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Long-Term Health-Related Quality of Life in Patients With Rectal Cancer After Preoperative Short-Course and Long-Course (Chemo) Radiotherapy

Open AccessPublished:February 12, 2016DOI:https://doi.org/10.1016/j.clcc.2016.02.012

      Abstract

      Background

      Both preoperative short-course radiotherapy (SC-PRT) and preoperative long-course chemo radiotherapy (CRT) have shown to reduce local recurrence rates after total mesorectal excision (TME), but neither resulted in improved survival. This study compared the long-term health-related quality of life (HRQL) and symptoms between CRT and SC-PRT.

      Methods

      Patients who were preoperatively treated with a total dose of 50.0 to 50.4 Gy for locally advanced rectal cancers were identified from 2 hospital registries. Starting from 2011, all patients who were disease-free in the study population (n = 105) were sent a HRQL-questionnaire composed of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and questions on bowel and urinary function. Patients who underwent SC-PRT in the TME trial were used as a reference group.

      Results

      HRQL results from 85 patients receiving CRT (81.0%), with a median follow-up time of 58 months, were compared with the results of patients who underwent SC-PRT (n = 306). Apart from more nausea and vomiting reported by patients receiving CRT (mean score for CRT 5.9 vs. 1.3 for SC-PRT; P < .01; not clinically relevant) and less satisfaction with urinary function indicated by patients who received CRT (mean score for CRT 71.2 vs. 81.2 for SC-PRT; P < .01), no significant differences were found in HRQL and symptoms between patients who received CRT and SC-PRT.

      Conclusions

      This analysis of HRQL in patients who received CRT shows no clinically relevant differences in long-term HRQL and symptoms between patients who received CRT and SC-PRT, apart from less satisfaction with urinary function reported by patients who received CRT. These results indicate that both approaches have a comparable impact on long-term HRQL.

      Keywords

      Introduction

      The surgical treatment for resectable rectal cancer consists of a total mesorectal excision (TME). Depending on the tumor location, infiltration depth of the tumor, and lymph node involvement, treatment is combined with preoperative short-course radiotherapy (SC-PRT) or preoperative long-course chemo radiotherapy (CRT). There is no international consensus on the use of these treatment schedules or the most appropriate patient selection for these schedules. Both SC-PRT and CRT have shown to reduce local recurrence rates.
      Local recurrence rate in a randomised multicentre trial of preoperative radiotherapy compared with operation alone in resectable rectal carcinoma. Swedish Rectal Cancer Trial.
      • van Gijn W.
      • Marijnen C.A.
      • Nagtegaal I.D.
      • et al.
      Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial.
      • Sebag-Montefiore D.
      • Stephens R.J.
      • Steele R.
      • et al.
      Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial.
      • Gerard J.P.
      • Conroy T.
      • Bonnetain F.
      • et al.
      Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203.
      • Bosset J.F.
      • Collette L.
      • Calais G.
      • et al.
      Chemotherapy with preoperative radiotherapy in rectal cancer.
      • Sauer R.
      • Liersch T.
      • Merkel S.
      • 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.
      However, none of these neoadjuvant therapies resulted in an improved overall survival,
      • van Gijn W.
      • Marijnen C.A.
      • Nagtegaal I.D.
      • et al.
      Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial.
      • Sebag-Montefiore D.
      • Stephens R.J.
      • Steele R.
      • et al.
      Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial.
      • Gerard J.P.
      • Conroy T.
      • Bonnetain F.
      • et al.
      Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203.
      • Bosset J.F.
      • Collette L.
      • Calais G.
      • et al.
      Chemotherapy with preoperative radiotherapy in rectal cancer.
      • Sauer R.
      • Liersch T.
      • Merkel S.
      • 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.
      which emphasizes the importance of knowledge of health-related quality of life (HRQL) after these different treatment schedules. A randomized Polish trial compared the HRQL after SC-PRT (5 × 5 Gy) and CRT (28 × 1.8 Gy, 5-fluorouracil and leucovorin) followed by TME. After a median follow-up time of 12 months, no difference in HRQL was found between these groups.
      • Pietrzak L.
      • Bujko K.
      • Nowacki M.P.
      • et al.
      Quality of life, anorectal and sexual functions after preoperative radiotherapy for rectal cancer: report of a randomised trial.
      However, since SC-PRT uses a higher dose per fraction in a short overall treatment time, there may be a risk for more late radiation-related toxicity compared with CRT. Long-term reported HRQL outcomes can provide additional information, which can be used to inform patients and healthcare providers and support evidence-based shared decision-making. Therefore, the aim of this study is to compare patient-reported symptoms and HRQL of patients treated with CRT to patients treated with SC-PRT for rectal cancer with a long follow-up time.

