P < .001 (trend test) for all except those with tumors 1 cm or smaller (trend test, P = .04).
P = .93 (log-rank test).
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Chai CY, Tran Cao HS, Awad S, Massarweh NN. Management of Stage I Squamous Cell Carcinoma of the Anal Canal. JAMA Surg. 2018;153(3):209–215. doi:10.1001/jamasurg.2017.3151
Is concurrent chemotherapy and radiotherapy required to treat patients with T1N0 (stage I) squamous cell carcinoma of the anal canal?
In this cohort study of 2243 patients with squamous cell carcinoma of the anal canal, 503 were treated with local excision with increasing proportional use over time. Relative to concurrent chemotherapy and radiotherapy, local excision alone was not associated with an increased risk of death.
This study suggests the need for future trials to confirm the oncologic efficacy of local excision for the management of select patients with squamous cell carcinoma of the anal canal.
The incidence of squamous cell carcinoma of the anal canal (SCCAC) is increasing. Although standard management of SCCAC includes the use of concurrent chemotherapy and radiotherapy (chemoradiotherapy), data are lacking on potentially less morbid, alternative management strategies, such as local excision, among patients with node-negative T1 disease.
To examine the use of local excision among patients with T1 SCCAC and to compare overall survival relative to those who received standard treatment with chemoradiotherapy.
Design, Setting, and Participants
This retrospective cohort study assessed 2243 patients in the National Cancer Database (2004-2012) between 18 and 80 years of age with T1N0M0 SCCAC. The association between the type of treatment received and overall risk of death was evaluated using multivariable Cox proportional hazards regression models. Data analysis was performed from June 29, 2016, to April 17, 2017.
Main Outcomes and Measures
Among 2243 patients with T1N0 SCCAC, 503 (22.4%) were treated with local excision alone (mean [SD] age, 54.5 [12.1] years; 240 [47.7%] male; 419 [83.3%] white) and 1740 with chemoradiotherapy (mean [SD] age, 57.0 [10.6] years; 562 [32.3%] male; 1547 [88.9%] white). Among those treated with chemoradiotherapy, 12 patients underwent a subsequent abdominoperineal resection. There was a statistically significant increase in the use of local excision during the study period (34 [17.3%] in 2004 to 68 [30.8%] in 2012; trend test, P < .001). This increase in use was observed among patients with primary tumors that measured 1 cm or smaller and greater than 1 cm to 2 cm or smaller (trend test, P < .001 for both). Overall survival at 5 years was not significantly different for the 2 management strategies (85.3% in the local excision cohort and 86.8% in the chemoradiotherapy cohort; log-rank test, P = .93). Overall risk of death was not significantly different for local excision alone relative to that for treatment with chemoradiotherapy (hazard ratio, 1.06; 95% CI, 0.78-1.44). These findings were robust when stratified by tumor size and when patients who underwent abdominoperineal resection after chemoradiotherapy were excluded.
Conclusions and Relevance
The use of local excision alone for the management of T1N0 SCCAC has significantly increased over time, with no clear decrement in overall survival. Because local excision may represent a lower-cost, less morbid treatment option for select patients with SCCAC, future studies are needed to better delineate its role and efficacy relative to the current standard of chemoradiotherapy.
During the past 3 decades, the incidence of anal cancer in the United States has been steadily increasing without significant changes in overall survival (OS).1 Squamous cell carcinoma of the anal canal (SCCAC), commonly called anal cancer, has been a stigmatized condition that frequently presents as a late-stage disease with a correspondingly poor prognosis.2 The treatment of SCCAC has evolved significantly since Nigro and colleagues3 published a case report of 3 patients with locally advanced SCCAC who were successfully treated with chemotherapy and radiotherapy. Contemporary practice guidelines recommend definitive concurrent chemotherapy and radiotherapy (chemoradiotherapy) for all patients with localized and/or regional SCCAC.4
However, chemoradiotherapy is associated with several potentially severe early and late adverse effects, such as hematologic and gastrointestinal tract toxic effects, skin dermatitis, proctitis, anal and vaginal stenosis, incontinence, and fecal urgency.5-8 Furthermore, most data that support the use of chemoradiotherapy are derived from patients with intermediate or more locally advanced (T2 lesions or greater) disease (Table 1).3,9-15 As such, it is not clear whether definitive chemoradiotherapy should be used in the treatment of patients with early-stage (T1N0M0) SCCAC. Recently published data suggest that less aggressive, and potentially less morbid, management options, such as local excision alone, may be feasible in select patients.16-18 In addition, with increasing efforts to raise anal cancer awareness in at-risk patients and to improve screening in these populations, there may be opportunities going forward to identify patients with earlier-stage disease.19
Given the uncertainty about the generalizability of historical data regarding use of chemoradiotherapy in patients with early-stage SCCAC and the recent emphasis in US health care on identifying management options that not only decrease costs but are also patient centered, potentially effective, less morbid treatment options for SCCAC should be considered. We examine contemporary trends in the treatment of patients with early-stage (T1N0M0) SCCAC and evaluate the association between varying management strategies and OS. We hypothesized that patients with early-stage SCCAC can be treated with local excision alone without an adverse effect on OS.
