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AbstractPurposeTreatment outcomes of locally advanced rectal cancer have improved significantly in recent decades. This retrospective study aimed to assess the efficacy of neoadjuvant chemoradiotherapy (nCRT) followed by surgery in patients with T4 rectal cancer and the different outcomes between T4a and T4b patients.
Materials and MethodsA total of 60 clinically T4 rectal cancer patients who underwent nCRT were included in the analysis. Patient characteristics, treatment regimens, down-staging rates, pathological response, and overall survival (OS) were evaluated.
ResultsBoth T4a and T4b patients experienced down-staging following nCRT (36.6% and 6.2% respectively; p = 0.021). T4a patients exhibited a higher rate of pathological complete response (pCR) than T4b patients (13.3% in T4a vs. 0% in T4b; p = 0.122). After a median follow-up of 36 months, the OS and recurrence-free survival (RFS) of T4a patients were significantly higher compared to T4b patients (hazard ratio [HR] = 2.52, 95% confidence interval [CI] 1.05–6.05, p = 0.038 for OS; HR = 2.32, 95% CI 1.09–4.92, p = 0.025 for RFS).
ConclusionThis study provides valuable insights into the effectiveness of nCRT in T4 rectal cancer patients. Although down-staging was observed in both T4a and T4b subgroups, achieving a pCR remains a challenge, particularly in T4b patients. Further research is needed to optimize treatment strategies and enhance pCR rates in T4 rectal cancer patients to improve oncologic outcomes.
IntroductionApproximately 40% of colorectal cancers occur in the rectum [1]. Interestingly, the recent rise in the incidence of rectal cancer has been about twice the other segments of the colon [2]. Various therapeutic strategies are being used to treat rectal cancer based on clinical condition, patients' expectations, and stage. T4 rectal cancer is a locally advanced tumor characterized by local invasion into nearby organs, further categorized as T4a (invasion to the visceral peritoneum) and T4b (invasion to adjacent organs such as bladder or prostate and seminal vesicle in men and uterus, cervix, and vagina in women) [3].
The modern treatment strategy for locally advanced rectal cancer includes a multimodality approach comprising neoadjuvant chemoradiotherapy (nCRT), a curative intent resection, followed by adjuvant chemotherapy [4]. Most clinical trials addressing locally advanced rectal cancer patients have incorporated T4 patients as well. Thus, T4 tumors as other less aggressive stages are eligible for nCRT. On the other hand, many locally advanced rectal cancers with T4 stage are unresectable at the time of diagnosis or need an extensive multi-visceral resection with a lower chance of R0 resection and a higher chance of local failure and postoperative morbidity [5]. Based on the available evidence, nCRT has been shown to increase the R0 resection rate in T4 rectal cancer patients by downstaging tumors [6]. However, due to the high risk of resistance to radiotherapy (RT), the outcomes of these tumors are expected to be worse than those of T2-3 tumors [7]. More recent studies such as RAPIDO [8] and PRODIGE 23 [9] have included the T4 stage as a high-risk feature and as an eligibility for a total neoadjuvant therapy protocol. Total neoadjuvant treatment protocols have been shown to yield the maximal response in locally advanced rectal cancer [10].
Despite access to these therapeutic options, the prognosis of T4 patients still appears to be controversial [7]. Thus, the present study aims to investigate the outcomes of T4 rectal cancer patients treated with nCRT and to compare the two subgroups (T4a and T4b).
Materials and Methods1. Study populationThis study retrospectively evaluated a consecutive series of clinical T4 rectal cancer patients referred to the Department of Radiation Oncology at the Cancer Institute in Tehran (Iran) between January 2008 and December 2019. Data were extracted from a prospectively maintained database.
This study was approved by the Institutional Review Board (#1402-2-495-67291) and also the ethics committee of Tehran University of Medical Sciences (IR.TUMS.IKHC.REC.1402.253). All patients provided a written and informed consent on admission regarding the use of their personal data for research purposes.
