In locally advanced low rectal cancer with anal canal invasion, should elective inguinal irradiation be performed?

Abstract

Background

In patients with locally advanced low rectal cancer (LALRC), the use of neoadjuvant chemoradiotherapy(CRT) reduces the risk of a positive circumferential margin (CRM) and local recurrence [1-3]. Two prospective randomized trials in the adjuvant setting also showed the benefits of CRT in stage II/III rectal cancer, revealing that postoperative CRT significantly reduced local recurrence rate compared to observation or either modality alone[4,5].

To cover regions at risk of occult metastasis and avoid unnecessary irradiation-related complications, the clinical target volume (CTV) must be properly selected during (chemo)radiotherapy (RT). Lymphatic drainage to inguinal lymph nodes (ILN) through the perirectal and pudendal lymphatics [6] and lymphatics of the infra-dentate and perianal skin [7] may be involved in ILN metastases of LALRC with ACI. Furthermore, an advanced rectal primary tumor with proximal lymphatic obstruction may promote retrograde nodal spread [8]. The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines proposed in 2010 that medial ILNs should be prophylactically irradiated when cancers grow at or below the dentate line [9]. The coverage of ILNs for tumors extending into the anal sphincter was advocated by the 2016 International consensus guidelines on CTV delineation [10]. ILNs and external iliac nodes should be conditionally included in the CTV for patients with rectal malignancies with ACI according to the 2020 American Society for Radiation Oncology (ASTRO) Clinical Practice Guidelines [11]. Meanwhile, the contouring atlas of the Radiation Therapy Oncology Group (RTOG) had no consensus on the subject [12].

In three retrospective trials [8,13-14], the inguinal nodal failure rate in rectal cancer patients with ACI who received neoadjuvant or adjuvant (chemo)RT without elective inguinal irradiation was not high enough (3-year failure rates were 3.7%[8], 5-year actuarial rate 3.5-4%[13-14]) to justify elective inguinal irradiation as a standard procedure.

The treatment policy at our institution for LALRC with ACI and clinically negative ILN at presentation was based on the practice of the attending oncologist. We looked at whether omitting elective irradiation is feasible for patients with LALRC with ACI and clinically negative ILN.

Methods And Materials

Data collection

From 2011 to 2021, clinical data of 113 patients with LALRC with ACI who received neoadjuvant or adjuvant (chemo)RT in a tertiary oncology center were retrieved from the institutional database and retrospectively reviewed. The inclusion criteria were (1) histologically confirmed rectal adenocarcinoma, clinical or pathological any stage T and N tumors without distant metastasis (based on the eighth edition of the American Joint Committee on Cancer) , (2) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, (3) tumors with ACI, defined as the tumor's lower edge being within 3 cm of the anal verge (or being located at or below the dentate line) on digital rectal examination, colonoscopy, or magnetic resonance imaging (MRI). 

The exclusion criteria were (1) inguinal metastasis on presentation (2) occurrence of distant failure before surgery, (3) unsuitability for radical surgery by clinical examination and imaging, (4) local excision, (5) incomplete (chemo)RT, (6) previous recurrent rectal cancer, and (7) second malignancies within 5 years.

Pretreatment workups

Digital rectal examination, complete blood count, liver and renal function tests, serum carcinoembryonic antigen (CEA) tests, colonoscopy, chest radiography, computed tomography (CT) scanning of the thorax, abdomen and pelvis with or without transrectal ultrasonography, and pelvic MRI were all part of the pretreatment workups for clinical staging. According to physician discretion and patient accessibility, 18F-deoxyfluoroglucose positron emission tomography-computed tomography (PET-CT) was performed.

Chemoradiotherapy treatment

Long course radiotherapy was given to the entire pelvis at a dose of 45 Gy in 25 daily fractions, followed by a 5.4-Gy boost in three daily fractions within 5.5 weeks. Short course radiotherapy was delivered to the whole pelvis at a dose of 25Gy in 5 daily fractions within 1 week. All patients underwent CT simulation for three-dimensional conformal planning, with comfortably full bladder and empty rectum. Without elective inguinal irradiation, a three-field treatment plan was adopted using posterior-anterior field and lateral opposing beams. With elective inguinal irradiation, a pair of anterior-posterior opposing fields were used. The prescription dose was set at the 100% isodose line. The initial radiation field encompassed the gross tumor (preoperative (chemo)RT) or tumor bed (postoperative CRT), and the regional lymphatics including the mesorectal, internal iliac, presacral and distal common iliac lymphatics +/- ILN. The superior boundary was put at L5/S1 junction, the inferior border was set 3 cm caudal to the gross tumor or tumor bed, the anterior border was placed 3 cm anterior to the sacral promontory, and the posterior border was placed 1 cm behind the sacrum. The gross tumor volume (preoperative (chemo)RT) or tumor bed (postoperative CRT) were included in the boost field, which included a 3 cm margin in all directions. 

