Real-world Outcomes of Sequential Androgen-receptor Targeting Therapies with or Without Interposed Life-prolonging Drugs in Metastatic Castration-resistant Prostate Cancer: Results from the Dutch Castration-resistant Prostate Cancer Registry.

BACKGROUND: Cross resistance between androgen-receptor targeting therapies (ARTs) (abiraterone acetate plus prednisone [ABI+P] or enzalutamide [ENZ]) for treatment of metastatic castration-resistant prostate cancer (mCRPC) may affect responses to second ART (ART2). OBJECTIVE: To establish treatment duration and prostate-specific antigen (PSA) response of ART2 in real-world mCRPC patients treated with or without other life-prolonging drugs (LPDs; ie, docetaxel, cabazitaxel, or radium-223) between ART1 and ART2. DESIGN, SETTING, AND PARTICIPANTS: Castration-resistant prostate cancer patients, diagnosed between 2010 and 2016 were retrospectively registered in Castration-resistant Prostate Cancer Registry (CAPRI). Patients treated with both ARTs were clustered into two subgroups: ART1>ART2 or ART1>LPD>ART2. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were ≥50% PSA response and treatment duration of ART2. Descriptive statistics and binary logistic regression after multiple imputations were performed. RESULTS AND LIMITATIONS: A total of 273 patients were included with a median follow-up of 8.4 mo from ART2. Patients with ART1>ART2 were older and had favourable prognostic characteristics at ART2 baseline compared with patients with ART1>LPD>ART2. No differences between ART1>ART2 and ART1>LPD>ART2 were found in PSA response and treatment duration. Multivariate analysis suggested that PSA response of ART2 was less likely in patients with visceral metastases (odds ratio [OR] 0.143, p=0.04) and more likely in patients with a relatively longer duration of androgen-deprivation treatment (OR 1.028, p=0.01) and with ABI + P before ENZ (OR 3.192, p=0.02). A major limitation of this study was missing data, a common problem in retrospective observational research. CONCLUSIONS: The effect of ART2 seems to be low, with a low PSA response rate and a short treatment duration irrespective of interposed chemotherapy or radium-223, especially in patients with short time on castration, visceral disease, and ENZ before ABI+P. PATIENT SUMMARY: We observed no differences in outcomes of patients treated with sequential abiraterone acetate plus prednisone (ABI+P) and enzalutamide (ENZ) with or without interposed chemotherapy or radium-223. In general, outcomes were lower than those in randomised trials, questioning the additional effect of second treatment with ABI+P or ENZ in daily practice.

Survival of patients with deficient mismatch repair metastatic colorectal cancer in the pre-immunotherapy era.

BACKGROUND: Metastatic colorectal cancer patients with deficient mismatch repair (dMMR mCRC) benefit from immunotherapy. Interpretation of the single-arm immunotherapy trials is complicated by insignificant survival data during systemic non-immunotherapy. We present survival data on a large, comprehensive cohort of dMMR mCRC patients, treated with or without systemic non-immunotherapy. METHODS: Two hundred and eighty-one dMMR mCRC patients (n = 54 from three prospective Phase 3 CAIRO trials; n = 227 from the Netherlands Cancer Registry). Overall survival was analysed from diagnosis of mCRC (OS), from initiation of first-line (OS1) and second-line (OS2) systemic treatment. Cox regression analysis examined prognostic factors. As comparison for OS 2746 MMR proficient mCRC patients were identified. RESULTS: Of 281 dMMR patients, 62% received first-line and 26% second-line treatment. Median OS was 16.0 months (13.8-19.6) with antitumour therapy and 2.5 months (1.8-3.5) in untreated patients. OS1 was 12.8 months (10.7-15.2) and OS2 6.2 months (5.4-8.9) in treated dMMR patients. Treated dMMR patients had a 7.6-month shorter median OS than pMMR patients. CONCLUSION: Available data from immunotherapy trials lack a control arm with standard systemic treatment. Given the poor outcome compared to the immunotherapy results, our data strongly suggest a survival benefit of immunotherapy in dMMR mCRC patients.

