FT, Vermaas M, Hofer SO, Verhoef C, Eggermont anal canal. Am J Clin Oncol. 1993;16(6):536–40. AM, de Wilt JH. Salvage abdominoperineal resection and per- 36. Eng C, Chang GJ, You YN, et al. The role of systemic ineal wound healing in local recurrent or persistent anal cancer. chemotherapy and multidisciplinary management in improving World J Surg. 2005;29(11):1452–57. the overall survival of patients with metastatic squamous cell carcinoma of the anal canal. Oncotarget. 2014;5(22):11133–42. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Surgical Oncology Springer Journals

Salvage Abdominoperineal Resection for Squamous Cell Anal Cancer: A 30-Year Single-Institution Experience

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Abstract

Ann Surg Oncol (2018) 25:1970–1979 https://doi.org/10.1245/s10434-018-6483-9 OR IGINAL ARTIC L E – COLORECTAL CANCER Salvage Abdominoperineal Resection for Squamous Cell Anal Cancer: A 30-Year Single-Institution Experience 1 2 2 3 J. A. W. Hagemans, MD , S. E. Blinde, MD , J. J. Nuyttens, MD, PhD , W. G. Morshuis, MD , M. A. M. Mureau, 4 1 1 1 MD, PhD , J. Rothbarth, MD, PhD , C. Verhoef, MD, PhD , and J. W. A. Burger, MD, PhD Department of Surgical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Radiation Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Anesthesiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Plastic and Reconstructive Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands ABSTRACT repeat salvage surgery and 4 months (95% CI 2.8–5.1 Background. Failure of chemoradiotherapy (CRT) for months) following palliative treatment (p = 0.055). anal squamous cell carcinoma (SCC) results in persistent or Conclusions. Salvage APR for anal SCC after failed CRT recurrent anal SCC. Treatment with salvage resulted in adequate survival, with 5-year survival of abdominoperineal resection (APR) can potentially achieve 41.6%. Negative prognostic factors for survival were cure. The aims of this study are to analyze oncological and increased tumor size, lymph node involvement, and irrad- surgical outcomes of our 30-year experience with salvage ical resection. Patients with recurrent anal SCC after APR for anal SCC after failed CRT and identify prognostic salvage APR had poor prognosis, irrespective of perfor- factors for overall survival (OS). mance of repeat salvage surgery, which never resulted in Methods. All consecutive patients who underwent salvage cure. APR between 1990 and 2016 for histologically confirmed persistent or recurrent anal SCC after failed CRT were Squamous cell carcinoma (SCC) of the anal canal is a retrospectively analyzed. Results. Forty-seven patients underwent salvage APR for relatively rare malignancy, but its incidence has increased over the last few years. Currently, chemoradiotherapy either persistent (n = 24) or recurrent SCC (n = 23). Median OS was 47 months [95% confidence interval (CI) (CRT) is standard of care for anal cancer, resulting in superior local control compared with radiotherapy alone 10.0–84.0 months] and 5-year survival was 41.6%, which 2–8 with 5-year survival rates of 60–80%. CRT leads to did not differ significantly between persistent or recurrent disease (p = 0.551). Increased pathological tumor size (p\ preservation of the anal sphincter by avoiding surgery. Unfortunately, CRT fails in 20–30% of patients, resulting 0.001) and lymph node involvement (p = 0.014) were associated with impaired hazard for OS on multivariable in persistent (10–15%) or local recurrent disease 2–7,9 (10–15%). analysis, and irradical resection only (p = 0.001) on uni- variable analysis. Twenty-one patients developed local Salvage abdominoperineal resection (APR) is often the only option for patients with persistent or recurrent anal recurrence after salvage APR, of whom 8 underwent repeat salvage surgery and 13 received palliative treatment. SCC to achieve durable local control and survival. Several institutes have reported case series on this topic. However, Median OS was 9 months (95% CI 7.2–10.8 months) after due to heterogeneity in treatment protocols, results on 10–20 patient outcomes vary widely. Our