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Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus
Available online at www.sciencedirect.com
ScienceDirect EJSO xx (2016) 1e6
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Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus Y. Alamri, P. Buchwald, L. Dixon, B. Dobbs, T. Eglinton, J. McCormick, C. Wakeman, F.A. Frizelle* Colorectal Unit, Christchurch Hospital, Christchurch, New Zealand Accepted 12 May 2016 Available online - - -
Abstract Introduction: Anal squamous cell cancers are uncommon, and primary treatment is radical chemoradiotherapy. The role of radical surgery is in salvage of patients with residual and recurrent disease. The primary aim of the study is to determine how often such salvage surgery is required, while the secondary aim is to determine which features indicate salvage surgery may be required and to determine the outcome of salvage surgery. Methods: A prospective database was analysed of all patients with anal cancer over an 18 year period (Dec 1996eJan 2015). The records of patients requiring salvage surgery were reviewed. Results: 203 Patients were identified with anal cancers, of which 180 had squamous cell anal carcinoma. 112 Female (median age 59.4, range 33e92) 68 male (median age 63.8 range 36e87). Of these 27 patients (15%) required salvage surgery. 23 Patients had a R0 resection. 18 Patients had an extended resection (16 R0) while 9 had a routine APR (7 R0). The 30-day post-operative mortality rate was 0%. The overall 5 year survival was 78%, not significantly different from those not requiring salvage surgery (p ¼ 0.23). Age, gender, AJCC stage, T stage, radiation therapy alone, were not predicators of the need for salvage surgery. Conclusions: Salvage surgery is uncommonly required. Extended surgery beyond routine APR is often required to obtain an R0 resection. Excellent patient survival can be achieved in highly selected cases. There were no identifiable clinical predictors of those needing salvage surgery, and consideration should be given to explore molecular and genetic factors. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: Anal cancer; Salvage surgery; Extended surgery outcomes
What does my paper add to the literature?
This manuscript shows that salvage surgery for anal SCC is uncommon (15%). No predicative factors could be identified. When salvage surgery is needed, an extended resection is often required to obtain an R0 resection. With salvage surgery long term survival can be similar to those who respond to initial chemoradiation.
* Corresponding author. Colorectal Unit, Department of Surgery, Christchurch Hospital, Riccarton Ave, Christchurch, New Zealand. Tel.: þ64 3 3640 640; fax: þ64 3 3640 352. E-mail address: [email protected] (F.A. Frizelle).
Introduction Cancer of the anus is an uncommon malignancy of the gastrointestinal tract accounting for less than 1% of all lower gastrointestinal cancers.1 The most common type of anal cancer is a squamous cell carcinoma (SCC) associated with human papilloma virus (HPV).2 Since the mid-1970s, the incidence of anal cancer has considerably risen, with a larger increase seen in women compared to men.1e3 Surgical excision of anal SCC is no longer the mainstay of treatment, which has become chemoradiotherapy (CRT) after the seminal work of Nigro and his colleagues in 1974.4 They showed that a combination of radiotherapy (RT) with 5-fluorouracil (5FU) and mitomycin C (MMC)
http://dx.doi.org/10.1016/j.ejso.2016.05.006 0748-7983/Ó 2016 Elsevier Ltd. All rights reserved. Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006
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Y. Alamri et al. / EJSO xx (2016) 1e6
resulted in a complete pathological response in six out of nine anal cancer patients, and this evolved into the mainstay of treatment for anal cancer as a result, with the aim of avoiding a permanent stoma. The evolution of this regimen which later became known as the “Nigro protocol”, involved the use of other chemotherapy (CT) agents, such cisplatin5 which has have improved the results. The outcome of such treatment has more recently however raised doubts about the avoidance of stoma as many patients have significant faecal incontinence following radical chemoradiation, which has lead to a high incidence of permanent stoma to manage this problem.6 Patients with residual or recurrent disease still require surgery for local control. The reported rate of patients who suffer local failure post treatment is 14e37%,7e18 however this information is often misrepresented because the numeratoredenominator are not from the same population, as patients are referred for radical surgery to specialised units therefore causing an inflated proportion requiring extenuative surgery in referral centres. The primary aim of the study is to determine how often such surgery is required, while the secondary outcomes are to determine which features indicate such surgery may be likely and to determine what the outcome of salvage surgery is. Methods Patient selection A search of the prospective departmental anal cancer database was undertaken. The database included all anal cancer patients treated at a tertiary referral hospital (Christchurch Public Hospital) in Christchurch, NZ (referral population approx. 650,000) over an 18 year period (January 1998 e December 2014). Additional patients were identified through the NZ national cancer database,19 as well as a manual search of medical, pathological and operation notes. The Upper South A Ethics Committee approved this study (URB11/06/010). Patients referred for extenuative surgery from outside regions who did not have initial treatment (radiation or chemoradiation) within region were excluded.
