Colorectal cancer (CRC) represents a major public health problem in developed countries, especially in parts of Europe (Hungary, Slovenia, Slovakia, the Netherlands and Norway).1 In Slovenia CRC is most frequently diagnosed among age group 50–74.2 The standard treatment for LARC consists of capecitabine-based chemoradiation (CRT) followed by counseling surgery and adjuvant chemotherapy (ChT). Advances in multimodality treatments have significantly reduced 5-year local recurrence rates to less than 10% but this fact is not reflected in better survival.3,4 High rate of distant metastases (30% at 10 years) represents the main problem in achieving even better results of rectal cancer treatment.5 Thus, to achieve better control of systemic disease and consequently better survival, intensified systemic therapy is warranted.
The main guideline in developing the most optimal rectal cancer treatment regimen is elimination of subclinical micrometastases or/and interruption of the metastatic cascade. Angiogenesis plays a significant role in tumor growth, invasion and metastasis. The benefit of antiangiogenic inhibitors on better survival is already known in the treatment of metastatic colorectal cancer.6 Pre-clinical experiments in a variety of tumor models have shown encouraging results with the combination of anti-angiogenic strategies with cytotoxic agents such as chemotherapy, ionizing radiation, or both in rectal cancer.7,8 Although bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial cell growth factor (VEGF), is widely tested in the preoperative treatment of LARC, there are only few studies evaluating survival benefit.9, 10, 11 Consequently, safety and efficacy of adding bevacizumab in the preoperative treatment of LARC remain unclear.
Significant progress in various approaches to rectal cancer treatment has led to the fact that longterm results and assessment of a patient’s quality of life (QOL) has become increasingly important for offering patient optimal treatment. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and its tumor-specific 38-item questionnaire module Quality of Life Questionnaire Colorectal Cancer Module (QLQ-CR38), that later got its successor QLQ-CR29 with revised and fewer questions, were the first questionnaires introduced specifically for CRC.12, 13, 14 In addition to these QOL assessment tools for CRC, the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) is also widely used.13
The FACT-C places a larger emphasis on emotional aspects of QOL while the QLQ-CR38 and QLQ-CR29 have greater dominance in the assessment of disease- and treatment-related symptoms.13
Our phase II trial was originally designed to determine the pathologic complete response rate of CRT and bevacizumab as a part of a combined modality approach. This report includes the long-term outcome, late complications and health related QOL of patients treated in CRAB study
The trial design, eligibility criteria, treatment and assessments have been published previously in detail.15 All patients provided signed informed consent based on international standards. The study was approved by the National Medical Ethics Committee of the Republic of Slovenia (Number 173/07/08) and was in agreement with the Declaration of Helsinki. It was registered in the
In brief, patients with histologically proven stage II/III adenocarcinoma of the rectum within 15 cm of the anal verge and without contraindications for ChT or targeted agents were included. Local extend of the disease was determined by magnetic resonance imaging.
Radiotherapy (RT) was delivered using three-dimensional conformal computed tomography (CT)-based treatment planning. Four-field box technique with all fields treated daily was used. Patients received 45 Gy to the pelvis plus 5.4 Gy as a boost to the primary tumor in 1.8 Gy over 5.5 weeks. Capecitabine 825 mg/m2 twice daily was administered concomitantly continuously throughout of RT without interruptions on weekends. Patients received bevacizumab intravenously at a dose 5 mg/kg 14 days prior and on days 1, 15 and 29 during chemoradiotherapy (CRT). Resection (low anterior resection or abdominoperineal amputation with total mesorectal excision) was performed 6–8 weeks after the completion of CRT. Patients with histopathological R0 resection received 6 cycles of adjuvant chemotherapy with capecitabine, while in those with R1 additional 2 cycles were given. Pathologic response after CRT with bevacizumab was determined according to Dworak tumor regression grade (TRG) system. The pathological complete response (pCR) was defined as TRG 4, meaning no tumor cells in surgical specimen.
