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Introduction
Anal cancer is a rare malignancy, representing approximately 0.1% of all newly diagnosed cancers [1,2]. The predominant histologic subtype is squamous cell carcinoma, accounting for 70%-90% of anal cancers [2]. Definitive chemoradiotherapy is the current standard of care for localized squamous cell carcinoma of the anus, with a 5-year overall survival (OS) rate of approximately 80% [3,4].
Factors that are widely known to affect survival are tumor size, nodal metastasis and sex [5]. Additionally, as etiology of anal cancer is closely related with human papillomavirus (HPV) or human immunodeficiency virus infection, immunologic factors such as p16 expression, leukocytopenia, neutropenia, and lymphocytosis have been related with improved survival [6-11].
Nodal staging for anal cancer was divided into four groups; N0, N1a, N1b, and N1c in previous American Joint Committee on Cancer (AJCC) 8th staging system [12]. However, current AJCC staging system 9th edition incorporate nodal staging as either N0 and N1. Meanwhile, there have been several reports that the size of nodal metastasis affects survival and treatment outcomes in squamous cell carcinoma of uterine cervix and oropharynx [13-15]. Moreover, the size of lymph node metastasis is incorporated in oropharyngeal cancer staging system [15]. As cancer of uterine cervix, oropharyngeal cancer, and anal cancer share biologic similarities due to association with squamous entity and chronic HPV infection, we hypothesized that the nodal size may also be a prognosticator for anal cancer. Additionally, we aimed to incorporate bulky nodes into nodal staging to better predict treatment outcomes. Of note, preliminary analysis on the potential impact of bulky nodes in anal cancer was recently reported in abstract form as detailed in the declaration section [16].
Materials and Methods
1. Patients
Medical records of patients with anal squamous cell cancer diagnosed from 2004 to 2021 at three institutions were retrospectively reviewed. All patients were pathologically confirmed by biopsy and had either computed tomography (CT) or magnetic resonance imaging (MRI) for anal cancer staging work up. Positron emission tomography was selectively performed for patients with advanced disease to rule out any distant metastasis. Patients who had distant metastasis or patients with past medical history of double primary cancer within 5 years from the diagnosis of anal cancer were excluded from analysis. Patients treated with abdominoperineal resection or patients undergoing salvage treatment for recurrence were also excluded. Factors such as T category, N category according to AJCC 8th edition, nodal size, age, sex, p16 presentation, baseline and post-treatment complete blood count test were collected. This study was approved by Institutional Review Board at participating institutions.
2. Treatment
All patients underwent definitive chemoradiotherapy. Patients who were treated with conventional radiotherapy technique were excluded for treatment homogeneity, leaving either 3D-conformal radiotherapy (3D-CRT) or intensity modulated radiotherapy (IMRT) as employed radiotherapy technique. Prescribed dose to the pelvis was 40-50 Gy followed by sequential boost of 5.4-10.8 Gy, depending on the extent or residuum of disease for 3D-CRT. Simultaneous integrated boost of 50-55 Gy to gross primary and nodal disease and 40-45 Gy to elective pelvic nodes were common prescription for IMRT. Nodal size was measured as the longest axis in pretreatment CT or MRI. Bulky N+ was defined as longest axis nodal size of 2 cm or greater. For patients with lymphocyte less than 500/μL was defined as having lymphopenia.
3. Statistics
R project ver. 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria) was used for all statistical analysis. For comparing variables between multiple groups, one-way ANOVA was used for continuous variables while chi-square test was used for categorical variables. Kaplan-Meier method was used for survival plots. Loco-regional recurrence-free survival (LRRFS), progression-free survival (PFS), and OS were defined as time between the day of diagnosis to the corresponding event. Log-rank test was used to compare survival and Cox model was used for univariate analysis. Factors with p-value less than 0.10 in univariate analysis was selected for multivariate Cox regression model with backward elimination method. Factors with p-value less than 0.05 were considered as statistically significant.
Results
One hundred four patients meeting inclusion criteria were accrued. Median age was 60 years and 76% were female. T1/T2 disease consisted of 77.7% of the patients and approximately half of patients (51.0%) had nodal involvement. Average prescription radiation dose was 54.1 Gy (range, 40.0 to 64.8 Gy) for primary and gross nodal diseases and 44.1 Gy (range, 32.0 to 54.0 Gy) for elective nodal station, respectively. Most patients (80.4%) received concurrent chemoradiotherapy with two cycles of 5-fluorouracil and mitomycin C (Table 1). Among 104 patients, 83 patients received elective inguinal radiotherapy, with a median dose of 45 Gy ranging from 30.6 to 54.0 Gy.