Residual disease was defined as incomplete clinical response to the primary treatment. Due to concerns for false-negative results, biopsy confirmation of residual disease was not always obtained prior to surgery, however patients required histologic confirmation (in the resected specimen) of recurrence to be included in this study. Recurrent disease was defined as clinical evidence of tumour regrowth despite an initial complete pathological (for at least 6 months) response to primary treatment. Salvage treatment The type of surgery (abdominal perineal resection (APR) or extended surgery (EXS) e.g. APR plus resection of prostate, vagina, sacrum, pelvic side wall lymph node resection, etc.) and other therapy modalities were recorded including RT alone, or CRT. Any post-resection surgical reconstruction (e.g. Vertical rectus abdominis muscle flap VRAM) of the pelvic soft tissues was recorded.21 Resection margin status was defined as clear (R0), microscopic residual (margin <2 mm) (R1) or macroscopic residual (R2). End points Follow-up data including survival, adverse events and cause of death was recorded. The data was verified by a retrospective review of electronic medical notes and, where necessary, the national deaths register. The primary endpoints of the study were overall and cancer free 5 year survival. These were calculated from the date of diagnosis to the date of death or date of last follow-up. Treatmentrelated adverse events were defined as events not directly attributable to residual or recurrent tumour. Statistical analysis KaplaneMeier survival analysis was used to estimate five-year survival outcomes (Fig. 2). The cumulative incidence method was used to analyse patient and treatment characteristics. Follow-up data were collected through April 2014. Statistical analysis was performed with StatView 5.0 (BrainPower Inc, California, USA). Results
Pre-treatment evaluation
Patient characteristics
Patients were staged according to the 2010 TNM staging system for anal cancer.20 Cancers of the anal canal, anal verge and anal margin were included. Data on all anal cancers was collected however, only the anal SCC which had salvage surgery are presented; other rarer types, such as melanoma and sarcoma, were recorded but excluded from outcomes analysis in order to minimise heterogeneity of outcome based on disease viability affecting biological behaviour and outcomes.
203 Patients with anal cancers were identified, of which 180 had anal SCC’s (Fig. 1). 112 were female (median age 59.4, range 33e92) and 68 were male (median age 63.8 range 36e87) Of these 27 patients (15%) required salvage surgery for recurrent or residual disease. 18 Patients had an extended resection while 9 had a routine APR. Twenty-seven patients with residual or recurrent anal cancer were identified. Key patient characteristics are
Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006
Y. Alamri et al. / EJSO xx (2016) 1e6
3
203 anal cancer
180
13
5
SCC
Adenocarcinoma
Melanoma
4 Small cell or neuroendocrine
1 Carcinosarcoma
pallaƟve intent to start 10
CuraƟve intent 168
127 Remission
14 Recurent/residual &MetastaƟc disease
27 Residual or Local recurrence only
Figure 1. Types of anal cancer and treatment goals for anal SCC. Kaplan-Meier Cum . Survival Plot for Surv Censor Variable: CaDeath Grouping Variable: SalvSurg 1
Cum. Survival
.8
.6 Cum. Survival (0) Cum. Survival (1) .4
.2
0 0
1
2
3
4
5
Time
153 27
101 24
78 21
65 17
57 14
50 13
Figure 2. KaplaneMeier estimates of post-salvage survival for 27 patients with residual or recurrent anal cancer after primary treatment. 0 is all patients with anal cancer tread with curative intent. 1 is patients treated with salvage therapy. Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006
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Y. Alamri et al. / EJSO xx (2016) 1e6
Table 1 Patient characteristics. Variable
Table 3 Clinical predicative factors for salvage surgery (univariant analysis). Salvage (n ¼ 27)
Age, median (range), y 66 (42e84) Sex, n (%) Female 17 (63) Male 10 (37) Context of salvage surgery, n (%) Residual disease 13 (48) Recurrent disease 14 (52)
Others (n ¼ 153)
Factor
68 (34e88)
Age Sex (f) AJCC stage T stage Radiation alone
95 (63) 58 (37)
OR 2.1 (0.8e5.7)
0.5 (0.1e2.3)
p Value 0.11 0.12 0.43 0.25 0.38
Salvage treatment characteristics detailed in Table 1. The median time interval from initial diagnosis to salvage APR was 15 months (range, 6e53 months). Primary treatment characteristics All patients had initially received curative-intent CRT or RT. The median initial RT dose was 42.5 Gy (range; 36e55.8). Of the 20 patient who had received primary concurrent CRT, 18 had 5FU and MMC, while two had 5FU, one of which had 5FU and cisplatin. Three patients were unable to complete their primary treatment due to sideeffects. One each due to; anal pain and fatigue, rectal bleeding, and severe radiation-induced skin reaction in the other.
