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High dose chemoradiotherapy increases chance of organ preservation with satisfactory functional outcome for rectal cancer

High dose chemoradiotherapy increases chance of organ preservation with satisfactory functional... Background: High dose chemoradiotherapy offers a curative chance for patients with rectal cancer that are unfit or unwilling to undergo surgical resection, yet its long‑term survival and functional outcomes have been rarely investigated. Methods: Patients with non‑metastatic rectal adenocarcinoma who received pelvic radiation for curative intent from April 2006 to July 2017 were retrospectively investigated. Survival rates were analyzed using the Kaplan–Meier method. Quality of life and functional outcomes were evaluated using the EORTC quality of life questionnaire. Results: A total of 57 patients were included, with a median age of 59.0 (range, 29–84) years. The numbers of patients who were diagnosed as stage I, II and III were 5 (8.8%), 16 (28.1%) and 36 (63.2%), respectively. 53 (93.0%) patients had tumor located within 5 cm from the anal verge. All patients received fluorouracil‑based concurrent chemoradiotherapy with a median radiation dose of 80 (range, 60–86) Gy. All kinds of grade 3–4 adverse events occurred in 18 (31.6%) patients. 42 (73.7%) patients achieved a clinical complete response after chemoradiotherapy. After a median follow‑up of 43.5 (range 14.9–163.2) months, 12 (21.1%) patients had local progression and 11 (19.3%) developed distant metastasis. The 3‑ year local recurrence‑free survival and distant metastasis‑free survival were 77.3% (95% CI, 65.7–88.8%) and 79.2% (95% CI, 68.2–90.2%), while the 3‑ year progression‑free survival, cancer ‑specific sur ‑ vival, overall survival were 61.9% (95% CI, 48.8–75.0%), 93.1% (95% CI, 85.8–100.0%) and 91.4% (95% CI, 83.6–99.2%), respectively. For patients who had tumor located within 3 cm from the anal verge, the sphincter preservation rate was 85.3% at last follow‑up. Long‑term adverse events mainly were anal blood loss. 21 patients completed the Qiao‑ Xuan Wang, Shu Zhang and Wei‑ Wei Xiao have contributed equally to this work Xiao‑ Jun Wu and Yuan‑Hong Gao are senior authors and have contributed equally to this work *Correspondence: gaoyh@sysucc.org.cn Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑ sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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Conclusions: High dose chemoradiation demonstrated promising survival outcomes with acceptable short‑term and long‑term side effects, and satisfying long‑term functional outcomes and quality of life. It could be considered as a non‑invasive alternative for rectal cancer patients who refuse surgery. Keywords: Rectal cancer, High dose chemoradiotherapy, Oncological safety, Functional outcomes, Quality of life Introduction long-term survival outcome and adverse events related Surgery remains the essential treatment for non-meta- to high dose radiotherapy remain unclear due to lim- static rectal adenocarcinoma. However, for patients with ited data. Thus, we conducted this retrospective study to tumor located in the distal part of the rectum, abdomin- assess the feasibility of high dose chemoradiotherapy by operineal resection might be necessitated in certain cases analyzing the long-term survival outcome, toxicity, and but at the expense of a permanent stoma and impaired quality of life of these patients. quality of life [1]. For locally advanced rectal cancer, the combination of neoadjuvant chemoradiotherapy and Materials and methods surgical resection may lead to an increased risk of perio- Patient selection perative complications such as anastomotic leaks, post- This study comprised of subjects identified from a pro - operative anorectal, and sexual dysfunction [1–5]. For spective database maintained at the Sun Yat-sen Uni- elderly patients aged over 80  years old, the 30-day post- versity Cancer Center (Guangzhou, China) during the operative mortality remains quite high, ranging between period of April 2006 to July 2017. All patients provided 10 and 15%, and the 6-month mortality ranges between written informed consent for the collection and pub- 15 and 25% [6]. These risks of impaired functional out - lication of their medical information at the first visit to comes and life-threatening postoperative complications our center, which was filed in their medical records. All have stimulated research on non-operative approaches data were retrieved from electronic data records. The for managing patients with rectal cancer. inclusion criteria were as follows: (1) pathologically con- According to previous studies [7–9], patients with rec- firmed rectal adenocarcinoma; (2) tumor located within tal cancer who achieved a clinical complete response 10  cm from the anal verge; (3) without distant metasta- (cCR) after neoadjuvant chemoradiotherapy and man- ses; (4) receive pelvic radiation with a total dose ≥ 60  Gy aged by intensive surveillance could have similar survival for curative intent; (5) a complete set of clinical informa- outcomes, in comparison to patients who undergo stand- tion and follow-up of more than 1 year. The study proto - ard surgery. This treatment strategy was called the watch- col was approved by the ethics committee of Sun Yat-sen and-wait strategy. From the year 2004 [7] to now, the University Cancer Center and was registered at Clinical- watch-and-wait strategy has been accepted by a growing Trials.gov (identifier: NCT03541304). number of oncologists as this has shown to be a prom- ising therapeutic option for patients who achieved cCR. Treatment schedule However, only approximately 15–40% of the patients Patients in our center who received high dose chemo- could achieve cCR after neoadjuvant chemoradiotherapy radiotherapy mainly underwent the following two [10], leaving the remaining patients with residual tumor types of processes. First, patients who refused surgery no choice except for surgery. Therefore, increasing the before any treatment were given one course of high probability of cCR is of great significance for patients dose radiotherapy, with 60–70  Gy radiation at the pri- who wish to receive the non-operative management. mary tumor site and suspected positive lymph nodes, Currently, most patients received long course chemo- and 45–50 Gy radiation to regional lymphatic drainage radiotherapy at the dose level of 45–50  Gy. However, including the mesorectal, presacral, and internal iliac a highly significant dose–response relationship was lymph nodes up to the bottom level of the fifth lum - observed in rectal cancer patients who underwent neoad- bar vertebra. Second, for those who had not decided juvant chemoradiotherapy [11]. This has led to growing whether to undergo surgery or not at the beginning of interests for increasing the dose of radiotherapy with the treatment, neoadjuvant chemoradiotherapy was given. goal of achieving cCR. In a study conducted by Appelt The neoadjuvant radiation consisted of 45–50  Gy et al. [12], high dose chemoradiotherapy was found asso- radiation to the primary tumor and suspected posi- ciated with an impressive cCR rate of 78.4%, indicating tive lymph nodes, and 45–46  Gy to regional lymphatic the possibility for further validation studies. However, the drainage, delivered in 25 fractions over 5  weeks. After W ang et al. Radiation Oncology (2022) 17:98 Page 3 of 10 neoadjuvant chemoradiotherapy, a second course of review, physician records, patient correspondence, and radiotherapy with 20–30  Gy to the primary tumor and telephone interviews. positive lymph node was given for those patients who decided to give up surgery. Radiation was delivered in Quality of life assessment standard fraction with 6 MV photons through three- Quality of life, toxicity and functional outcomes were dimensional conformal radiation therapy (3D-CRT) or evaluated for patients who were alive and without local intensity-modulated radiation therapy (IMRT) tech- disease progression using the European Organization for nique. Patients lied down in a prone position, with Research and Treatment of Cancer (EORTC) quality of filling of bladder. Electronic Portal Imaging Device life questionnaire, the QLQ-CR29 [15] and the QLQ-C30 was implied for position validation. The inductive, modules [16]. QLQ-CR29 addressed gastrointestinal and concurrent, and consolidative chemotherapy regi- urinary symptoms, and anorectal and sexual function. mens including CapeOX (Oxaliplatin 130  mg/m , day And QLQ-CR30 mainly focused on overall quality of life. 1. Capecitabin 1000  mg/m , twice daily for 14  days. The questionnaires were completed by the patients at the Repeat  every 3  weeks),  mFOLFOX6 (Oxaliplatin latest follow-up in the clinic or online on December 1st 2 2 85  mg/m , day 1. Leucovorin 400  mg/m day 1.  