      Patients and Methods

      Study Population and Treatment

      For this retrospective study, patients with locally advanced rectal cancer treated with long-course (chemo) radiotherapy between January 2003 and October 2010 were identified in the registries of the Leiden University Medical Center (LUMC) and Radiotherapy Center West (RCW). Locally advanced rectal cancer was defined as a tumor with growth into an adjacent organ, in close proximity to the mesorectal fascia, or any tumor accompanied by N2-status. Exclusion criteria were prior malignancies, local recurrences, metastatic disease at presentation, a higher received dose than 50.4 Gy, and prior pelvic radiotherapy.
      Patients were treated with chemotherapy (capecitabine alone, capecitabine and oxaliplatin, 5-fluorouracil and leucovorin, or capacetibine and bevacizumab) and a total radiation dose of 50 to 50.4 Gy in daily fractions of 1.8 to 2.0 Gy delivered by a 4-field technique. The primary tumor and the mesentery containing the perirectal and presacral nodes, as well as the internal iliac nodes up to the S1/S2 junction, were included in the clinical target volume, as well as the perineum if an abdominoperineal resection (APR) was planned. Otherwise, the lower border was at least 3 cm caudally to the primary tumor. Five to 8 weeks after the last radiation treatment, patients underwent surgery according to the TME principles.
      Patients treated with SC-PRT in the Dutch TME trial were used as a reference group. These patients had a clinically resectable adenocarcinoma without evidence of distant metastases and an inferior margin of the tumor located below the level of S1/S2 and within 15 cm of the anal verge. Patients who received SC-PRT were treated with 25 Gy in 5 fractions delivered with a 3 or 4-field technique. Within 10 days of the start of radiotherapy, patients underwent surgery according to the TME principles. More details on the TME trial design are reported in previous studies.
      • Kapiteijn E.
      • Marijnen C.A.
      • Nagtegaal I.D.
      • et al.
      Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.
      • Peeters K.C.
      • van de Velde C.J.
      • Leer J.W.
      • et al.
      Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients–a Dutch colorectal cancer group study.
      • Marijnen C.A.
      • van de Velde C.J.
      • Putter H.
      • et al.
      Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial.
      • Wiltink L.M.
      • Chen T.Y.
      • Nout R.A.
      • et al.
      Health-related quality of life 14 years after preoperative short-term radiotherapy and total mesorectal excision for rectal cancer: report of a multicenter randomised trial.
      The local ethics committee approved this retrospective study, and informed consent for the questionnaire was obtained from all patients.