institute has a well- established protocol for treatment of anal SCC, which has The Author(s) 2018 changed little in the last three decades. The aims of the First Received: 13 September 2017; present study are to analyze the results of a 30-year Published Online: 24 April 2018 experience with salvage APR for recurrent and persistent J. A. W. Hagemans, MD anal SCC after failed CRT in a large single-center cohort e-mail: j.hagemans@erasmusmc.nl Salvage Surgery for Anal Cancer 1971 and to identify prognostic factors for overall survival. In and abdomen were used to confirm absence of metastatic addition, outcomes of patients treated for local recurrence disease prior to surgery. developed after primary salvage APR for persistent or recurrent SCC were also analyzed. To the best of the Surgery authors’ knowledge, results of repeat surgery for treatment of local recurrence after salvage APR have never been All patients deemed eligible for complete, curative previously studied. resection underwent salvage APR. Multivisceral resection was performed if necessary. If possible, omentoplasty was PATIENTS AND METHODS performed to fill the pelvis. Primary closure of the perineal defect was routinely performed up to 1999, and if this was not feasible, the open wound was packed for healing by Data of all consecutive patients who underwent salvage APR with curative intent for histologically confirmed secondary intention. From 2000 onwards, the perineal defect was reconstructed with either a vertical rectus persistent or recurrent anal SCC between 1990 and 2016 at the Erasmus MC Cancer Institute, a tertiary referral center abdominis myocutaneous (VRAM) or gracilis muscle 21,22 flap. Inguinal lymph node dissection was performed in in The Netherlands, were retrospectively analyzed. Patient demographics, perioperative variables, tumor characteris- case of biopsy-proven positive lymph nodes. Postoperative tics, neoadjuvant therapy, short- and long-term outcomes, complications were graded according to the Dindo–Clavien and postoperative mortality and morbidity were collected classification. Local recurrence after salvage APR was from medical records, the municipality register, and gen- defined as any local recurrence after salvage APR, eral practitioners. All patients were followed up by our regardless of whether the indication for salvage APR was institute; last update of follow-up was 22 January 2018. for persistent or recurrent anal SCC. The present study was approved by the Erasmus MC local medical ethics committee (registration number MEC-2017- Statistics 448). Survival analysis was performed by Kaplan–Meier Primary Treatment method, and comparisons were made using log-rank tests. Survival was calculated from day of APR until data of All primary malignancies were initially treated with death or last follow-up. Survival rates for recurrence after radiotherapy, and the majority (78.7%) also received con- salvage APR were calculated from date of diagnosis of comitant chemotherapy. Radiotherapy was administered recurrent anal SCC until death or last follow-up. Cox with median dose of 60 Gy [interquartile range (IQR) proportional-hazard models were constructed to identify 60–60 Gy], and chemotherapy was administered in the first prognostic factors in univariable and multivariable analy- sis. Mann–Whitney U and chi-squared test were performed four days of the first week [5-fluorouracil (1000 mg/m ) and mitomycin C (10 mg/m )]. Patients with histologically as appropriate. Covariables with a trend towards signifi- cance (p\ 0.100) were selected for multivariable analysis, proven anal SCC within 6 months after the last day of radiotherapy, or patients with incomplete response, were with a maximum of three considering the number of classified as having persistent disease. Initial complete events. Two-sided p-values \ 0.05 were considered sta- responders to (chemo)radiotherapy, who were diagnosed tistically significant. Statistical analysis was performed with biopsy-proven recurrent anal SCC, after 6 months or using IBM SPSS Statistics version 24.0.0 for Windows more since the last day of radiotherapy, were