2. Preoperative and surgical planningThe preoperative staging work-up included a total colonoscopy including biopsy from all suspicious sites, routine lab tests as well as carcinoembryonic antigen (CEA) levels, gadolinium-enhanced pelvic magnetic resonance imaging (MRI), and/or endoscopic ultrasonography. Also, a contrast-enhanced thoracoabdominal computed tomography (CT) was acquired from all patients.
All patients received neoadjuvant chemoradiation with a curative intention. RT was performed in long-course or short-course fashion. Long-course RT consisted of 45 Gy to the whole pelvis and a 5.4 Gy boost to the mesorectum in 1.8 Gy daily fractions over 5.5 weeks. Short-course RT consisted of 25 Gy to the whole pelvis in 5 Gy daily fractions over one week. During long-course RT, all patients received capecitabine orally 825 mg/m2 twice daily during RT if not contraindicated. The time interval between the completion of neoadjuvant treatment and the surgery was around 8 to 16 weeks per institutional preferences.
All patients were initially planned to undergo total mesorectal excision with the most commonly utilized techniques being low anterior resection and abdominoperineal resection for low-lying tumors not amenable to organ sparing.
3. Postoperative outcomes and follow-upPathological staging was modified according to the American Joint Committee on Cancer (AJCC) 8th edition staging system during data review [11]. The 2010 AJCC tumor regression grading system was used to uniformly record the extent of tumor regression in pathology reports [12].
For patients with pathologic nodal metastases, positive resection margins, or pathologic T3-T4 tumors, adjuvant chemotherapy was administered. Other patients received adjuvant chemotherapy with the CAPEOX regimen (oxaliplatin 130 mg/m2 intravenous day 1 and capecitabine 1,000 mg/m2 orally twice daily days 1 to 14 every 3 weeks). at the discretion of their physicians in charge.
Institutional follow-up included: physical examination and serum CEA assay every 3 months for the first 2 years, thereafter every 6 months (CEA was not required beyond the fifth year); chest/abdominopelvic CT every 6 months for the first 3 years then annually until the fifth year; and colonoscopy at 1, 3, and 5 years after surgery if normal. Additional tests, including pelvic MRI or positron emission tomography scan, were performed as needed.
The primary outcome was achieving pathological complete response (pCR) defined as no evidence of malignant cells on the permanent surgical pathology report. The secondary outcomes were overall survival (OS), and recurrence-free survival (RFS); including local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). OS was measured from the date of RT completion to that of death or last follow-up; RFS to that of tumor recurrence; LRFS to that of local recurrence, and DMFS to that of distant recurrence. Recurrence was diagnosed through radiological detection of enlarging lesions or by histological confirmation. All survival times were estimated from the time of RT termination to the specific event or death due to any cause or last follow-up for survivors. This study follows the STROBE statement for cohort studies [13].
4. Statistical analysisPatient characteristics were summarized using basic descriptive statistics. Categorical variables were expressed as proportions and analyzed using the chi-squared test. For comparing pCR between the groups, the chi-squared test and multivariate logistic regression were applied. Survival and recurrence rates were estimated through the Kaplan-Meier method and compared by the log-rank test. Cox regression was used to identify predictors of survival outcomes and to achieve hazard ratios (HR) between survival curves. Confidence intervals (CIs) were estimated at 95%, and the significance level was set at p = 0.05. Statistical analysis was performed using IBM SPSS Statistics, version 23 (IBM Corp., Armonk, NY, USA).
Results1. Patient characteristicsThe patients' characteristics are reported in Table 1. A total of 60 patients with T4 stage rectal cancer comprising 33 T4a and 27 T4b patients were included, with a male-to-female ratio of 1.3. The overall mean (standard deviation) age was 56.6 ± 14.1 years; the mean age of T4a patients was slightly higher than that of T4b patients with 57.8 ± 13.7 years and 55.2 ± 14.8 years, respectively.