Results for primary endpoint of this prospective phase II study, the pCR rate, and on some secondary endpoints (pathological response rate, rate of sphincter-sparing surgical procedure, radical resection rate, acute and perioperative toxicity of combined modality treatment) have been reported previously.15 Here we report results on other secondary endpoints of this updated analysis: local control (LC), disease free (DFS) recurrence-free (RFS) and overall survival (OS), late toxicity and health related QOL. Survival rates were calculated using Kaplan-Meier technique. All time intervals were calculating from the date of inclusion. The end day for LC was the date of last follow-up or recurrence in the pelvis; for OS the date of last follow up or death from any cause; for DFS the date of relapse, secondary cancer, death for any cause or the last follow-up.
Separate analysis was performed for health related QLQ applying the questionnaires launched by the EORTC. For this study the core questionnaire EORTC QLQ-C3016 adjoined with the colo-rectal module EORTC QLQ-CR3812 was delivered to the patients twice: before starting the treatment and one year after the treatment was finished. The EORTC QLQ-C30 is a questionnaire assessing individual HRQL during the previous week. The EORTC QLQ-C30 has 30 items and is divided into five function scales (physical, role, cognitive, emotional and social functions); three symptom scales (fatigue, pain, nausea or vomiting) and one global health-status/quality of life dimension. The six single items address specific symptoms: dyspnoea, appetite loss, insomnia, constipation, diarrhoea and a question addressing the financial impact of the disease. The EORTC QLQ-CR38 has 38 questions and is divided into four functional and seven scales of symptoms/problems. The answers recorded by the questionnaires were transformed into dimensions ranged 0–100 according to the EORTC scoring instructions.17 For functional scales and single items higher scores represent a higher level of functioning, but for symptom scales and single items, a higher score represents a higher level of symptoms. To examine the statistically significant changes in QLQ scores over time the Wilcoxon signed-rank test was applied.
All statistical analysis was performed using the SPSS statistical software package, version 24 (SPSS Inc, Chicago, IL, USA). Values of p < 0.05 were considered statistically significant.
Between February 2009 and March 2010, 61 patients entered the study protocol at our institution. The detailed characteristics of the patients have been presented previously.15 Baseline assessment included complete history, physical examination, full blood count, serum biochemistry, carcinoembryonic antigen, chest radiography, ultrasonography and/or computed tomography (CT) scan of the whole abdomen. Twelve pts (19.7%) presented with stage II and all other with stage III of disease. In 28 patients (45.9%) the tumor invaded the mesorectal fascia. Radical resection was achieved in 57 pts (95%). Sixty patients were eligible for efficacy analysis. TRG 4 (pCR) was recorded in 8 pts (13.3%) and TRG 3 in 9 pts (15%). Fifty-one pts (83.6%) received capecitabine postoperatively. An intention-to-treat analysis was performed on 60/61 pts as one was misdiagnosed. Median follow-up was 67 months (range, 7 to 79 months). During the follow-up period, 16 patients (26.7%) died. A total of 13 (21.7%) of these deaths were a consequence of rectal cancer progression and the remaining 3 due to unrelated causes.
The 5-year OS was 72.2% (95% CI 58.2–84). Recurrences were observed in 14 patients (23.3%) and in one secondary cancer occurred. The latest distant recurrence was observed 54 months after the operation. The 5-years recurrence-free survival and DFS were 75.6% (95% CI 64.6–81.3) and 70% (95% CI 58.5–81.5), respectively. Local recurrence as any component of first failure occurred in 4 patients (6.7%), with isolated local recurrence in 1 (1.7%). The 5-year LC rate was 92.4% (95% CI 85.4– 99.4). Figure 1 illustrates OS, DFS and recurrence-free survival and LC of patients treated in CRAB trial.