      Measurements

      Starting from June 2011, HRQL questionnaires were sent to patients who were disease-free. Patients who did not respond received 2 reminders. Patients were asked to complete the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (EORTC QLQ-C30) and an additional questionnaire on bowel and urinary function. The EORTC QLQ-C30 is a general cancer HRQL-questionnaire composed of 30 items. It includes a global health status scale, 5 functional scales (physical, role, emotional, cognitive, social), 3 symptom scales (fatigue, pain, nausea and vomiting), and 6 single-item scales (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).
      • Aaronson N.K.
      • Ahmedzai S.
      • Bergman B.
      • et al.
      The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
      The additional questionnaire on bowel and urinary function was previously used in the Dutch TME trial.
      • Peeters K.C.
      • van de Velde C.J.
      • Leer J.W.
      • et al.
      Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients–a Dutch colorectal cancer group study.
      All items of this questionnaire are reported in the Appendix. Scores of the additional questionnaire on urinary and bowel function were compared between the study group and the patients of the TME trial who received SC-PRT (n = 306) after a median follow-up of 5 years.
      • Peeters K.C.
      • van de Velde C.J.
      • Leer J.W.
      • et al.
      Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients–a Dutch colorectal cancer group study.
      However, since the QLQ-C30 was not included in the HRQL questionnaire sent to patients in the TME trial at 5 years, but was included in the questionnaire sent at 14 years, the 14-year QLQ-C30 scores of the SC-PRT were used. This is based on a previous longitudinal study of the TME trial, which reported that the QLQ-C30 scores between 5 and 14 years after treatment were mostly only influenced by age.
      • Wiltink L.M.
      • Marijnen C.A.
      • Meershoek-Klein Kranenbarg E.
      • van de Velde C.J.
      • Nout R.A.
      A comprehensive longitudinal overview of health-related quality of life and symptoms after treatment for rectal cancer in the TME trial.
      This is also supported by population-based studies.
      • van de Poll-Franse L.V.
      • Mols F.
      • Gundy C.M.
      • et al.
      Normative data for the EORTC QLQ-C30 and EORTC-sexuality items in the general Dutch population.
      • Schwarz R.
      • Hinz A.
      Reference data for the quality of life questionnaire EORTC QLQ-C30 in the general German population.
      • Hjermstad M.J.
      • Fayers P.M.
      • Bjordal K.
      • Kaasa S.
      Health-related quality of life in the general Norwegian population assessed by the European Organization for Research and Treatment of Cancer Core Quality-of-Life Questionnaire: the QLQ = C30 (+3).
      • Michelson H.
      • Bolund C.
      • Nilsson B.
      • Brandberg Y.
      Health-related quality of life measured by the EORTC QLQ-C30–reference values from a large sample of Swedish population.
      Likert-type scales were used for all questions, except for 3 dichotomous questions. All single-item and subscale responses were linearly converted to 0 to 100 scales. A higher score for functioning reflects better functioning, whereas a higher score for symptoms represents a higher level of symptoms and decreased HRQL.

      Statistics

      Analyses were performed with IBM SPSS Statistics, version 20.0. The Reverse Kaplan-Meier methodology was used to compute the median follow-up time. Mean scores were calculated, and missing values were handled according to the guidelines provided by the EORTC Quality of Life Group.
      • Fayers P.M.
      • Aaronson N.K.
      • Bjordal K.
      • Groenvold M.
      • Curran D.
      • Bottomley A.
      on behalf of the EORTC Quality of Life Group
      EORTC QLQ-C30 scoring manual.
      To prevent against false-positive results owing to multiple testing, a 2-sided P value of .01 was regarded statistically significant. Differences in mean scores were considered clinically relevant if the differences were larger than 5 points on a scale of 100 points.
      • Osoba D.
      • Rodrigues G.
      • Myles J.
      • Zee B.
      • Pater J.
      Interpreting the significance of changes in health-related quality-of-life scores.
      Matching of the reference data was based on previous analysis in the Dutch TME trial (data not shown). This analysis showed that the T status, N status, the positive or negative circumferential resection margin, tumor height, type of operation, and presence of a stoma did not influence HRQL and urinary symptoms. However, HRQL was associated with gender and age. Therefore, the reference data of the TME trial were matched for age and gender with the CRT group. Linear regression and logistic regression models were used to compare the HRQL and symptoms between the groups that received CRT and SC-PRT.