Table 2 Salvage treatment characteristics and treatment-related adverse events. Variable Type of salvage APR, n (27) No flap VRAM flap ALT flap Preoperative treatment, n (27) RT alone CRT Margin status after resection, n (27) R0 R1 R2 Type of surgery APR EXS TAHBSO/vaginal Sacrum Lateral pelvic sidewall resection Prostate/bladder Treatment-related adverse events Chest infection Ileal conduit leak Urinary sepsis Central line sepsis Prolonged ileus Stoma problems Minor wound dehiscence Major wound dehiscence Ulnar nerve palsy
Of these 27 patients who required salvage surgery for recurrent or residual disease, 23 patients had a R0 resection, one an R1 resection, and three a R2 resection. 18 Patients had an EXS with 16 having an R0 resection. In the 9 patients who had a routine APR with 7 having R0 resection. Details of extended resection are in Table 2. The median length of hospitalisation was 20 days (range, 8e81 days). Treatment-related adverse events There was a total of fifteen patients had treatmentrelated adverse events (some more than one): Chest infection 7, ileal conduit leak 1, urinary sepsis 4, central lines sepsis 2, prolonged ileus 2, early parastomal herniation 2, other stomal problems 1, minor wound dehiscence 3, major wound dehiscence 3 and anaesthesia-related ulnar nerve palsy 1. The 30-day post-operative mortality rate was 0%. Predictors of need for salvage surgery
Value (%) 10 (37) 16 (59) 1 (4)
There were no early clinical predicative factors identified for determining which patients would need salvage surgery (Table 3).
2 (7) 25 (93)
Discussion
23 (85) 1 (4) 3 (11) 9 18 12 2 4 6 7 1 4 2 2 3 3 3 1
In the present study, we evaluated how many patients came to salvage surgery for residual or recurrent anal SCC after primary treatment, and the outcomes of these patients. We found that salvage surgery is uncommonly required for patients with anal SCC in that only 27 patients of 180 patients (15%) required salvage surgery. Publications over the last twenty years have are very variable results from the management of recurrent and residual anal SCC.8e18,22 The studies are generally of small patients number (median 32, range 14e83), with R0 resection being obtained most (median of 84%, range 50e99%).8e18,22 A median 2 year survival of 70% (range 21e90%) and a median 5 year survival of 40% (range 23e78%) is reported.8e18,22 Unlike other studies we found that the overall survival rates were similar to those who did not require salvage therapy (perhaps due to patient selection bias) and these were better generally than older published
Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006
Y. Alamri et al. / EJSO xx (2016) 1e6
series,8e18,22 however we were unable to determine any factors that would predict the need for salvage surgery. In patients with residual or recurrent anal SCC after their primary treatment, surgical resection of the disease remains at present the principle treatment modality that offers a chance, of cure. Unfortunately, a sizeable sub-group of this population requires extensive surgery beyond that achieved with a routine APR. In patients with resectable disease, surgical margin positivity remains the most significant prognostic factor.9e12,22 A reason why those who had salvage surgery for recurrent or residual disease did better than we expected might be related to the high select nature of patients who have surgery for this. Over the study period the increased preoperative use of CT-PET has led to better patients selection and possibly outcomes.23,24 As well the time between initial diagnosis and subsequent treatment for recurrent/residual disease means that patients who do come to resection have had more time to declare the underlying metastatic potential of their disease. This selection of patients means that those who had salvage surgery may be more likely to truly have localised disease and not occult metastatic disease. In recurrent/residual anal SCC it is very difficult to assess the local extent of disease and when treatment has been successful especially with large primary tumours. Imaging with CT, MRI and CT-PET helps select patients with apparent recurrence and localised disease suitable for resection, however, imaging often fails to show the true extent of local invasion. The decision to operate is delayed for long as possible as regression can continue for long periods, and only after clinical or radiological proof of progression is surgery considered (at least 3 months following chemoradiotherapy). While luminal disease is what often attracts clinical attention, residual/recurrent disease can often have extensive extraluminal spread, which can be difficult to define on imaging due to the post radiotherapy scarring and the desmoplastic nature of residual/recurrent disease. The result of this residual/recurrent disease pattern means that surgery often has to be locally extensive and that a simple salvage APR is likely to result in positive margins as others have also reported.9e19 The lack of definitive assessment of extent of local disease on imaging means that selection of patients to undergo surgery is difficult and reflects the subjective nature of ascertaining surgical resectability. This subjective patient selection of resectability also hinders direct comparison between studies. With improved surgical techniques, and increased experience at extended resections for other diseases (such as recurrent rectal cancer and T4 rectal cancers) one might expect improved results, however the increased “resectability” may also have flattened outcome results as more radical surgery is untaken in patients previously considered not resectable. The expansion of resectability is seen in the fact that the recent Mayo Clinic report on their 33 patients having salvage surgery for anal SCC had