Based on the Cox proportional hazards regression model, there were no significant association between OS or DFS and gender, age, performance status, cT, cN, TRG and adjuvant ChT. Patients with pathological positive nodes or pathological T3–4 tumors had significantly worse survival than patients with pathological negative nodes or T0–2 tumor (Table 1 and Figure 2).
Overall survival (OS) and disease free survival (DSF) according to pTumor and pNodal stage on univariate analysis
Factor | OS | DFS | ||
---|---|---|---|---|
pTumor stage | ||||
pT0-2 | 85% | 85.7% | ||
pT3-4 | 60.9% | p=0.043 | 61.8% | p=0.044 |
pNodal stage | ||||
pN0 | 81% | 81% | ||
pN+ | 37.5% | 41.7% | p=0.003 |
Nine patients (14.8%) developed grade 3 late complications of combined modality treatment (Common Terminology Criteria for Adverse Events version 4.0) for which hospitalization and/or urgent intervention was needed. We recorded the first event 12 months and the last 87 months after the operation with the median time to occurrence of 48 months. All these complications, time to occurrence after surgery of primary cancer and procedures needed are presented in Table 2. Among patients without mentioned complications, we observed permanent defecation complications in 11: constipation in 4, defecation urgency in 3 and fecal incontinence in 4 colostomy free patients. Two patients with stoma experienced permanent urinary complications: 1 incompleted bladder emptying and 1 urinary incontinence.
Late grade 33 adverse events in CRAB trial
Event | N | Time to appearance (after the operation) | Procedure |
---|---|---|---|
Fistula rectovaginalis | 1 | 12 months | Hartman operation |
1 | 31 months | ||
Fistula enteroperinealis | 1 | 74 months | No action due to local and distant progression of the disease |
Fistula enteroglutealis | 1 | 54 months | Incision, drain |
Fistula uretroperinealis | 1 | 87 months | Conservative |
Fistula enteroperinealis | 1 | 54 months | No action due to poor performance status |
Abscessus perinealis | 1 | 48 months | Incision, drain |
Abscessus presacralis | 1 | 36 months | Incision, transversostomy |
Stenosis ureteri bill. | 1 | 43 months | J splint bill |
The results of the health related QOL analysis is summarized in Table 3. One year after treatment there were no significant changes in global quality of life, however the physical and social functioning significantly decreased. On the other hand, there was a significant decrease in three symptoms: pain, insomnia and diarrhea.
Health related quality of life analysis: Comparisons of mean scores with standard deviations (SD) before and 1 year after completed treatment for all scales of EORTC QLQ-C30 and EORTC QLQ-CR38
Scale | Item | Number responding before and 1 year after treatment | Before treatment | 1 year after treatment | p value Wilcoxon signed-rank test statistically significant values (p < 0.050) are bolded |
---|---|---|---|---|---|
29,30 | 50 | 62.5 (20.8) | 68.0 (19.7) | 0.087 | |
Physical functioning | 1 to 5 | 50 | 89.9 (15.3) | 84.7 (14.9) | |
Role functioning | 6.7 | 50 | 85.3 (23.4) | 81.3 (24.4) | 0.557 |
Emotional functioning | 21 to 24 | 50 | 80.6 (19.0) | 83.0 (20.8) | 0.259 |
Cognitive functioning | 20,25 | 50 | 89.4 (17.1) | 86.7 (20.2) | 0.346 |
Social functioning | 26,27 | 50 | 86.7 (16.2) | 77.7 (21.7) | |