5-Fu to December 31th, 2019. A standardized score was calcu- 2 2 400  mg/m bolus on day 1, followed by 1200  mg/m / lated according to the EORTC QLQ-CR29 and QLQ-C30 day × 2  days. Repeat every 2 weeks), or capecitabine, Scoring manual. prescribed at the discretion of the treating physician. Statistical analysis Characteristics were described in terms of frequency for Treatment evaluation and follow up the categorical variables and medians for non-normally Pretreatment evaluation included digital rectal exami- distributed data. Scores for the quality of life assessment nation, computed tomography (CT) scan of the chest were recorded as mean ± SD. The follow-up and survival and abdomen, magnetic resonance image (MRI) of periods were defined as the time span from the date of the pelvis, endorectal ultrasound or colonoscopy with pathological diagnosis until death or censoring. Local a pathological examination, and serum carcinoem- progression was defined as a clinically proven lesion bryonic antigen (CEA) level assessment. Treatment anywhere within the pelvis, either regrowth after initial response was evaluated 6–8 weeks after the completion decrease in size or appearance after complete remission. of radiation therapy and consisted of all the above-men- Distant metastasis was any tumor dissemination out- tioned pretreatment examinations, except pathologi- side the pelvis including peritoneal carcinomatosis that cal examination. Patients were staged according to the occurred during follow-up. Progression-free survival 2010 American Joint Committee on Cancer/Interna- (PFS) was defined as the time from diagnosis until local tional Union Against Cancer (AJCC/UICC) staging sys- progression or distant metastasis, or death related to can- tem [13]. cCR after chemoradiotherapy was defined as cer. Cancer specific survival (CSS) was defined from the the absence of residual tumor on digital rectal exami- date of diagnosis until death from rectal cancer. Overall nation, pelvic MRI, and colonoscopy, accompanied by survival (OS) was defined from the date of diagnosis until a normal CEA level, and chest and abdominal CT scan death from any cause. Local progression-free survival to rule out distant metastasis. Toxicities were evaluated (LPFS), distant metastasis-free survival (DMFS), PFS, according to the National Cancer Institute Common CSS and OS were calculated using the Kaplan–Meier Toxicity Criteria 3.0 [14], and complications emerged method and were compared using the log-rank test. after treatment were evaluated at post-treatment visits. Subgroup differences were examined using the log-rank All patients were followed at 3-month intervals dur- test, and prognostic factors for survival were analyzed ing the first 2  years after the completion of treatment using the Cox proportional hazards regression model. and every 6-month thereafter for an additional period All statistical tests were two-sided. Significance was set of 3  years. Digital rectal examination, CEA levels, and at p < 0.05. Statistical analyses were performed using the colonoscopy were carried out every 3  months in the Statistical Package for the Social Sciences Program (SPSS first 2 years. Chest and abdominal CT scans, and pelvic Inc. Chicago, IL, version 19.0 for Windows). MRI were performed twice a year in the first 2  years, and once every year for another 3 years. Other investi- Results gations were performed when clinically indicated dur- Clinical characteristics ing follow-up. Follow-up data, primarily obtained from From April 1st, 2006 to July 30, 2017, 62 patients were the institution database, was updated by clinical chart diagnosed with rectal cancer and received radiother- apy with a total dose ≥ 60  Gy in Sun Yat-sen University Wang et al. Radiation Oncology (2022) 17:98 Page 4 of 10 Cancer Center. Among them, five patients had metasta - at diagnosis was 59.0 (range, 29–84) years. More males ses diseases at diagnosis and were not included in this (77.2%) were included than female. The majority of study. Patients’ demographics and tumor characteristics enrolled patients were with stage II and III diseases (52, were provided in Table  1. The median age of patients 91.2%). Nine patients had adjacent organs invasion and were defined as T4b. Most patients had their tumor located in distal rectum (46, 80.7%). Table 1 Baseline clinical characteristics of patients receiving Treatment and response evaluation high dose chemoradiotherapy Treatment details were provided in Table  2. The median Variable N = 57 radiation dose of the whole group was 80 (range, 60–86) Gy. Eleven patients who refused surgery at their Age at diagnosis, n (%) first visit were given one course of radiation therapy, Median, y (range) 59 (29–84) with a median dose of 66 (range 60–70) Gy. The other < 60y 30 (52.6) 46 patients received two courses of radiation, with a ≥ 60y 27 (47.4) median total dose of 80 (range 66–86) Gy. For patients Sex, n (%) received two courses of radiotherapy, the most fre- Male 44 (77.2) quently used radiation dose was 50  Gy in 25 fractions Female 13 (22.8) in the first course (42/46, 91.3%), and 30  Gy in 15 frac - Baseline CEA (mg/mL) tions as a second boost (38/46, 82.6%). The time interval < 5.00 mg/mL 35 (61.4) between the two courses of radiotherapy was 77 (range, ≥ 5.00 mg/mL 22 (38.6) 35 to 168) days. Thirteen patients had an interval longer T stage, n (%) than 12  weeks. All patients received fluorouracil-based T1 1 (1.8) T2 10 (17.5) T3 33 (57.9) Table 2 Treatment information, acute adverse events and T4 13 (22.8) response to therapy N stage, n (%) Characteristic No. of patients (%) N0 21 (36.8) Courses of radiotherapy N1 23 (40.4) One course 11 (19.3) N2 13 (22.8) Two courses 46 (80.7) AJCC/UICC stage, n (%) Stage I 5 (8.8) Dose of radiotherapy Stage II 16 (28.1) Median, Gy (range) 80 (60–86) Stage III 36 (63.2) Radiation technology 3D‑ CRT 7 (12.3) Histopathology (differentiation), n (%) IMRT 50 (87.7) Poorly differentiated 8 (14.0) Chemotherapy regime Moderately differentiated 33 (57.9) mFolfox6 2 (3.5) Undefined 16 (28.1) CapeOX 37 (64.9) Distance to the anal verge, n (%) Capecitabine 18 (31.6) Median, cm (range) 3.0 (0.0–10.0) Cycles of chemotherapy ≤ 5.0 cm 53 (93.0) > 5.0 cm 4 (7.0) Median (range) 8 (1–11) Length, n (%) Grade 3–4 complications during treatment Median, cm (range) 5.0 (2.0–11.0) Any types 18 (31.6) < 5.0 cm 28 (49.1) Proctitis 6 (10.5) Diarrhea 2 (3.5) ≥ 5.0 cm 29 (50.9) Dermatitis associated with radiation 7 (12.3) Adjacent organ invasion, n (%) Leukopenia 4 (7.0) Yes 9 (15.8) Thrombocytopenia 6 (10.5) No 48 (84.2) Response to treatment Comorbidities, n (%) cCR 42 (73.7) Yes 10 (17.5) No 47 (82.5) Non‑ cCR 15 (26.3) CEA carcinoembryonic antigen, AJCC/UICC American Joint Committee on 3D-CRT three-dimensional conformal radiation therapy, IMRT intensity- Cancer/International Union Against Cancer modulated radiation therapy, cCR clinical complete response W ang et al. Radiation Oncology (2022) 17:98 Page 5 of 10 concurrent chemotherapy. Among them, 37 (64.9%) Eleven (19.3%) patients developed distant metasta- received CapeOX, 18 (31.6%) had capecitabine mono- sis. Of them, eight (72.7%)  patients had lung metasta- therapy, and 2 (3.5%) were treated with the mFOLFOX6 sis, two (18.2%)  patients had liver metastasis, and one regimen. The median cycles of chemotherapy were 8 (9.1%)  patient had multiple organ metastasis detected at (range, 1 to 11). 50 (87.7%) patients received ≥ 4 cycles the same time. The median time to the development of of chemotherapy. Among these 57 patients, 45 (78.9%) distant metastasis was 22.0 (range, 9.0–30.9) months. As refused surgery because of a permanent colostomy; eight shown in Fig.  1B, 3-year and 5-year DMFS of the whole (12.9%) patients had surgical contraindication that were cohort were 79.2% (95% CI, 68.2–90.2%), and 79.2% (95% deemed impossible to tolerate the operations; four (6.5%) CI, 68.2–90.2%). Five patients receive resection or abla- patients were assessed as unable to achieve R0 resec- tion of metastasis with or without chemotherapy; two tion after the first course of radiotherapy and therefore patients were treated by chemotherapy only; the other received a radiation boost. four patients refused further treatment and were lost to Acute adverse toxicity was acceptable. All patients follow. experienced increased stool frequency (57/57), which The 3-year and 5-year PFS (Fig.  1C) were 61.9% (95% were all classified as grade 1–2. Other commonly CI, 48.8–75.0%) and 60.8% (95% CI, 47.7–73.9%), respec- reported any grade complications were leukopenia tively. Twelve patients died during follow-up, of whom (17/57), thrombocytopenia (20/57), and perianal dis- seven died from rectal cancer and the other five died comfort (25/57). All kinds of grade 3–4 adverse events from other diseases. The 3-year and 5-year OS (Fig.  1D) occurred in 18 (31.6%) patients and were provided in of the whole cohort were 91.4% (95% CI, 83.6–99.2%) and Table  2. Of these, the most frequently reported was 80.7% (95% CI, 66.4–95.0%), respectively. For there were radiodermatitis (12.3%), followed by thrombocytopenia 42.7% of deaths caused by diseases not related to rectal (10.5%), proctitis related to radiotherapy (10.5%), leuko- cancer, we calculated the CSS as another endpoint. As penia (7.0%), and diarrhea (3.5%). shown in Fig.  2, the 3-year and 5-year CSS of the whole All patients underwent an evaluation for treatment effi - cohort were 93.1% (95% CI, 85.8–100.0%) and 84.0% cacy 6–8 weeks after the completion of the first course of (95% CI, 70.5–97.5%), respectively. radiotherapy. For patients receiving two courses of radio- Univariate analysis was performed to screening the therapy, reassessment was done 3 months after the finish factors correlating to CSS. No significant in CSS was of the second course of radiotherapy. 