5
only 50% had an R0 resection. This ‘selection bias’ perhaps explains the largely unchanged survival rates over the last 20 years. Intra-operative radiotherapy has been a “fringe” treatment for many years. The benefit of intra-operative radiotherapy in such patients is yet to be demonstrated though it is widely thought likely to be of benefit in those were a close margin is a concern. There is considerable additional costs, resources and technical support required (of both the apparatus and the operating theatre design), and it may be associated with more severe treatment-related adverse events, with reported benefits at best modest.9,10 We have not been able to identify any clinical factors that prognosticate on the possible need for salvage surgery. There is need for further research to better determine which patients will respond to initial chemoradiation treatment. There is also hope that targeted molecular therapies may become available to treat a range of solid and haematological malignancies. This holds exciting potential for patients with anal cancer, allowing the identification of potential novel therapeutic avenues to improve on the treatment outcomes for those patients with local failure or distant disease. Other patients may require palliative surgery for local control even in the presence of metastatic disease, or were radiation has previously been used to treat other cancer (e.g. prostate of cervical) and there are limited other primary treatment options. These patients were not included in this analysis which was of patient treated with curative intent with recurrent or residual disease. The patients having salvage surgery with palliative intent we have found have done poorly with rapid progression of disease and multiple post-operative complications. There are many limitations of our series. This is a uncommon tumour which is reflected in our small sample size, which limits further data examination as the series was not sufficiently powered to allow for rigorous analysis, and some of the data is incomplete. The use of PET-CT restaging in stage 2 upwards cancer has only become part of our clinical practise as evidence to support this has become available for the past 5 years.23,24 Despite these limitations, the findings provide novel data on surgical salvage therapy in patients with residual or recurrent anal cancer following primary treatment. We have shown that salvage surgery is uncommonly required for anal SCC (15%). When it is required it is possible and can produce good patient survival zero 30day post-operative mortality; 78% 5 year survival. We were unable to identifiable clinical predictors of those needing salvage surgery, and consideration should be given to explore molecular and genetic factors.
Funding No external financial support.
Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006
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Conflict of interest statement The authors have no financial conflict of interest.
References 1. Anal cancer. In: Schottenfeld D, Fraumeni JF, editors. Cancer epidemiology and prevention. 3rd ed. New York: Oxford University Press; 2006; p. 831–40. 2. HPV Information Centre. Human papillomavirus and related cancers: New Zealand. [Internet] Jan 2010. [cited 2014 May 6]. Available from: https://www.health.govt.nz/system/files/documents/pages/hpv-relatedcancers-summary-report.pdf. 3. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006;118:3030–44. 4. Nigro ND, Vaitkevicius VK, Considine Jr B. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974;17:354–6. 5. Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of US GI intergroup RTO G 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin vs fluorouracil/cisplatin. J Clin Oncol 2012;30:4344–51. 6. Young SC, Solomon MJ, Hruby G, Frizelle FA. Review of 120 anal cancer patients. Colorectal Dis 2009;11:909–14. 7. Renehan AG, O’Dwyer ST. Initial management through the anal cancer multidisciplinary team meeting. Colorectal Dis 2011;13(Suppl. 1): 21–8. 8. Tomaszewski JM, Link E, Leong T, et al. Twenty-five-year experience with radical chemoradiation for anal cancer. Int J Radiat Oncol Biol Phys 2012;83:552–8. 9. Hallemeier CL, You YN, Larson DW, et al. Multimodality therapy including salvage surgical resection and intraoperative radiotherapy for patients with squamous-cell carcinoma of the anus with residual or recurrent disease after primary chemoradiotherapy. Dis Colon Rectum 2014;57:442–8. 10. Wright JL, Gollub MJ, Weiser MR, et al. Surgery and high-dose-rate intraoperative radiation therapy for recurrent squamous-cell carcinoma of the anal canal. Dis Colon Rectum 2011;54:1090–7.
