Locally recurrent rectal cancer: Oncological outcomes for patients with a pathological complete response after neoadjuvant therapy.

BACKGROUND: For patients with locally recurrent rectal cancer, it is an ongoing pursuit to establish factors predicting or improving oncological outcomes. In locally advanced rectal cancer, a pCR appears to be associated with improved outcomes. The aim of this retrospective cohort study was to compare the oncological outcomes of patients with locally recurrent rectal cancer with and without a pCR. METHODS: Patients who underwent neoadjuvant treatment and surgery for locally recurrent rectal cancer with curative intent between January 2004 and June 2020 at a tertiary referral hospital were analysed. Primary outcomes included overall survival, disease-free survival, metastasis-free survival, and local re-recurrence-free survival, stratified according to whether the patient had a pCR. RESULTS: Of a total of 345 patients, 51 (14.8 per cent) had a pCR. Median follow-up was 36 (i.q.r. 16-60) months. The 3-year overall survival rate was 77 per cent for patients with a pCR and 51.1 per cent for those without (P < 0.001). The 3-year disease-free survival rate was 56 per cent for patients with a pCR and 26.1 per cent for those without (P < 0.001). The 3-year local re-recurrence-free survival rate was 82 and 44 per cent respectively (P < 0.001). Surgical procedures (for example soft tissue, sacrum, and urogenital organ resections) and postoperative complications were comparable between patients with and without a pCR. CONCLUSION: This study showed that patients with a pCR have superior oncological outcomes to those without a pCR. It may therefore be safe to consider a watch-and-wait approach in highly selected patients, potentially improving quality of life by omitting extensive surgical procedures without compromising oncological outcomes.

Phase I study of intraperitoneal irinotecan combined with palliative systemic chemotherapy in patients with colorectal peritoneal metastases.

BACKGROUND: Patients with colorectal peritoneal metastases who are not eligible for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) owing to extensive peritoneal disease have a poor prognosis. It was hypothesized that these patients may benefit from the addition of intraperitoneal irinotecan to standard palliative systemic chemotherapy. METHODS: This was a classical 3 + 3 phase I dose-escalation trial in patients with colorectal peritoneal metastases who were not eligible for CRS-HIPEC. Intraperitoneal irinotecan was administered every 2 weeks, concomitantly with systemic FOLFOX (5-fluorouracil, folinic acid, oxaliplatin)-bevacizumab. The primary objective was to determine the maximum tolerated dose and dose-limiting toxicities. Secondary objectives were to elucidate the systemic and intraperitoneal pharmacokinetics, safety profile, and efficacy. RESULTS: Eighteen patients were treated. No dose-limiting toxicities were observed with 50 mg (4 patients) and 75 mg (9 patients) intraperitoneal irinotecan. Two dose-limiting toxicities occurred with 100 mg irinotecan among five patients. The maximum tolerated dose of intraperitoneal irinotecan was established to be 75 mg, and it was well tolerated. Intraperitoneal exposure to SN-38 (active metabolite of irinotecan) was high compared with systemic exposure (median intraperitoneal area under the curve (AUC) to systemic AUC ratio 4.6). Thirteen patients had a partial radiological response and five had stable disease. Four patients showed a complete response during post-treatment diagnostic laparoscopy. Five patients underwent salvage resection or CRS-HIPEC. Median overall survival was 23.9 months. CONCLUSION: Administration of 75 mg intraperitoneal irinotecan concomitantly with systemic FOLFOX-bevacizumab was safe and well tolerated. Intraperitoneal SN-38 exposure was high and prolonged. As oncological outcomes were promising, intraperitoneal administration of irinotecan may be a good alternative to other, more invasive and costly treatment options. A phase II study is currently accruing.

Patients with extensive colorectal peritoneal metastases who are not eligible for surgery and heated intraperitoneal chemotherapy have poor survival. The authors tried to improve the survival of these patients by adding intraperitoneal (inside the abdominal cavity) chemotherapy to standard palliative chemotherapy which is administered into the bloodstream. In this trial, irinotecan (a type of chemotherapy) was administered into the abdomen of patients with extensive colorectal peritoneal metastases. The authors investigated which dose could be administered safely in combination with standard palliative chemotherapy. They also looked into toxicity, safety, benefit, and movement of the drug in the body. Eighteen patients were treated in this study. The maximum tolerated dose of intraperitoneal irinotecan was 75 mg. It was well tolerated and could be administered safely. The intra-abdominal amount of irinotecan was high, whereas the amount of irinotecan in the blood remained low. The benefits of intra-abdominal irinotecan were promising. Because of this, a new study has been started to further investigate this new combination chemotherapy for colorectal cancer.