42 (73.7%) patients observed regarding baseline characteristics including age, were assessed as having a cCR and 15 (26.3%) were iden- gender, TNM stage, length of tumor, histological grade, tified as non-cCR. serum concentration of CEA, location of the tumor and treatment modality including courses of radiotherapy and cycles of chemotherapy (Table  3). Only response to Survival of the whole group treatment showed significant difference (p = 0.018, Addi- The last follow-up was on December 16, 2019, and the tional file  1). Widely accepted predictors and response median follow-up time of the study was 43.5 (range to treatment were selected for the multivariate analysis 14.9–163.2) months. A total of 12 (21.1%) patients expe- (Table  4), which showed that cCR after treatment had rienced local progression. Of them, three had distant significant predictive value for CSS (cCR vs. non-cCR, metastasis detected at the same time. The median time HR = 16.6, p = 0.011). No significant difference was from diagnosis to local progression was 20.7 (range, 10.4 observed in LPFS, DMFS, PFS, OS and CSS between to 37.2) months. Most local recurrences (11/12, 91.7%) patients who received one and two courses of radiother- occurred within the first 3 years after diagnosis. As dem - apy (Additional file 2). onstrated in Fig. 1A, 3-year and 5-year LPFS of the whole cohort were 77.3% (95% CI, 65.7–88.8%) and 77.0% (95% Long‑term toxicity and quality of life CI, 65.4–88.6%). Seven patients who experienced local During the follow-up time, 25 (43.9%) patients had progression underwent salvage surgery, of whom, two anal blood loss of any severity. Of these patients, four underwent Dixon procedure and four underwent Miles (7.0%) needed blood transfusion because of severe ane- procedure. Three patients received chemotherapy, while mia. Blood loss were related to mucositis in the rectum, other two patients refused further treatment and were with most serious symptoms in the first 2  years after lost to follow-up after the diagnosis of local progression. radiotherapy and relieved after the second year. Besides, The ultimate sphincter preservation rate was 82.5% for rectum stenosis was identified in two (3.5%) cases by the whole cohort. For patients who had tumor located colonoscopy but both of them claimed no difficulty for within 3 cm from the anal verge, the sphincter preserva- defecation. tion rate was 85.3% at last follow-up. Wang et al. Radiation Oncology (2022) 17:98 Page 6 of 10 Fig. 1 Survival of the whole cohort (N = 57). A Local progression‑free survival; B distant metastasis‑free survival; C progression‑free survival; D overall survival the score above 70 as satisfactory. In general, 15 (71.4%) Patients who experienced local progression (n = 12) or patients reported satisfactory overall quality of life. 85.7% death (n = 12) were exclude form quality of life assess- of all responders reported satisfactory physical function- ment. Thus, 35 patients remained assessable. Of these ing and role functioning; 95.2% reported satisfactory patients, 21 returned the questionnaire, resulting in a emotional functioning; 81% reported satisfactory cogni- response rate of 60%. The median follow-up time since tive functioning; while 76.2% patients reported satisfac- diagnosis for these patients was 45.8 (range, 24.0–163.2) tory social functioning. months. Of these 21 patients who completed the QLQ- For symptom and function related questions, eight C30 and the QLQ-CR29 questionnaires, 17 were male (38.1%) patients reported mild symptoms of urinary fre- and four were female. Questions of the QLQ-C30 and quency, while only one (4.8%) patient-reported urinary QLQ-CR29 were completed for all items in 100% of the incontinences (Fig.  3A). Reports of defection related responders. Standardized scores of the questionnaires questions were shown in Fig. 3B. Fifteen (71.4%) patients were shown in Additional file 3. reported rectal bleeding in any severity, of whom thirteen According to the QLQ-C30 questionnaires, the score (86.7%) described it as occasional. One (4.8%) patient of global health status/quality of life (GHS/QoL) was described the extent of symptom of fecal incontinence 78.57 ± 17.59. For functional scale questions, we defined W ang et al. Radiation Oncology (2022) 17:98 Page 7 of 10 reported a little discomfort during intercourse, while the other three (75%) reported no such symptoms. Discussion This study analyzed the clinical efficacy of patients with non-metastatic rectal cancer who underwent high dose radiotherapy with concurrent chemotherapy followed by the watch-and-wait management. An important precon- dition for implementing organ-sparing strategies in rectal cancer management is the complete remission of tumor after chemoradiotherapy. In order to achieve a higher cCR rate, researchers are attempting to increase the radi- ation doses for such patients. In line with previous stud- ies, our study demonstrated that a high radiation dose could lead to a higher cCR rate. The cCR rate (72.6%) in this present study was comparable to previous stud- Fig. 2 Cancer‑specific survival of the whole cohort (N = 57) ies. Gerard et al. [17] reported a cCR rate of 92% on high dose radiotherapy alone for T N M rectal cancer with 2-3 0-1 0 80 Gy contact X-rays, 39 Gy external beam radiotherapy as moderate, while two patients (9.6%) described it as and 4  Gy concomitant boost. Appelt et  al. [12] showed mild. The other 18 patients (85.7%) reported no such that 78.4% of their patients with T N M rectal cancer 2-3 0-1 0 symptoms. Among 13 male patients aged < 60  years old, achieved cCR after completion of 66 Gy of radiation and 8 (61.5%) preserved normal sexual function and reported concomitant oral tegafur-uracil. These results showed no difficulty in erection; 4 (23.5%) reported a little dif - that high dose  radiation could provide more opportu- ficulty in erection; and only one (5.9%) described it as nities for patients wish to undergo the watch-and-wait quite a bit. Of the four female responders, one (25.0%) strategy. Table 3 Univariate analysis of the risk factors for CSS (N = 57) Variables Univariate analysis HR (95% CI) p value Log‑rank p Age (< 60 vs. ≥ 60) 1.308 (0.292–5.855) 0.725 0.725 Gender (male vs. female) 1.657 (0.309–8.888) 0.555 0.551 AJCC/UICC stage 0.573 I Reference 0.603 II 0.327 (0.02–5.240) 0.429 III 0.966 (0.110–8.457) 0.975 Length (< 5 vs. ≥ 5 cm) 1.308 (0.292–5.855) 0.725 0.960 Histopathology 0.629 Poorly differentiated Reference 0.641 Moderately differentiated 1.022 (0.105–9.920) 0.985 Undefined 2.089 (0.216–20.179) 0.524 CEA levels (< 5 vs. ≥ 5 ng/ml) 1.483 (0.329–6.689) 0.608 0.606 Distance to the anal verge (< 5 vs. ≥ 5 cm) 0.432 (0.051–3.645) 0.441 0.428 Courses of radiotherapy (one course vs. two course) 1.075 (0.129–8.980) 0.946 0.946 Chemotherapy regime (Capecitabine vs. Capoex/folfox) 1.005 (0.195–5.187) 0.996 0.996 Cycles of chemotherapy (≤ 4 vs. > 4) 2.052 (0.241–17.441) 0.510 0.502 Response to treatment (cCR vs. non‑ cCR) 6.361 (1.380–29.328) 0.018 0.007* Comorbidities (yes vs. no) 39.757 (0.033–48,411.962) 0.310 0.083 CSS cancer specific survival, HR hazard ratio, AJCC/UICC American Joint Committee on Cancer/International Union Against Cancer, CEA carcinoembryonic antigen, cCR clinical complete response *Statistically significant Wang et al. Radiation Oncology (2022) 17:98 Page 8 of 10 Table 4 Multivariate analysis of the risk factors for CSS (N = 57) Variables Multivariate analysis HR (95% CI) p value Age (< 60 vs. ≥ 60) 3.618 (0.543–24.082) 0.184 Gender (male vs. female) 4.367 (0.503–37.888) 0.181 AJCC/UICC stage I Reference 0.543 II 0.176 (0.008–3.856) 0.270 III 0.384 (0.029–5.118) 0.469 Courses of radiotherapy (one course vs. two course) 0.366 (0.016–8.127) 0.525 Cycles of chemotherapy (≤ 4 vs. > 4) 3.246 (0.148–71.163) 0.455 Response to treatment (cCR vs. non‑ cCR) 16.616 (1.883–146.634) 0.011* CSS cancer specific survival, HR hazard ratio, AJCC/UICC American Joint Committee on Cancer/International Union Against Cancer, cCR clinical complete response *Statistically significant study on high dose chemoradiotherapy which reported a 5-year local recurrence rate of 31%. According to van der Valk’s report [19], most local regrowth occurred in the first 2 years after treatment. Thus, the follow-up time of 40  months in our study was to some extent enough to demonstrate the safety in local control of high dose radiotherapy. Meanwhile, 3-year PFS in our study (61.9%) was also comparable to Appelt’s study (2-year PFS of 58%). The