Efficacy of hypofractionated preoperative chemoradiotherapy in rectal cancer
- Authors:
- Published online on: May 3, 2023 https://doi.org/10.3892/ol.2023.13849
- Article Number: 263
-
Copyright: © Cho et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Preoperative long-course radiotherapy (LRT) of typically 50.4 Gy in 28 fractions is the standard treatment for locally advanced rectal cancer; it gained popularity from the German CAO/ARO/AIO-94 trial, which reported several advantages of preoperative chemoradiotherapy (CRT), such as lower local recurrence, a higher rate of sphincter preservation and lower acute toxicity than postoperative CRT (1). Along with the ongoing practice of LRT, clinical trials assessing the change in radiotherapy schedule to short-course radiotherapy (SRT) consisting of 25 Gy in 5 fractions were carried out (2–4) which advocated a higher local control rate in SRT compared with that in surgery alone, as well as SRT being a simpler treatment than LRT in view of a much shorter schedule. It is challenging to compare the two schedules due to the difference in patient selection for each trial. Randomized trials were performed to compare the relative advantages of LRT and SRT, which reported no statistically significant difference in oncological outcomes (5,6) or health-related quality of life (7,8). However, advocates for SRT emphasize its lower acute toxicity, lower cost and greater convenience for patients with cancer compared with LRT (5,9,10). Meanwhile, advocates for LRT highlight higher rates of pathological complete remission (pCR), a higher sphincter preservation rate and lower local recurrence, especially in distant tumors, compared with SRT (11,12). In the clinical setting, some patients prefer shorter CRT followed by minimally invasive surgery, such as local excision for clinical T1-2N0 stages according to the American Joint Committee on Cancer staging system (AJCC), 8th edition (13). Without compromising the advantages of LRT, a shorter radiotherapy schedule would be preferable for patients who want to avoid multiple hospital visits for LRT or for those with distant metastases or double primary cancers requiring early intervention. To optimize the advantages of LRT and SRT, a phase II multi-institutional clinical trial was carried out for locally advanced rectal cancer, involving a 2-week course of preoperative CRT of 33 Gy in 10 fractions, which included oral capecitabine followed by radical surgery performed 6–8 weeks after completion of CRT (14). The long-term outcomes of this 2-week course were recently updated and they were comparable to historical SRT or LRT in view of survival rates and acceptable toxicities (15). The radiotherapy of this study was delivered by a 3D three- or four-field box technique (16). However, in the present study, intensity-modulated radiotherapy (IMRT) was performed for hypofractionated preoperative CRT (HPCRT) of 33 Gy or 35 Gy in 10 fractions combined with oral capecitabin in patients in various stages of rectal cancer. The results of these fractionation schedules were analyzed to investigate toxicities, tumor responses and survival outcomes in patients with rectal cancer.
Materials and methods
Patients
Between June 2016 and May 2021, patients who were diagnosed with rectal adenocarcinoma and had adequate laboratory data, such as information regarding bone marrow, liver and kidney function, were eligible for inclusion in this study. Patients were required to have an Eastern Cooperative Oncology Group (17) performance status of 0–2 and be ≥18 years old. Pretreatment workups included an estimation of carcinoembryonic antigen (CEA) level, colonoscopy, chest radiography, computed tomography of the abdomen and pelvis, magnetic resonance imaging and 18 F-fluorodeoxyglucose positron emission tomography, if required. The study also included patients with clinical stage IVA or simultaneous presence of additional primary cancers who preferentially received HPCRT rather than the conventional LRT for early intervention. The study was approved by the Institutional Review Board of Chonnam National University Hwasun Hospital (Hwasun, South Korea; approval no. CNUHH-2010-009), and all patients submitted written informed consent upon enrollment.
Treatment
HPCRT was delivered either by a schedule that included the following: i) 33 Gy in 10 fractions to the whole pelvis with IMRT, the protocol of which was performed during the earlier study period; or ii) 35 Gy in 10 fractions to the primary bulky tumor via simultaneous integrated boost (SIB) and 33 Gy to the remaining pelvis with IMRT, the protocol of which was performed during later study period. In most patients, oral capecitabine was concurrently administered at a dose of 1,650 mg/m2/day 5 days/week (from Monday to Friday) for up to 10 days during radiotherapy. Follow-up examinations were repeated before surgery. Radical surgery was performed 4–8 weeks after the completion of HPCRT. After surgery, the pathological stage was determined according to the AJCC staging system. Postoperative chemotherapy was recommended 4 weeks after surgery, according to the postoperative pathological stage and patient performance status (Fig. 1).