Fatigue | 10,12,18 | 50 | 21.5 (22.0) | 20.7 (18.8) | 0.607 |
Nausea and vomiting | 14,15 | 50 | 2,5 (6.0) | 2.3 (6.7) | 1.000 |
Pain | 9,19 | 50 | 19.7 (27.5) | 11.7 (15.9) | |
Dyspnoea | 8 | 50 | 3.3 (11.8) | 4.7 (13.5) | 0.782 |
Insomnia | 11 | 50 | 24.4 (25.9) | 15.3 (22.5) | |
Appetite loss | 13 | 50 | 7.8 (20.7) | 6.7 (17.8) | 0.726 |
Constipation | 16 | 50 | 4.4 (14.3) | 12.0 (23.1) | 0.126 |
Diarrhoea | 17 | 50 | 31.1 (30.6) | 12.0 (18.8) | |
Financial difficulties | 28 | 49 | 11.9 (22.1) | 18.0 (24.5) | 0.103 |
Body image | 13,14,15 | 50 | 8.8 (16.1) | 23.1 (24.9) | |
Sexual functioning | 17,18 | 47 | 28.7 (22.9) | 29.4 (26.5) | 0.859 |
Future perspective | 16 | 50 | 54.0 (30.5) | 49.7 (30.1) | 0.420 |
Sexual enjoyment | 19 | 22 | 44.4 (24.6) | 48.1 (29.7) | 0.527 |
Chemotherapy side effects | 10,11,12 | 51 | 7.3 (11.8) | 10.7 (13.7) | |
General gastrointestinal symptoms | 4 to 8 | 51 | 22.1 (19.3) | 18.0 (18.3) | 0.084 |
Defecation problems | 25 to 31 | 26 | 27.5 (21.1) | 30.2 (16.4) | 0.456 |
Stoma-related problems | 32 to 38 | 0 | 28.0 (12.3) | ||
Sexual dysfunction of men | 20,21 | 23 | 15.3 (18.0) | 42.6 (35.6) | |
Sexual dysfunction of women | 22,23 | 4 | 16.7 (18.6) | 11.1 (27.2) | 1.000 |
Radiation-induced effects micturition | 1,2,3 | 51 | 21.1 (18.3) | 21.4 (19.0) | 0.945 |
Weight loss | 9 | 50 | 19.9 (27.4) | 8.5 (18.7) |
Based on QLQ-CR38 scores there were no significant change on three functional scales (i.e. future perspectives, sexual functioning and enjoyment), but the body image scores significantly increase. One year after treatment has been completed our patients reported significantly less problems with weight loss, but there was a significant increase in ChT side effects (dry mouth, thin or lifeless hair and different taste) and sexual dysfunction in men.
The final results of CRAB study show that preoperative CRT with bevacizumab and capecitabine is feasible with good compliance and acceptable toxicity.15 The pCR rate of 13% was similar to an earlier phase II study by our group examining neoadjuvant single-agent capecitabine plus RT in LARC.18
Direct comparison of long term results could only be possible with the study from Gasparini
Compared to our study, Willett
Furthermore, patient characteristics (sex and age) predict survival. In the largest analysis examining the impact of demographic characteristics on the survival of patients with rectal cancer, older age and male gender are associated with worse cancer-specific and OS.23 One of the possible causes for our worse OS could be in the older population that was included in the CRAB study compared to American study (median age with range; 60 years [31–80]
A comparison between neoadjuvant single-agent capecitabine CRT and the current study revealed promising oncologic outcome with adding bevacizumab in the standard neoadjuvant treatment of LARC in Slovenia (5-year OS, DFS and LC; 61.4, 52.4% and 87.4
Bevacizumab may cause severe late side effects in metastatic setting but late side effects are relatively rare.26 Most often described bevacizumab related late adverse events are spontaneous intestinal perforation and delayed anastomotic leak.27, 28 The addition of bevacizumab to standard CRT could be one of the possible causes for a higher proportion of fistulas in our study.