overall survival in our study was slightly lower than that of patients in the studies of van der Valk et  al. [19] and Dizdarevic et al. [20], which could be due to the more advanced tumor stage in some patients in current study. And there were more elderly patients in our study, who eventually died of diseases other than cancer, which could also lead to lower OS. Apart from survival outcomes, the main concern about high dose radiotherapy was the associated adverse events. Acute adverse events were fully investigated in previous studies, mostly demonstrating a low incidence of associated adverse events [21], and was in line with our study. However, data on late toxicity were limited. In this study, we showed that the incidence of late toxicity was also relatively low. Consistent with Dizdarevic et  al. [20], the most common long-term high-dose chemo- Fig. 3 Selected patient‑reported symptoms at the latest follow up radiotherapy toxicity in our study was rectal bleeding, according to the QLQ‑ CR29 questionnaires, reported as proportions which the researchers attributed to their administered of patients with symptoms of different severity. A Reports of urinary brachytherapy boost. In our study, only an external beam function related questions; B reports of defection related questions boost was used, but yet rectal bleeding was still observed in some patients though most were mild. Our study also shown that mucositis resulted in rectal bleeding peaked Although the local control reported in this present in the first to second years after treatment, and gradually study was lower than previous reports with patients who relieved after the second year. Most patients didn’t need underwent standard treatment [18], our findings are still medical intervention. satisfactory considering that all patients in our study Quality of life is an important facet of cancer treat- refused to have surgery. And the 5-year local control rate ments, especially for the organ-sparing treatment of 77.0% in our study was comparable to Dizdarevic’s W ang et al. Radiation Oncology (2022) 17:98 Page 9 of 10 strategy. Hupkens [22] demonstrated that the quality of different time points after the completion of radiother - life after successful watch-and-wait approach was bet- apy for different patients and were only a one-point sur - ter than after chemoradiation and surgery. However, vey. However, according to previous report [20], overall there were still one-third of the watch-and-wait patients scores of these questions at different time-points showed experienced major low anterior resection syndrome little variation after 2 years. As all of the patients finished symptoms. In regard to high dose radiotherapy for rec- the questionnaires were followed for at least 2 years, our tal cancer, there have been few studies assessing quality one-point survey still preserves its power to reflect the of life in long-term profiles. In Dizdarevic’s study [20], quality of life for these patients. high-dose chemoradiotherapy followed by nonsurgical management for distal rectal cancer showed excellent Conclusions general colorectal cancer quality of life and local symp- In conclusion, this study demonstrated that high dose tom scores. In regard to fecal incontinence, only two in chemoradiotherapy could provide high chance of organ 36 patients reported severe symptom (5.6%), and this preservation, good oncologic control with acceptable was in agreement with our study (4.8%). The question - acute and chronic side effects, and satisfactory long-term naires collected from patients in our study also showed quality of life. Therefore, for rectal cancer patients who that most patients retained their anal, sexual, and urinary refuse to undergo surgery, high dose chemoradiotherapy function, and most had a satisfying quality of life. could be offered as a potentially curative option. Further According to previous studies, approximately 15–40% prospective studies will be carried out to explore this of the patients could achieve cCR after neoadjuvant treatment strategy. chemoradiotherapy [10], this meant that 50  Gy dose could be sufficient for about one-third of all rectal can - cer. According to Appelt’s study [12], if we increased the Abbreviations cCR: Clinical complete response; 3D‑ CRT : Three‑ dimensional conformal radia‑ dose to 65  Gy, cCR rate could be increased to around tion therapy; IMRT: Intensity‑modulated radiation therapy; CT: Computed 78%. And this means that 65  Gy might be sufficient for tomography; MRI: Magnetic resonance image; CEA: Carcinoembryonic anti‑ another one-third of patients. However, it is noteworthy gen; AJCC: American Joint Committee on Cancer; UICC: International Union Against Cancer; EORTC : European Organization for Research and Treatment of that some patients in our study decided to avoid surgery Cancer; PFS: Progression‑free survival; CSS: Cancer specific survival; OS: Overall before treatment, while the majority made this decision survival; LPFS: Local progression‑free survival; DMFS: Distant metastasis‑free after neoadjuvant chemoradiotherapy. In the former, we survival. could make a complete plan to give one course of high dose radiation, while in the latter, there was a long inter- Supplementary Information val between the two courses of radiation. It was chal- The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s13014‑ 022‑ 02066‑7. lenging to decide the optimal radiation dose that would be effective and within the maximum dose constraints of Additional file 1. Cancer ‑specific survival for patients who had clinical normal tissue, as there was no suitable calculation model complete response (n = 42) after treatment and those who hadn’t (n = evaluating the biologically effective dose. In this study, 15). the general clinical practice dealing with such problem Additional file 2. Survival cures for patients who received one course was to prescribe 20–30  Gy boosting to the gross tumor of radiotherapy (n = 11) and two courses of radiotherapy (n = 46). (A) Local progression‑free survival; (B) distant metastasis‑free survival; (C) volume, so the primary tumor would receive a total progression‑free survival; (D) cancer specific survival; (E) overall survival. dose of 70–80  Gy. The satisfied clinical efficacy and few Additional file 3. Standardized scores of the QLQ ‑ C30 and the QLQ‑ CR29 adverse events indicated that this dose prescribing model questionnaires. might be reasonable. Though there were no study giving such high dose using external beam radiation therapy in Acknowledgements literature, there were several studies in which a second We would like to thank all the included patients and participants for the sup‑ boost was given using brachytherapy after neoadjuvant ports of this study. chemoradiotherapy, and the total doses were as high as Author contributions 75 to 80  Gy [23]. In modern era of IMRT, delivery of a XJW and YHG conceived the idea and designed the study. QXW and SZ high dose of radiation to the residual tumor while spar- collected the data. QXW, SZ and WWX analyzed the data and draw the draft of the manuscript. All authors participated in the treatment of patients, the ing the normal surrounding tissues is technically achiev- interpretation of the results, writing, revising and approving the final version of able using external beam radiation therapy. These studies this work. All authors read and approved the final manuscript. together with our study, demonstrated the safety of this Funding clinical practice.The limitations of this study were the This study was supported by the grants from the National Natural Science retrospective design and small sample size. Other limi- Foundation of China (No. 81672987; 82073329); Natural Science Foundation of tations were that the questionnaires were answered at Guangdong Province (2020A1515011286). Wang et al. Radiation Oncology (2022) 17:98 Page 10 of 10 Availability of data and materials with complete clinical response after neoadjuvant therapy. Ann Surg. Data of this study is available at Research Data Deposit, and the URL is https:// 2012;256(6):965–72. www. resea rchda ta. org. cn. 10. Sammour T, Price BA, Krause KJ, Chang GJ. Nonoperative management or “watch and wait” for rectal cancer with complete clinical response after neoadjuvant chemoradiotherapy: a critical appraisal. Ann Surg Oncol. Declarations 2017;24(7):1904–15. 11. Appelt AL, Pløen J, Vogelius IR, Bentzen SM, Jakobsen A. Radiation dose‑ Ethics approval and consent to participate response model for locally advanced rectal cancer after preoperative All the procedures were approved by the ethical committee in Sun Yat‑sen chemoradiation therapy. Int J Radiat Oncol Biol Phys. 2013;85(1):74–80. University Cancer Center (Guangzhou, China). All patients provided written 12. Appelt AL, Pløen J, Harling H, Jensen FS, Jensen LH, Jørgensen JC, informed consent for the collection and publication of their medical informa‑ Lindebjerg J, Rafaelsen SR, Jakobsen A. High‑ dose chemoradiotherapy tion at the first visit to our center, which was filed in their medical records. and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol. 2015;16(8):919–27. Consent for publication 13. AJCC Cancer Staging Manual, 7th edn. 2010. Not applicable. 