2. Patients' treatment coursesOf the 27 patients with T4b stage, cancer invaded other pelvic organs including bladder (n = 8), prostate (n = 6), pelvic wall (n = 7), and cervix/uterus (n = 4). Six of the T4b patients developed a fistula: four of them had a fistula between the rectum and bladder, one had a fistula between the rectum and prostate, and one had a rectovaginal fistula.
Concurrent chemotherapy with capecitabine was applied to most patients, including 31/33 patients (93.9%) in the T4a group and 26/27 patients (96.3%) in the T4b group. Induction chemotherapy was performed at almost the same rate in the T4a and T4b groups in 6/33 (18.2%) and 5/27 (18.5%) patients, respectively. However, consolidation chemotherapy was more commonly used among patients classified with T4a stage compared to T4b patients, with 16/33 patients (48.5%) versus 8/27 patients (29.6%), respectively. The chemotherapy regimen used for induction or consolidation chemotherapy was the CAPEOX regimen. Oxaliplatin-based concurrent chemotherapy was also given slightly more frequently in T4a patients (n = 6/33; 18.2%) versus T4b patients (n = 3/27; 11.1%) during RT (Oxaliplatin 50 mg/m2 intravenous weekly with capecitabine 625 mg/m2 twice daily on radiation days). Of all patients receiving neoadjuvant treatment, four patients with T4a stage received short-course RT (2,500 cGy in 5 fractions) with concurrent chemotherapy (CAPEOX regimen) because short-course treatment was considered a neoadjuvant option in our institution at the time. All others received a long-course chemoradiotherapy (5,000–5,580 cGy in 25–31 fractions) scheme.
Following surgical intervention, 80% of T4a patients (24/30 individuals) underwent adjuvant chemotherapy, whereas only 50% of T4b patients (8/16 individuals) received adjuvant chemotherapy.
3. Operative courseAmong all the patients, 48/60 (80%) underwent surgery (Table 2). The interval between the RT end date and the surgery date was a median of 81 days (interquartile range, 52 to 134 days). Among non-resected patients in the T4a group, two were diagnosed with metastasis in the preoperative re-staging imaging work-up and one was medically unfit for surgery. In the T4b group, three were unresectable (two other patients were opened and closed due to intraoperative findings), four were diagnosed with metastasis, and two were medically unfit for surgery.
4. Pathological responsesFour (13.3%) cT4a patients achieved a pCR while none of the cT4b patients achieved pCR. Downstaging to ypT1-2N0 was evident in 7/30 (23.3%) versus 1/16 (6.2%) patients with T4a and T4b stages, respectively (p = 0.021). Furthermore, 13/30 (43.3%) versus 2/16 (12.5%) patients in the T4a versus T4b group experienced downstaging to ypT0-2 (p = 0.026). Notably, the occurrence of N-downstaging (ypN0) was reported in 17/30 (56.6%) versus 8/16 (50%) patients in the T4a versus T4b group (p = 0.498). Only 2/16 (12.5%) T4b patients displayed positive margins, while no such instances were observed among the T4a patients.
The frequency of downstaging based on receiving preoperative chemotherapy is illustrated in Fig. 1. As evident there was not a significant correlation between receipt of preoperative chemotherapy and downstaging in either of the groups (p = 0.182 in T4a and p = 0.583 in T4b patients).