Chemotherapy was given concurrently with RT on Days 1-3 and 29-31 using bolus 5-Fluorouracail (5FU). In light of new evidence suggesting superior treatment outcomes [15,16], continuous oral capecitabine has been employed as a concurrent chemotherapeutic agent from 4/2021. Either abdominal perineal resection or low anterior resection with complete mesorectal excision was performed. Typically, the interval between preoperative CRT and surgery was 8 weeks, and the time between surgery and postoperative CRT was 10 weeks. 4 months of adjuvant chemotherapy was administered using 6 cycles of capecitabine and oxaliplatin (CAPOX), 8 cycles of modified leucovorin/fluorouracil/oxaliplatin (mFOLFOX6), or 6 cycles of capecitabine depending on patients’ tolerance.

Study endpoints 

The 3-year inguinal failure rate, locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS) and failure pattern were analysed. LRFS, DMFS, and OS risk factors were also investigated. LRFS was measured from the start of treatment to the locoregional relapse, death, or last follow-up. This study measured DMFS from the start of treatment to distant relapse, death or last follow-up. OS was calculated from the date of the first treatment to the date of death or the last follow-up.

Follow-up

Patients were evaluated for symptoms, physical examinations, CEA, and blood tests in outpatient clinics on a regular basis. When there was clinical suspicion of disease recurrence, a thorax, abdomen and pelvic CT or PET-CT would be arranged. Colonoscopies were conducted one year after surgery and then every three years after that.

Statistical analysis

The LRFS, DMFS, and OS rates were presented using the Kaplan-Meier method. Clinicopathologic variables were entered into a Cox proportional hazard regression multivariate model and analyzed for effects on LRFS, DMFS and OS. All analyses are performed using the IBM SPSS Statistics 21 software (Unites States). P values <0.05 were considered statistically significant.

Results

Patient characteristics

This study eventually comprised 90 eligible individuals from a larger primary cohort of 113 patients. The full course of (chemo)RT was completed by all patients. The study excluded five patients who refused surgery or were ineligible for surgery, six patients who had local excision only, one patient with upfront distant metastasis, four patients who developed distant metastasis after neoadjuvant (chemo)RT, two patients with upfront inguinal metastasis, and two patients with recurrent rectal cancer.

The median duration of follow-up was 45 months (range, 2-118 months). Table 1 lists the patients' and treatment characteristics.

Failure rates and patterns 

Patients who did not receive elective inguinal radiation (n=81) had a 3-year ILN failure rate of 4.94% (4 out of 81). Patients who received elective inguinal radiation (n=9), on the other hand, did not have any inguinal failure. Among the 4 patients with ILN failure, only one patient had isolated ILN failure, while the other three patients had synchronous locoregional recurrence and/or distant failure. Salvage surgery was successfully done for the patient with isolated ILN failure. He was in remission and still survive at last follow up visit. Palliative chemotherapy was given to patients with synchronous locoregional recurrence and/or distant failure, and two of whom died owing to disease progression.

Failure patterns of patients without elective inguinal irradiation are shown in figure 1.

Failure patterns and characteristics of patients with ILN recurrence are listed in Table 2.

Survival outcomes and prognostic factors

Kaplan–Meier curves are illustrated in Figure 2.

The 3-year LRFS, DMRFS, and OS were 81.1%, 77.0%, and 86.8% respectively.

In multivariate cox regression analysis, positive pathological lymph node after neoadjuvant treatment predicted worse LRFS (odd ratio [OR] 10.57; 95% CI, 3.588-31.17; P= 0.00001), DMRFS (OR 9.17; 95% CI 2.82-29.84; P= 0.0002), and OS (OR 12.92; 95% CI 3.15-52.90); P= 0.0005). Positive tumour resection margin correlated with worse LRFS (OR 23.53; 95% CI, 3.97-139.66; P= 0.001), DMRFS (OR 12.62; 95% CI, 2.48-64.25; P= 0.002) and OS (OR 47.24; 95% CI, 3.92-568.92; P= 0.002).   Chemotherapy concurrent to RT was associated with better LRFS (OR 28.32, 95% CI, 3.27-245.66; P= 0.002). Details of univariate and multivariate analysis can be found in table 3.