14. Trotti A, Colevas A, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman C. CTCAE v3.0: development of a com‑ Competing interests prehensive grading system for the adverse effects of cancer treatment. We declare no competing interests. Semin Radiat Oncol. 2003;13(3):176–81. 15. Whistance RN, Conroy T, Chie W, Costantini A, Sezer O, Koller M, Johnson Author details CD, Pilkington SA, Arraras J, Ben‑ Josef E, et al. Clinical and psychometric Department of Radiation Oncology, State Key Laboratory of Oncology validation of the EORTC QLQ‑ CR29 questionnaire module to assess in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑ health‑related quality of life in patients with colorectal cancer. Eur J sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, Cancer. 2009;45(17):3017–26. People’s Republic of China. Department of Medical Imaging and Interven‑ 16. 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Wait‑and‑see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011;29(35):4633–40. 9. Smith JD, Ruby JA, Goodman KA, Saltz LB, Guillem JG, Weiser MR, Temple LK, Nash GM, Paty PB. Nonoperative management of rectal cancer http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

High dose chemoradiotherapy increases chance of organ preservation with satisfactory functional outcome for rectal cancer

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Abstract

Background: High dose chemoradiotherapy offers a curative chance for patients with rectal cancer that are unfit or unwilling to undergo surgical resection, yet its long‑term survival and functional outcomes have been rarely investigated. Methods: Patients with non‑metastatic rectal adenocarcinoma who received pelvic radiation for curative intent from April 2006 to July 2017 were retrospectively investigated. Survival rates were analyzed using the Kaplan–Meier method. Quality of life and functional outcomes were evaluated using the EORTC quality of life questionnaire. Results: A total of 57 patients were included, with a median age of 59.0 (range, 29–84) years. The numbers of patients who were diagnosed as stage I, II and III were 5 (8.8%), 16 (28.1%) and 36 (63.2%), respectively. 53 (93.0%) patients had tumor located within 5 cm from the anal verge. All patients received fluorouracil‑based concurrent chemoradiotherapy with a median radiation dose of 80 (range, 60–86) Gy. All kinds of grade 3–4 adverse events occurred in 18 (31.6%) patients. 42 (73.7%) patients achieved a clinical complete response after chemoradiotherapy. After a median follow‑up of 43.5 (range 14.9–163.2) months, 12 (21.1%) patients had local progression and 11 (19.3%) developed distant metastasis. The 3‑ year local recurrence‑free survival and distant metastasis‑free survival were 77.3% (95% CI, 65.7–88.8%) and 79.2% (95% CI, 68.2–90.2%), while the 3‑ year progression‑free survival, cancer ‑specific sur ‑ vival, overall survival were 61.9% (95% CI, 48.8–75.0%), 93.1% (95% CI, 85.8–100.0%) and 91.4% (95% CI, 83.6–99.2%), respectively. For patients who had tumor located within 3 cm from the anal verge, the sphincter preservation rate was 85.3% at last follow‑up. Long‑term adverse events mainly were anal blood loss. 21 patients completed the Qiao‑ Xuan Wang, Shu Zhang and Wei‑ Wei Xiao have contributed equally to this work Xiao‑ Jun Wu and Yuan‑Hong Gao are senior authors and have contributed equally to this work *Correspondence: gaoyh@sysucc.org.cn Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑ sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. Radiation Oncology (2022) 17:98 Page 2 of 10 quality‑ of‑life questionnaire and had a score of the global health status of 78.57 ± 17.59. Of them, 95.2% reported no urinary incontinence and 85.7% reported no fecal incontinence. Conclusions: High dose chemoradiation demonstrated promising survival outcomes with acceptable short‑term and long‑term side effects, and satisfying long‑term functional outcomes and quality of life. It could be considered as a non‑invasive alternative for rectal cancer patients who refuse surgery. Keywords: Rectal cancer, High dose chemoradiotherapy, Oncological safety, Functional outcomes, Quality of life Introduction long-term survival outcome and adverse events related Surgery remains the essential treatment for non-meta- to high dose radiotherapy remain unclear due to lim- static rectal adenocarcinoma. However, for patients with ited data. Thus, we conducted this retrospective study to tumor located in the distal part of the rectum, abdomin- assess the feasibility of high dose chemoradiotherapy by operineal resection might be necessitated in certain cases analyzing the long-term survival outcome, toxicity, and but at the expense of a permanent stoma and impaired quality of life of these patients. quality of life [1]. For locally advanced rectal cancer, the combination of neoadjuvant chemoradiotherapy and Materials and methods surgical resection may lead to an increased risk of perio- Patient selection perative complications such as anastomotic leaks, post- This study comprised of subjects identified from a pro - operative anorectal, and sexual dysfunction [1–5]. For spective database maintained at the Sun Yat-sen Uni- elderly patients aged over 80  years old, the 30-day post- versity Cancer Center (Guangzhou, China) during the operative mortality remains quite high, ranging between period of April 2006 to July 2017. All patients provided 10 and 15%, and the 6-month mortality ranges between written informed consent for the collection and pub- 15 and 25% [6]. These risks of impaired functional out - lication of their medical information at the first visit to comes and life-threatening postoperative complications our center, which was filed in their medical records. All have stimulated research on non-operative approaches data were retrieved from electronic data records. The for managing patients with rectal cancer. inclusion criteria were as follows: (1) pathologically con- According to previous studies [7–9], patients with rec- firmed rectal adenocarcinoma; (2) tumor located within tal cancer who achieved a clinical complete response 10  cm from the anal verge; (3) without distant metasta- (cCR) after neoadjuvant chemoradiotherapy and man- ses; (4) receive pelvic radiation with a total dose ≥ 60  Gy aged by intensive surveillance could have similar survival for curative intent; (5) a complete set of clinical informa- outcomes, in comparison to patients who undergo stand- tion and follow-up of more than 1 year. The study proto - ard surgery. This treatment strategy was called the watch- col was approved by the ethics committee of Sun Yat-sen and-wait strategy. From the year 2004 [7] to now, the University Cancer Center and was registered at Clinical- watch-and-wait strategy has been accepted by a growing Trials.gov (identifier: NCT03541304). number of oncologists as this has shown to be a prom- ising therapeutic option for patients who achieved cCR. Treatment schedule However, only approximately 15–40% of the patients Patients in our center who received high dose chemo- could achieve cCR after neoadjuvant chemoradiotherapy radiotherapy mainly underwent the following two [10], leaving the remaining patients with residual tumor types of processes. First, patients who refused surgery no choice except for surgery. Therefore, increasing the before any treatment were given one course of high probability of cCR is of great significance for patients dose radiotherapy, with 60–70  Gy radiation at the pri- who wish to receive the non-operative management. mary tumor site and suspected positive lymph nodes, Currently, most patients received long course chemo- and 45–50 Gy radiation to regional lymphatic drainage radiotherapy at the dose level of 45–50  Gy. However, including the mesorectal, presacral, and internal iliac a highly significant dose–response relationship was lymph nodes up to the bottom level of the fifth lum - observed in rectal cancer patients who underwent neoad- bar vertebra. Second, for those who had not decided juvant chemoradiotherapy [11]. This has led to growing whether to undergo surgery or not at the beginning of interests for increasing the dose of radiotherapy with the treatment, neoadjuvant chemoradiotherapy was given. goal of achieving cCR. In a study conducted by Appelt The neoadjuvant radiation consisted of 45–50  Gy et al. [12], high dose chemoradiotherapy was found asso- radiation to the primary tumor and suspected posi- ciated with an impressive cCR rate of 78.4%, indicating tive lymph nodes, and 45–46  Gy to regional lymphatic the possibility for further validation studies. However, the drainage, delivered in 25 fractions over 5  weeks. After W ang et al. Radiation Oncology (2022) 17:98 Page 3 of 10 neoadjuvant chemoradiotherapy, a second course of review, physician records, patient correspondence, and radiotherapy with 20–30  Gy to the primary tumor and telephone interviews. positive lymph node was given for those patients who decided to give up surgery. Radiation was delivered in Quality of life assessment standard fraction with 6 MV photons through three- Quality of life, toxicity and functional outcomes were dimensional conformal radiation therapy (3D-CRT) or evaluated for patients who were alive and without local intensity-modulated radiation therapy (IMRT) tech- disease progression using the European Organization for nique. Patients lied down in a prone position, with Research and Treatment of Cancer (EORTC) quality of filling of bladder. Electronic Portal Imaging Device life questionnaire, the QLQ-CR29 [15] and the QLQ-C30 was implied for position validation. The inductive, modules [16]. QLQ-CR29 addressed gastrointestinal and concurrent, and consolidative chemotherapy regi- urinary symptoms, and anorectal and sexual function. mens including CapeOX (Oxaliplatin 130  mg/m , day And QLQ-CR30 mainly focused on overall quality of life. 1. Capecitabin 1000  mg/m , twice daily for 14  days. The questionnaires were completed by the patients at the Repeat  every 3  weeks),  mFOLFOX6 (Oxaliplatin latest follow-up in the clinic or online on December 1st 2 2 85  mg/m , day 1. Leucovorin 400  mg/m day 1.  