Health-Related Quality of Life in Colorectal Cancer Patients Treated With Liver Transplantation Compared to Chemotherapy.

Liver transplantation (LT) for patients with non-resectable colorectal liver metastases (CRLM) offers improved survival and has gained increased interest internationally the last years. The aim of this study was to describe the health-related quality of life (HRQoL) in patients with non-resectable CRLM receiving LT and how baseline HRQoL factors affect overall survival (OS). HRQoL data in the SECA (SEcondary CAncer) LT cohort was compared to data obtained from colorectal cancer patients starting first-line chemotherapy for metastatic disease in a clinical trial and data from a Norwegian normal population. HRQoL data from the QLQ-C30 questionnaire used in the SECA LT study and the NORDIC- VII study were reported. The relationship between patient-reported symptom burden at baseline and OS was investigated. In the SECA study longitudinal HRQoL assessment was used to describe the time until definitive deterioration as well as mean values at different time points. Patients in the SECA and NORDIC-VII studies reported similar baseline HRQoL. The median time until definitive deterioration in the transplanted patients was estimated to 36 months. In the SECA study appetite loss and pain at baseline had negative impact on OS (25.3 versus 71.7 months, p = 0.002 and 39.7 versus 71.7 months, p = 0.038, respectively). Despite a relapse in most of the LT patients the Global Health Score (GHS) remained good. Pain, and especially appetite loss at time of transplantation is associated with poor outcome after LT.

Clinicopathological factors associated with tumour-specific mutation detection in plasma of patients with RAS-mutated or BRAF-mutated metastatic colorectal cancer.

Detection of tumour-specific circulating cell-free DNA in plasma (ctDNA) fails in a significant number of cases depending on the clinical context. The primary aim was to investigate clinicopathological factors associated with detection of ctDNA in patients with RAS-/BRAF-mutated metastatic colorectal cancer (mCRC) prior to first-line therapy. A secondary aim was to evaluate the prognostic impact of ctDNA compared to other biomarkers. Patients were included from the NORDIC-VII study (N = 253). ctDNA was sampled prior to treatment and analysed for hotspot tissue mutations (KRAS, NRAS, and BRAF) using droplet digital PCR. Multivariable regression models were constructed to predict the probability of mutation detection and survival. Increasing radiological size of target lesions by increments of 1 cm (odds ratio [OR] = 1.18; 95% confidence interval [CI] 1.09-1.27; P < .001), intact primary tumour (OR = 3.17; 95% CI 1.22-8.22; P = .018) and more than one metastatic site (OR = 3.08; 95% CI 1.32-7.19; P = .009) were associated with mutation detection in plasma. Metastatic involvement of the lung was associated with non-detection (OR = 0.26; 95% CI 0.12-0.58; P = .001). Preanalytical and analytical factors modulated detection. High allele frequencies of ctDNA indicated poor prognosis independently of CEA and CA19-9 (hazard ratio [HR] = 2.38; 95% CI 1.74-3.26; P < .001; N = 206). Clinicopathological characteristics should be carefully considered when evaluating ctDNA results from mCRC patients, especially when confronted with a plasma negative result. ctDNA may prove to be a clinically useful marker in the evaluation of mCRC treatment.

Prognostic role of carcinoembryonic antigen and carbohydrate antigen 19-9 in metastatic colorectal cancer: a BRAF-mutant subset with high CA 19-9 level and poor outcome.