11. Eeson G, Foo M, Harrow S, et al. Outcomes of salvage surgery for epidermoid carcinoma of the anus following failed combined modality treatment. Am J Surg 2011;201:628–33. 12. Mariani P, Ghanneme A, De la Rochefordiere A, et al. Abdominoperineal resection for anal cancer. Dis Colon Rectum 2008;51:1495–501. 13. Stewart D, Yan Y, Kodner IJ, et al. Salvage surgery after failed chemoradiation for anal canal cancer: should the paradigm be changed for high-risk tumors? J Gastrointest Surg 2007;11:1744–51. 14. Schiller DE, Cummings BJ, Rai S, et al. Outcomes of salvage surgery for squamous cell carcinoma of the anal canal. Ann Surg Oncol 2007; 14:2780–9. 15. Mullen JT, Rodriguez-Bigas MA, Chang GJ, et al. Results of surgical salvage after failed chemoradiation therapy for epidermoid carcinoma of the anal canal. Ann Surg Oncol 2007;14:478–83. 16. Akbari RP, Paty PB, Guillem JG, et al. Oncologic outcomes of salvage surgery for epidermoid carcinoma of the anus initially managed with combined modality therapy. Dis Colon Rectum 2004;47:1136–44. 17. Nilsson PJ, Svensson C, Goldman S, et al. Salvage abdominoperineal resection in anal epidermoid cancer. Br J Surg 2002;89:1425–9. 18. Allal AS, Laurencet FM, Reymond MA, et al. Effectiveness of surgical salvage therapy for patients with locally uncontrolled anal carcinoma after sphincter-conserving treatment. Cancer 1999;86:405–9. 19. New Zealand Health Information Service. Cancer registrations and deaths. [Internet] 2002. [cited 2015 June 20]. Available from: http:// www.nzhis.govt.nz/stats/tables/cancer2002.xls. 20. Anus. In: Edge SB, Byrd DR, Compton CC, et al, editorss. AJCC cancer staging manual. 7th ed. New York, NY: Springer; 2010; p. 167–9. 21. Creagh TA, Dixon L, Frizelle FA. Reconstruction with vertical rectus abdominus myocutaneous flap in advanced pelvic malignancy. J Plast Reconstr Aesthet Surg 2012;65:791–7. 22. Tan KK, Pal S, Lee PJ, Rodwell L, Solomon MJ. Pelvic exenteration for recurrent squamous cell carcinoma of the pelvic organs arising from the cloacaea single institution’s experience over 16 years. Colorectal Dis 2013;15:1227–31. 23. Jones M, Hruby G, Solomon M, Rutherford N, Martin J. The role of FDG-PET in the initial staging and response assessment of anal cancer: a systematic review and meta-analysis. Ann Surg Oncol 2015; 22:3574–81. 24. Deantonio L, Milia ME, Cena T, et al. Anal cancer FDG-PET standard uptake value: correlation with tumor characteristics, treatment response and survival. Radiol Med 2016;121(1):54–9.
Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006
ScienceDirect EJSO xx (2016) 1e6
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Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus Y. Alamri, P. Buchwald, L. Dixon, B. Dobbs, T. Eglinton, J. McCormick, C. Wakeman, F.A. Frizelle* Colorectal Unit, Christchurch Hospital, Christchurch, New Zealand Accepted 12 May 2016 Available online - - -
Abstract Introduction: Anal squamous cell cancers are uncommon, and primary treatment is radical chemoradiotherapy. The role of radical surgery is in salvage of patients with residual and recurrent disease. The primary aim of the study is to determine how often such salvage surgery is required, while the secondary aim is to determine which features indicate salvage surgery may be required and to determine the outcome of salvage surgery. Methods: A prospective database was analysed of all patients with anal cancer over an 18 year period (Dec 1996eJan 2015). The records of patients requiring salvage surgery were reviewed. Results: 203 Patients were identified with anal cancers, of which 180 had squamous cell anal carcinoma. 112 Female (median age 59.4, range 33e92) 68 male (median age 63.8 range 36e87). Of these 27 patients (15%) required salvage surgery. 23 Patients had a R0 resection. 18 Patients had an extended resection (16 R0) while 9 had a routine APR (7 R0). The 30-day post-operative mortality rate was 0%. The overall 5 year survival was 78%, not significantly different from those not requiring salvage surgery (p ¼ 0.23). Age, gender, AJCC stage, T stage, radiation therapy alone, were not predicators of the need for salvage surgery. Conclusions: Salvage surgery is uncommonly required. Extended surgery beyond routine APR is often required to obtain an R0 resection. Excellent patient survival can be achieved in highly selected cases. There were no identifiable clinical predictors of those needing salvage surgery, and consideration should be given to explore molecular and genetic factors. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: Anal cancer; Salvage surgery; Extended surgery outcomes
What does my paper add to the literature?
This manuscript shows that salvage surgery for anal SCC is uncommon (15%). No predicative factors could be identified. When salvage surgery is needed, an extended resection is often required to obtain an R0 resection. With salvage surgery long term survival can be similar to those who respond to initial chemoradiation.
* Corresponding author. Colorectal Unit, Department of Surgery, Christchurch Hospital, Riccarton Ave, Christchurch, New Zealand. Tel.: þ64 3 3640 640; fax: þ64 3 3640 352. E-mail address: [email protected] (F.A. Frizelle).