5. Survival patternsIn this study, living patients were followed up for a median of 36 months (95% CI 28–44 with reverse Kaplan-Meier). During the follow-up period, 9/60 (15%) patients had local and 10/60 (16.7%) patients had distant recurrences and 22/60 (36.7%) patients had died. The Cox regression analysis revealed that patients who had T4a stage had higher OS and RFS rates than those who had T4b clinical stage (HR = 2.52, 95% CI 1.05–6.05, p = 0.038 for OS; and HR = 2.32, 95% CI 1.09–4.92, p = 0.025 for RFS). Moreover, we identified age, preoperative CEA, receipt of curative surgery, and T dow-staging (to become T1-2) to be predictive of OS (Table 3). The median OS and RFS were 54.4 months (95% CI 23.7–85.2) and 41 months (95% CI 19.4–62.7), respectively. The median LRFS and DMFS were 51.4 (95% CI 35.5–67.2) and 51.4 (95% CI 20.6–82.1) months, respectively. The estimated 3-year OS, RFS, LRFS, and DMFS rates were 67% (95% CI 53.28–80.72), 50% (95% CI 35.60–65.00), 62% (95% CI 48.30–77.70), and 53% (95% CI 39.61–69.79), respectively. The Kaplan-Meier curves based on the clinical T stages are illustrated in Fig. 2.
Among the subset of patients with known earliest recurrence sites (12 patients), the recurrence frequency was distributed as follows: intra-luminal and peritoneal; three cases each (25%), pelvic extra-luminal and lung; two cases each (16.7%), and distant nodes and brain; one case each (8.3%). A depiction of recurrence frequency based on the primary clinical T stage is illustrated in Fig. 3.
Discussion and ConclusionNumerous studies have reported the efficacy of nCRT in locally advanced rectal cancer (T3 and T4 together) but there seems to be less data specifically addressing the results in T4 patients.
In this retrospective study, the efficacy of nCRT was assessed in patients with T4 rectal cancer, and outcomes were compared between T4a and T4b patients. Overall, this study revealed the effectiveness of nCRT in downstaging of T4 patients with acceptable long-term oncologic outcomes.
The rate of pCR in rectal cancer patients after nCRT has been reported to range from less than 10% to more than 30% in different studies [14]. This reflects the difference in the study population, nCRT protocols, and timing of surgery [15]. Specifically, recent clinical trials are addressing the efficacy of total neoadjuvant therapy in rectal cancer with intriguing results. In the RAPIDO trial, one-third of the participants were in stage T4 rectal cancer, and 30% of patients receiving short-course RT plus consolidation chemotherapy achieved pCR versus 17% of those receiving standard neoadjuvant chemoradiation before total mesorectal excision (p < 0.001) [8]. In a meta-analysis including 28 studies with more than 3,500 patients, the pCR rate was reported to be 22.4%, and total neoadjuvant therapy was found to increase the odds of pCR by 39% [16]. In our study, 15.4% of T4a patients achieved pCR based on permanent pathology reports, whereas none of the T4b patients achieved pCR. The rate of pCR in our study aligned more closely with a previous study in T4 patients, which reported an overall pCR rate of approximately 13.3% [6].
No positive margins were observed among the T4a patients who underwent nCRT prior to surgery, while only two T4b (7.4% of all and 12.5% of resected patients) patients showed positive margins, and R0 resection was successfully performed in 44.5% of all and 75% of resected patients. In a study by Haung et al. [6] on T4 rectal cancer patients who underwent preoperative nCRT, the rate of R0 resection was approximately 92%. In another study in T4 rectal cancer patients, the rate of R0 resection was 83% [17]. These findings prove the efficacy of nCRT in tumor downstaging and reduction of tumor size which would facilitate surgical resection with negative margins. The importance of margin status on long-term oncologic outcome was determined in previous studies that showed that negative resection margin is associated with higher disease-free survival and OS [6,13].
Despite the improved downstaging and more successful R0 resections, our study showed that many T4b patients do not get to receive curative surgery because of unresectability or metastasis development. Only 16 of 27 (59.3%) T4b patients underwent curative surgery compared to 30 of 33 (90.9%) T4a patients (p = 0.004) in our study. This important factor was reflected as a HR of 2.5 (95% CI 1.05–6.05, p = 0.038) on overall survival for T4b patients as was demonstrated by the Cox regression analysis.