      Results

      Study Population and Compliance

      In total, 247 patients with locally advanced rectal cancer were treated between January 2003 and October 2010. Of these, 189 patients (123 LUMC; 66 RCW) met the inclusion criteria. In June 2011, 105 of the 189 study patients were disease-free. These patients were sent a HRQL questionnaire, and 85 patients responded (response rate, 81.0%). Except for 13 patients (15.3%), all responders received chemotherapy during long-course radiotherapy. For most patients (70.6%), concurrent chemotherapy consisted of twice-daily oral capecitabine (825 mg/m2), 6 patients (7.1%) received capecitabine and oxaliplatin, 1 patient (1.2%) received 5-fluorouracil and leucovorin, and 5 patients (5.9%) received capecetibine and bevacizumab. The median follow-up time since diagnosis was 58 months (range, 15-98 months).
      Questions of the QLQ-C30 were completed for all items in 92.9% of the responders. With regard to the questions on bowel function, patients without a stoma completed all items in 72.2% and patients with stoma in 77.6%. When up to 2 missing items were allowed, these rates were 88.9% and 92.6%, respectively. Patient characteristics of the patients who received CRT and SC-PRT are listed in Table 1. As expected, patients who received CRT had more advanced TNM stages compared with patients who received SC-PRT, and 75.3% of the patients who received CRT underwent an APR or Hartmann operation compared with 34.6% of those who received SC-PRT. As described in the methods section, these differences in patient characteristics did not influence HRQL or urinary symptoms.
      Table 1Patient and Clinical Characteristics for the HRQL Responders
      CharacteristicsCRT (n = 85)SC-PRT (n = 306)
      No. of Patients%No. of Patients%
      Age, years
       Median6968
       Range26-8940-91
      Gender
       Male5564.719965.0
       Female3035.310735.0
      TNM stage
       00082.6
       I11.214045.8
       II1416.58427.5
       III6475.37424.2
       IV0000
       Unknown67.100
      Distance to anal verge, cm
       0-53237.68628.1
       5-103035.312340.2
       10-201618.89631.4
       Unknown78.210.3
      Operation type
       LAR2023.520065.4
       APR4755.39129.7
       Hartmann1720.0154.9
       No resection11.200
      Stoma present
       Yes6778.812942.2
       No1821.217757.8
      To compare HRQL, data of the SC-PRT patients were matched for age and gender with the CRT patients.
      Abbreviations: APR = Abdominoperineal resection; CRT = preoperative long-course chemo radiotherapy; HRQL = health-related quality of life; LAR = low anterior resection; SC-PRT = preoperative short-course radiotherapy.

      Bowel and Urinary Symptoms

      No significant differences in bowel or urinary function were found between patients who received CRT and SC-PRT, matched for age and gender (Table 2). However, for bowel symptoms, trends were observed towards increased anal mucus loss and more limitation in work or household activities caused by bowel function in the patients who received CRT. For urinary symptoms, patients who received CRT showed a trend towards more urine-retention after miction and a trend towards more difficulty to start miction. Furthermore, patients who received CRT were significantly less satisfied with their urinary function.
      Table 2Bowel and Urinary Function
      Mean Scores CRTMean Scores SC-PRTP
      Bowel function
       Fecal incontinence42.234.6.34
       Fecal incontinence at night22.913.4.15
       Ability to delay bowel emptying65.666.5.86
       Anal blood loss6.34.8.78
       Anal mucus loss22.911.2.07
       Peristomal skin irritation18.216.8.54
       Stoma smell16.421.1.27
       Stoma bleeding11.514.1.47
       Stoma leakage10.612.0.70
       Painful stoma7.06.3.65
       Noisy stoma26.625.65
       Blood loss from stump8.07.1.60
       Mucus loss from stump14.617.9.40
      Impact of bowel dysfunction on
       Work or household activities22.515.5.03
       Activities outside the house like shopping24.822.2.41
       Social activities like theater or cinema visiting23.824.8.89
      Urinary function
       Urinary frequency during the day6.36.3.77
       Frequency urinary incontinence57.154.2.86
       Use of pads for urinary incontinence41.229.3.18
       Urine retention after miction24.218.0.08
       Need to urinate again within 2 hours26.225.9.85
       Stream hesitation23.118.9.24
       Difficulty postponing miction28.224.7.35
       Weak urinary stream31.226.2.16
       Difficult to start miction15.810.3.06
      Satisfaction
       Bowel functiona83.176.3.11
       Urinary functiona71.281.2<.01
      A higher score for functioning (a) reflects better functioning, whereas a higher score for symptoms represents a higher level of symptoms and decreased health-related quality of life.
      Abbreviations: CRT = Preoperative long-course (chemo) radiotherapy; SC-PRT = preoperative short-course radiotherapy.