Preferences to receive unsolicited findings of germline genome sequencing in a large population of patients with cancer.

BACKGROUND: In precision medicine, somatic and germline DNA sequencing are essential to make genome-guided treatment decisions in patients with cancer. However, it can also uncover unsolicited findings (UFs) in germline DNA that could have a substantial impact on the lives of patients and their relatives. It is therefore critical to understand the preferences of patients with cancer concerning UFs derived from whole-exome (WES) or whole-genome sequencing (WGS). METHODS: In a quantitative multicentre study, adult patients with cancer (any stage and origin of disease) were surveyed through a digital questionnaire based on previous semi-structured interviews. Background knowledge was provided by showing two videos, introducing basic concepts of genetics and general information about different categories of UFs (actionable, non-actionable, reproductive significance, unknown significance). RESULTS: In total 1072 patients were included of whom 701 participants completed the whole questionnaire. Overall, 686 (85.1%) participants wanted to be informed about UFs in general. After introduction of four UFs categories, 113 participants (14.8%) changed their answer: 718 (94.2%) participants opted for actionable variants, 537 (72.4%) for non-actionable variants, 635 (87.0%) participants for UFs of reproductive significance and 521 (71.8%) for UFs of unknown significance. Men were more interested in receiving certain UFs than women: non-actionable: OR 3.32; 95% CI 2.05 to 5.37, reproductive significance: OR 1.97; 95% CI 1.05 to 3.67 and unknown significance: OR 2.00; 95% CI 1.25 to 3.21. In total, 244 (33%) participants conceded family members to have access to their UFs while still alive. 603 (82%) participants agreed to information being shared with relatives, after they would pass away. CONCLUSION: Our study showed that the vast majority of patients with cancer desires to receive all UFs of genome testing, although a substantial minority does not wish to receive non-actionable findings. Incorporation of categories in informed consent procedures supports patients in making informed decisions on UFs.

Second-Line Cabazitaxel Treatment in Castration-Resistant Prostate Cancer Clinical Trials Compared to Standard of Care in CAPRI: Observational Study in the Netherlands.

BACKGROUND: Cabazitaxel has been shown to improve overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel in the TROPIC trial. However, trial populations may not reflect the real-world population. We compared patient characteristics and outcomes of cabazitaxel within and outside trials (standard of care, SOC). PATIENTS AND METHODS: mCRPC patients treated with cabazitaxel directly after docetaxel therapy before 2017 were retrospectively identified and followed to 2018. Patients were grouped on the basis of treatment within a trial or SOC. Outcomes included OS and prostate-specific antigen (PSA) response. RESULTS: From 3616 patients in the CAPRI registry, we identified 356 patients treated with cabazitaxel, with 173 patients treated in the second line. Trial patients had favorable prognostic factors: fewer symptoms, less visceral disease, lower lactate dehydrogenase, higher hemoglobin, more docetaxel cycles, and longer treatment-free interval since docetaxel therapy. PSA response (≥ 50% decline) was 28 versus 12%, respectively (P = .209). Median OS was 13.6 versus 9.6 months for trial and SOC subgroups, respectively (hazard ratio = 0.73, P = .067). After correction for prognostic factors, there was no difference in survival (hazard ratio = 1.00, P = .999). Longer duration of androgen deprivation therapy treatment, lower lactate dehydrogenase, and lower PSA were associated with longer OS; visceral disease had a trend for shorter OS. CONCLUSION: Patients treated with cabazitaxel in trials were fitter and showed outcomes comparable to registration trials. Conversely, those treated in daily practice showed features of more aggressive disease and worse outcome. This underlines the importance of adequate estimation of trial eligibility and health status of mCRPC patients in daily practice to ensure optimal outcomes.

The impact of colorectal surgery on health-related quality of life in older functionally dependent patients with cancer - A longitudinal follow-up study.