Evaluation of response and toxicity
After HPCRT, tumor response was evaluated based on the pathological finding of tumor and nodal status and tumor regression grade (TRG), as determined by pathologists. Primary tumor (T) and nodal (N) downstaging was defined as the lowering of the T and N stage from clinical staging to postoperative pathological staging, respectively. Overall downstaging was defined as overall pathological stage being lower than the initial clinical stage. TRG was defined as follows: grade 0, no regression; grade I, minor regression and fibrosis of ≤25%; grade II, moderate regression and fibrosis of 26–50%; grade III, good regression and fibrosis of 51–99%; or grade IV, total regression and fibrosis of 100% (18). Acute toxicities of the gastrointestinal and genitourinary system were assessed from the initiation of HPCRT and throughout the first 3 months after surgery. Late toxicities were defined as those that occurred thereafter. Toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (19).
Statistical analysis
Locoregional recurrence was defined as recurrence within the pelvic cavity and anastomosis site. Distant metastasis was defined as recurrence outside of the pelvis. Locoregional failure-free survival (LRFS) was defined as the interval between the start of HPCRT and the date of locoregional recurrence, censoring the last follow-up case without locoregional recurrence. The last follow-up was defined as the date of the last patient visit to hospital or date of death. Disease-free survival (DFS) was defined as the interval between the initiation of HPCRT and the date of any first recurrence, censoring the last follow-up case without any recurrence. Overall survival (OS) was calculated from the initiation of HPCRT to the date of death or last follow-up. Survival for all patients was calculated using the Kaplan-Meier method. Statistical significance between the groups was analyzed using a log-rank test. A Cox proportional hazard regression model was used for multivariate analysis. Statistical analyses were performed using SPSS (version 25.0; IBM Corp.). P<0.05 was considered to indicate a statistically significant difference.
Results
Patient and treatment characteristics
A total of 116 patients received HPCRT. A total of 40/116 patients were excluded, as they underwent surgery at other hospital, they refused to receive surgery or they received systemic chemotherapy for newly developed distant metastases after HPCRT but before surgery. The remaining 76 patients were included in the study and patient characteristics are detailed in Table I. The number of patients with initial clinical stages I, II, III and IVA were 5, 29, 36 and 6, respectively. By MRI, the distal extent of the tumor ≤5 cm from the anal verge (AV) and the distal extent of the tumor >5 cm from the AV were observed in 32 and 44 patients, respectively. A total of 6 patients had initial distant metastasis, including metastases of the lung in 3 patients and of the liver 3 patients. In total, 3 patients initially had synchronous double primary cancers, and each had either lung, gall bladder or colon cancer. Radiotherapy was performed with a daily fraction size of 3.3 and 3.5 Gy in 37/76 (48.7%) and 39/76 (51.3%) patients, respectively, for a median of 14 days (range, 12–23 days). Concurrent chemotherapy with capecitabine was administered to most patients; however, a single patient received Taxol® and cisplatin for the treatment of double primary lung cancer, and another patient only received radiotherapy due to immune thrombocytopenia. The median interval between HPCRT and surgery was 52 days (range, 16–86 days). The surgeries performed included low anterior resection, laparoscopic abdominal transanal proctosigmoidectomy with coloanal anastomosis, ultra-low anterior resection and abdominoperineal resection in 32 (42.1%), 20 (26.3%), 9 (11.8%) and 8 (10.5%) patients, respectively. Postoperative adjuvant chemotherapy was administered to 52/76 (68.4%) patients according to pathological stage or performance status. The treatment information is detailed in Table I and Fig. 1.