      EORTC QLQ-C30

      Patients who received CRT and SC-PRT reported no differences in global health status and patient functioning (Table 3; Figure 1). Although patients who received CRT reported significantly more nausea and vomiting compared with those who received SC-PRT (mean score for CRT 5.9 vs. 1.3 for SC-PRT; P < .01), this difference is below a clinically relevant level. Moreover, patients who received SC-PRT reported a trend towards more diarrhea than those who received CRT (Table 3).
      Table 3Scores of EORTC QLQ-C30
      Mean Scores CRTMean Scores SC-PRTP
      Difference between CRT and SC-PRT.
      Global health status79.678.9.90
      Functional scales
       Physical functioning84.582.6.56
       Role functioning82.583.3.73
       Emotional functioning86.986.3.85
       Cognitive functioning84.084.1.90
       Social functioning84.687.7.27
      Symptom items
       Fatigue23.822.5.59
       Nausea and vomiting5.91.3<.01
       Pain symptoms11.211.1.92
       Dyspnoea11.811.6.89
       Insomnia15.418.5.42
       Appetite loss8.54.6.12
       Constipation8.610.8.51
       Diarrhea5.810.6.09
       Financial difficulties9.56.8.27
      A higher score for functioning reflects better functioning, whereas a higher score for symptoms represents a higher level of symptoms and decreased health-related quality of life.
      Abbreviations: CRT = Preoperative long-course (chemo) radiotherapy; EORTC = European Organisation for Research and Treatment of Cancer; SC-PRT = preoperative short-course radiotherapy.
      a Difference between CRT and SC-PRT.
      Figure thumbnail gr1
      Figure 1Global Health Status and Patient Functioning Scores of the QLQ-C30
      Abbreviations: CRT = preoperative long-Course (chemo) radiotherapy; HRQL = health-related quality of life; SC-PRT = preoperative short-Course radiotherapy. A higher Score for functioning represents better functioning.