With a median follow-up of 54.0 months (range, 6.4 to 162.2 months), 18 relapses (17.3%) were observed. There were 15 loco-regional failure, with seven local, two local and regional, and six regional relapses. Among regional relapse, four were in pelvic, three were in inguinal, and one in both pelvic and inguinal region. Eleven patients (10.6%) experienced distant metastasis with three in liver, five in lung, and three in non-regional lymph node such as para-aortic and mediastinal stations. Three patients had distant metastasis without loco-regional relapse. During the follow-up, 19 patients (18.3%) expired, of which nine were cancer-related. Estimated 5-year LRRFS, PFS, and OS of entire study population were 76.2%, 74.8%, and 84.5%, respectively.
In univariate analysis, performance status, tumor grade, advanced T category, and bulky N+ were related with poor LRRFS. Performance status and bulky N+ remained statistically significant after multivariate analysis. For PFS, performance status, tumor grade, advanced T category, and bulky N+ were poor prognosticators. T category remained statistically significant after multivariate analysis, while bulky N+ was marginally significant (p=0.089). Bulky N+ and performance status were related with OS in both univariate and multivariate analysis. When compared to the combined entity of N0 and non-bulky N+ disease, bulky N+ exhibited hazard ratios of 4.11 for LRRFS (p=0.007), 2.60 for PFS (p=0.089), and 4.51 for OS (p=0.029) (Table 2). However, no significant LRRFS or PFS difference was observed between the N0 and non-bulky N+ groups (S1 Table).
There were 51 patients as N0, 46 with non-bulky N+, and seven with bulky N+. Between three groups, there were more patients with T3/T4 disease in node-positive groups compared to N0 group (p=0.002). Additionally, higher dose was given to primary site and gross nodes in bulky N+ group (Table 3). Detailed patient characteristics of seven patients with bulky N+ is separately shown in S2 Table. Five patients had bulky nodes at the inguinal station, while two patients had bulky nodes at the internal iliac station. Estimated 5-year LRRFS, PFS, and OS of patients with bulky N+ were 42.9%, 42.9%, and 47.6%, respectively (Fig. 1).
In current study, both AJCC 8th and 9th edition staging system failed to demonstrate a significant survival difference between stages (S3 Fig.). As bulky N+ was closely related with poor prognosis compared to the remaining patients, bulky N+ was designated as new N2 entity. Patient groups were divided into five categories, incorporating bulky nodal component to current staging system: T1-2N0, T3-4N0, T1-2N1, T3-4N1, and any N2. Interestingly, similar outcomes between the T1-2N0 and T1-2N1 groups, as well as between the T3-4N0 and T3-4N1 groups were observed (S4 Fig.). Thus, a new staging system was revised, categorizing T1-2N0-1 as stage I, T3-4N0-1 as stage II, and any N2 disease as stage III. Estimated LRRFS, PFS, and OS at 5 years were as follows: 81.1%, 80.6%, and 86.2%; 67.7%, 60.9%, and 93.3%; and 42.9%, 42.9%, and 47.6% for patients with stage I, II, and III disease, respectively (p=0.005 for LRRFS, p=0.005 for PFS, p=0.099 for OS) (Fig. 2), demonstrating improved predictive value of newly constructed staging system over others.
Acute adverse event of grade 2 or greater were observed in 38 patients (36.5%), from which all patients recovered. Eleven patients (10.6%) experienced delayed adverse event of grade 2 or greater. Specifically, seven patients had grade 2 toxicity, including three cases of proctitis, two of anal fibrosis and two of vagina fistula. Three patients suffered grade 3 toxicities: two proctitis and one anal perforation. One patient succumbed to mitomycin C–induced thrombotic microangiopathy within 5 months from undergoing treatment.
Discussion
In this study, bulky N+ was a poor prognosticator in patients with anal cancer. Additionally, new staging system was proposed with bulky N+ designated as N2 disease, which clearly corresponds better to treatment outcomes in current analysis.
Among seven patients with bulky N+, four patients experienced loco-regional recurrence and two patients with distant metastasis eventually succumbed to disease. Even though relatively high dose radiotherapy with median 58.9 Gy (range, 54.0 to 60.4 Gy) was prescribed to both primary and gross lymph nodes, more than half of patients have failed loco-regionally. It is noteworthy that though radiation dose and chemotherapy regimen failed to demonstrate prognostic value in all patients, only one patient out of four with bulky N+ treated with radiation dose higher than 55 Gy and concurrent chemotherapy experienced disease relapse. This suggests the possibility that higher radiation dose may be required for effective cancer control. Although ACCORD 03 failed to demonstrate the benefit of boost dose escalation, post-hoc analysis of ACT II suggested possible radiation dose-response relationship [17,18]. Currently on-going PLATO ACT5 trial is investigating dose intensification, comparing standard arm 53.2 Gy against escalated arm 58.8 or 61.6 Gy, in patients with advanced anal cancer, which may help to elucidate the role of dose intensification in advanced anal cancer [19].