Treatment outcomes
A total of 9/76 (11.8%) patients achieved a pCR, and the treatment characteristics of pCR are shown in Table II. The number of patients in pathological overall stage 0, I, II, III and IVA was 9 (11.8%), 13 (17.1%), 30 (39.5%), 18 (23.7%) and 6 (7.9%), respectively. The median post-CRT distal extent of the tumor from the AV by MRI was 5.75 cm (range, 1.8-10.8 cm), which increased from the pre-CRT extent of 5.5 cm (range, 1.3-9.5 cm). The median post-CRT tumor length by MRI was 2.0 cm (range, 0–4.0), which decreased from the pre-CRT length of 4.2 cm (range, 2.0-6.6). Sphincter preservation was achieved in 24/32 (75.0%) patients with an initial tumor distal extent ≤5 cm from the AV and in all 44 (100.0%) patients with an initial distal extent of >5 cm. Prior to HPCRT, 27 patients were candidates for abdominoperineal resection (≤4 cm from AV; clinical stage T3-4), and 20 of these patients (74.1%) underwent anal sphincter-saving surgery. The overall rate of sphincter preservation was 89.5% (68/76 patients). The median postoperative CEA nadir level was 1.73 ng/ml (range, 0.49-10.87 ng/ml), which decreased from the pre-CRT median level of 4.99 ng/ml (range, 0.9-53.7 ng/ml) and post-CRT/preoperative level of 3.17 ng/ml (range, 0.50-35.5 ng/ml). The other outcomes are presented in Table I. A total of 28/76 (36.8%) patients achieved T-downstaging and 25/76 (32.9%) patients achieved N-downstaging. Overall downstaging was achieved in 34/76 (44.7%) patients. A detailed breakdown of the downstaging is shown in Table III, Table IV, Table V. According to the 5-cm cut-off of tumor distal extent from the AV or the cut off of a median 52 days between radiotherapy and surgery, there were no marked differences in TRG or downstaging between the two groups.
 | Table II.Patient and treatment characteristics of patients who achieved a pathological complete response. |
Survival and prognostic factors
The follow-up period ranged from 3 to 71 months (median, 54). In all 76 patients, the 5-year LRFS, DFS and OS were 90.6, 76.5 and 90.6%, respectively (Fig. 2). The results of univariate analyses for LRFS, DFS and OS are shown in Table VI. The results of multivariate analyses are shown in Table VII. The pT stage was found to be the only significant prognostic factor for LRFS (P<0.001; Fig. 3A). However, there was no statistical significance between pT-stage subgroups, as the hazard ratios for pT3 or pT4 stage were extremely high compared to those for pT0-2 stage with no locoregional failure (Tables VI and VII). In the multivariate analysis for DFS, notable variables included pN stage (Fig. 3B) and lymphovascular space invasion (LVI; Fig. 3C). The 5-year DFS rate of patients with negativity for both LVI and PNI (LVI− and PNI−) versus patients with positivity for either LVI or PNI (LVI+ or PNI+) was also significantly higher (P=0.015; Fig. 3D). Upon multivariate analysis for OS, no significant variables were found. A total of 6/76 (7.9%) patients with initial stage IVA had one or more salvage treatments such as surgery, chemotherapy or stereotactic radiotherapy after completion of HPCRT, and all were alive at the last follow-up. A single patient with colon cancer and a single patient with gall bladder cancer out of a total of 3 with initial double primary tumors underwent surgical resection, and the other patient with lung cancer was treated with concurrent CRT. All 3 patients were followed up and demonstrated no evidence of disease or stable disease.
Patterns of failures and complications
A local failure occurred in 4/76 (5.3%) patients, a regional failure occurred in 4/76 patients (5.3%) and distant metastasis occurred in 13/76 patients (17.1%) as a component of failure. The pattern of failure is illustrated in Fig. 4. Sites of distant metastasis were identified in the lung, bone, distant lymph nodes and liver in 10 (13.2%), 2 (2.6%), 2 (2.6%) and 1 (1.3%) patients, respectively. Patients with two or more sites were separately counted. Only 1 patient (1.3%) developed an acute grade 3 complication of anastomosis leakage, while 3 patients (3.9%) experienced late grade 3 complications such as rectovaginal fistula at anastomosis, anal bleeding from anastomosis and anastomotic leakage. No grade 4 toxicity was observed. A detailed breakdown of the complications of all grades is shown in Table VIII.