5-Fu to December 31th, 2019. A standardized score was calcu- 2 2 400  mg/m bolus on day 1, followed by 1200  mg/m / lated according to the EORTC QLQ-CR29 and QLQ-C30 day × 2  days. Repeat every 2 weeks), or capecitabine, Scoring manual. prescribed at the discretion of the treating physician. Statistical analysis Characteristics were described in terms of frequency for Treatment evaluation and follow up the categorical variables and medians for non-normally Pretreatment evaluation included digital rectal exami- distributed data. Scores for the quality of life assessment nation, computed tomography (CT) scan of the chest were recorded as mean ± SD. The follow-up and survival and abdomen, magnetic resonance image (MRI) of periods were defined as the time span from the date of the pelvis, endorectal ultrasound or colonoscopy with pathological diagnosis until death or censoring. Local a pathological examination, and serum carcinoem- progression was defined as a clinically proven lesion bryonic antigen (CEA) level assessment. Treatment anywhere within the pelvis, either regrowth after initial response was evaluated 6–8 weeks after the completion decrease in size or appearance after complete remission. of radiation therapy and consisted of all the above-men- Distant metastasis was any tumor dissemination out- tioned pretreatment examinations, except pathologi- side the pelvis including peritoneal carcinomatosis that cal examination. Patients were staged according to the occurred during follow-up. Progression-free survival 2010 American Joint Committee on Cancer/Interna- (PFS) was defined as the time from diagnosis until local tional Union Against Cancer (AJCC/UICC) staging sys- progression or distant metastasis, or death related to can- tem [13]. cCR after chemoradiotherapy was defined as cer. Cancer specific survival (CSS) was defined from the the absence of residual tumor on digital rectal exami- date of diagnosis until death from rectal cancer. Overall nation, pelvic MRI, and colonoscopy, accompanied by survival (OS) was defined from the date of diagnosis until a normal CEA level, and chest and abdominal CT scan death from any cause. Local progression-free survival to rule out distant metastasis. Toxicities were evaluated (LPFS), distant metastasis-free survival (DMFS), PFS, according to the National Cancer Institute Common CSS and OS were calculated using the Kaplan–Meier Toxicity Criteria 3.0 [14], and complications emerged method and were compared using the log-rank test. after treatment were evaluated at post-treatment visits. Subgroup differences were examined using the log-rank All patients were followed at 3-month intervals dur- test, and prognostic factors for survival were analyzed ing the first 2  years after the completion of treatment using the Cox proportional hazards regression model. and every 6-month thereafter for an additional period All statistical tests were two-sided. Significance was set of 3  years. Digital rectal examination, CEA levels, and at p < 0.05. Statistical analyses were performed using the colonoscopy were carried out every 3  months in the Statistical Package for the Social Sciences Program (SPSS first 2 years. Chest and abdominal CT scans, and pelvic Inc. Chicago, IL, version 19.0 for Windows). MRI were performed twice a year in the first 2  years, and once every year for another 3 years. Other investi- Results gations were performed when clinically indicated dur- Clinical characteristics ing follow-up. Follow-up data, primarily obtained from From April 1st, 2006 to July 30, 2017, 62 patients were the institution database, was updated by clinical chart diagnosed with rectal cancer and received radiother- apy with a total dose ≥ 60  Gy in Sun Yat-sen University Wang et al. Radiation Oncology (2022) 17:98 Page 4 of 10 Cancer Center. Among them, five patients had metasta - at diagnosis was 59.0 (range, 29–84) years. More males ses diseases at diagnosis and were not included in this (77.2%) were included than female. The majority of study. Patients’ demographics and tumor characteristics enrolled patients were with stage II and III diseases (52, were provided in Table  1. The median age of patients 91.2%). Nine patients had adjacent organs invasion and were defined as T4b. Most patients had their tumor located in distal rectum (46, 80.7%). Table 1 Baseline clinical characteristics of patients receiving Treatment and response evaluation high dose chemoradiotherapy Treatment details were provided in Table  2. The median Variable N = 57 radiation dose of the whole group was 80 (range, 60–86) Gy. Eleven patients who refused surgery at their Age at diagnosis, n (%) first visit were given one course of radiation therapy, Median, y (range) 59 (29–84) with a median dose of 66 (range 60–70) Gy. The other < 60y 30 (52.6) 46 patients received two courses of radiation, with a ≥ 60y 27 (47.4) median total dose of 80 (range 66–86) Gy. For patients Sex, n (%) received two courses of radiotherapy, the most fre- Male 44 (77.2) quently used radiation dose was 50  Gy in 25 fractions Female 13 (22.8) in the first course (42/46, 91.3%), and 30  Gy in 15 frac - Baseline CEA (mg/mL) tions as a second boost (38/46, 82.6%). The time interval < 5.00 mg/mL 35 (61.4) between the two courses of radiotherapy was 77 (range, ≥ 5.00 mg/mL 22 (38.6) 35 to 168) days. Thirteen patients had an interval longer T stage, n (%) than 12  weeks. All patients received fluorouracil-based T1 1 (1.8) T2 10 (17.5) T3 33 (57.9) Table 2 Treatment information, acute adverse events and T4 13 (22.8) response to therapy N stage, n (%) Characteristic No. of patients (%) N0 21 (36.8) Courses of radiotherapy N1 23 (40.4) One course 11 (19.3) N2 13 (22.8) Two courses 46 (80.7) AJCC/UICC stage, n (%) Stage I 5 (8.8) Dose of radiotherapy Stage II 16 (28.1) Median, Gy (range) 80 (60–86) Stage III 36 (63.2) Radiation technology 3D‑ CRT 7 (12.3) Histopathology (differentiation), n (%) IMRT 50 (87.7) Poorly differentiated 8 (14.0) Chemotherapy regime Moderately differentiated 33 (57.9) mFolfox6 2 (3.5) Undefined 16 (28.1) CapeOX 37 (64.9) Distance to the anal verge, n (%) Capecitabine 18 (31.6) Median, cm (range) 3.0 (0.0–10.0) Cycles of chemotherapy ≤ 5.0 cm 53 (93.0) > 5.0 cm 4 (7.0) Median (range) 8 (1–11) Length, n (%) Grade 3–4 complications during treatment Median, cm (range) 5.0 (2.0–11.0) Any types 18 (31.6) < 5.0 cm 28 (49.1) Proctitis 6 (10.5) Diarrhea 2 (3.5) ≥ 5.0 cm 29 (50.9) Dermatitis associated with radiation 7 (12.3) Adjacent organ invasion, n (%) Leukopenia 4 (7.0) Yes 9 (15.8) Thrombocytopenia 6 (10.5) No 48 (84.2) Response to treatment Comorbidities, n (%) cCR 42 (73.7) Yes 10 (17.5) No 47 (82.5) Non‑ cCR 15 (26.3) CEA carcinoembryonic antigen, AJCC/UICC American Joint Committee on 3D-CRT three-dimensional conformal radiation therapy, IMRT intensity- Cancer/International Union Against Cancer modulated radiation therapy, cCR clinical complete response W ang et al. Radiation Oncology (2022) 17:98 Page 5 of 10 concurrent chemotherapy. Among them, 37 (64.9%) Eleven (19.3%) patients developed distant metasta- received CapeOX, 18 (31.6%) had capecitabine mono- sis. Of them, eight (72.7%)  patients had lung metasta- therapy, and 2 (3.5%) were treated with the mFOLFOX6 sis, two (18.2%)  patients had liver metastasis, and one regimen. The median cycles of chemotherapy were 8 (9.1%)  patient had multiple organ metastasis detected at (range, 1 to 11). 