classified as (IBM Corp, Armonk, New York, USA). having recurrent disease. RESULTS Staging Forty-seven consecutive patients underwent salvage Tumor stage was assessed by physical examination and APR for anal SCC between 1990 and 2016. Patient char- radiologic imaging according to the American Joint Com- acteristics are depicted in Table 1. mittee on Cancer (AJCC) tumor–node–metastasis (TNM) staging system (7th edition) for cancer of the anal canal. Surgical Results Nodal stage was assessed by pelvic magnetic resonance imaging (MRI), and suspicious inguinal lymph nodes were Indications for surgery were either persistent (n = 24; biopsied. Computed tomography (CT) scans of the chest 48.9%) or recurrent disease (n = 23; 51.1%). Median time between the last day of (chemo)radiotherapy and date of 1972 J. A. W. Hagemans et al. TABLE 1 Patient and tumor characteristics before and after TABLE 1 continued abdominoperineal resection (N = 47) N % N % Wound closure and/or reconstruction Gender Primary closure 10 21.3 Male 27 57.4 Wound left open 1 2.1 Female 20 42.6 VRAM-flap 31 66.0 Age Gracilis flap 3 6.4 At time of diagnosis primary 53 (46–66)* Pudendus flap 1 2.1 At time of operation 56 (48–66)* Gluteal flap 1 2.1 Clinical tumor stage Operating time T1 8 17.0 Minutes 378.6 ± 129.9** T2 20 42.6 Pathological tumor size T3 13 27.7 Maximum diameter (millimeter) 30.0 (20.0–48.3)* T4 6 12.8 Pathological nodal stage Clinical nodal stage N0/Nx 41 87.2 N0/Nx 40 85.1 N1 2 4.3 N1 5 10.6 N2 4 8.5 N2 2 4.3 Pathological metastases stage Clinical Metastasis stage M0/Mx 43 91.5 M0 45 95.7 M1 4 8.5 M? 2 4.3 Vasoinvasion Histology Yes 11 23.3 Squamous cell carcinoma 47 100 No 18 38.3 Pretreatment Unknown 18 38.3 Radiotherapy 47 100 Perineural growth Mean dose Gy 60 (60–60)* Yes 14 29.8 Concomitant chemotherapy No 15 31.3 5-FU Mitomycin C 36 76.6 Unknown 18 38.3 5-FU only 1 2.1 Pathological resection margins No chemotherapy 10 21.3 R0 38 80.9 Indication for surgery R1 8 17.0 Persistent disease 24 48.9 R2 1 2.1 Recurrent disease 23 51.1 *Median and interquartile range, **Mean and standard deviation Time interval radiotherapy and surgery (in APR abdominoperineal resection, IORT intra-operative radiotherapy, months) VRAM vertical rectus abdominus muscle, ILND Inguinal lymph node Persistent disease 5 (4–7)* dissection, 5-FU 5-fluorouracil Recurrent disease 15.0 (9.5–37.5)* Surgical procedure APR 35 74.5 APR and posterior vaginal wall 4 8.5 surgery was 5 months (IQR 4–7 months) for patients with Posterior exenteration 4 8.5 persistent disease and 15 months (IQR 9.5–37.5 months) Total pelvic exenteration 2 4.3 for patients with recurrent disease. APR without additional Posterior exenteration and vulvectomie 2 44.3 resections was performed in 35 patients, APR with poste- Additional procedures rior vaginal wall resection in 4 patients, posterior Partial sacrectomy 2 4.3 exenteration in 6 patients (including vulvectomy in 2 Synchronous ILND 2 4.3 patients), and total pelvic exenteration in 2 patients. Other Omentoplasty 33 70.2 additional procedures were partial sacrectomy (n = 2), IORT 2 4.3 synchronous inguinal lymph node dissection (n = 2), and intraoperative radiotherapy (IORT, n = 2). Omentoplasty was performed in 33 patients. One patient had two lesions Salvage Surgery for Anal Cancer 1973 in the liver suspicious for metastases, which were TABLE 2 Mortality, morbidity, and perineal wound complications histopathologically confirmed by frozen section. Salvage N % APR was performed, but the liver metastases were not resected. Until 1999, primary perineal closure was per- Mortality formed in seven patients, one open wound was packed for \ 30 days after surgery 0 0 secondary healing, and one gluteal transposition flap was During hospital admission 1 2.1 performed for reconstruction. In 38 patients treated from Dindo-Clavien 2000 onwards, primary perineal closure was performed None 17 36.2 three times, while a locoregional flap for perineal closure Dindo 1 6 12.8 was used 35 times [VRAM flap (n = 31), gracilis muscle Dindo 2 10 21.3 flap (n = 3), and bilateral pudendal flap (n = 1)]. Surgical Dindo 3A 1 