      Discussion

      This analysis of HRQL in patients who received CRT after a median follow-up time of 58 months shows no clinically relevant differences in long-term HRQL and patient-reported symptoms between CRT and SC-PRT, apart from less satisfaction with urinary function reported by patients who received CRT. These results are in line with the short-term HRQL of the Polish trial at 12 months after treatment.
      • Pietrzak L.
      • Bujko K.
      • Nowacki M.P.
      • et al.
      Quality of life, anorectal and sexual functions after preoperative radiotherapy for rectal cancer: report of a randomised trial.
      Also, in a study comparing 10 × 2.9 Gy followed by immediate surgery (n = 108) versus 28 × 1.8 Gy with concomitant chemotherapy and delayed surgery (n = 117), no differences in HRQL were found after 67 months, except for a better score for physical functioning in the group that received CRT (mean scores 77 vs. 82, respectively; P = .04).
      • Guckenberger M.
      • Saur G.
      • Wehner D.
      • et al.
      Long-term quality-of-life after neoadjuvant short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer.
      These results support our findings that long-term patient-reported HRQL is similar in patients who received SC-PRT and CRT. In addition, a randomized trial comparing 25 × 2 Gy with or without 5-fluorouracil and leucovorin, which included 78 patients with locally advanced rectal cancer, revealed no differences in HRQL, evaluated with the EORTC QLQ-C30 several years after treatment.
      • Braendengen M.
      • Tveit K.M.
      • Hjermstad M.J.
      • et al.
      Health-related quality of life (HRQoL) after multimodal treatment for primarily non-resectable rectal cancer. Long-term results from a phase III study.
      Thus, chemotherapy does not seem to aggravate long-term HRQL either when added to these radiotherapy schedules. However, a study by Tiv et al, which included 1011 patients randomized between PRT, CRT, PRT and postoperative chemotherapy, and CRT and postoperative chemotherapy, found a decrease in some long-term HRQL variables and an increase in diarrhea after adding chemotherapy.
      • Tiv M.
      • Puyraveau M.
      • Mineur L.
      • et al.
      Long-term quality of life in patients with rectal cancer treated with preoperative (chemo)-radiotherapy within a randomized trial.
      In this study, 73% of the patients underwent sphincter-sparing surgery, which can lead to the Low Anterior Resection Syndrome. This syndrome is associated with a decrease of HRQL.
      • Chen T.Y.
      • Wiltink L.M.
      • Nout R.A.
      • et al.
      Bowel function 14 years after preoperative short-course radiotherapy and total mesorectal excision for rectal cancer: report of a multicenter randomized trial.
      In addition to the long-term HRQL, analysis of the physician-reported toxicity at 4 years in the Polish trial also demonstrated no significant difference in the crude overall incidence of late toxicity (28.3% and 27.0%, respectively; P = .81).
      • Bujko K.
      • Nowacki M.P.
      • Nasierowska-Guttmejer A.
      • Michalski W.
      • Bebenek M.
      • Kryj M.
      Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer.
      Taken together, these results show that long-term patient-reported HRQL and physician-observed toxicity do not differ between SC-PRT and CRT. This is in contrast with the thought that the higher dose per fraction and short overall treatment time of SC-PRT would increase the risk for late radiation-related toxicity compared with the lower doses per fraction within CRT.
      Acute toxicity after CRT and SC-PRT is reported in several studies. The Polish trial found more early radiation toxicity after CRT compared with SC-PRT (18.2% vs. 3.2%, respectively; P < .001).
      • Bujko K.
      • Nowacki M.P.
      • Nasierowska-Guttmejer A.
      • Michalski W.
      • Bebenek M.
      • Kryj M.
      Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer.
      This was also found in the randomized trial comparing 25 × 2 Gy with or without 5-fluorouracil and leucovorin: grade 3 and grade 4 acute toxicity was seen in 29% of the patients after CRT and in 6% of the patients after RT alone.
      • Braendengen M.
      • Tveit K.M.
      • Berglund A.
      • et al.
      Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer.
      However, as described above, none of these studies reported a difference in the long-term toxicity or HRQL between the treatment groups. Furthermore, in the Stockholm III trial, in which patients were randomly allocated to either SC-PRT followed by surgery within 1 week, SC-PRT and surgery after 4 to 8 weeks, or long-course radiotherapy (25 × 2 Gy) followed by surgery after 4 to 8 weeks, no differences in the incidence of severe acute radiation toxicity were found.
      • Pettersson D.
      • Cedermark B.
      • Holm T.
      • et al.
      Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer.
      Long-term toxicity and HRQL of this trial should still be awaited.
      For locally advanced tumors, down-staging is required to facilitate surgical resection with negative resection margins. The previously described Polish trial found more down-staging after CRT (16%) compared with SC-PRT (1%).
      • Braendengen M.
      • Tveit K.M.
      • Berglund A.
      • et al.
      Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer.
      This difference in down-staging did not result in a difference in local recurrence rate, disease-free survival, or overall survival between the treatment groups.
      • Bujko K.
      • Nowacki M.P.
      • Nasierowska-Guttmejer A.
      • Michalski W.
      • Bebenek M.
      • Kryj M.
      Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer.
      Moreover, the Trans-Tasman Radiation Oncology Group study, in which 326 rectal cancer patients were randomized between 5 × 5 Gy followed by early surgery and 6 courses of adjuvant chemotherapy versus 28 × 1.8 Gy and continuous fluorouracil followed by surgery in 4 to 6 weeks and 4 courses of adjuvant chemotherapy, more down-staging was also found after CRT (45%) compared with SC-PRT (28%). However, no significant difference in local recurrence rate, relapse-free survival, and overall survival were found as well.
      • Ngan S.Y.
      • Burmeister B.
      • Fisher R.J.
      • 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.
      Thus, while these trials reported more downsizing and down-staging effects after CRT, this did not result in differences in overall survival.
      An alternative strategy is SC-PRT with delayed surgery to allow for tumor regression. The interim results of the Stockholm III trial showed pathologic complete responses of 0.8% after SC-PRT followed by surgery within 1 week, 12.5% after SC-PRT and surgery after 4 to 8 weeks, and 5% after long-course radiotherapy followed by surgery after 4 to 8 weeks, indicating that there is more tumor regression with SC-PRT and delayed surgery.
      • Pettersson D.
      • Cedermark B.
      • Holm T.
      • et al.
      Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer.
      At present, new initiatives like the RAPIDO (Radiotherapy And Preoperative Induction therapy followed by Dedicated Operation) trial, which compares CRT with SC-PRT followed by chemotherapy and delayed surgery, are accruing patients.
      • Nilsson P.J.
      • van Etten B.
      • Hospers G.A.
      • et al.
      Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer–the RAPIDO trial.
      Long-term oncological outcomes have to be awaited before an evidence-based decision about the optimal patient selection and treatment can be made, since no benefit of CRT over SC-PRT is found based on local control, survival, acute toxicity, and long-term HRQL, according to the studies described above.
      A strength of our study is the high response rate of 81.0% and a median follow-up of 58 months. Also, while some studies excluded patients with a stoma, we included these and even asked specific stoma-related questions. These questions were very useful in our analysis, since 78.8% of the CRT responders had a stoma at time of the HRQL questionnaire. Study patients were treated with CRT, since the Dutch guideline indicated this treatment by this tumor infiltration depth and the lymph node involvement. The patients included in the TME trial had less locally advanced tumors, and were treated with SC-PRT. To be able to correct for this possible confounding by indication, we assessed the influence of the T status, N status, the positive or negative circumferential resection margin, tumor height, type of operation, and the presence of a stoma on HRQL and urinary symptoms in the TME trial. None of these items influenced HRQL. However, gender and age were associated with HRQL, so we corrected for these variables. The finding that the clinical T and N status and tumor location have no or limited influence on HRQL is also supported by an analysis of Guckenberger et al, who also stated that no study in the literature has reported a correlation between HRQL and any clinical T or N stage.
      • Guckenberger M.
      • Saur G.
      • Wehner D.
      • et al.
      Long-term quality-of-life after neoadjuvant short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer.
      In conclusion, patients who received CRT and SC-PRT reported no clinically relevant differences in long-term HRQL and late symptoms after a median follow-up period of 58 months, apart from less satisfaction with urinary function reported by those who received CRT. These results indicate that both approaches have a comparable impact on long-term HRQL, and a preference for either of them can therefore not be based on long-term HRQL.