Discussion
In the present study, the rates of T-downstaging, N-downstaging and overall downstaging were 36.8, 32.9 and 44.7%, respectively. In total, 1 out of 3 patients with synchronous double primary cancer achieved overall downstaging of primary rectal cancer. The pCR rate was 11.8%, and the overall rate of sphincter preservation was 89.5%. These results were comparable with those of historical LRT studies (1,6) and similar to the 2-week course KROG study (14). The comparable outcomes of the present study could be attributed to dose prescription of 33 Gy [biological equivalent dose assuming α/β=10 by linear-quadratic model (BED10), 43.9 Gy],or 35 Gy (BED10, 47.3 Gy), which is between SRT of 25 Gy (BED10 37.5 Gy) and LRT of 50.4 Gy (BED10, 59.5 Gy). Oral capecitabine was prescribed as the concurrent chemotherapy agent, followed by delayed surgery with a median interval of 52 days to allow tumor regression before surgery. This study showed comparable toxicities to previous LRT results (1,6). Only 4/76 (5.3%) patients developed acute or late grade 3 toxicities and there were no grade 4 toxicities in any patients, including the SIB IMRT 35 Gy patient cohort. A single patient received 35 Gy and was treated with Taxol® and cisplatin concurrently due to synchronous lung cancer and acute grade 2 diarrhea. All patients had one or more weekend to rest without receiving HPCRT, but received IMRT to limit the radiation dose to normal organs. SIB IMRT of 35 Gy was performed to the gross tumor to improve the pathological regression. However, in the groups of patients with 35 Gy versus 33 Gy, the pCR rate was 12.8 and 10.8%, respectively (P=0.786), the sphincter preservation rate was 87.2 and 91.9%, respectively (P=0.503), and the 5-year DFS was 85.7 and 63.9% (P=0.067), respectively. None of these differences were statistically significant between the two groups. The 5-year LRFS, DFS and OS rates were 90.6, 76.5 and 90.6%, respectively. These survival rates were comparable to previous LRT results (1,6) or the recently updated 2-week CRT KROG study (15), despite the fact that the present study included patients with synchronous double primary or distant metastasis. A total of 5/76 patients with early clinical stages, such as T1-2N0, were included. Of these patients, 2 had synchronous double primary cancers, 2 preferred HPCRT followed by local excision rather than upfront radical surgery and 1 strongly demanded SRT due to having to travel long-distances to receive CRT. A total of 4/5 patients underwent sphincter preservation surgery. Thus, all the patients had a median radiotherapy duration of 2 weeks, which is 4 weeks shorter than the conventional 6-week LRT, and due to the shorter CRT duration, patients could receive surgery 4 weeks earlier than those receiving traditional LRT.
In the multivariate analysis for LRFS in this study, only pT-stage was an independent prognostic factor. It is well known that patients with sterilized tumors after preoperative CRT have an excellent prognosis with respect to LRFS or DFS (18,20). A total of 9 patients who achieved pCR in the current study had experienced no recurrence at the last follow-up. In the multivariate analysis for DFS, pN stage and LVI were significant prognostic variables. The pN stage is a well-known prognostic factor for survival, and is integral to the AJCC staging system (21). The prognosis of patients with remnant lymph node metastasis after CRT is poor, even in cases of complete primary tumor response (22). Likewise, patients with more advanced pathological primary tumors (pT3-4) with pN0 stage showed slightly better recurrence-free survival or OS than those who were pT0-2, but pN+ (23). It is well known that the LVI is an independent prognostic factor for survival. Song et al (24) reported that LVI was a significant prognostic factor affecting distant failure-free survival. Saadoun et al (25) developed a nomogram with eight variables, including pathological stage, LVI and PNI, which provided individual risk prediction for recurrence. In the current study, DFS of patients who were both LVI− and PNI− versus that of patients who were LVI+ or PNI+ significantly differed, although patients who were LVI+ or PNI+ received postoperative adjuvant chemotherapy (5-fluorouracil and oxaliplatin) more frequently than patients who were LVI− and PNI− (18/20 vs. 34/56; P=0.023). Therefore, more aggressive adjuvant chemotherapy should be considered to improve DFS for these patients.