2.1 characteristics are presented in Table 1. Radical resection Dindo 3B 10 21.3 (R0) was achieved in 38 patients (80.9%), microscopically Dindo 4 3 6.4 irradical resection (R1) in 8 patients (17.0%), and macro- Dindo 5 0 0 scopically irradical resection (R2) in 1 patient (2.1%). One Major complications patient had liver metastases, and three patients had inguinal Pulmonary embolism 1 2.1 lymph node metastases. Tumor characteristics are listed in Aspiration pneumonia 2 4 Table 1. Gastric ulcer bleeding 1 2.1 Major complications requiring surgery Mortality and Morbidity Stoma necrosis 1 2.1 Abdominal wound necrosis 1 2.1 None of the patients died within 30 days of surgery. Fascia dehiscence 1 2.1 Within 2 months, there was one case of euthanasia due to Perineal wound complications MFR No MFR unbearable suffering from severe wound infection and no (N = 36) (N = 11) perspective of cure considering confirmed liver metastases. The majority of patients (n = 33; 70.3%) experienced no or Additional muscle flap reconstruction 1 1 minor complications (Dindo–Clavien B 2), and 14 patients Vacuum assisted therapy 3 2 (29.7%) developed major complications (Dindo–Clavien Wound complication treated conservative 4 3 C 3). Mortality and morbidity are displayed in Table 2. Six Wound complication requiring debridement 2 0 out of 10 patients with primary closure of the perineal Perineal hernia 1 1 defect and 9 out of 36 patients with muscle flap recon- MFR muscle flap reconstruction struction (MFR) experienced perineal wound complications. Nine patients required surgery for perineal respectively; p = 0.551). Survival curves are shown in wound complications. The latter were treated with Fig. 1. On both univariable and multivariable analysis, debridement with (n = 5) or without vacuum-assisted clo- increased pathological tumor size (p\ 0.001) and positive sure therapy (n = 2) and muscle flap necrosectomy lymph nodes (p = 0.014) were significantly associated with followed by repeat reconstruction (n = 2). Median time worse OS. Irradical resection was only significantly asso- between last day of radiotherapy and surgery did not sig- ciated on univariable analysis (p = 0.001) but not on nificantly influence perineal wound complications (p = multivariable analysis (p = 0.087). Analyses are presented 0.909). The proportion of patients with perineal wound in Table 3, and the influence on survival in Fig. 2. complications was lower in patients treated with MFR (25%; 9/36) compared with patients treated without MFR Recurrence after Salvage APR (54.5%; 6/11), however this was not significant (p = 0.066). The overall rate of disease recurrence after salvage APR Survival was 55.3%. Twenty-one patients (44.7%) developed local recurrence after salvage APR, including 13 patients with Median follow-up time was 80 months (95% CI simultaneous locoregional recurrence or distant metastases 68.6–91.4 months). At last follow-up, 19 patients (40.4%) [inguinal lymph node (n = 7), liver (n = 2), adrenal gland were alive. Median overall survival (OS) was 47 months (n = 1), retroperitoneal lymph nodes (n = 1), peritoneal (95% CI 10.0–84.0 months), and the estimated 5-year carcinomatosis (n = 1), and cervical lymph node ? liver survival rate was 41.6%. Survival curves did not differ metastasis (n = 1)]. Five patients developed distant significantly between patients with persistent versus metastases or locoregional recurrence only [inguinal lymph recurrent disease (5-year survival rate 40.4 vs. 41.7%, 1974 J. A. W. Hagemans et al. FIG. 1 a Overall survival a b 100 100 (OS). b Local recurrence-free LRES OS survival (LRFS). c OS for 80 80 persistent versus recurrent 60 60 disease. d OS for local recurrence after salvage APR; 40 40 repeat salvage surgery versus palliative treatment 20 20 0 0 0 1224364860 0 12 24 36 48 60 Months Months No. at risk 47 34 24 22 19 14 No. at risk 47 27 23 21 17 14 Repeat salvage surgery c d Recurrent Palliative treatment Persistent p=0.055 p=0.551 60 60 40 40 20 20 0 0 0 12 24 36 48 60 0 12 24 36 48 60 Months Months No. at risk No. at risk Recurrent 23 19 12 10 8 7 Salvage surgery 8 4 0 0 0 0 Persistent 