This was a retrospective cohort study using the National Cancer Data Base (NCDB), a joint program of the American College of Surgeons Commission on Cancer (CoC) and the American Cancer Society. The NCDB is a prospective, hospital-based cancer registry that collects and reports data on more than 70% of cancer incidents diagnosed at more than 1500 CoC-accredited centers in the United States. This study was approved and granted a waiver of consent by the institutional review board of the Baylor College of Medicine and the Michael E. DeBakey Veterans Affairs Medical Center Research & Development Committee. All data were deidentified.
From 2004 to 2012, a total of 38 821 patients between 18 and 80 years of age with a diagnosis of SCCAC were identified. Sequential exclusions, yielding a final cohort of 2243 patients with T1N0M0 disease, are displayed in Figure 1. The exclusion based on treatment at the reporting facility was intended to enhance the accuracy of treatment ascertainment. Data analysis was performed from June 29, 2016, to April 17, 2017.
The NCDB provides demographic, clinical, and treatment data. Educational level and income were derived from 2012 American Community Survey data. A Charlson-Deyo index is provided as a measure of comorbid conditions (index range, 0 to ≥2; higher values indicate greater burden of comorbid conditions). In addition, information on tumor size was used to stratify patients as having a primary tumor that was 1 cm or smaller or greater than 1 cm to 2 cm or smaller. All patients were categorized as having undergone local excision or receiving chemoradiotherapy. Because patients who underwent a local excision subsequently followed by chemoradiotherapy may have had their surgical procedure performed with the intent of establishing a diagnosis, they were categorized as having been primarily treated with chemoradiotherapy. Patients who underwent an abdominoperineal resection (APR) after chemoradiotherapy (n = 12) were handled in an intention-to-treat fashion and were included in the chemoradiotherapy group.
Standard descriptive statistics were used to evaluate categorical and continuous variable distributions. A nonparametric test for trend was applied to evaluate changes in treatment use over time. Logistic regression was used to evaluate the association between the use of local excision and patient demographic and clinical factors (C statistic = 0.74). The primary outcome of interest was OS, defined as time from diagnosis to death. The Kaplan-Meier method and log-rank test were used to compare OS based on the type of treatment received. The association between treatment approach and risk of death was evaluated using multivariable Cox proportional hazards regression. The assumption of proportional hazards was evaluated graphically and using Schoenfeld residuals. For all the logistic and Cox proportional hazards regression models, covariate selection was performed nonparsimoniously and included age, sex, race, insurance type, income, educational level, comorbidity, rurality, histologic grade, and treatment facility type. In all models, robust SEs were used to account for clustering of patients within a facility. Sensitivity analyses were performed by stratifying patients based on primary tumor size and excluding patients who underwent APR after chemoradiotherapy.
Our cohort included 10.7% of patients with at least 1 missing covariate data point. The OS at 5 years was not significantly different among patients with (84.7%) and without (86.8%) missing data (log-rank test, P = .87). To address missing values, modeling was conducted in a case-complete fashion and using multiple imputation by chained equations. Similar results were obtained, and thus imputed results are presented. Statistical comparisons were 2-sided and considered to be significant at P < .05. All analyses were performed using STATA, version 14.0 (StataCorp).
Among 2243 patients with T1N0 SCCAC, 503 (22.4%) were managed with local excision alone (mean [SD] age, 54.5 [12.1] years; 240 [47.7%] male; 419 [83.3%] white) and 1740 with chemoradiotherapy (mean [SD] age, 57.0 [10.6] years; 562 [32.3%] male; 1547 [88.9%] white). Table 2 provides sociodemographic and clinical patient data for the study cohort. Among those treated with chemoradiotherapy, 12 patients subsequently underwent APR. Patients treated with local excision more frequently had tumors that were 1 cm or smaller.