As aforementioned, etiology of uterine cervical cancer, oropharyngeal cancer, and anal cancer are quite similar. First, they are all related to HPV infection. Population-based cohort from Surveillance, Epidemiology and End Results have reported that uterine cervical cancer survivors had 4.36 increased risk of oropharyngeal cancer and 2.20 of anal cancer diagnosis [20]. Additionally, meta-analysis has reported that each of HPV-associated tumors has increased incidence of other HPV-associated tumors [20]. Moreover, p16 expression was related with improved survival in not only oropharyngeal cancer, but also in anal cancer [21]. There have been multiple reports regarding nodal size in oropharyngeal and uterine cervical cancer, but not in anal cancer (S5 Table) [13-15,22-24]. In uterine cervical cancer, nodal size more than 1.5-2.0 cm has been reported to have more recurrences, compared to others [13,14,24]. Additionally, bulky lymph nodes have been related with poor OS or disease-free survival in oropharyngeal or oral cavity cancer, though definition of bulky nodes in oropharyngeal cancer was quite large at 6 cm or larger [15,22,23].
Although HPV infection or p16 expression was closely related with nodal involvement in both oral cavity cancer and oropharyngeal cancer [15,25,26], p16 expression is related with superior treatment outcomes in oropharyngeal cancer [15,27]. In anal cancer, two studies have reported on HPV and p16 status, where HPV expression was related with improved local control [6,7]. In current study, p16 or HPV infection were not routinely tested, thus relationship between p16 status and bulky nodal involvement was not explored. Considering findings related with p16 expression in anal cancer and head and neck cancers, it would be necessary to evaluate relationship between p16 status and bulky nodal disease in future studies.
In addition to HPV infection, immune system is known to play a role in treatment outcomes for anal cancer. Previous studies have suggested that leukocyte related factors, such as neutrophilia, higher neutrophil-lymphocyte ratio (NLR), leukocytosis, and lymphopenia, are associated with deteriorated treatment outcomes [5,8-10]. Although current study showed increase of hazard ratio related with higher NLR or lymphopenia, statistical significance was not found (Table 2). It would be important to note that both current study and previous studies had a small proportion of patients with neutrophilia or lymphopenia. To validate the impact of leukocyte-related factors in anal cancer, further research with larger cohort would be required.
As previously mentioned, currently employed AJCC 9th edition staging system for anal cancer employs nodal involvement without further substaging. As a result, current staging system lacks the ability to account for the diversity of nodal involvement. Furthermore, nodal disease was downstaged in the AJCC staging system 9th edition compared to the 8th edition, for example, T1-2N1, which was stage IIIA in the AJCC 8th edition, is now IIB in the AJCC 9th edition. However, in current cohort, we identified three cases of bulky nodes with T stage 1-2, and among them, two patients experienced treatment failure. This suggests that the current staging system would underestimate the poor prognosis associated with bulky N+.
Nodal status failed to demonstrate statistically significance in terms of LRRFS and PFS. Additionally, when patients with nodal disease was subdivided to non-bulky N+ against bulky N+, no significant difference was observed between patients with N0 and non-bulky N+. As a result, we proposed a 3-tier staging system stressing the bulky nodal disease, which accurately predict survival outcomes in the studied cohort. While nodal status is recognized as one of the key prognostic factors, we observed that the distinction between N0 and non-bulky N+ disease becomes less pronounced, while that of bulky node disease retained the impact.
This study is not free from the limitations. Limitations of this study stems from retrospective design. Several cofounding factors that are known to affect treatment outcomes were not evenly distributed. However, many factors were not closely related in this study, and multivariate analysis showed that nodal size retained its impact on both LRRFS and PFS. Additionally, as the number of patients with bulky nodes was relatively small, statistical significance of analyzed parameters including predictive value of current staging system may have been underscored and further analysis such as propensity score matching was not possible. Lastly, suggested new staging model was not validated externally. Considering the limited number of patients in both the overall cohort and the bulky N+ group, there is a possibility of selection bias, which should be externally validated. Nevertheless, bulky N+ in patients with anal cancer carries distinctive prognosis and thus may be incorporated into tumor staging, as suggested in current analysis, for improved predictability.
Bulky nodal disease was distinctive prognosticator for patients with squamous cell carcinoma of anus undergoing standard of care chemoradiotherapy, which calls for further treatment intensification. Additionally, newly suggested staging system incorporating bulky nodal disease as N2 disease showed promise in improving patient outcomes prediction.
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