BACKGROUND: Older patients who are functionally compromised or frail may be at risk for loss of quality of life (QoL) after colorectal cancer (CRC) surgery. We prospectively studied health-related QoL (HRQoL) and its association with functional dependency on multiple time points before and after CRC surgery. METHODS: Included were patients aged 70 years and older who underwent elective CRC surgery between 2014 and 2015 in combination with an oncogeriatric care path. HRQoL (EORTC QLQ-C30 and CR38) and activities of daily living (ADL, Barthel Index) were measured at four time-points; prior to (T0) and at 3 (T3), 6 (T6), and 12 (T12) months after surgery. Functional dependency was defined as a Barthel Index <19. Using mixed-model regression analysis associations between dependency, time and HRQoL outcomes were tested and corrected for confounders. RESULTS: Response rate was 67% (n = 106) to two or more questionnaires; 26 (25%) patients were functionally dependent. Overall, functionally independent patients experienced a higher HRQoL than dependent patients. Compared to T0, significant and clinically relevant improvements in HRQoL after surgery were observed in functionally dependent patients: better role functioning, a higher global health, a higher summary score, less fatigue and less gastrointestinal problems (p < .05). In functional independent patients, we observed no clinically relevant change in HRQoL. CONCLUSION: Colorectal surgery embedded in geriatric-oncological care has a positive impact on HRQoL in older functionally dependent patients with cancer. Moderate functional dependency should not be considered a generic reason for withholding surgical treatment. Information derived from this study could be used in shared decision making.

Four-year effects of exercise on fatigue and physical activity in patients with cancer.

BACKGROUND: In the earlier randomized controlled Physical Activity during Cancer Treatment (PACT) study, we found beneficial effects of an 18-week supervised exercise program on fatigue in patients with newly diagnosed breast or colon cancer undergoing adjuvant treatment. The present study assessed long-term effects of the exercise program on levels of fatigue and physical activity 4 years after participation in the PACT study. METHODS: The original study was a two-armed, multicenter randomized controlled trial comparing an 18-week supervised exercise program to usual care among 204 breast cancer patients and 33 colon cancer patients undergoing adjuvant treatment. Of the 237 PACT participants, 197 participants were eligible and approached to participate in the 4-year post-baseline measurements, and 128 patients responded. We assessed fatigue and physical activity levels at 4 years post-baseline and compared this to levels at baseline, post-intervention (18 weeks post-baseline), and at 36 weeks post-baseline. RESULTS: Intention-to-treat mixed linear effects model analyses showed that cancer patients in the intervention group reported significantly higher moderate-to-vigorous total physical activity levels (141.46 min/week (95% confidence interval (CI) 1.31, 281.61, effect size (ES) = 0.22) after 4 years compared to the usual care group. Furthermore, cancer patients in the intervention group tended to experience less physical fatigue at 4 years post-baseline compared to the usual care group (- 1.13, 95% CI -2.45, 0.20, ES = 0.22), although the result was not statistically significant. CONCLUSION: Patients with breast or colon cancer who participated in the 18-week exercise intervention showed significant higher levels of moderate-to-vigorous total physical activity levels and a tendency towards lower physical fatigue levels 4 years post-baseline. Our result indicate that exercising during chemotherapy is a promising strategy for minimizing treatment-related side effects, both short and long term. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571 , Dutch Trial Register NTR2138 . Trial registered on 9 December 2009.

Tolerability, Safety, and Outcomes of Neoadjuvant Chemoradiotherapy With Capecitabine for Patients Aged ≥ 70 Years With Locally Advanced Rectal Cancer.