BACKGROUND: Mutation status of RAS and BRAF, as well as serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), are biomarkers used in clinical management of patients with gastrointestinal cancers. This study aimed to examine the prognostic role of these biomarkers in a patient population that started first-line chemotherapy for unresectable metastatic colorectal cancer (mCRC) in the NORDIC-VII study. METHODS: CEA and CA 19-9 were measured in serum samples from 545 patients obtained before the start of chemotherapy. Four hundred and ninety-four patients had detectable levels of carbohydrate antigen 19-9 (CA 19-9). RAS (exons 2-4) and BRAF (V600E) mutation status were available from 440 patients. Overall survival (OS) was estimated in patient groups defined by serum CEA or CA 19-9 levels using cut-off values of 5 µg/L and 35 kU/L, respectively, in the total population and in subgroups according to RAS and BRAF mutation status. RESULTS: For both CEA and CA 19-9, elevated serum levels were associated with reduced OS in adjusted analyses which included RAS and BRAF mutation status, baseline World Health Organization performance status, and levels of alkaline phosphatase and C-reactive protein. The negative prognostic information provided by an elevated CA 19-9 level was particularly marked in patients with BRAF mutation (hazard ratio = 4.35, interaction P = 0.003, in an adjusted model for OS). CONCLUSIONS: High baseline serum concentrations of CEA and CA 19-9 provide independent information of impaired prognosis in mCRC. In patients with BRAF-mutant tumours, elevated serum CA 19-9 may identify a subgroup with highly aggressive disease and could contribute to improving therapeutic decisions.

Long-Term Effectiveness of Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality in Women and Men: A Randomized Trial.

Background: The long-term effects of sigmoidoscopy screening on colorectal cancer (CRC) incidence and mortality in women and men are unclear. Objective: To determine the effectiveness of flexible sigmoidoscopy screening after 15 years of follow-up in women and men. Design: Randomized controlled trial. (ClinicalTrials.gov: NCT00119912). Setting: Oslo and Telemark County, Norway. Participants: Adults aged 50 to 64 years at baseline without prior CRC. Intervention: Screening (between 1999 and 2001) with flexible sigmoidoscopy with and without additional fecal blood testing versus no screening. Participants with positive screening results were offered colonoscopy. Measurements: Age-adjusted CRC incidence and mortality stratified by sex. Results: Of 98 678 persons, 20 552 were randomly assigned to screening and 78 126 to no screening. Adherence rates were 64.7% in women and 61.4% in men. Median follow-up was 14.8 years. The absolute risks for CRC in women were 1.86% in the screening group and 2.05% in the control group (risk difference, -0.19 percentage point [95% CI, -0.49 to 0.11 percentage point]; HR, 0.92 [CI, 0.79 to 1.07]). In men, the corresponding risks were 1.72% and 2.50%, respectively (risk difference, -0.78 percentage point [CI, -1.08 to -0.48 percentage points]; hazard ratio [HR], 0.66 [CI, 0.57 to 0.78]) (P for heterogeneity = 0.004). The absolute risks for death from CRC in women were 0.60% in the screening group and 0.59% in the control group (risk difference, 0.01 percentage point [CI, -0.16 to 0.18 percentage point]; HR, 1.01 [CI, 0.77 to 1.33]). The corresponding risks for death from CRC in men were 0.49% and 0.81%, respectively (risk difference, -0.33 percentage point [CI, -0.49 to -0.16 percentage point]; HR, 0.63 [CI, 0.47 to 0.83]) (P for heterogeneity = 0.014). Limitation: Follow-up through national registries. Conclusion: Offering sigmoidoscopy screening in Norway reduced CRC incidence and mortality in men but had little or no effect in women. Primary Funding Source: Norwegian government and Norwegian Cancer Society.

Health-related quality of life in patients with metastatic colorectal cancer, association with systemic inflammatory response and RAS and BRAF mutation status.

BACKGROUND: The aim of this study was to evaluate the effect of cetuximab on health-related quality of life (HRQoL) in the NORDIC-VII trial on metastatic colorectal cancer (mCRC), and to assess HRQoL in relation to RAS and BRAF mutation status and inflammatory biomarkers. PATIENT AND METHODS: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, after every fourth cycle of chemotherapy, and at the end of treatment. HRQoL during 12 cycles of chemotherapy was evaluated over time, compared between treatment arms, and assessed for association with tumour mutation status and inflammatory markers. RESULTS: QLQ-C30 was completed by 512 patients (90%) before start of treatment. HRQoL variables were well balanced across treatment arms at baseline, and no statistically significant differences during treatment were seen. Patients with BRAF-mutated tumours reported poorer HRQoL at baseline and subsequent time points than patients with RAS-mutated or RAS/BRAF wild-type tumours. Patients with high serum interleukin-6 (IL-6) or C-reactive protein (CRP) had markedly impaired HRQoL compared to patients with normal levels. There was a statistically significant association between reduction in IL-6 and CRP levels and improvement in HRQoL during treatment from baseline to cycle 4. CONCLUSION: The addition of cetuximab to chemotherapy did not affect HRQoL in mCRC patients. Patients with BRAF-mutated tumours have both a worse prognosis and a poor HRQoL. The associations between levels of systemic inflammatory markers and reduced HRQoL suggest that the patients might benefit from anti-inflammatory treatment.

Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study.

BACKGROUND: The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status, 5 years after the primary analysis. METHODS: A total of 566 patients were included in the intention-to-treat (ITT) population of the NORDIC-VII study. Updated survival status was obtained from 176 patients who were alive in the primary survival analyses. Samples from 223 tumours previously found to be KRAS (exon 2) and BRAF (V600E) wild-type, were re-analysed for KRAS (exons 3 and 4) and NRAS (exons 2-4) mutations. RESULTS: Including the extended RAS analyses, RAS and BRAF mutational status was available from 457 patients (81% of the ITT population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy. CONCLUSIONS: Adding cetuximab to Nordic FLOX did not provide any clinical benefit, but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort. The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone.

Interleukin-6 and C-reactive protein as prognostic biomarkers in metastatic colorectal cancer.

OBJECTIVES: The aim was to explore the prognostic significance of IL-6 and markers of systemic inflammatory response (SIR), in particular C-reactive protein (CRP), in metastatic colorectal cancer (mCRC) patients, in the total study population and according to RAS and BRAF mutation status. RESULTS: High levels of pretreatment serum IL-6 or CRP were associated with impaired outcome, in terms of reduced PFS and OS. Patients with low versus high serum IL-6 levels had median OS of 26.0 versus 16.6 months, respectively (P < 0.001). Stratified according to increasing CRP levels, median OS varied from 24.3 months to 12.3 months, (P < 0.001). IL-6 and CRP levels affected overall prognosis also in adjusted analyses. The effect of IL-6 was particularly pronounced in patients with BRAF mutation (interaction P = 0.004). MATERIALS AND METHODS: IL-6 and CRP were determined in pre-treatment serum samples from 393 patients included in the NORDIC-VII trial, in which patients with mCRC received first line treatment. The effect of serum IL-6 and CRP on progression-free survival (PFS) and overall survival (OS) was estimated. CONCLUSIONS: High baseline serum consentrations of IL-6 or CRP were associated with impaired prognosis in mCRC. IL-6 and CRP give independent prognostic information in addition to RAS and BRAF mutation status.

Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer.

Perivascular cells (PC) were recently implied as regulators of metastasis and immune cell activity. Perivascular heterogeneity in clinical samples, and associations with other tumor features and outcome, remain largely unknown.Here we report a novel method for digital quantitative analyses of vessel characteristics and PC, which was applied to two collections of human metastatic colorectal cancer (mCRC).Initial analyses identified marker-defined subsets of PC, including cells expressing PDGFR-ß or α-SMA or both markers. PC subsets were largely independently expressed in a manner unrelated to vessel density and size. Association studies implied specific oncogenic mutations in malignant cells as determinants of PC status. Semi-quantitative and digital-image-analyses-based scoring of the NORDIC-VII cohort identified significant associations between low expression of perivascular PDGFR-α and -ß and shorter overall survival. Analyses of the SPCRC cohort confirmed these findings. Perivascular PDGFR-α and -ß remained independent factors for survival in multivariate analyses.Overall, our study identified host vasculature and oncogenic status as determinants of tumor perivascular features. Perivascular PDGFR-α and -ß were identified as novel independent markers predicting survival in mCRC. The novel methodology should be suitable for similar analyses in other tumor collections.

A review of the evolution of systemic chemotherapy in the management of colorectal cancer.