Trajectories of emotional functioning and experienced care of relatives in the last year of life of patients with advanced cancer: A longitudinal analysis of the eQuiPe study.

OBJECTIVE: Advanced cancer has a major impact on both patients and their relatives. To allow for personalized support, it is important to recognize which relatives will experience a decline in emotional functioning during the patient's last year of life, when this decline will occur, and what factors are associated with it. This study aimed to examine the trajectory of emotional functioning of relatives during that time and the characteristics associated with changes in this trajectory. METHODS: A prospective, longitudinal, multicenter, observational study in patients with advanced cancer and their relatives was conducted (eQuiPe). We analyzed relatives' changes in emotional functioning in the patient's last year using the EORTC QLQ-C30 and assessed associations with sociodemographic and care characteristics using multivariable mixed-effects analysis. RESULTS: 409 relatives completed ≥1 questionnaires during the patient's last year of life. Mean age was 64 years, 61% were female and 75% were the patient's partner. During this year, mean emotional functioning declined significantly over time from 73.9 to 64.6 (p = 0.023, effect size = 0.43). The type of relationship between relatives and patients (p = 0.002), patient' sleep problems (p = 0.033), and continuity of care (p = 0.002) were significantly associated with changes in emotional functioning. CONCLUSIONS: Relatives' emotional functioning declined during the patient's last year of life. Support for them, especially partners and relatives of patients with sleep problems, is important. Relatives who experienced more continuity of care had a less steep decline in emotional functioning.

Beyond Median Overall Survival: Estimating Trends for Multiple Survival Scenarios in Patients With Metastatic Esophagogastric Cancer.

BACKGROUND: In recent years, clinical trials have shown improved survival of patients with metastatic esophageal or gastric cancer. The number of patients participating in clinical trials is limited, and survival improvements observed from clinical trials are unrepresentative for the full population. The aim of our study was to assess trends in survival for the best-case, typical, and worst-case scenarios in patients with metastatic esophageal or gastric cancer. METHODS: We selected patients with metastatic esophageal or gastric cancer diagnosed between 2006 and 2020 from the nationwide Netherlands Cancer Registry. Survival was calculated for different percentiles of the survival curve for each incidence year (eg, the 10th percentile [p10] represents the top 10% of patients with the best survival): p10 (best-case), p25 (upper-typical), p50 (median), p75 (lower-typical), and p90 (worst-case). Weighted linear regression analyses were performed to test whether changes in survival were significant. RESULTS: The overall median survival between 2006 and 2020 remained unchanged for patients with esophageal cancer (n=10,448; from 5.2 to 5.2 months, respectively; P=.06) and improved for patients with gastric cancer (n=10,512; from 3.5 to 4.3 months, respectively; P=.001). For patients with esophageal cancer, survival for the best-case scenario (p10; best 10% of patients) significantly improved from 17.2 to 21.0 months (P=.006). For patients with gastric cancer, survival significantly improved for the best-case scenario (p10) from 15.9 to 23.5 months (P<.001) and the upper-typical scenario (p25) scenario improved from 7.9 to 9.9 months (P<.001). CONCLUSIONS: Despite significant survival improvements in clinical trials, survival improvements were not observed for the majority of patients treated in daily clinical practice. An increase in survival was only observed for patients with the best prognosis.

Emotional functioning during bereavement after the death of patients with advanced cancer and associated factors.