Treatment toxicities

≥ grade 3 acute toxicity occurred in 16 out of 81 of patients (19.8%) who did not receive inguinal radiation and 4 out of 9 patients (44.4%) who underwent inguinal RT. Inguinal irradiation caused 4 out of 9 patients (44.4%) of patients to develop ≥ grade 3 perineal dermatitis, compared to just 12 out of 81 patients (14.8%) who did not have inguinal irradiation. Table 4 shows the acute toxicities profile (Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or above).

In terms of chronic toxicity, 1 out of 9 patients (11.1%) who had elective inguinal irradiation developed a protracted gap wound after excision of a perineal recurrence, while there were no recorded chronic perineal skin toxicities in patients who did not receive inguinal irradiation. Among the 81 patients without elective inguinal irradiation, 6 patients (7.41%) experienced intestinal obstruction, 2 patients (2.47%) developed parastomal hernia, and 1 patient (1.23%) developed fistulation. On the contrary, no chronic gastrointestinal toxicities have been reported in patients with elective inguinal irradiation.

Discussion

For rectal cancers, determination of optimal irradiation targets based on their location and invasion pattern is a critical challenge. Despite the theoretical risk that tumor cells in LALRC with ACI can spread to the ILN region, there is no uniform agreement on whether the nodal region should be included in the CTV for this patient subgroup. More clinical evidence is required to optimize the CTV delineation for these patients in order to reduce irradiation of normal tissues.

The low ILN failure rate (4.94%) in our study, which mirrored other retrospective studies' findings, showed that most patients with LALRC with ACI would not benefit from elective inguinal irradiation during neoadjuvant or adjuvant (chemo)RT. Some experts, however, still recommends elective ILN irradiation based on acceptable morbidities. In our study, the acute toxicity associated with inguinal irradiation cannot be neglected. There were more acute grade 3 perineal dermatitis among patients who received elective inguinal irradiation (44.4% vs. 14.8%), though none required treatment break. Meanwhile, the reported chronic complications of elective inguinal irradiation appeared minimal in our study. Only 1 out of 9 patients (11.1%) who had elective inguinal irradiation developed a protracted gap wound after perineal recurrence. 

Measures were developed to identify patients who were at a higher risk of developing inguinal nodal metastasis. Firstly, Maxiaowei Song et al. created a normogram to predict the probability of ILN failures according to tumor location, histological grade, and presence of perineural invasion⁸. It can be used as a guide to choose patients for elective inguinal irradiation who have a high chance of ILN failure, but the presence of perineural invasion can only be known after operation. Secondly, PET-CT was suggested to find out patient with inguinal uptake for inguinal nodal region irradiation. FDG-uptake of inguinal nodes at PET/CT may be present in up to 17% of patients with distal rectal cancer, particularly with ultra-low tumours [17]. Nevertheless, false positivity rate may be high, as nearly half of these nodes no longer demonstrated uptake after CRT despite that the inguinal region was not included in the radiation field [17]. Moreover, none of these patients in that study developed inguinal recurrence after 22 months of follow up [17]. A review of sentinel nodes in anal cancer found out that 44% of all node metastases located in lymph nodes measured less than 5 mm in diameter [18]. The spatial resolution of PET/CT is limited to several millimeters. Therefore, PET/CT may not have good enough sensitivity and specificity to select out patients for elective inguinal irradiation. Thirdly, the sentinel node technique was also investigated in rectal cancer with ACI. One small prospective study of 15 patients found that there was no inguinal recurrence for patient with sentinel nodes identified as negative for metastatic adenocarcinoma [19]. However, a systemic review commented that the sentinel-lymph-node procedure showed only a fair sensitivity rate of 82% (95% CI 60% to 93%), regardless of T stage, localisation or pathological technique [20]. Due to the relatively low sensitivity, technically demanding procedures, risk of surgical morbidity and doubtful impact to subsequent clinical management, this is not a standard practice for LALRC with ACI at the moment.

Only one patient (25%) developed isolated ILN metastases among all the 4 patients with inguinal recurrence. Salvage treatment for isolated ILN recurrence can provide long-term ILN control in our study. As a result, prophylactic treatment of the inguinal region may not be necessary. The other three patients (3 out of 4, 75% who experienced inguinal recurrence) had synchronous locoregional and/or distant recurrences. One may question whether early detection and treatment of occult inguinal nodal metastases can help prevent subsequent distant metastases. D. C. Damin et al observed that despite inguinal dissection, 75% of sentinel inguinal lymph node positive cases developed hepatic or pulmonary metastases within 6 months of the surgery [19]. Thus, localized treatment of the inguinal region may not influence the final clinical outcome, which is mainly determined by the emergence of metastases in distant organs [19]. In this context, a SLN metastasis could represent a potential marker for systemic dissemination of the disease [19].

