Definitive CRT offers a high rate of cure in ASCC. The rarity of this tumor and low failure rate after CRT make research into the treatment of LRF difficult. In our series of 467 patients, 63 patients experienced LRF, translating to a 5-year LRF rate of 14% (95% CI, 11%–19%). This is consistent with Radiation Therapy Oncology Group 98-11 results (5-year LRF rate of 20%).29 When patient and tumor factors of the entire pretreatment cohort were examined for prediction of LRF, only T stage reached statistical significance on multivariate analysis. This is in contrast to the results of the European Organisation for Research and Treatment of Cancer trial, which also demonstrated that nodal involvement was an independent predictor of local recurrence over time, irrelevant of the site or extent of nodal disease.9 Given that the majority of patients in our cohort are from the mid-1990s onward, our results may reflect improvements in the delivery of treatment compared with the period of time over which the European Organisation for Research and Treatment of Cancer study was undertaken.
For the cohort of patients who experience LRF, the majority can be salvaged with surgery offering an improved OS. In our cohort, 41 patients (65%) underwent curative-intent local salvage surgery with a 30-day mortality rate of zero, and a 5-year OS and DFS of 51% and 47%. The OS of our cohort sits midway within the range quoted in the literature of 23% to 78%.14 , 15 , 17 , 18 , 20–23 However, this approach often necessitates aggressive and complex surgery. Although APR +/– posterior vaginectomy was the most common operation until the early 2000s, more than 50% of our salvage patients underwent an extended resection in the second half of our study period. This has provided the ability to offer a further line of treatment with an aim of cure to patients who would otherwise face palliation.
There has been longstanding conjecture on what is the appropriate time period to wait before declaring a patient as having achieved a complete response or as having persistent disease. This is not dissimilar to determining a posttreatment response in rectal SCC or, more recently, in rectal adenocarcinoma, which has gained much attention since the advent of the novel watch-and-wait approach.32 , 33 In our series, median time to assessment was 87 days in the LRF group, with a range of 27 to 235 days posttreatment completion. A recent re-analysis of the ACTII trial identified that a number of ASCC patients do not attain a complete response to primary treatment until the 6-month mark.34 This delayed regression is of particular importance in ensuring that patients are not salvaged prematurely, given the radical surgical approach and significant morbidity that accompanies it. Furthermore, delaying the assessment of response in patients without clear progression also provides time for occult metastatic disease to become apparent, further reducing the incidence of futile surgery. Given that our median assessment period was significantly less than that currently recommended, it may have increased the incidence of patients with persistent disease undergoing salvage surgery, and spuriously improved the survival of that subset.
Perineal wound healing in a radiotherapy-affected field is often poor, with flaps utilized in more recent times in an attempt to improve healing and reduce morbidity. Rectus abdominis flaps dominated as the flap of choice at our institution until 2014. Subsequently, the inferior gluteal artery myocutaneous flap became the standard for reconstruction, because it preserves the anterior abdominal wall for stoma siting, and can be performed entirely following the resection in the prone position. However, despite the proposed benefits, of the 21 patients in our salvage cohort who underwent flap closure, 38% (8 patients) experienced a complication requiring a return to the operating theater, with 2 requiring a second flap. This is significantly higher than that reported previously, and similar to perineal wound complications in those with primary closure.18 , 20 , 35 However, the majority of these complications occurred early in the study period, with only 1 complication affecting the last 9 flaps performed, and none since instituting the inferior gluteal artery myocutaneous flap (n = 6).
Although the salvage cohort has not achieved the same level of survival as primary therapy, it is likely that failure of CRT reflects a more biologically aggressive tumor, rendering itself more difficult to salvage by any means. Human papillomavirus-positive tumors are traditionally more radiosensitive, a variable that was not captured in our data set.36 It would be of interest to identify whether p16-negative patients have a higher local failure rate and whether this may act as a marker of resistance.
There are several limitations to the conclusions that can be drawn from our results. Despite our institution being a major referral center for anal cancer treatment, the infrequency of patients precludes a large cohort size, particularly when examining the salvage group. Furthermore, the data collection is retrospective, in some cases incomplete, and over a prolonged time period, during which there have been some changes in practice. These factors have limited the degree to which the data can be statistically analyzed and interpretations made. Given the limited number of HIV patients in this cohort, inferences regarding the effectiveness of salvage surgery also cannot be generalized to this population. Nonetheless, this study has provided insight into the success of local salvage surgery in patients with relapsed ASCC, and reaffirmed it as the best currently available line of treatment for this patient group.
In the current era, patients who do not respond to definitive CRT continue to present a treatment challenge. With the advent of new treatment modalities, there is the possibility of improved treatment options and response. The role of these therapies, either in conjunction with neoadjuvant or as a second line of therapy, are yet to be explored in anal cancer, however. Consequently, at present, salvage surgery remains the most successful course of treatment, offering long-term survival in over half of those salvaged for local relapse. Appropriate patient selection along with careful preoperative planning and frequently extended resections are required to achieve a negative resection margin, which is critical to the success of this treatment pathway.
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