Only few studies analyzed the incidence of the late anastomotic leakage after low anterior resection (LAR). Delayed anastomotic leakages that develop after 30 days after surgery are not uncommon. The incidence is between 0.3% and 9.8%.29, 30, 31, 32, 33, 34, 35 It is not clear whether early and late anastomotic leakage after LAR are different entities because some patients with late anastomotic leakage may show uneventful postoperative clinical recovery.29 Late leakages more frequently involve the fistula type (22–100%) than early postoperative leakage.29, 30, 31, 32, 34, 35 Pelvic abscess and anastomotic-vaginal fistula were the most common causes of delayed complications.35
In our study only one female patient developed anastomotic vaginal fistula 12 months after rectal surgery. In the two studies with higher number of female patients included, the overall rate of anastomotic-vaginal fistula after LAR was higher, 3% (11/371) and 5.1% (20/390).36, 37 Anastomotic-vaginal fistulas in both studies were diagnosed mostly late, on median postoperative day 83 (15–766) in the first study and 25 (5–172) in the second. Despite that only 3% of the female patients in the first study were treated with preoperative ChT and no one with RT, pre-op ChT was one of the independent risk factor for anastomotic-vaginal fistula formation.36 In the second study, risk factors for anastomotic-vaginal fistula were preoperative radiotherapy, anastomosis < 5 cm above the anal verge and cancer stage IV.37
The incidence of the delayed anastomotic leakage in present study was high (13.1%), but it is important that only three fistulas were diagnosed before 5 years of follow up. Comparing the incidence of the delayed anastomotic leakage in our study with other studies is controversial. Follow up in our study was the longest than it was in other published studies. The longest interval between the surgery and fistula formation we found in the literature was 5.7 years and in our study 7.25 years. RT and ChT were identified as an independent risk factor for the development of the late anastomotic complications.32, 34, 35 In all published studies patients with very mixed type of neo-adjuvant and adjuvant treatment or without treatment were included. On the other side, in our study all patients were treated with neo-adjuvant CRT. According to previous facts, it is important that we pay attention to the appearance of early signs of the fistula during follow up in the patient previous treated with bevacizumab even several years after the completion of treatment.
The global health status (mean 68), which refers to the general assessment of the health and quality of life of the last seven days, was similar over time, and also comparable to the Slovenian general (mean 71.1) and CRC patients (mean 68.3).38, 39
The values of social and physical functioning indicated by patients were significantly influenced by the time between diagnosis and 1 year after treatment indicating a high incidence of problems in this area. On the other hand, 1 year after treatment patients reported less pain, insomnia and diarrhea. These results are consistent with QLQ-C30 scores of Slovenian CRC patients after surgical treatment.39 However, compared above mentioned items with the general Slovenian population, patients 1 year after treatment report more diarrhea, lower physical and social functioning, but less pain and insomnia. The population-based QOL reference values should be taken into account in the interpretation of disease progress and treatment effects. For Slovenian general population it was shown that gender, age and self-rated social class are important confounders in the QOL scores descriptions.38
Our long-term trends in longitudinal QOL are in agreement with study published from Couwenberg
Based on QLQ-CR38 significantly more ChT side effects and sexual dysfunction of men were observed after 1 year of treatment. However, body image has improved and patients reported less weight loss. Male sexual dysfunction is common and remains high after multimodality treatment for rectal cancer, more precisely, surgical nerve damage remain the main cause.40 Patients treated with well-defined and standardized technique of total mesorectal excision together with minimally invasive techniques experienced less sexual dysfunction compared to conventional surgery.41 In addition, laparoscopic resection contributes more to the maintenance of the nerves.40
The main limitations of this study include the single center design of the study with small number of patients, which limits statistical power. To assess
the QOL we have chosen a QLQ-CR38 and not revised successor QLQ-CR29, because the latter was published later in 2007. Consequently, our results are less comparable to others that have been used QLQ-CR29.
The optimal treatment strategy for patients with LARC is still controversial. Neoadjuvant bevacizumab with standard CRT in LARC is acceptable strategy. Further studies of its effect on better longterm outcome are warranted. Patients with LARC with high risk factors, such as positive pathological lymph nodes and high pathological T stage, deserve more aggressive treatment in the light of improving long-term survival results. While advances in multimodality treatment of CRC are enormous, some of the QOL aspects and long-term safety are often not published and inadequately discussed with patients. LARC treatment may no longer be standardized, but adjusted to the wishes, needs and characteristics of an individual patient.