24 16 12 12 11 8 Palliative treatment 13 2 0 0 0 0 Tumor size >30 mm a b c 100 R0 100 N+ 100 Tumor size <30 mm R1/R2 N- p=0.000 80 80 80 p=0.000 p=0.009 60 60 60 40 40 20 20 0 0 0 0 12 36 48 60 0 12 24 36 48 60 0 12 24 4 36 8 60 24 Months Months Months No. at risk No. at risk No. at risk R1/R2 9 4 2 2 1 0 N+ 6 4 1 0 0 0 Tumor size >30 mm 17 7 4 4 2 2 R0 38 31 23 21 18 14 N- 41 31 23 22 19 14 Tumor size <30 mm 33 32 27 25 23 18 FIG. 2 Overall survival curves (prognostic factors): a resection margin, b nodal stage, and c pathological tumor size (diameter in millimeters with median as cutoff value) node (n = 2), retroperitoneal lymph nodes (n = 1), hilar Eight patients with local recurrence after salvage APR lymph nodes (n = 1), liver metastases (n = 1)]. Median OS underwent repeat salvage surgery by extensive local exci- for patients with local recurrence and/or distant metastases sion, including additional inguinal lymph node dissection after salvage APR was 12 months (95% CI 8.3–15.7 (n = 2), liver metastases resection (n = 1), and cervical months). Median local-recurrence-free survival after sal- lymph node dissection (n = 1). vage APR (LRFS) was not reached. The estimated 5-year Thirteen patients underwent palliative treatment for LRFS after salvage APR was 51.1%. None of the patients local recurrence after salvage APR, including fistula developed local recurrence after 42 months from salvage resection (n = 2), radiotherapy in combination with APR. Three patients received postoperative chemotherapy hyperthermia (n = 2), and chemotherapy for metastatic for metastatic disease, and none of the patients received disease (n = 2), while seven patients received best sup- standard adjuvant chemotherapy. portive care only. Median OS for all patients with local recurrence after salvage APR, calculated from date of Percent survival Percent survival Percent survival Percent survival Percent survival Percent survival Percent survival Salvage Surgery for Anal Cancer 1975 TABLE 3 Univariable and multivariable survival analysis for overall survival of squamous cell carcinoma Univariable P value Multivariable P value Hazard ratio [95% CI] Hazard ratio [95% CI] Male versus female 1.150 [0.536–2.466] 0.720 – – Age at time of operation 1.021 [0.986–1.058] 0.239 – – CTxRTx versus RTx 0.884 [0.332–2.351] 0.805 – – Recurrent disease versus persistent disease 0.794 [0.794–1.709] 0.556 – – Multivisceral resection 1.169 [0.524–2.608] 0.704 – – Irradical resection (R1/R2) 4.056 [1.746–9.423] 0.001 2.786 [0.862–9.005] 0.087 Node positive (N1/N2) 3.228 [1.255–8.302] 0.015 4.445 [1.356–14.563] 0.014 Metastasis positive (M1) 2.603 [0.878–7.712] 0.084 – – Vasoinvasion 2.081 [0.795–5.679] 0.144 – – Perineural growth 2.702 [0.973–7.504] 0.056 – – Pathological tumor size (maximum diameter in mm) 1.039 [1.023–1.055] \ 0.001 1.036 [1.018–1.054] \ 0.001 CTxRTx chemoradiotherapy, RTx radiotherapy diagnosis of local recurrence, was 7 months (95% CI eight patients received the standard protocol of 60 Gy. This 1.0–13.0 months). The 1-year survival rate was 19.0%, and in contrast to some other published series where the study all patients died within 15 months except for one patient, population was treated with a wide range of radiation 9–11,16 who had undergone repeat salvage surgery and was still doses. alive at last follow-up of 22 months. The percentages of radical resection and 30-day postop- 9,13,24–27 There was no significant difference (p = 0.055) in sur- erative mortality are comparable to previous studies. vival of patients with local recurrence after salvage APR Outcome measures of complications after salvage APR varied treated with repeat salvage surgery, with median OS of 9 widely in other studies, preventing adequate comparison. months (95% CI 7.2–10.8 months), compared with patients However, in the current study, surgical reinterventions were with palliative treatment, with median OS of 4 months slightly more common (25.5%) than the range reported by 13,24–26 (95% CI 2.8–5.1 months). others (12–20%). In this study, 31.9% of patients experienced perineal complications, while others reported perineal