A limitation of this study was the small patient cohort and the slow accrual rate given the study duration. The CRT option to select patients with a preference for HPCRT or even with synchronous distant disease or double primary cancer was provided. However, the treatment protocol was the same, except the total dose of 33 or 35 Gy, throughout the entire study period, and treatment consistency was maintained. A randomized controlled study comparing HPCRT and long-course CRT in a larger patient cohort is required in the future. Another limitation refers to the heterogenous patient characteristics, ranging from early to advanced clinical stage (I to IVA) or to the synchronous double primary cancer. However, most patients experienced the advantages of HPCRT, which include convenience, low cost, shorter radiotherapy time and earlier surgical or other radical treatments for distant disease or double primary cancer.
In conclusion, HPCRT of 33 or 35 Gy in 10 fractions showed comparable results to historical conventional LRT studies. This shorter fractionation scheme may be beneficial, without reducing oncological outcomes, for patients with early stage disease, locally advanced rectal cancer, simultaneous distant metastasis and other double primary cancer requiring early intervention, or for patients who cannot attend the hospital multiple times.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
TKN conceived and designed the study. IJC, YHK, JYS, MSY, SJA and SHC acquired data. TKN, IJC and JUJ confirm the authenticity of all the raw data. IJC and JUJ performed the statistical analysis. IJC, JUJ and TKN interpreted the results, analyzed the data and drafted the manuscript. All authors read and approved the final version of the manuscript.
Ethical approval and consent to participate
The study was established, according to the ethical guidelines of the Helsinki Declaration and was approved by Institutional Review Board of Chonnam National University Hwasun Hospital (Hwasun, South Korea; approval no. CNUHH-2010-009). Informed consent was obtained from all patients and/or their legal guardian(s).
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
AV |
anal verge |
|
BED10 |
biological equivalent dose assuming α/β=10 by linear-quadratic model |
|
CRT |
chemoradiotherapy |
|
DFS |
disease-free survival |
|
HPCRT |
hypofractionated preoperative CRT |
|
IMRT |
intensity-modulated radiotherapy |
|
LRT |
long-course radiotherapy |
|
LRFS |
locoregional failure-free survival |
|
LVI |
lymphovascular space invasion |
|
N |
nodal |
|
OS |
overall survival |
|
pCR |
pathological complete remission |
|
PNI |
perineural invasion |
|
SRT |
short-course radiotherapy |
|
SIB |
simultaneous integrated boost |
|
T |
tumor |
|
TRG |
tumor regression grade |
References
|
Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, et al: Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 30:1926–1933. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B and Gunnarsson U: Swedish rectal cancer trial: Long-lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol. 23:5644–5650. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EMK, Putter H, Wiggers T, Rutten HJT, Påhlman L, Glimelius B and van de Velde CJH; Dutch Colorectal Cancer Group, : Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 12:575–582. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, Quirke P, Couture J, de Metz C, Myint AS, et al: Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): A multicentre, randomised trial. Lancet. 373:811–820. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M and Kryj M: Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 93:1215–1223. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, Ackland SP, Schache D, McClure B, McLachlan SA, et al: Randomized trial of short course radiotherapy versus long course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman radiation oncology group trial 01.04. J Clin Oncol. 30:3827–3833. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Pietrzak L, Bujko K, Nowacki MP, Kepka L, Oledzki J, Rutkowski A, Szmeja J, Kladny J, Dymecki D, Wieczorek A, et al: Quality of life, anorectal and sexual functions after preoperative radiotherapy for rectal cancer: Report of a randomised trial. Radiother Oncol. 84:217–225. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Ngan S, Fisher R, Burmeister B, Mackay J, McLachlan S, Beresford J, McClure B, Goldstein D, Joseph D and Solomon M: Long-term quality of life in patients treated in TROG 01.04: A randomized trial comparing short course and long course preoperative radiation therapy for rectal cancer. Int J Radiat Oncol Biol Phys. 84:S143–S144. 2012. View Article : Google Scholar | |
|