After multivariable modeling, only histologic grade was consistently associated with the use of local excision. In the model for the overall cohort, age of 56 to 64 years (odds ratio [OR], 0.66; 95% CI, 0.48-0.90) and histologic grade (moderate: OR, 0.36; 95% CI, 0.27-0.47; poor or undifferentiated: OR, 0.27; 95% CI, 0.16-0.33) were associated with lower odds of being treated with local excision. Higher income was associated with higher odds of local excision (OR, 1.46; 95% CI, 1.07-2.00). For patients with tumors 1 cm or smaller, a Charlson-Deyo index of 2 or higher was associated with greater odds (OR, 3.05; 95% CI, 1.27-7.33) and histologic grade with lower odds (moderate: OR, 0.34; 95% CI, 0.20-0.59; poor or undifferentiated: OR, 0.20; 95% CI, 0.11-0.37) of local excision. For patients with tumors greater than 1 cm to 2 cm or smaller, age of 56 to 64 years (OR, 0.59; 95% CI, 0.36-0.97), female sex (OR, 0.64; 95% CI, 0.43-0.95), and histologic grade (moderate: OR, 0.36; 95% CI, 0.24-0.55; poor or undifferentiated: OR, 0.23; 95% CI, 0.14-0.40) were all associated with lower odds of local excision. No other factors were associated with the use of local excision.
Figure 2 shows the proportional use of local excision and chemoradiotherapy during the study period. There was an overall significant increase in the use of local excision over time (34 [17.3%] in 2004 to 68 [30.8%] in 2012; trend test, P < .001). Absolute proportional use of local excision alone was higher among patients with tumors 1 cm or smaller (10 [33.3%] in 2004 to 30 [44.8%] in 2012; trend test, P = .04). However, the relative increase was more pronounced among those with tumors greater than 1 cm to 2 cm or smaller (10 [10.1%] in 2004 to 30 [24.6%] in 2012; trend test, P < .001).
The 5-year OS for those treated with local excision and chemoradiotherapy is shown in Figure 3. No significant difference in OS was found between the 2 disease management strategies (85.3% for local excision and 86.8% for chemoradiotherapy; log-rank test, P = .93). These findings were similar among patients with primary tumors 1 cm or smaller (88.5% for local excision and 91.6% for chemoradiotherapy; log-rank test, P = .98) and between those with primary tumors greater than 1 cm to 2 cm or smaller (86.6% for local excision and 86.4% for chemoradiotherapy; log-rank test, P = .78) and when those who underwent APR after chemoradiotherapy were excluded. No significant association was found between the use of local excision and overall risk of death relative to the use of chemoradiotherapy (hazard ratio [HR], 1.06; 95% CI, 0.78-1.44). Findings were robust when patients were stratified by primary tumor size (≤1 cm: HR, 1.21; 95% CI, 0.63-2.33; >1 to ≤2 cm: HR, 1.04; 95% CI, 0.62-1.75). This was also unchanged when patients who subsequently underwent APR were excluded from the model (HR, 1.08; 95% CI, 0.80-1.47).
Although there have not been any recent, meaningful changes in the management of SCCAC, over time there have been several advances in our understanding of risk factors and anal cancer precursor lesions.19 With increasing awareness of SCCAC, large clinical trials, such as Topical or Ablative Treatment in Preventing Anal Cancer in Patients With HIV and Anal High-Grade Squamous Intraepithelial Lesions (ANCHOR),20 Study of the Prevention of Anal Cancer (SPANC),21 and Laser Ablation Versus Observation to Prevent Anal Cancer (LOPAC),22 are under way to clarify screening intervals and to define optimal management strategies for precancerous lesions. Identifying at-risk populations, implementing screening, and detecting SCCAC at an early stage may present an opportunity to evaluate less morbid and potentially less aggressive treatment strategies. In this regard, our data support 2 important conclusions. First, the use of local excision alone for the management of T1N0 SCCAC has significantly increased over time. Whether this increase has been primarily patient or physician driven is unclear. Second, relative to patients treated with chemoradiotherapy, the use of local excision alone was not associated with worse OS.
Currently, definitive chemoradiotherapy is recommended as the first-line treatment for all patients with SCCAC without distant metastasis.4 Treatment with concurrent chemoradiotherapy is associated with a 3-year local control rate of 75% to 90% and a colostomy-free survival rate of 40% to 50%.23 Although over time there have been numerous improvements in care provided during the administration of radiotherapy, such as the advent of intensity-modulated radiotherapy and better supportive care to address gastrointestinal tract and hematologic toxic effects from concurrent chemoradiotherapy, more than 30% of patients still experience severe toxic effects during treatment.17
Although there is a large body of data that support the benefits of chemoradiotherapy in the management of SCCAC, patients with T1N0 tumors have not been included in these studies.3,9-15 In fact, the data that support current management guidelines are predominantly derived from patients with stages II and III SCCAC (Table 1). The early studies3,9,10 providing proof of concept regarding the use of chemoradiotherapy did not include any patients with T1N0 disease, and subsequent landmark studies11-15 included few (10%-15%) patients with stage I disease. Therefore, it remains uncertain the extent to which these data can be generalized to patients with T1N0 disease and whether chemoradiotherapy is necessary in all such patients. The question is not whether chemoradiotherapy is an effective treatment for patients with SCCAC but rather whether it should be the only treatment option offered or whether select patients might be spared the toxic effects associated with such treatment. Because patient-centered approaches, shared decision-making models, and evidence-based practice are being emphasized, it is important to evaluate whether alternate approaches, which could help to avoid or mitigate the toxic effects of standard chemoradiotherapy, might be feasible. Given the significant increase in the use of local excision over time in this cohort, our data seem to suggest there is interest in alternative treatment strategies for patients with early-stage disease and that future evaluations of the efficacy of local excision in this population are needed.