INTRODUCTION: In studies of colorectal cancer, the elderly have been frequently underrepresented because comorbid conditions and functional status often lead to study exclusion. For elderly patients with an indication for neoadjuvant chemoradiotherapy (nCRT), physicians usually decide using clinical factors whether nCRT should be offered. The aim of the present retrospective study was to assess the tolerability of nCRT with capecitabine and the surgical outcomes in patients aged ≥ 70 years with locally advanced rectal cancer. PATIENTS AND METHODS: Data from 1372 rectal cancer patients diagnosed from 2002 to 2012 at 4 Dutch hospitals were used. Patients aged ≥ 70 years were included if they had received nCRT, and their data were analyzed for treatment deviations, postoperative complications, mortality, disease-free survival (DFS), and overall survival (OS). The data were stratified into 3 age groups (ie, 70-74, 75-79, and ≥ 80 years). RESULTS: We identified 447 patients aged ≥ 70 years. Of these patients, 42 had received nCRT, and 37 (88%) had completed nCRT. Radiation dermatitis, fatigue, and diarrhea were reported in 62%, 57%, and 43% of the 42 patients, respectively. Of the 42 patients, 40 (95%) underwent surgery, 1 patient refused resection, and 1 patient died during nCRT of severe mucositis due to dihydropyrimidine dehydrogenase deficiency. The postoperative complication rate was 30%, and the 30-day mortality rate was 0%. A pathologic complete response was found in 7.5%. The 2- and 5-year DFS and OS rates were 58.5% and 40.7% and 81.0% and 58.2%, respectively. CONCLUSION: The results of the present multicenter study have shown that if selected on clinical factors, nCRT with capecitabine is safe and well tolerated in elderly patients. No negative effect on surgical outcome was measured, and the beneficial effect (pathologic complete response, DFS, and OS) seemed comparable to that for younger age groups. We believe that elderly patients should not be excluded from nCRT on the basis of age only.

Cost-effectiveness analysis of an 18-week exercise programme for patients with breast and colon cancer undergoing adjuvant chemotherapy: the randomised PACT study.

OBJECTIVE: Meta-analyses show that exercise interventions during cancer treatment reduce cancer-related fatigue. However, little is known about the cost-effectiveness of such interventions. Here we aim to assess the cost-effectiveness of the 18-week physical activity during cancer treatment (PACT) intervention for patients with breast and colon cancer. The PACT trial showed beneficial effects for fatigue and physical fitness. DESIGN: Cost-effectiveness analyses with a 9-month time horizon (18 weeks of intervention and 18 weeks of follow-up) within the randomised controlled multicentre PACT study. SETTING: Outpatient clinics of 7 hospitals in the Netherlands (1 academic and 6 general hospitals) PARTICIPANTS: 204 patients with breast cancer and 33 with colon cancer undergoing adjuvant treatment including chemotherapy. INTERVENTION: Supervised 1-hour aerobic and resistance exercise (twice per week for 18 weeks) or usual care. MAIN OUTCOME MEASURES: Costs, quality-adjusted life years (QALY) and the incremental cost-effectiveness ratio. RESULTS: For colon cancer, the cost-effectiveness analysis showed beneficial effects of the exercise intervention with incremental costs savings of €4321 and QALY improvements of 0.03. 100% of bootstrap simulations indicated that the intervention is dominant (ie, cheaper and more effective). For breast cancer, the results did not indicate that the exercise intervention was cost-effective. Incremental costs were €2912, and the incremental effect was 0.01 QALY. At a Dutch threshold value of €20 000 per QALY, the probability that the intervention is cost-effective was 2%. CONCLUSIONS: Our results suggest that the 18-week exercise programme was cost-effective for colon cancer, but not for breast cancer. TRIAL REGISTRATION NUMBER: ISRCTN43801571.

Effects of an Exercise Program in Colon Cancer Patients undergoing Chemotherapy.