OBJECTIVE: The death of a loved one is considered to be the most stressful of all life events. However, the impact of bereavement on quality of life varies between individuals. The aim of our study was to assess emotional functioning (EF), which is a domain of quality of life, of bereaved relatives after the death of their loved one and its associated factors. METHOD: A prospective, longitudinal, multicenter, observational study on quality of care and quality of life of patients with advanced cancer and their relatives was conducted (eQuiPe). The association between EF of relatives during bereavement and the following factors was investigated: gender, type of relationship, educational level, pre-bereavement emotional and social functioning and global quality of life, social support pre- and during bereavement, anticipatory complicated grief, support of healthcare professionals during bereavement, age of patient and bereaved relative and duration of survival after primary cancer diagnosis. RESULTS: 150 bereaved relatives completed the bereavement questionnaire. In 41% of the bereaved relatives EF was ≤71, indicating clinically relevant low EF. Multivariable logistic regression showed that females experienced more often emotional problems (OR = 2.82). Emotional functioning pre-bereavement (OR = 0.96) and social support during bereavement (OR = 0.97) were associated with low EF during bereavement. CONCLUSIONS: Almost half of the bereaved relatives of patients with advanced cancer experienced low EF and this was associated with low EF pre-bereavement and low social support during bereavement. Support for relatives should be initiated before the patient's death. Future research is needed to investigate the impact of such support on relatives' wellbeing during bereavement.

Metabolic positron emission tomography/CT response after induction chemotherapy and chemo(re)irradiation is associated with higher negative resection margin rate in patients with locally recurrent rectal cancer.

AIM: Positron emission tomography (PET)/CT can be used to monitor the metabolic changes that occur after intensified treatment with induction chemotherapy and chemo(re)irradiation for locally recurrent rectal cancer (LRRC). This study aimed to analyse the correlation between the PET/CT response and final histopathological outcomes. METHODS: All LRRC patients who underwent induction chemotherapy prior to surgery between January 2010 and July 2020 and were monitored with pretreatment and post-treatment PET/CT were included. Visual qualitative analysis was performed, and patients were scored as having achieved a complete metabolic response (CMR), partial metabolic response (PMR) or no response (NR). The histopathological response was assessed according to the Mandard tumour regression (TRG) score and categorized as major (TRG 1-2), partial (TRG 3) or poor (TRG 4-5). The PET/CT and TRG categories were compared, and possible confounders were analysed. RESULTS: A total of 106 patients were eligible for analysis; 24 (23%) had a CMR, 54 (51%) had a PMR and 28 (26%) had NR. PET/CT response was a significant predictor of the negative resection margin rate, achieving 96% for CMR, 69% for PMR and 50% for NR. The overall accuracy between PET score and pathological TRG was 45%, and the positive predictive value for CMR was 63%. A longer interval between post-treatment PET/CT and surgery negatively influenced the predictive value. CONCLUSION: Metabolic PET/CT response evaluation after neoadjuvant treatment proves to be a complementary diagnostic tool to standard MRI in assessing tumour response, and may play a role for treatment planning in LRRC patients.

Patient-reported outcomes during repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for isolated unresectable colorectal peritoneal metastases in a multicenter, single-arm, phase 2 trial (CRC-PIPAC).

BACKGROUND: CRC-PIPAC prospectively assessed repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) as a palliative monotherapy (i.e., without concomitant systemic therapy in between subsequent procedures) for unresectable colorectal peritoneal metastases (CPM). The present study explored patient-reported outcomes (PROs) during trial treatment. METHODS: In this single-arm phase 2 trial in two tertiary centers, patients with isolated unresectable CPM received 6-weekly PIPAC-OX (92 mg/m2). PROs (calculated from EQ-5D-5L, and EORTC QLQ-C30 and QLQ-CR29) were compared between baseline and 1 and 4 weeks after the first three procedures using linear mixed modeling with determination of clinical relevance (Cohen's D ≥ 0.50) of statistically significant differences. RESULTS: Twenty patients underwent 59 procedures (median 3 [range 1-6]). Several PROs solely worsened 1 week after the first procedure (index value - 0.10, p < 0.001; physical functioning - 20, p < 0.001; role functioning - 27, p < 0.001; social functioning - 18, p < 0.001; C30 summary score - 16, p < 0.001; appetite loss + 15, p = 0.007; diarrhea + 15, p = 0.002; urinary frequency + 13, p = 0.004; flatulence + 13, p = 0.001). These PROs returned to baseline at subsequent time points. Other PROs worsened 1 week after the first procedure (fatigue + 23, p < 0.001; pain + 29, p < 0.001; abdominal pain + 32, p < 0.001), second procedure (fatigue + 20, p < 0.001; pain + 21, p < 0.001; abdominal pain + 20, p = 0.002), and third procedure (pain + 22, p < 0.001; abdominal pain + 22, p = 0.002). Except for appetite loss, all changes were clinically relevant. All analyzed PROs returned to baseline 4 weeks after the third procedure. CONCLUSIONS: Patients receiving repetitive PIPAC-OX monotherapy for unresectable CPM had clinically relevant but reversible worsening of several PROs, mainly 1 week after the first procedure. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03246321; Netherlands trial register: NL6426.