complications in 22–50% of patients, regardless of DISCUSSION 9,13,16,25,27 use of muscle flap reconstruction. We could not identify a group prone to perineal complications based on time The present study describes the results of salvage APR for SCC of the anal canal after failure of initial primary between radiotherapy and surgery or use of muscle flap reconstruction, possibly due to small numbers. therapy in 47 patients. Overall estimated 5-year survival was 41.6%. Negative prognostic factors were increased The 5-year OS in this study of 41.6% lies within the pathological tumor size and lymph node involvement on range of 23–69% reported by other authors. Survival of multivariable analysis, and positive resection margin only patients with persistent disease did not differ significantly on univariable analysis. Type of local failure did not affect from that of patients with recurrent disease, which is also in survival. The overall local recurrence rate after salvage agreement with results published previ- 10,11,14,15,17,19,28 APR was 44.7%. None of the patients who developed local ously, although some studies did report poorer survival rates in patients with persistent compared recurrence after salvage APR could be cured, and all had 10,16 poor prognosis. with recurrent disease. This could be explained by more aggressive behavior of tumor cells in persistent dis- Although surgery has been replaced by CRT for primary treatment of SCC of the anal canal, salvage APR has ease or fast regrowth. However, other studies reported significantly worse survival in patients with recurrent dis- remained the gold standard for patients with persistent 29,30 disease or local recurrent disease after failed CRT. Due to ease, which could not be explained clearly. the relative rarity of the procedure for this indication, most We found that increased pathological tumor size, lymph published series consist of only a small number of patients node involvement, and positive resection margins treated over a long period of time, and are therefore prone adversely affected survival, which is in concordance with 9–11,13–15,17,24,25,28,30–32 to a certain degree of bias. We present herein a rather most other series (Appendix 1). homogeneous group of patients. All patients were treated Although not identified on multivariable analysis in the present study, positive resection margin seems to remain with an adequate radiation dose of [ 45 Gy, and all but 1976 J. A. W. Hagemans et al. the most common factor negatively affecting survival. these patients. Some patients with local recurrence after sal- These findings emphasize the importance of achieving vage APR also had distant metastases or locoregional negative resection margins, which can sometimes only be recurrence, and type of surgery was not protocolled as it is for achieved by aggressive multivisceral resection or multi- the primary salvage APR. On the other hand, our results disciplinary treatment. clearly show that recurrence after salvage APR has poor Recently, Hallemeier et al. reported a multidisci- prognosis, regardless of the treatment. Palliative surgery may plinary approach, including reirradiation with or without still be considered for some patients, especially those with concomitant chemotherapy and IORT, in a small group of pain. Cure, however, does not seem to be possible. patients with persistent or recurrent anal cancer. Only 21% This study is limited by its retrospective nature and the developed recurrence within the reirradiated area. The small number of patients collected over a long time period. 