From our results, patients who had positive pathological lymph node(s) following neoadjuvant therapy and/or a positive resection margin had an inferior rate of 3-year LRFS, DMRFS, and OS. It could imply that more aggressive neoadjuvant treatment is needed to shrink the tumor before surgery, such as the addition of an induction or consolidation chemotherapy regimen. Several recently published large scaled randomized controlled trials consistently showed that total neoadjuvant treatment can improve DFS, pathological complete remission rate, and reduce the risk of disease-related treatment failure in patients with high risk rectal cancer [21-24]. Among them, the phase 3 STELLAR trial was the first trial to demonstrate OS benefit, which found that short-course RT followed by perioperative chemotherapy resulted in better 3-year OS rates than CRT followed by postoperative chemotherapy, with 86.5% vs 75.1% (HR, 0.67; 95% CI, 0.46-0.97; P =.033) [24]. Furthermore, in our study, as compared to radiation alone, concomitant chemotherapy was linked with a superior LRFS. This was consistent with a Cochrane comprehensive review, which found that preoperative CRT improved local control (OR 0.56, 95% CI 0.42-0.75, P<0.0001) in resectable stage II and III rectal cancer but did not increase OS (OR 1.01, 95%CI 0.85-1.20, P=0.88) [25]. 

Song M et al. also investigated the impact of excluding irradiation of ILNs during neoadjuvant (chemo)RT in LALRC with ACI [8]. Their 3-year inguinal ILN failure rate was 3.7%. Our 3-year DMRFS was comparable to their study (77.0% vs. 77.7%), but our 3-year LRFS (81.1% vs. 94.6%) and OS (86.8% vs. 91.9%) outcomes appeared slightly inferior. Reasons for our relatively inferior locoregional and overall survival may be multifactorial. Our research population had an older median age (67 years old vs. 57 years old). Our study also covered a small number of patients with worse performance status (ECOG2) (6.7%) whereas their study only included ECOG 0-1 individuals. Almost all of our patients (93.3%) received bolus 5-FU as concurrent chemotherapy, with the exception of one patient who received oral capecitabine, compared to 78.1% of capecitabine patients in their study. Patients who received a protracted infusion of 5-FU had a significantly longer time to relapse and improved survival when compared to bolus 5-FU [26]. Two randomized controlled trials have shown that rectal cancer patients who received neoadjuvant or adjuvant capecitabine CRT had non-inferior disease free and overall survival when compared to continuous 5-FU [15,16]. Therefore, concurrent chemotherapy with oral capecitabine should produce better outcomes compared with bolus 5-FU. In addition, induction (7.0%) and consolidation chemotherapy (30.8%) were used in their research, which might further boost treatment outcomes.

Our study had several limitations. To begin with, it was a retrospective study based on data from a single center, and this may add selection and information biases. Secondly, our small sample size reduced the power of the study. Thirdly, as there was no uniform follow-up imaging in our study population, the recurrence-free interval and OS may have been overstated.

Conclusion

Our study showed that the omission of elective ILN irradiation during neoadjuvant or adjuvant (chemo)RT was associated with a low risk of failure (3-year ILN failure rate 4.94%) for LALRC with ACI, and it can spare patients from unnecessary acute  radiotherapy toxicities. Isolated inguinal recurrence can be salvaged by inguinal dissection. These findings added to the body of evidence supporting the omission of elective ILN irradiation for this patient subgroup. Additional studies are encouraged to validate these findings and discover the best strategy for treatment escalation.

Declarations

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Wong Hiu Sang. The first draft of the manuscript was written by Wong Hiu Sang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval

Approval was granted by the The Kowloon West Cluster Research Ethics Committee.

Consent to participate

Patient data was retrieved from existing treatment records. A waiver of consent from the Research Ethics Committee was sought as study subjects were difficult to reach for consents and imposed risk is low.

Consent to publish

Patient data was retrieved from existing treatment records. A waiver of consent from the Research Ethics Committee was sought as study subjects were difficult to reach for consents and imposed risk is low.

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Tables

Table 1. Baseline characteristics. Abbreviations: ECOG = Eastern Cooperative Oncology Group; c = clinical; yp = yield pathological. NA= not available. CEA=carcinoembryonic antigen.

Table 2. Failure patterns and characteristics of patients with ILNs recurrence *From start of treatment **Up to last follow-up date from start of treatment

Table 3. Univariate and multivariate logistic regression models for the LRFS, DMFS, OS.

Table 4. Comparison of grade 3 or above acute RT toxicities with or without elective inguinal RT.