PURPOSE: Fatigue is a common problem among colon cancer patients and typically increases during chemotherapy. Exercise during chemotherapy might have beneficial effects on fatigue. To investigate the short- and long-term effects of an exercise program in colon cancer patients during adjuvant treatment, the Physical Activity During Cancer Treatment study was conducted. METHODS: In this multicenter randomized controlled trial, 33 colon cancer patients undergoing chemotherapy (21 men and 12 women) were randomly assigned to either a group receiving an 18-wk supervised exercise program (n = 17) or to usual care (n = 16). The primary outcome was fatigue as measured by the Multidimensional Fatigue Inventory and the Fatigue Quality List. Secondary outcomes were quality of life, physical fitness, anxiety, depression, body weight, and chemotherapy completion rate. Outcome assessment took place at baseline, postintervention (18 wk) and at 36 wk. RESULTS: Intention-to-treat mixed linear model analyses showed that patients in the intervention group experienced significantly less physical fatigue at 18 wk and general fatigue at 36 wk (mean between group differences, -3.2; 95% confidence interval [CI], -6.2 to -0.2; effect size [ES], -0.9 and -2.7; 95% CI, -5.2 to -0.1; ES, -0.8, respectively), and reported higher physical functioning (12.3; 95% CI, 3.3-21.4; ES, 1.0) compared with patients in the usual care group. CONCLUSION: The Physical Activity During Cancer Treatment trial shows that an 18-wk supervised exercise program in colon cancer patients during chemotherapy is safe and feasible. The intervention significantly reduced physical fatigue at 18 wk and general fatigue at 36 wk. Considering the number of patients included in the present study, replication in a larger study population is required.

Effects of an 18-week exercise programme started early during breast cancer treatment: a randomised controlled trial.

BACKGROUND: Exercise started shortly after breast cancer diagnosis might prevent or diminish fatigue complaints. The Physical Activity during Cancer Treatment (PACT) study was designed to primarily examine the effects of an 18-week exercise intervention, offered in the daily clinical practice setting and starting within 6 weeks after diagnosis, on preventing an increase in fatigue. METHODS: This multi-centre controlled trial randomly assigned 204 breast cancer patients to usual care (n = 102) or supervised aerobic and resistance exercise (n = 102). By design, all patients received chemotherapy between baseline and 18 weeks. Fatigue (i.e., primary outcome at 18 weeks), quality of life, anxiety, depression, and physical fitness were measured at 18 and 36 weeks. RESULTS: Intention-to-treat mixed linear model analyses showed that physical fatigue increased significantly less during cancer treatment in the intervention group compared to control (mean between-group differences at 18 weeks: -1.3; 95 % CI -2.5 to -0.1; effect size -0.30). Results for general fatigue were comparable but did not reach statistical significance (-1.0, 95%CI -2.1; 0.1; effect size -0.23). At 18 weeks, submaximal cardiorespiratory fitness and several muscle strength tests (leg extension and flexion) were significantly higher in the intervention group compared to control, whereas peak oxygen uptake did not differ between groups. At 36 weeks these differences were no longer statistically significant. Quality of life outcomes favoured the exercise group but were not significantly different between groups. CONCLUSIONS: A supervised 18-week exercise programme offered early in routine care during adjuvant breast cancer treatment showed positive effects on physical fatigue, submaximal cardiorespiratory fitness, and muscle strength. Exercise early during treatment of breast cancer can be recommended. At 36 weeks, these effects were no longer statistically significant. This might have been caused by the control participants' high physical activity levels during follow-up. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571, Dutch Trial Register NTR2138. Trial registered on December 9th, 2009.

Multidisciplinary decision-making on chemotherapy for colorectal cancer: an age-based comparison.