5-year OS was 23%, but they specifically treated patients Patients with persistent or recurrent disease have different with expected narrow or positive resection margins. In tumor biology, and mixing these cases could affect the the present study, only two patients received IORT, and outcomes of salvage APR. Advances in diagnostic imaging none received reirradiation prior to salvage surgery, and treatment were made during the study period and likely because of the high-dose radiotherapy used as primary contributed to heterogeneity in our study population and treatment. Wright et al. retrospectively analyzed 14 outcomes. patients with locoregional recurrent anal SCC who under- went salvage surgery and IORT. Addition of IORT was not CONCLUSIONS associated with locoregional control or survival benefit and did not compensate for positive surgical margins. Reir- The results of the present study show that salvage APR radiation and IORT could potentially decrease local for patients with SCC of the anal canal after failed CRT recurrence rate, but this remains unclear. provides adequate long-term survival and local control. Currently there is no role for standard adjuvant Prognostic factors for survival were advanced tumor stage, chemotherapy, however the combination of cisplatin and lymph node involvement, and positive resection margins. 5-fluorouracil (5-FU) is the gold standard in metastatic Patients with recurrent anal SCC after salvage APR had 34,35 disease, with an overall response rate of 60%. Eng poor prognosis irrespective of performance of repeat sal- et al. showed a prolonged OS for multidisciplinary vage surgery, which never resulted in cure. management with systemic chemotherapy and intervention compared with palliative chemotherapy only in patients OPEN ACCESS This article is distributed under the terms of the with unresectable and metastatic anal SCC. In the present Creative Commons Attribution 4.0 International License (http://crea study, three patients received postoperative chemotherapy tivecommons.org/licenses/by/4.0/), which permits unrestricted use, without additional intervention. Therefore, we could not distribution, and reproduction in any medium, provided you give clearly assess the effect on OS. Multidisciplinary treatment appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were for unresectable and metastatic anal SCC can potentially made. lead to prolonged OS. To our knowledge, this is the first study to present data on treatment of recurrent anal SCC after failed CRT for primary anal SCC and salvage APR for recurrent/persistent anal SCC. 27 24 Alamri et al. and Correa et al. only reported survival for Salvage Surgery for Anal Cancer 1977 APPENDIX 1: OVERVIEW OF CURRENT LITERATURE Ref. Year of publication No. of patients 5-Year OS (%) Prognostic factors for OS after salvage APR Zelnick et al. 1992 9 24 Not identified or not mentioned Ellenhorn et al. 1993 38 44 Nodal disease Tumor fixed to lateral pelvic wall Involvement of perirectal fat Longo et al. 1994 34 23–53 Stage Method of treatment Pocard et al. 1998 21 33 Not identified or not mentioned Allal et al. 1999 26 45 Not identified or not mentioned Smith et al. 2001 22 33 Not identified or not mentioned Van der Wal et al. 2001 17 47 Not identified or not mentioned Nilsson et al. 2002 35 52 Persistent disease Akbari et al. 2004 62 33 Tumor size [ 5cm Local extent Nodal disease Positive resection margins Ghouti et al. 2005 36 69 Not identified or not mentioned Ferenschild et al. 2005 18 30 Not identified or not mentioned Renehan et al. 2005 73 40 Positive resection margins Mullen et al. 2006 31 64 Nodal disease \ 55 Gy radiotherapy dose Stewart et al. 2007 22 24–48 Tumor differentiation Positive resection margins Schiller et al. 2007 40 39 Tumor size Sex (male) Mariani et al. 2008 83 57 Age [ 55 years Nodal disease T3–4 tumor Local extent Sunesen et al. 2009 49 61 Positive resection margins Eeson et al. 2011 51 29 Positive resection margins Correa et al. 2012 111 25 Nodal disease Positive resection margin Perineural and/or lymphovascular invasion Lefevre et al. 2012 105 61 T3–T4 status Positive resection margins Metastatic disease Hallemeier et al. 2014 32 23 Recurrent disease versus persistent disease Positive resection margins Viable disease in resection specimen Alamri et al. 2016 27 78 None identified Pesi et al. 2017 20 37 None published Present study 2017 47 41 Increased pathological tumor size (mm) – Nodal disease – Positive resection margins 1978 J. 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Journal

Annals of Surgical OncologySpringer Journals

Published: Apr 24, 2018

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