Introduction Cancer of the anus is an uncommon malignancy of the gastrointestinal tract accounting for less than 1% of all lower gastrointestinal cancers.1 The most common type of anal cancer is a squamous cell carcinoma (SCC) associated with human papilloma virus (HPV).2 Since the mid-1970s, the incidence of anal cancer has considerably risen, with a larger increase seen in women compared to men.1e3 Surgical excision of anal SCC is no longer the mainstay of treatment, which has become chemoradiotherapy (CRT) after the seminal work of Nigro and his colleagues in 1974.4 They showed that a combination of radiotherapy (RT) with 5-fluorouracil (5FU) and mitomycin C (MMC)
http://dx.doi.org/10.1016/j.ejso.2016.05.006 0748-7983/Ó 2016 Elsevier Ltd. All rights reserved. Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006
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Y. Alamri et al. / EJSO xx (2016) 1e6
resulted in a complete pathological response in six out of nine anal cancer patients, and this evolved into the mainstay of treatment for anal cancer as a result, with the aim of avoiding a permanent stoma. The evolution of this regimen which later became known as the “Nigro protocol”, involved the use of other chemotherapy (CT) agents, such cisplatin5 which has have improved the results. The outcome of such treatment has more recently however raised doubts about the avoidance of stoma as many patients have significant faecal incontinence following radical chemoradiation, which has lead to a high incidence of permanent stoma to manage this problem.6 Patients with residual or recurrent disease still require surgery for local control. The reported rate of patients who suffer local failure post treatment is 14e37%,7e18 however this information is often misrepresented because the numeratoredenominator are not from the same population, as patients are referred for radical surgery to specialised units therefore causing an inflated proportion requiring extenuative surgery in referral centres. The primary aim of the study is to determine how often such surgery is required, while the secondary outcomes are to determine which features indicate such surgery may be likely and to determine what the outcome of salvage surgery is. Methods Patient selection A search of the prospective departmental anal cancer database was undertaken. The database included all anal cancer patients treated at a tertiary referral hospital (Christchurch Public Hospital) in Christchurch, NZ (referral population approx. 650,000) over an 18 year period (January 1998 e December 2014). Additional patients were identified through the NZ national cancer database,19 as well as a manual search of medical, pathological and operation notes. The Upper South A Ethics Committee approved this study (URB11/06/010). Patients referred for extenuative surgery from outside regions who did not have initial treatment (radiation or chemoradiation) within region were excluded.
Residual disease was defined as incomplete clinical response to the primary treatment. Due to concerns for false-negative results, biopsy confirmation of residual disease was not always obtained prior to surgery, however patients required histologic confirmation (in the resected specimen) of recurrence to be included in this study. Recurrent disease was defined as clinical evidence of tumour regrowth despite an initial complete pathological (for at least 6 months) response to primary treatment. Salvage treatment The type of surgery (abdominal perineal resection (APR) or extended surgery (EXS) e.g. APR plus resection of prostate, vagina, sacrum, pelvic side wall lymph node resection, etc.) and other therapy modalities were recorded including RT alone, or CRT. Any post-resection surgical reconstruction (e.g. Vertical rectus abdominis muscle flap VRAM) of the pelvic soft tissues was recorded.21 Resection margin status was defined as clear (R0), microscopic residual (margin <2 mm) (R1) or macroscopic residual (R2). End points Follow-up data including survival, adverse events and cause of death was recorded. The data was verified by a retrospective review of electronic medical notes and, where necessary, the national deaths register. The primary endpoints of the study were overall and cancer free 5 year survival. These were calculated from the date of diagnosis to the date of death or date of last follow-up. Treatmentrelated adverse events were defined as events not directly attributable to residual or recurrent tumour. Statistical analysis KaplaneMeier survival analysis was used to estimate five-year survival outcomes (Fig. 2). The cumulative incidence method was used to analyse patient and treatment characteristics. Follow-up data were collected through April 2014. Statistical analysis was performed with StatView 5.0 (BrainPower Inc, California, USA). Results
Pre-treatment evaluation
Patient characteristics
Patients were staged according to the 2010 TNM staging system for anal cancer.20 Cancers of the anal canal, anal verge and anal margin were included. Data on all anal cancers was collected however, only the anal SCC which had salvage surgery are presented; other rarer types, such as melanoma and sarcoma, were recorded but excluded from outcomes analysis in order to minimise heterogeneity of outcome based on disease viability affecting biological behaviour and outcomes.