INTRODUCTION: With the ageing of society, optimising decision-making for older patients with cancer becomes increasingly important. A first step is awareness of current clinical practice. We analysed how treatment decisions regarding chemotherapy for older and younger patients with colorectal cancer are currently being made by the multidisciplinary team, the oncologist and the patient. METHODS: A total of 316 patients with colorectal cancer (median age 68.3 years), discussed at the multidisciplinary gastrointestinal oncology team meetings between 2010 and 2013, were reviewed to select patients for whom guidelines recommended chemotherapy. Multidisciplinary decision-making and subsequent clinical course were extracted from medical files. RESULTS: The multidisciplinary team recommended chemotherapy in 97% of younger patients treated with curative intent, compared to 65% of older patients; 86% of younger patients and 42% of older patients subsequently received chemotherapy. In a palliative setting, the multidisciplinary team recommended chemotherapy in 98% of younger and 69% of older patients and 81% and 45%, respectively, subsequently received this treatment. In addition to comorbidity and the patient's physical condition, chronological age was an important reason for withholding chemotherapy. When older patients did receive chemotherapy, reduced intensity regimens were often effectuated. CONCLUSION: Multidisciplinary decision-making regarding chemotherapy for older patients with colorectal cancer is still frequently based on clinical impressions, preconceptions or chronological age alone. Rather, treatment decisions should be made after thorough evaluation of the patient's health status across multiple domains, either by a geriatrician or within the oncology team itself. Given the preference-sensitive nature of chemotherapy decisions in the elderly, shared decision-making should be strived for whenever possible.

The effect of a geriatric evaluation on treatment decisions for older cancer patients--a systematic review.

AIM: The aim of this systematic review is to summarise all available data on the effect of a geriatric evaluation on the multidisciplinary treatment of older cancer patients, focussing on oncologic treatment decisions and the implementation of non-oncologic interventions. METHODS: A systematic search in MEDLINE and EMBASE for studies on the effect of a geriatric evaluation on oncologic and non-oncologic treatment for older cancer patients. RESULTS: Literature search identified 1654 reports (624 from Medline and 1030 from Embase), of which 10 studies were included in the review. Three studies used a geriatric consultation while seven used a geriatric assessment performed by a cancer specialist, healthcare worker or (research) nurse. Six studies addressed a change in oncologic treatment, the initial treatment plan was modified in a median of 39% of patients after geriatric evaluation, of which two thirds resulted in less intensive treatment. Seven studies focused on the implementation of non-oncologic interventions based on the results of the geriatric evaluation; all but one reported that interventions were suggested for over 70% of patients, even in studies that did not focus specifically on frail older patients. In the other study, implementation of non-oncologic interventions was left to the cancer specialist's discretion. CONCLUSION: A geriatric evaluation has significant impact on oncologic and non-oncologic treatment decisions in older cancer patients and deserves consideration in the oncologic work-up for these patients.

Influence of body mass index on outcome in advanced colorectal cancer patients receiving chemotherapy with or without targeted therapy.

PURPOSE: Obesity is associated with an increased risk of development and recurrence of colorectal cancer. However, the role of obesity in advanced colorectal cancer (ACC) patients is unknown. We investigated the effect of body mass index (BMI) on overall survival (OS) in ACC patients receiving systemic treatment in two large phase III studies (CAIRO and CAIRO2). PATIENTS AND METHODS: Treatment data were obtained and analysed from 796 ACC patients who were treated with chemotherapy in the CAIRO study, and from 730 ACC patients who were treated with chemotherapy plus targeted therapy in the CAIRO2 study. Baseline height and weight were used to assign patients to one of the following BMI categories: A (<18.5 kg/m(2)), B (18.5-24.9 kg/m(2)), C (25.0-29.9 kg/m(2)) and D (≥30.0 kg/m(2)). RESULTS: In 796 patients of the CAIRO study a high BMI was associated with better median OS (8.0, 14.9, 18.4 and 19.5 months for BMI categories A, B, C, and D, respectively; P=0.001), and was an independent prognostic factor for OS in a multivariate analysis. BMI was not associated with OS in 730 patients who participated in the CAIRO2 study, although a trend was observed. CONCLUSIONS: These results show that BMI is an independent prognostic factor for survival in patients receiving chemotherapy, but not in patients receiving chemotherapy and targeted therapy. The possible decreased efficacy of bevacizumab in obese patients may explain this discrepant result. The role of BMI in patients receiving targeted therapy should be further tested.