Herein we present a historical review of the development of systemic chemotherapy for colorectal cancer (CRC) in the metastatic and adjuvant treatment settings. We describe the discovery of 5-fluorouracil (5-FU) by Heidelberger and colleagues in 1957, the potentiation of 5-FU cytotoxicity by the reduced folate leucovorin, and the advent of novel cytotoxic agents, including the topoisomerase I inhibitor irinotecan, the platinum-containing agent oxaliplatin, and the 5-FU prodrug capecitabine. The combination therapies, FOLFOX (5-FU/leucovorin and oxaliplatin) and FOLFIRI (5-FU/leucovorin and irinotecan), have become established as efficacious cytotoxic regimens for the treatment of metastatic CRC, resulting in overall survival times of approximately 2 years. When used as adjuvant therapy, FOLFOX also improves survival and is now the gold standard of care in this setting. Biological agents have been discovered that enhance the effect of cytotoxic therapy, including bevacizumab (a humanized monoclonal antibody that targets vascular endothelial growth factor, a central regulator of angiogenesis) and cetuximab/panitumumab (monoclonal antibodies directed against the epidermal growth factor receptor). Despite the ongoing development of novel antitumor agents and therapeutic principles as we enter the era of personalized cancer medicine, systemic chemotherapy involving infusional 5-FU/leucovorin continues to be the cornerstone of treatment for patients with CRC.

Is Liver Transplantation an Option in Colorectal Cancer Patients with Nonresectable Liver Metastases and Progression on All Lines of Standard Chemotherapy?

BACKGROUND: About 50 % of patients with metastatic colorectal cancer (CRC) will develop metastatic disease with liver as primary metastatic site. The majority of CRC patients has nonresectable disease and receives palliative chemotherapy. Overall survival (OS) from time of progression on last line of chemotherapy in metastatic CRC is about 5 months. CLM have been considered a contraindication for liver transplantation. However, we have previously reported 5-year OS of 60 % after liver transplantation for nonresectable CLM. There were six patients who had progressive disease (PD) on last line of standard chemotherapy at the time of liver transplantation; here we report the outcome for these six patients. METHODS: Patients with nonresectable liver-only CLM received liver transplantation in the SECA study, a subgroup of six patients whose disease had progressed on all standard lines of chemotherapy. RESULTS: These patients with nonresectable disease and PD on the last line of standard chemotherapy at time of liver transplantation had 8-35 metastatic lesions in the liver with the largest diameter at 2.8-13.0 cm. All patients had a relapse within 2.1-12.4 months after liver transplantation. Some patients received treatment with curative intent at the time of relapse, and median OS after transplantation was 41 months with a Kaplan-Meier calculated 5-year OS of 44 %. CONCLUSIONS: Liver transplantation in nonresectable CLM patients with extensive tumor load and PD on the last line of chemotherapy had extended OS compared with any other treatment option reported in the literature.

Anal carcinoma - Survival and recurrence in a large cohort of patients treated according to Nordic guidelines.

OBJECTIVE: To evaluate treatment outcome in a large population-based cohort of patients with anal cancer treated according to Nordic guidelines. MATERIAL: Clinical data were collected on 1266 patients with anal squamous cell carcinoma diagnosed from 2000 to 2007 in Sweden, Norway and Denmark. 886 of the patients received radiotherapy 54-64Gy with or without chemotherapy (5-fluorouracil plus cisplatin or mitomycin) according to different protocols, stratified by tumor stage. RESULTS: High age, male gender, large primary tumor, lymph node metastases, distant metastases, poor performance status, and non-inclusion into a protocol were all independent factors associated with worse outcome. Among patients treated according to any of the protocols, the 3-year recurrence-free survival ranged from 63% to 76%, with locoregional recurrences in 17% and distant metastases in 11% of patients. The highest rate of inguinal recurrence (11%) was seen in patients with small primary tumors, treated without inguinal irradiation. CONCLUSIONS: Good treatment efficacy was obtained with Nordic, widely implemented, guidelines for treatment of anal cancer. Inguinal prophylactic irradiation should be recommended also for small primary tumors.

Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality: a randomized clinical trial.