203 Patients with anal cancers were identified, of which 180 had anal SCC’s (Fig. 1). 112 were female (median age 59.4, range 33e92) and 68 were male (median age 63.8 range 36e87) Of these 27 patients (15%) required salvage surgery for recurrent or residual disease. 18 Patients had an extended resection while 9 had a routine APR. Twenty-seven patients with residual or recurrent anal cancer were identified. Key patient characteristics are
Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006
Y. Alamri et al. / EJSO xx (2016) 1e6
3
203 anal cancer
180
13
5
SCC
Adenocarcinoma
Melanoma
4 Small cell or neuroendocrine
1 Carcinosarcoma
pallaƟve intent to start 10
CuraƟve intent 168
127 Remission
14 Recurent/residual &MetastaƟc disease
27 Residual or Local recurrence only
Figure 1. Types of anal cancer and treatment goals for anal SCC. Kaplan-Meier Cum . Survival Plot for Surv Censor Variable: CaDeath Grouping Variable: SalvSurg 1
Cum. Survival
.8
.6 Cum. Survival (0) Cum. Survival (1) .4
.2
0 0
1
2
3
4
5
Time
153 27
101 24
78 21
65 17
57 14
50 13
Figure 2. KaplaneMeier estimates of post-salvage survival for 27 patients with residual or recurrent anal cancer after primary treatment. 0 is all patients with anal cancer tread with curative intent. 1 is patients treated with salvage therapy. Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006
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Y. Alamri et al. / EJSO xx (2016) 1e6
Table 1 Patient characteristics. Variable
Table 3 Clinical predicative factors for salvage surgery (univariant analysis). Salvage (n ¼ 27)
Age, median (range), y 66 (42e84) Sex, n (%) Female 17 (63) Male 10 (37) Context of salvage surgery, n (%) Residual disease 13 (48) Recurrent disease 14 (52)
Others (n ¼ 153)
Factor
68 (34e88)
Age Sex (f) AJCC stage T stage Radiation alone
95 (63) 58 (37)
OR 2.1 (0.8e5.7)
0.5 (0.1e2.3)
p Value 0.11 0.12 0.43 0.25 0.38
Salvage treatment characteristics detailed in Table 1. The median time interval from initial diagnosis to salvage APR was 15 months (range, 6e53 months). Primary treatment characteristics All patients had initially received curative-intent CRT or RT. The median initial RT dose was 42.5 Gy (range; 36e55.8). Of the 20 patient who had received primary concurrent CRT, 18 had 5FU and MMC, while two had 5FU, one of which had 5FU and cisplatin. Three patients were unable to complete their primary treatment due to sideeffects. One each due to; anal pain and fatigue, rectal bleeding, and severe radiation-induced skin reaction in the other.
Table 2 Salvage treatment characteristics and treatment-related adverse events. Variable Type of salvage APR, n (27) No flap VRAM flap ALT flap Preoperative treatment, n (27) RT alone CRT Margin status after resection, n (27) R0 R1 R2 Type of surgery APR EXS TAHBSO/vaginal Sacrum Lateral pelvic sidewall resection Prostate/bladder Treatment-related adverse events Chest infection Ileal conduit leak Urinary sepsis Central line sepsis Prolonged ileus Stoma problems Minor wound dehiscence Major wound dehiscence Ulnar nerve palsy
Of these 27 patients who required salvage surgery for recurrent or residual disease, 23 patients had a R0 resection, one an R1 resection, and three a R2 resection. 18 Patients had an EXS with 16 having an R0 resection. In the 9 patients who had a routine APR with 7 having R0 resection. Details of extended resection are in Table 2. The median length of hospitalisation was 20 days (range, 8e81 days). Treatment-related adverse events There was a total of fifteen patients had treatmentrelated adverse events (some more than one): Chest infection 7, ileal conduit leak 1, urinary sepsis 4, central lines sepsis 2, prolonged ileus 2, early parastomal herniation 2, other stomal problems 1, minor wound dehiscence 3, major wound dehiscence 3 and anaesthesia-related ulnar nerve palsy 1. The 30-day post-operative mortality rate was 0%. Predictors of need for salvage surgery
Value (%) 10 (37) 16 (59) 1 (4)
There were no early clinical predicative factors identified for determining which patients would need salvage surgery (Table 3).