50 (87.7%) patients received ≥ 4 cycles the same time. The median time to the development of of chemotherapy. Among these 57 patients, 45 (78.9%) distant metastasis was 22.0 (range, 9.0–30.9) months. As refused surgery because of a permanent colostomy; eight shown in Fig.  1B, 3-year and 5-year DMFS of the whole (12.9%) patients had surgical contraindication that were cohort were 79.2% (95% CI, 68.2–90.2%), and 79.2% (95% deemed impossible to tolerate the operations; four (6.5%) CI, 68.2–90.2%). Five patients receive resection or abla- patients were assessed as unable to achieve R0 resec- tion of metastasis with or without chemotherapy; two tion after the first course of radiotherapy and therefore patients were treated by chemotherapy only; the other received a radiation boost. four patients refused further treatment and were lost to Acute adverse toxicity was acceptable. All patients follow. experienced increased stool frequency (57/57), which The 3-year and 5-year PFS (Fig.  1C) were 61.9% (95% were all classified as grade 1–2. Other commonly CI, 48.8–75.0%) and 60.8% (95% CI, 47.7–73.9%), respec- reported any grade complications were leukopenia tively. Twelve patients died during follow-up, of whom (17/57), thrombocytopenia (20/57), and perianal dis- seven died from rectal cancer and the other five died comfort (25/57). All kinds of grade 3–4 adverse events from other diseases. The 3-year and 5-year OS (Fig.  1D) occurred in 18 (31.6%) patients and were provided in of the whole cohort were 91.4% (95% CI, 83.6–99.2%) and Table  2. Of these, the most frequently reported was 80.7% (95% CI, 66.4–95.0%), respectively. For there were radiodermatitis (12.3%), followed by thrombocytopenia 42.7% of deaths caused by diseases not related to rectal (10.5%), proctitis related to radiotherapy (10.5%), leuko- cancer, we calculated the CSS as another endpoint. As penia (7.0%), and diarrhea (3.5%). shown in Fig.  2, the 3-year and 5-year CSS of the whole All patients underwent an evaluation for treatment effi - cohort were 93.1% (95% CI, 85.8–100.0%) and 84.0% cacy 6–8 weeks after the completion of the first course of (95% CI, 70.5–97.5%), respectively. radiotherapy. For patients receiving two courses of radio- Univariate analysis was performed to screening the therapy, reassessment was done 3 months after the finish factors correlating to CSS. No significant in CSS was of the second course of radiotherapy. 42 (73.7%) patients observed regarding baseline characteristics including age, were assessed as having a cCR and 15 (26.3%) were iden- gender, TNM stage, length of tumor, histological grade, tified as non-cCR. serum concentration of CEA, location of the tumor and treatment modality including courses of radiotherapy and cycles of chemotherapy (Table  3). Only response to Survival of the whole group treatment showed significant difference (p = 0.018, Addi- The last follow-up was on December 16, 2019, and the tional file  1). Widely accepted predictors and response median follow-up time of the study was 43.5 (range to treatment were selected for the multivariate analysis 14.9–163.2) months. A total of 12 (21.1%) patients expe- (Table  4), which showed that cCR after treatment had rienced local progression. Of them, three had distant significant predictive value for CSS (cCR vs. non-cCR, metastasis detected at the same time. The median time HR = 16.6, p = 0.011). No significant difference was from diagnosis to local progression was 20.7 (range, 10.4 observed in LPFS, DMFS, PFS, OS and CSS between to 37.2) months. Most local recurrences (11/12, 91.7%) patients who received one and two courses of radiother- occurred within the first 3 years after diagnosis. As dem - apy (Additional file 2). onstrated in Fig. 1A, 3-year and 5-year LPFS of the whole cohort were 77.3% (95% CI, 65.7–88.8%) and 77.0% (95% Long‑term toxicity and quality of life CI, 65.4–88.6%). Seven patients who experienced local During the follow-up time, 25 (43.9%) patients had progression underwent salvage surgery, of whom, two anal blood loss of any severity. Of these patients, four underwent Dixon procedure and four underwent Miles (7.0%) needed blood transfusion because of severe ane- procedure. Three patients received chemotherapy, while mia. Blood loss were related to mucositis in the rectum, other two patients refused further treatment and were with most serious symptoms in the first 2  years after lost to follow-up after the diagnosis of local progression. radiotherapy and relieved after the second year. Besides, The ultimate sphincter preservation rate was 82.5% for rectum stenosis was identified in two (3.5%) cases by the whole cohort. For patients who had tumor located colonoscopy but both of them claimed no difficulty for within 3 cm from the anal verge, the sphincter preserva- defecation. tion rate was 85.3% at last follow-up. Wang et al. Radiation Oncology (2022) 17:98 Page 6 of 10 Fig. 1 Survival of the whole cohort (N = 57). A Local progression‑free survival; B distant metastasis‑free survival; C progression‑free survival; D overall survival the score above 70 as satisfactory. In general, 15 (71.4%) Patients who experienced local progression (n = 12) or patients reported satisfactory overall quality of life. 85.7% death (n = 12) were exclude form quality of life assess- of all responders reported satisfactory physical function- ment. Thus, 35 patients remained assessable. Of these ing and role functioning; 95.2% reported satisfactory patients, 21 returned the questionnaire, resulting in a emotional functioning; 81% reported satisfactory cogni- response rate of 60%. The median follow-up time since tive functioning; while 76.2% patients reported satisfac- diagnosis for these patients was 45.8 (range, 24.0–163.2) tory social functioning. months. Of these 21 patients who completed the QLQ- For symptom and function related questions, eight C30 and the QLQ-CR29 questionnaires, 17 were male (38.1%) patients reported mild symptoms of urinary fre- and four were female. Questions of the QLQ-C30 and quency, while only one (4.8%) patient-reported urinary QLQ-CR29 were completed for all items in 100% of the incontinences (Fig.  3A). Reports of defection related responders. Standardized scores of the questionnaires questions were shown in Fig. 3B. Fifteen (71.4%) patients were shown in Additional file 3. reported rectal bleeding in any severity, of whom thirteen According to the QLQ-C30 questionnaires, the score (86.7%) described it as occasional. One (4.8%) patient of global health status/quality of life (GHS/QoL) was described the extent of symptom of fecal incontinence 78.57 ± 17.59. For functional scale questions, we defined W ang et al. Radiation Oncology (2022) 17:98 Page 7 of 10 reported a little discomfort during intercourse, while the other three (75%) reported no such symptoms. Discussion This study analyzed the clinical efficacy of patients with non-metastatic rectal cancer who underwent high dose radiotherapy with concurrent chemotherapy followed by the watch-and-wait management. An important precon- dition for implementing organ-sparing strategies in rectal cancer management is the complete remission of tumor after chemoradiotherapy. In order to achieve a higher cCR rate, researchers are attempting to increase the radi- ation doses for such patients. In line with previous stud- ies, our study demonstrated that a high radiation dose could lead to a higher cCR rate. The cCR rate (72.6%) in this present study was comparable to previous stud- Fig. 2 Cancer‑specific survival of the whole cohort (N = 57) ies. Gerard et al. [17] reported a cCR rate of 92% on high dose radiotherapy alone for T N M rectal cancer with 2-3 0-1 0 80 Gy contact X-rays, 39 Gy external beam radiotherapy as moderate, while two patients (9.6%) described it as and 4  Gy concomitant boost. Appelt et  al. [12] showed mild. The other 18 patients (85.7%) reported no such that 78.4% of their patients with T N M rectal cancer 2-3 0-1 0 symptoms. Among 13 male patients aged < 60  years old, achieved cCR after completion of 66 Gy of radiation and 8 (61.5%) preserved normal sexual function and reported concomitant oral tegafur-uracil. These results showed no difficulty in erection; 4 (23.5%) reported a little dif - that high dose  radiation could provide more opportu- ficulty in erection; and only one (5.9%) described it as nities for patients wish to undergo the watch-and-wait quite a bit. Of the four female responders, one (25.0%) strategy. Table 3 Univariate analysis of the risk factors for CSS (N = 57) Variables Univariate analysis HR (95% CI) p value Log‑rank p Age (< 60 vs. ≥ 60) 1.308 (0.292–5.855) 0.725 0.725 Gender (male vs. female) 1.657 (0.309–8.888) 0.555 0.551 AJCC/UICC stage 0.573 I Reference 0.603 II 0.327 (0.02–5.240) 0.429 III 0.966 (0.110–8.457) 0.975 Length (< 5 vs. ≥ 5 cm) 1.308 (0.292–5.855) 0.725 0.960 Histopathology 0.629 Poorly differentiated Reference 0.641 Moderately differentiated 1.022 (0.105–9.920) 0.985 Undefined 2.089 (0.216–20.179) 0.524 CEA levels (< 5 vs. ≥ 5 ng/ml) 1.483 (0.329–6.689) 0.608 0.606 Distance to the anal verge (< 5 vs. ≥ 5 cm) 0.432 (0.051–3.645) 0.441 0.428 Courses of radiotherapy (one course vs. two course) 1.075 (0.129–8.980) 0.946 0.946 Chemotherapy regime (Capecitabine vs. Capoex/folfox) 1.005 (0.195–5.187) 0.996 0.996 Cycles of chemotherapy (≤ 4 vs. > 4) 2.052 (0.241–17.441) 0.510 0.502 Response to treatment (cCR vs. non‑ cCR) 6.361 (1.380–29.328) 0.018 0.007* Comorbidities (yes vs. no) 