IMPORTANCE: Colorectal cancer is a major health burden. Screening is recommended in many countries. OBJECTIVE: To estimate the effectiveness of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality in a population-based trial. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 100,210 individuals aged 50 to 64 years, identified from the population of Oslo city and Telemark County, Norway. Screening was performed in 1999-2000 (55-64-year age group) and in 2001 (50-54-year age group), with follow-up ending December 31, 2011. Of those selected, 1415 were excluded due to prior colorectal cancer, emigration, or death, and 3 could not be traced in the population registry. INTERVENTIONS: Participants randomized to the screening group were invited to undergo screening. Within the screening group, participants were randomized 1:1 to receive once-only flexible sigmoidoscopy or combination of once-only flexible sigmoidoscopy and fecal occult blood testing (FOBT). Participants with positive screening test results (cancer, adenoma, polyp ≥10 mm, or positive FOBT) were offered colonoscopy. The control group received no intervention. MAIN OUTCOMES AND MEASURES: Colorectal cancer incidence and mortality. RESULTS: A total of 98,792 participants were included in the intention-to-screen analyses, of whom 78,220 comprised the control group and 20,572 comprised the screening group (10,283 randomized to receive a flexible sigmoidoscopy and 10,289 to receive flexible sigmoidoscopy and FOBT). Adherence with screening was 63%. After a median of 10.9 years, 71 participants died of colorectal cancer in the screening group vs 330 in the control group (31.4 vs 43.1 deaths per 100,000 person-years; absolute rate difference, 11.7 [95% CI, 3.0-20.4]; hazard ratio [HR], 0.73 [95% CI, 0.56-0.94]). Colorectal cancer was diagnosed in 253 participants in the screening group vs 1086 in the control group (112.6 vs 141.0 cases per 100,000 person-years; absolute rate difference, 28.4 [95% CI, 12.1-44.7]; HR, 0.80 [95% CI, 0.70-0.92]). Colorectal cancer incidence was reduced in both the 50- to 54-year age group (HR, 0.68; 95% CI, 0.49-0.94) and the 55- to 64-year age group (HR, 0.83; 95% CI, 0.71-0.96). There was no difference between the flexible sigmoidoscopy only vs the flexible sigmoidoscopy and FOBT screening groups. CONCLUSIONS AND RELEVANCE: In Norway, once-only flexible sigmoidoscopy screening or flexible sigmoidoscopy and FOBT reduced colorectal cancer incidence and mortality on a population level compared with no screening. Screening was effective both in the 50- to 54-year and the 55- to 64-year age groups. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00119912.

Plasma YKL-40 in patients with metastatic colorectal cancer treated with first line oxaliplatin-based regimen with or without cetuximab: RESULTS from the NORDIC VII Study.

BACKGROUND: We aim to test the hypothesis that high plasma YKL-40 is associated with short progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with first-line oxaliplatin and 5-flourouracil with or without cetuximab. PATIENTS AND METHODS: A total of 566 patients in the NORDIC VII Study were randomized 1∶1∶1 to arm A (Nordic FLOX), arm B (Nordic FLOX + cetuximab), or arm C (Nordic FLOX + cetuximab for 16 weeks followed by cetuximab alone as maintenance therapy). Pretreatment plasma samples were available from 510 patients. Plasma YKL-40 was determined by ELISA and dichotomized according to the age-corrected 95% YKL-40 level in 3130 healthy subjects. RESULTS: Pretreatment plasma YKL-40 was elevated in 204 patients (40%), and median YKL-40 was higher in patients with mCRC than in healthy subjects (age adjusted, P<0.001). Patients with elevated YKL-40 had shorter PFS than patients with normal YKL-40 (7.5 vs. 8.2 months; hazard ratio (HR)  = 1.27 95% confidence interval (CI) 1.05-1.53 P = 0.013) and shorter OS (16.8 vs. 23.9 months; HR = 1.33, 1.04-1.69, P = 0.024). Multivariate Cox analysis demonstrated that elevated pretreatment YKL-40 was an independent biomarker of short OS (HR = 1.12, 1.01-1.25, P = 0.033). The ratio of the updated plasma YKL-40 (i.e. level after 1, 2, 8 weeks of treatment, and at end of treatment compared to the baseline level) was associated with OS (HR = 1.27, 1.06-1.52, P = 0.011). CONCLUSIONS: Plasma YKL-40 is an independent prognostic biomarker in patients with mCRC treated with first-line oxaliplatin-based therapy alone or combined with cetuximab.