2 (7) 25 (93)
Discussion
23 (85) 1 (4) 3 (11) 9 18 12 2 4 6 7 1 4 2 2 3 3 3 1
In the present study, we evaluated how many patients came to salvage surgery for residual or recurrent anal SCC after primary treatment, and the outcomes of these patients. We found that salvage surgery is uncommonly required for patients with anal SCC in that only 27 patients of 180 patients (15%) required salvage surgery. Publications over the last twenty years have are very variable results from the management of recurrent and residual anal SCC.8e18,22 The studies are generally of small patients number (median 32, range 14e83), with R0 resection being obtained most (median of 84%, range 50e99%).8e18,22 A median 2 year survival of 70% (range 21e90%) and a median 5 year survival of 40% (range 23e78%) is reported.8e18,22 Unlike other studies we found that the overall survival rates were similar to those who did not require salvage therapy (perhaps due to patient selection bias) and these were better generally than older published
Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006
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series,8e18,22 however we were unable to determine any factors that would predict the need for salvage surgery. In patients with residual or recurrent anal SCC after their primary treatment, surgical resection of the disease remains at present the principle treatment modality that offers a chance, of cure. Unfortunately, a sizeable sub-group of this population requires extensive surgery beyond that achieved with a routine APR. In patients with resectable disease, surgical margin positivity remains the most significant prognostic factor.9e12,22 A reason why those who had salvage surgery for recurrent or residual disease did better than we expected might be related to the high select nature of patients who have surgery for this. Over the study period the increased preoperative use of CT-PET has led to better patients selection and possibly outcomes.23,24 As well the time between initial diagnosis and subsequent treatment for recurrent/residual disease means that patients who do come to resection have had more time to declare the underlying metastatic potential of their disease. This selection of patients means that those who had salvage surgery may be more likely to truly have localised disease and not occult metastatic disease. In recurrent/residual anal SCC it is very difficult to assess the local extent of disease and when treatment has been successful especially with large primary tumours. Imaging with CT, MRI and CT-PET helps select patients with apparent recurrence and localised disease suitable for resection, however, imaging often fails to show the true extent of local invasion. The decision to operate is delayed for long as possible as regression can continue for long periods, and only after clinical or radiological proof of progression is surgery considered (at least 3 months following chemoradiotherapy). While luminal disease is what often attracts clinical attention, residual/recurrent disease can often have extensive extraluminal spread, which can be difficult to define on imaging due to the post radiotherapy scarring and the desmoplastic nature of residual/recurrent disease. The result of this residual/recurrent disease pattern means that surgery often has to be locally extensive and that a simple salvage APR is likely to result in positive margins as others have also reported.9e19 The lack of definitive assessment of extent of local disease on imaging means that selection of patients to undergo surgery is difficult and reflects the subjective nature of ascertaining surgical resectability. This subjective patient selection of resectability also hinders direct comparison between studies. With improved surgical techniques, and increased experience at extended resections for other diseases (such as recurrent rectal cancer and T4 rectal cancers) one might expect improved results, however the increased “resectability” may also have flattened outcome results as more radical surgery is untaken in patients previously considered not resectable. The expansion of resectability is seen in the fact that the recent Mayo Clinic report on their 33 patients having salvage surgery for anal SCC had
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only 50% had an R0 resection. This ‘selection bias’ perhaps explains the largely unchanged survival rates over the last 20 years. Intra-operative radiotherapy has been a “fringe” treatment for many years. The benefit of intra-operative radiotherapy in such patients is yet to be demonstrated though it is widely thought likely to be of benefit in those were a close margin is a concern. There is considerable additional costs, resources and technical support required (of both the apparatus and the operating theatre design), and it may be associated with more severe treatment-related adverse events, with reported benefits at best modest.9,10 We have not been able to identify any clinical factors that prognosticate on the possible need for salvage surgery. There is need for further research to better determine which patients will respond to initial chemoradiation treatment. There is also hope that targeted molecular therapies may become available to treat a range of solid and haematological malignancies. This holds exciting potential for patients with anal cancer, allowing the identification of potential novel therapeutic avenues to improve on the treatment outcomes for those patients with local failure or distant disease. Other patients may require palliative surgery for local control even in the presence of metastatic disease, or were radiation has previously been used to treat other cancer (e.g. prostate of cervical) and there are limited other primary treatment options. These patients were not included in this analysis which was of patient treated with curative intent with recurrent or residual disease. The patients having salvage surgery with palliative intent we have found have done poorly with rapid progression of disease and multiple post-operative complications. There are many limitations of our series. This is a uncommon tumour which is reflected in our small sample size, which limits further data examination as the series was not sufficiently powered to allow for rigorous analysis, and some of the data is incomplete. The use of PET-CT restaging in stage 2 upwards cancer has only become part of our clinical practise as evidence to support this has become available for the past 5 years.23,24 Despite these limitations, the findings provide novel data on surgical salvage therapy in patients with residual or recurrent anal cancer following primary treatment. We have shown that salvage surgery is uncommonly required for anal SCC (15%). When it is required it is possible and can produce good patient survival zero 30day post-operative mortality; 78% 5 year survival. We were unable to identifiable clinical predictors of those needing salvage surgery, and consideration should be given to explore molecular and genetic factors.
Funding No external financial support.
Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006
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Y. Alamri et al. / EJSO xx (2016) 1e6
Conflict of interest statement The authors have no financial conflict of interest.
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Please cite this article in press as: Alamri Y, et al., Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.05.006