Initial report from a Swedish multicentre study examining the role of preoperative irradiation in the treatment of patients with resectable rectal carcinoma. Swedish rectal cancer trial. Br J Surg. 80:1333–1336. 1993.PubMed/NCBI | |
|
Marijnen CAM, Kapiteijn E, van de Velde CJH, Martijin H, Steup WH, Wiggers T, Kranenbarg EK and Leer JWH; Cooperative Investigators of the Dutch Colorectal Cancer Group, : Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: Report of a multicenter randomized trial. J Clin Oncol. 20:817–825. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Bujko K, Nowacki MP, Nasierowska-Guttmejer A, Michalski W, Bebenek M, Pudelko M, Kryj M, Oledzki J, Szmeja J, Słuszniak J, et al: Sphincter preservation following preoperative radiotherapy for rectal cancer: Report of a randomised trial comparing short-term radiotherapy vs. conventionally fractionated radiochemotherapy. Radiother Oncol. 72:15–24. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Gerard JP, Chapet O, Nemoz C, Hartweig J, Romestaing P, Coquard R, Barbet N, Maingon P, Mahe M, Baulieux J, et al: Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: The Lyon R96- 02 randomized trial. J Clin Oncol. 22:2404–2409. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, et al: AJCC cancer staging manual (8th edition). Springer International Publishing: American Joint Commission on Cancer; 2017 | |
|
Lee JH, Kim JG, Oh ST, Lee MA, Chun HG, Kim DY, Kim TH, Kim SY, Baek JY, Park JW, et al: Two-week course of preoperative chemoradiotherapy followed by delayed surgery for rectal cancer: A phase II multi-institutional clinical trial (KROG 11–02). Radiother Oncol. 110:150–154. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Sung SY, Kim DY, Jang HS, Kim TH, Park HC, Chie EK, Nam TK, Kim SH and Lee JH: One-week versus two-week chemoradiotherapy followed by curative surgery in rectal cancer: Long-term comparative pooled analysis of two prospective multicenter phase II trials. Cancer Res Treat. 2023.(Epub ahead of print). View Article : Google Scholar | |
|
Halperin EC, Wazer DE, Perez CA and Brady LW: Perez & Brady's principles and practice of radiation oncology, 7th ed. Wolters Kluwer; Philadelphia: 2018 | |
|
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET and Carbone PP: Toxicity and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 5:649–655. 1982. View Article : Google Scholar : PubMed/NCBI | |
|
Rödel C, Martus P, Papadoupolos T, Füzesi L, Klimpfinger M, Fietkau R, Liersch T, Hohenberger W, Raab R, Sauer R and Wittekind C: Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 23:8688–8696. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
US Department Of Health and Human Services, . Common terminology criteria for adverse events (CTCAE) version 5.0. United States: National Cancer Institute; 2017, https://ctep.Cancer.Gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5×11.pdf | |
|
Gavioli M, Luppi G, Losi L, Bertolini F, Santantonio M, Falchi AM, D'Amico R, Conte PF and Natalini G: Incidence and clinical impact of sterilized disease and minimal residual disease after preoperative radiochemotherapy for rectal cancer. Dis Colon Rectum. 48:1851–1857. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Dinaux AM, Leijssen L, Bordeianou LG, Kunitake H, Amri R and Berger DL: Outcomes of persistent lymph node involvement after neoadjuvant therapy for stage III rectal cancer. Surgery. 163:784–788. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Yeo SG, Kim DY, Kim TH, Chang HJ, Oh JH, Park W, Choi DH, Nam HR, Kim JS, Cho MJ, et al: Pathological complete response of primary tumor following preoperative chemoradiotherapy for locally advanced rectal cancer: Long-term outcomes and prognostic significance of pathological nodal status (KROG 09-01). Ann Surg. 252:998–1004. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Cho E, Park IJ, Hong SM, Lee JL, Kim CW, Yoon YS, Lim SB, Yu CS and Kim JC: Poorer oncologic outcome of good responders to PCRT with remnant lymph nodes defies the oncologic paradox in patients with rectal cancer. Clin Colorectal Cancer. 18:e171–e178. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Song JH, Yu M, Kang KM, Lee JH, Kim SH, Nam TK, Jeong JU, Jang HS, Lee JW and Jung JH: Significance of perineural and lymphovascular invasion in locally advanced rectal cancer treated by preoperative chemoradiotherapy and radical surgery: Can perineural invasion be an indication of adjuvant chemotherapy? Radiother Oncol. 133:125–131. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Saadoun JE, Meillat H, Zemmour C, Brunelle S, Lapeyre A, de Chaisemartin C and Lelong B: Nomogram to predict disease recurrence in patients with locally advanced rectal cancer undergoing rectal surgery after neoadjuvant therapy: Retrospective cohort study. BJS Open. 6:zrac1382022. View Article : Google Scholar : PubMed/NCBI |