Reirradiation of locally recurrent rectal cancer: a systematic review.

BACKGROUND: Many patients with rectal cancer receive radiotherapy as a component of primary multimodality treatment. Although local recurrence is infrequent, reirradiation may be needed to improve resectability and outcomes. This systematic review investigated the effects of reirradiation in terms of feasibility, toxicity, and long-term outcomes. METHODS: A Medline, Embase and Cochrane search resulted in 353 titles/abstracts. Ten publications describing seven prospective or retrospective studies were included, presenting results of 375 patients reirradiated for rectal cancer. RESULTS: Median initial radiation dose was 50.4Gy, median 8-30months before reirradiation. Reirradiation was mostly administered using hyperfractionated (1.2-1.5Gy twice-daily) or 1.8Gy once-daily chemoradiotherapy. Median total dose was 30-40Gy to the gross tumour volume with 2-4cm margins. Median survival was 39-60months in resected patients and 12-16months in palliative patients. Good symptomatic relief was reported in 82-100%. Acute toxicity with diarrhoea was reported in 9-20%, late toxicity was insufficiently reported. CONCLUSIONS: Reirradiation of rectal cancer to limited volumes is feasible. When curative resection is possible, the goal is radical resection and long-term survival, and hyperfractionated chemoradiotherapy should be preferred to limit late toxicity. Reirradiation yielded good symptomatic relief in palliative treatment.

Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study.

PURPOSE: The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated. PATIENTS AND METHODS: Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points. RESULTS: Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated. CONCLUSION: Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.

Late patient-reported toxicity after preoperative radiotherapy or chemoradiotherapy in nonresectable rectal cancer: results from a randomized Phase III study.

PURPOSE: Preoperative chemoradiotherapy (CRT) is superior to radiotherapy (RT) in locally advanced rectal cancer, but the survival gain is limited. Late toxicity is, therefore, important. The aim was to compare late bowel, urinary, and sexual functions after CRT or RT. METHODS AND MATERIALS: Patients (N = 207) with nonresectable rectal cancer were randomized to preoperative CRT or RT (2 Gy × 25 ± 5-fluorouracil/leucovorin). Extended surgery was often required. Self-reported late toxicity was scored according to the LENT SOMA criteria in a structured telephone interview and with questionnaires European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), International Index of Erectile Function (IIEF), and sexual function-vaginal changes questionnaire (SVQ). RESULTS: Of the 105 patients alive in Norway and Sweden after 4 to 12 years of follow-up, 78 (74%) responded. More patients in the CRT group had received a stoma (73% vs. 52%, p = 0.09). Most patients without a stoma (7 of 12 in CRT group and 9 of 16 in RT group) had incontinence for liquid stools or gas. No stoma and good anal function were seen in 5 patients (11%) in the CRT group and in 11 (30%) in the RT group (p = 0.046). Of 44 patients in the CRT group, 12 (28%) had had bowel obstruction compared with 5 of 33 (15%) in the RT group (p = 0.27). One-quarter of the patients reported urinary incontinence. The majority of men had severe erectile dysfunction. Few women reported sexual activity during the previous month. However, the majority did not have concerns about their sex life. CONCLUSIONS: Fecal incontinence and erectile dysfunction are frequent after combined treatment for locally advanced rectal cancer. There was a clear tendency for the problems to be more common after CRT than after RT.

Sexual function in females after radiotherapy for rectal cancer.