      Clinical Practice Points

      • Both preoperative short-course radiotherapy (PRT) and preoperative long-course chemo radiotherapy (CRT) have shown to reduce local recurrence rates. However, none of these neoadjuvant therapies resulted in an improved overall survival.
      • After a short follow-up time, no differences in health-related quality of life (HRQL) are reported between both treatment schedules.
      • After a median follow-up of 58 months, the only clinically relevant difference in HRQL between the groups was less satisfaction with urinary function indicated by patients who received CRT (mean score for CRT 71.2 vs. 81.2 for SC-PRT; P < .01).
      • No benefit of CRT over SC-PRT is found based on long-term HRQL, acute toxicity, local control, and survival.
      • However, after CRT, more downsizing and down-staging of rectal cancer tumors is reported. On the other hand, tumor regression is also found after SC-PRT followed by delayed surgery.
      • Long-term oncological outcomes of new initiatives like the RAPIDO trial have to be awaited before an evidence-based decision about the optimal patient selection and treatment can be made.

      Disclosure

      The authors have stated that they have no conflicts of interest.

      Acknowledgments

      This work was supported by a research grant from the Dutch Cancer Society (CKVO 95-04) and the Dutch National Health Council (OWG 97/026). The study sponsors had no involvement in the study design, data collection, analysis, interpretation of the data, writing the manuscript or the decision to submit the manuscript for publication.

      Appendix

      Tabled 1Items of the Questionnaire on Bowel and Urinary Function
      Bowel function
       Mean bowel frequency at day and night
       Description stool
       Anal blood and mucus loss
       Fecal incontinence at day and night
       Use of pads for fecal incontinence
       Ability to delay bowel emptying
      Stoma function
       Peristomal skin irritation
       Stoma smell
       Stoma bleeding
       Stoma leakage
       Painful stoma
       Noisy stoma
       Blood and mucus loss from stump
      Impact of bowel dysfunction on
       Work or household activities
       Activities outside the house like shopping
       Social activities like theater or cinema visiting
      Urinary function
       Urinary frequency during the day
       Frequency urinary incontinence
       Relation of urinary incontinence to stress and urge
       Use of pads for urinary incontinence
       Urine-retention after miction
       Need to urinate again within 2 hours
       Stream hesitation
       Difficulty postponing miction
       Weak urinary stream
       Difficult to start miction
      Satisfaction with bowel and urinary function

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