The use of local excision in carefully selected patients with T1N0 SCCAC (such as those with lesions measuring less than 1 cm in the distal anal canal with no evidence of invasion of the underlying muscle) was described in the historical literature, with excellent survival and local control rates.24-26 Several more recent studies16-18 have also suggested local excision to be a potentially feasible management option. Other retrospective studies27-29 have also found that external beam radiotherapy alone, brachytherapy alone, or a combination of the two might be effective for patients with T1N0 disease in the absence of concurrent chemotherapy. Deshmukh et al17 evaluated survival differences associated with varying management strategies for patients with T1N0 SCCAC and did not find any significant OS differences among those treated with chemoradiotherapy, radiotherapy alone, or local surgical treatment only. Furthermore, previous studies17,30 demonstrated a substantial treatment-associated economic burden, which led to the conclusion that, given the lack of difference in long-term outcome, local excision may be a more cost-effective approach in these patients. Our work builds on these findings derived from Surveillance, Epidemiology, and End Results data linked to Medicare claims and helps to enhance the generalizability of these findings. Taken together, these data emphasize the need for future studies to better delineate the need for chemoradiotherapy and the role for local excision in select patients with early-stage SCCAC.
Our data must be interpreted in the context of several notable limitations. The NCDB does not provide information regarding local or regional recurrence. Such data would be important to understand the effectiveness of any alternative management strategy relative to the standard of chemoradiotherapy. The NCDB does not provide any information on the specific type of chemotherapy regimen used or the duration of treatment with systemic therapy. Data regarding complications and treatment-associated toxic effects are not available. Although the NCDB is a national data set that captures most incident cancers in the United States, all participating hospitals are CoC accredited. This could affect the generalizability of our findings with regard to care provided at other non–CoC-accredited hospitals in the general community.31,32 Information regarding HIV status, human papillomavirus infection, and other known risk factors are either not included or not consistently reported in the NCDB data. The data do not provide any information regarding the availability of medical and radiation oncology services. Therefore, we could not explore how access to care may have affected our results. Finally, the NCDB does not include any information regarding the intent of treatment, clinical decision making by the physician, or patient preferences. Thus, it was not possible to ascertain the reason patients were treated with local excision.
Although the use of chemoradiotherapy for the management of SCCAC has been a paradigm for organ-preserving treatment approaches, our data suggest that future work evaluating the effectiveness of local excision for select patients with T1N0 disease would be of substantial value.13 Efforts directed at increasing disease awareness and screening of at-risk populations would likely improve early detection rates, thereby making local excision a reasonable treatment option. Further investigations designed to more fully assess the comparative effectiveness of local excision, including evaluation of cost-effectiveness, local recurrence rate, and patient quality of life, should be considered.
Corresponding Author: Christy Y. Chai, MD, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd, Operative Care Line 112, Houston, TX 77030 (firstname.lastname@example.org).
Accepted for Publication: July 2, 2017.
Correction: This article was corrected on May 23, 2018, to fix errors in the presentation of Hop S. Tran Cao’s name.
Published Online: October 18, 2017. doi:10.1001/jamasurg.2017.3151
Author Contributions: Dr Massarweh had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Chai, Massarweh.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Chai.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Chai, Awad, Massarweh.
Obtained funding: Massarweh.
Administrative, technical, or material support: Chai, Awad, Massarweh.
Study supervision: Chai, Massarweh.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by grant CIN 13-413 from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, and the Center for Innovations in Quality, Effectiveness and Safety.
Role of the Funder/Sponsor: The funding sources had no role in the design and/or general conduct of this study; had no access to the data or role in data collection, management, analysis, or interpretation; had no role in the preparation, review, or approval of the manuscript; and had no role in the decision to submit the manuscript for publication.
Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or Baylor College of Medicine. The data used in this study were derived from a deidentified National Cancer Data Base file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methods used or the conclusions drawn from these data.
Meeting Presentation: This paper was presented at the Association of VA Surgeons Annual Meeting; May 8, 2017; Houston, Texas.
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