39.757 (0.033–48,411.962) 0.310 0.083 CSS cancer specific survival, HR hazard ratio, AJCC/UICC American Joint Committee on Cancer/International Union Against Cancer, CEA carcinoembryonic antigen, cCR clinical complete response *Statistically significant Wang et al. Radiation Oncology (2022) 17:98 Page 8 of 10 Table 4 Multivariate analysis of the risk factors for CSS (N = 57) Variables Multivariate analysis HR (95% CI) p value Age (< 60 vs. ≥ 60) 3.618 (0.543–24.082) 0.184 Gender (male vs. female) 4.367 (0.503–37.888) 0.181 AJCC/UICC stage I Reference 0.543 II 0.176 (0.008–3.856) 0.270 III 0.384 (0.029–5.118) 0.469 Courses of radiotherapy (one course vs. two course) 0.366 (0.016–8.127) 0.525 Cycles of chemotherapy (≤ 4 vs. > 4) 3.246 (0.148–71.163) 0.455 Response to treatment (cCR vs. non‑ cCR) 16.616 (1.883–146.634) 0.011* CSS cancer specific survival, HR hazard ratio, AJCC/UICC American Joint Committee on Cancer/International Union Against Cancer, cCR clinical complete response *Statistically significant study on high dose chemoradiotherapy which reported a 5-year local recurrence rate of 31%. According to van der Valk’s report [19], most local regrowth occurred in the first 2 years after treatment. Thus, the follow-up time of 40  months in our study was to some extent enough to demonstrate the safety in local control of high dose radiotherapy. Meanwhile, 3-year PFS in our study (61.9%) was also comparable to Appelt’s study (2-year PFS of 58%). The overall survival in our study was slightly lower than that of patients in the studies of van der Valk et  al. [19] and Dizdarevic et al. [20], which could be due to the more advanced tumor stage in some patients in current study. And there were more elderly patients in our study, who eventually died of diseases other than cancer, which could also lead to lower OS. Apart from survival outcomes, the main concern about high dose radiotherapy was the associated adverse events. Acute adverse events were fully investigated in previous studies, mostly demonstrating a low incidence of associated adverse events [21], and was in line with our study. However, data on late toxicity were limited. In this study, we showed that the incidence of late toxicity was also relatively low. Consistent with Dizdarevic et  al. [20], the most common long-term high-dose chemo- Fig. 3 Selected patient‑reported symptoms at the latest follow up radiotherapy toxicity in our study was rectal bleeding, according to the QLQ‑ CR29 questionnaires, reported as proportions which the researchers attributed to their administered of patients with symptoms of different severity. A Reports of urinary brachytherapy boost. In our study, only an external beam function related questions; B reports of defection related questions boost was used, but yet rectal bleeding was still observed in some patients though most were mild. Our study also shown that mucositis resulted in rectal bleeding peaked Although the local control reported in this present in the first to second years after treatment, and gradually study was lower than previous reports with patients who relieved after the second year. Most patients didn’t need underwent standard treatment [18], our findings are still medical intervention. satisfactory considering that all patients in our study Quality of life is an important facet of cancer treat- refused to have surgery. And the 5-year local control rate ments, especially for the organ-sparing treatment of 77.0% in our study was comparable to Dizdarevic’s W ang et al. Radiation Oncology (2022) 17:98 Page 9 of 10 strategy. Hupkens [22] demonstrated that the quality of different time points after the completion of radiother - life after successful watch-and-wait approach was bet- apy for different patients and were only a one-point sur - ter than after chemoradiation and surgery. However, vey. However, according to previous report [20], overall there were still one-third of the watch-and-wait patients scores of these questions at different time-points showed experienced major low anterior resection syndrome little variation after 2 years. As all of the patients finished symptoms. In regard to high dose radiotherapy for rec- the questionnaires were followed for at least 2 years, our tal cancer, there have been few studies assessing quality one-point survey still preserves its power to reflect the of life in long-term profiles. In Dizdarevic’s study [20], quality of life for these patients. high-dose chemoradiotherapy followed by nonsurgical management for distal rectal cancer showed excellent Conclusions general colorectal cancer quality of life and local symp- In conclusion, this study demonstrated that high dose tom scores. In regard to fecal incontinence, only two in chemoradiotherapy could provide high chance of organ 36 patients reported severe symptom (5.6%), and this preservation, good oncologic control with acceptable was in agreement with our study (4.8%). The question - acute and chronic side effects, and satisfactory long-term naires collected from patients in our study also showed quality of life. Therefore, for rectal cancer patients who that most patients retained their anal, sexual, and urinary refuse to undergo surgery, high dose chemoradiotherapy function, and most had a satisfying quality of life. could be offered as a potentially curative option. Further According to previous studies, approximately 15–40% prospective studies will be carried out to explore this of the patients could achieve cCR after neoadjuvant treatment strategy. chemoradiotherapy [10], this meant that 50  Gy dose could be sufficient for about one-third of all rectal can - cer. According to Appelt’s study [12], if we increased the Abbreviations cCR: Clinical complete response; 3D‑ CRT : Three‑ dimensional conformal radia‑ dose to 65  Gy, cCR rate could be increased to around tion therapy; IMRT: Intensity‑modulated radiation therapy; CT: Computed 78%. And this means that 65  Gy might be sufficient for tomography; MRI: Magnetic resonance image; CEA: Carcinoembryonic anti‑ another one-third of patients. However, it is noteworthy gen; AJCC: American Joint Committee on Cancer; UICC: International Union Against Cancer; EORTC : European Organization for Research and Treatment of that some patients in our study decided to avoid surgery Cancer; PFS: Progression‑free survival; CSS: Cancer specific survival; OS: Overall before treatment, while the majority made this decision survival; LPFS: Local progression‑free survival; DMFS: Distant metastasis‑free after neoadjuvant chemoradiotherapy. In the former, we survival. could make a complete plan to give one course of high dose radiation, while in the latter, there was a long inter- Supplementary Information val between the two courses of radiation. It was chal- The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s13014‑ 022‑ 02066‑7. lenging to decide the optimal radiation dose that would be effective and within the maximum dose constraints of Additional file 1. Cancer ‑specific survival for patients who had clinical normal tissue, as there was no suitable calculation model complete response (n = 42) after treatment and those who hadn’t (n = evaluating the biologically effective dose. In this study, 15). the general clinical practice dealing with such problem Additional file 2. Survival cures for patients who received one course was to prescribe 20–30  Gy boosting to the gross tumor of radiotherapy (n = 11) and two courses of radiotherapy (n = 46). (A) Local progression‑free survival; (B) distant metastasis‑free survival; (C) volume, so the primary tumor would receive a total progression‑free survival; (D) cancer specific survival; (E) overall survival. dose of 70–80  Gy. The satisfied clinical efficacy and few Additional file 3. Standardized scores of the QLQ ‑ C30 and the QLQ‑ CR29 adverse events indicated that this dose prescribing model questionnaires. might be reasonable. Though there were no study giving such high dose using external beam radiation therapy in Acknowledgements literature, there were several studies in which a second We would like to thank all the included patients and participants for the sup‑ boost was given using brachytherapy after neoadjuvant ports of this study. chemoradiotherapy, and the total doses were as high as Author contributions 75 to 80  Gy [23]. In modern era of IMRT, delivery of a XJW and YHG conceived the idea and designed the study. QXW and SZ high dose of radiation to the residual tumor while spar- collected the data. QXW, SZ and WWX analyzed the data and draw the draft of the manuscript. All authors participated in the treatment of patients, the ing the normal surrounding tissues is technically achiev- interpretation of the results, writing, revising and approving the final version of able using external beam radiation therapy. These studies this work. 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Journal

Radiation OncologySpringer Journals

Published: May 18, 2022

Keywords: Rectal cancer; High dose chemoradiotherapy; Oncological safety; Functional outcomes; Quality of life

References