BACKGROUND: Knowledge about female sexual problems after pre- or postoperative (chemo-)radiotherapy and radical resection of rectal cancer is limited. The aim of this study was to compare self-rated sexual functioning in women treated with or without radiotherapy (RT+ vs. RT-), at least two years after surgery for rectal cancer. METHODS AND MATERIALS: Female patients diagnosed from 1993 to 2003 were identified from a national database, the Norwegian Rectal Cancer Registry. Eligible patients were without recurrence or metastases at the time of the study. The Sexual function and Vaginal Changes Questionnaire (SVQ) was used to measure sexual functioning. RESULTS: Questionnaires were returned from 172 of 332 invited and eligible women (52%). The mean age was 65 years (range 42-79) and the time since surgery for rectal cancer was 4.5 years (range 2.6-12.4). Sexual interest was not significantly impaired in RT+ (n=62) compared to RT- (n=110) women. RT+ women reported more vaginal problems in terms of vaginal dryness (50% vs. 24%), dyspareunia (35% vs. 11%) and reduced vaginal dimension (35% vs. 6%) compared with RT- patients; however, they did not have significantly more worries about their sex life. CONCLUSION: An increased risk of dyspareunia and vaginal dryness was observed in women following surgery combined with (chemo-)radiotherapy compared with women treated with surgery alone. Further research is required to determine the effect of adjuvant therapy on female sexual function.

Sexual function in males after radiotherapy for rectal cancer.

PURPOSE: Knowledge of sexual problems after pre- or postoperative radiotherapy (RT) with 50 Gy for rectal cancer is limited. In this study, we aimed to compare self-rated sexual functioning in irradiated (RT+) and nonirradiated (RT-) male patients at least 2 years after surgery for rectal cancer. METHODS AND MATERIALS: Patients diagnosed with rectal cancer from 1993 to 2003 were identified from the Norwegian Rectal Cancer Registry. Male patients without recurrence at the time of the study. The International Index of Erectile Function, a self-rated instrument, was used to assess sexual functioning, and serum levels of serum testosterone were measured. RESULTS: Questionnaires were returned from 241 patients a median of 4.5 years after surgery. The median age was 67 years at survey. RT+ patients (n = 108) had significantly poorer scores for erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction with sex life compared with RT- patients (n = 133). In multiple age-adjusted analysis, the odds ratio for moderate-severe erectile dysfunction in RT+ patients was 7.3 compared with RT- patients (p <0.001). Furthermore, erectile dysfunction of this degree was associated with low serum testosterone (p = 0.01). CONCLUSION: RT for rectal cancer is associated with significant long-term effects on sexual function in males.

Late side effects and quality of life after radiotherapy for rectal cancer.

PURPOSE: There is little knowledge on long-term morbidity after radiotherapy (50 Gy) and total mesorectal excision for rectal cancer. Therefore, late effects on bowel, anorectal, and urinary function, and health-related quality of life (QoL), were studied in a national cohort (n = 535). METHODS AND MATERIALS: All Norwegian patients who received pre- or postoperative (chemo-)radiotherapy for rectal cancer from 1993 to 2003 were identified. Patients treated with surgery alone served as controls. Patients were without recurrence or metastases. Bowel and urinary function was scored with the LENT SOMA scale and the St. Marks Score for fecal incontinence and QoL with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). RESULTS: Median time since surgery was 4.8 years. Radiation-treated (RT+) patients (n = 199) had increased bowel frequency compared with non-radiation-treated (RT-) patients (n = 336); 19% vs. 6% had more than eight daily bowel movements (p < 0.001). In patients without stoma, a higher proportion of RT+ (n = 69) compared with RT- patients (n = 240), were incontinent for liquid stools (49% vs. 15%, p < 0.001), needed a sanitary pad (52% vs. 13%, p < 0.001), and lacked the ability to defer defecation (44% vs. 16%, p < 0.001). Daily urinary incontinence occurred more frequently after radiotherapy (9% vs. 2%, p = 0.001). Radiation-treated patients had worse social function than RT- patients, and patients with fecal or urinary incontinence had impaired scores for global quality of life and social function (p < 0.001). CONCLUSIONS: Radiotherapy for rectal cancer is associated with considerable long-term effects on anorectal function, especially in terms of bowel frequency and fecal incontinence. RT+ patients have worse social function, and fecal incontinence has a negative impact on QoL.