An additional finding of this study was that the rate of N downstaging was higher than that of T downstaging. The same finding was reported in a study of preoperative nCRT in T4 rectal cancer where ypN0 was seen in 72% of patients while ypT0-2 was seen in only 15% [18]. Whether this is a reflection of the possible overestimation in clinical N staging or a higher efficacy of nCRT on lower-burden disease in the lymph nodes compared to the larger primary site disease is not clear.
The Kaplan-Meier analysis in the present study revealed that patients who had T4a stage had higher OS and RFS rates than those who had T4b clinical stage. Lim et al. [7] reported that being in the T4a stage was associated with greater OS rates than being in the T4b stage. With a median OS of 54.4 months and median RFS of 41 months in our study, these values were significantly higher compared to a study by Joachim et al. [19], which reported a median OS of about 24 months. These differences may be attributed to variations in patient characteristics, treatment approaches, and other factors.
The results of the present study revealed that local failure and distant failure are both important patterns of failure in T4 patients which is inconsistent with the overall pattern of failure in rectal cancer patients where distant disease is the dominant site of failure [20]. In a report on the pattern of first failure in T4 rectal cancer patients, the 5-year cumulative incidences of local, both local and distant, and isolated distant failure, were 8%, 6%, and 18%, respectively [17]. Whether the pattern of failure is affected by tumor T stage needs to be evaluated.
The most noticeable strength of our study is that there are very few studies in the literature focusing on T4 stage rectal cancer patients generally with very small sample sizes, which makes the present study more appealing. The most important limitation of this study is its retrospective nature, which might have introduced some unwanted bias when selecting and recording the data especially in heterogeneity of the treatment regimens. In addition, in our study, the time interval between the completion of nCRT and surgery was longer than the typical duration. This could be attributed to the fact that the T4 rectal cancer patients were more prone to prolonged intervals to see the maximal effects of chemoradiotherapy and also to receive extended cycles of consolidation chemotherapy, somehow a neoadjuvant treatment-like approach, in order to enhance the likelihood of achieving an R0 resection. Additionally, our institution, being a referral center, has a lengthy waiting list for surgical procedures most of the time.
In conclusion, with similar overall treatment strategies, T4b patients had a lower probability of achieving downstaging and pCR and had a lower median overall survival. This hints that we should consider augmented treatment techniques using intensified chemoradiotherapy regimens or total neoadjuvant therapy approaches for T4b patients. As T4b patients do not achieve a pCR by routine practice, they are not suitable candidates for organ preservation approaches, a critical issue that should be discussed with patients when disclosing expectations of neoadjuvant treatment. For T4a patients there is a limited chance for pathological and hence clinical complete response that would theoretically make them potential candidates for organ preservation approaches.
Statement of Ethics This study was conducted according to the ethical regulations by the Declaration of Helsinki and was approved by the Institutional Review Board (#1402-2-495-67291) and the ethics committee of Tehran University of Medical Sciences (IR.TUMS.IKHC.REC.1402.253). All patients provided a written and informed consent on admission regarding the use of their personal data for research purposes. Author Contributions Conceptualization, RG; Investigation and methodology, RG, KK, GNP, SR, NMD, RB, BB, MA, FC, AS, FB, MAT, MF, FF; Project administration, KK, GNP, SR, ZS, FC, AS, FB, RN, NN, MB, MAT, MF, FF; Resources, NMD, RB, BB, MA; Supervision, RG; Writing of the original draft, KK, SR, ZS, AS, FB, RN, NN, MB, MAT, MF, FF; Writing of the review and editing, RG, GNP, NMD, RB, BB, MA, FC; Formal analysis, RG, KK; Data curation, KK, SR, ZS, AS, FB, RN, NN, MB, MAT, MF, FF. Fig. 2.Kaplan-Meier curves for (A) overall survival, (B) recurrence-free survival, (C) local recurrence-free survival, and (D) distant metastasis-free survival based on clinical T4 stage. RT, radiotherapy; HR, hazard ratio; CI, confidence interval. ![]() Table 1.Patients and treatment characteristics Table 2.Pathological results, surgery information, and tumor responses to therapy
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