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.

Pressurized Intraperitoneal Aerosol Chemotherapy (Oxaliplatin) for Unresectable Colorectal Peritoneal Metastases: A Multicenter, Single-Arm, Phase II Trial (CRC-PIPAC).

BACKGROUND: Despite its increasing use, pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (PIPAC-OX) has never been prospectively investigated as a palliative monotherapy for colorectal peritoneal metastases in clinical trials. This trial aimed to assess the safety (primary aim) and antitumor activity (key secondary aim) of PIPAC-OX monotherapy in patients with unresectable colorectal peritoneal metastases. METHODS: In this two-center, single-arm, phase II trial, patients with isolated unresectable colorectal peritoneal metastases in any line of palliative treatment underwent 6-weekly PIPAC-OX (92 mg/m2). Key outcomes were major treatment-related adverse events (primary outcome), minor treatment-related adverse events, hospital stay, tumor response (radiological, biochemical, pathological, ascites), progression-free survival, and overall survival. RESULTS: Twenty enrolled patients underwent 59 (median 3, range 1-6) PIPAC-OX procedures. Major treatment-related adverse events occurred in 3 of 20 (15%) patients after 5 of 59 (8%) procedures (abdominal pain, intraperitoneal hemorrhage, iatrogenic pneumothorax, transient liver toxicity), including one possibly treatment-related death (sepsis of unknown origin). Minor treatment-related adverse events occurred in all patients after 57 of 59 (97%) procedures, the most common being abdominal pain (all patients after 88% of procedures) and nausea (65% of patients after 39% of procedures). Median hospital stay was 1 day (range 0-3). Response rates were 0% (radiological), 50% (biochemical), 56% (pathological), and 56% (ascites). Median progression-free and overall survival were 3.5 months (interquartile range [IQR] 2.5-5.7) and 8.0 months (IQR 6.3-12.6), respectively. CONCLUSIONS: In patients with unresectable colorectal peritoneal metastases undergoing PIPAC-OX monotherapy, some major adverse events occurred and minor adverse events were common. The clinical relevance of observed biochemical, pathological, and ascites responses remains to be determined, especially since radiological response was absent.

First- and Second-Line Palliative Systemic Treatment Outcomes in a Real-World Metastatic Pancreatic Cancer Cohort.

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor survival rate, which can be improved by systemic treatment. Consensus on the most optimal first- and second-line palliative systemic treatment is lacking. The aim of this study was to describe the use of first- and second-line systemic treatment, overall survival (OS), and time to failure (TTF) of first- and second-line treatment in metastatic PDAC in a real-world setting. PATIENTS AND METHODS: Patients with synchronous metastatic PDAC diagnosed between 2015 and 2018 who received systemic treatment were selected from the nationwide Netherlands Cancer Registry. OS and TTF were evaluated using Kaplan-Meier curves with log-rank test and multivariable Cox proportional hazard analyses. RESULTS: The majority of 1,586 included patients received FOLFIRINOX (65%), followed by gemcitabine (18%), and gemcitabine + nab-paclitaxel (13%) in the first line. Median OS for first-line FOLFIRINOX, gemcitabine + nab-paclitaxel, and gemcitabine monotherapy was 6.6, 4.7, and 2.9 months, respectively. Compared to FOLFIRINOX, gemcitabine + nab-paclitaxel showed significantly inferior OS after adjustment for confounders (hazard ratio [HR], 1.20; 95% CI, 1.02-1.41), and gemcitabine monotherapy was independently associated with a shorter OS and TTF (HR, 1.98; 95% CI, 1.71-2.30 and HR, 2.31; 95% CI, 1.88-2.83, respectively). Of the 121 patients who received second-line systemic treatment, 33% received gemcitabine + nab-paclitaxel, followed by gemcitabine (31%) and FOLFIRINOX (10%). CONCLUSIONS: Based on population-based data in patients with metastatic PDAC, treatment predominantly consists of FOLFIRINOX in the first line and gemcitabine with or without nab-paclitaxel in the second line. FOLFIRINOX in the first line shows superior OS compared with gemcitabine with or without nab-paclitaxel.

Heterogeneity of first-line palliative systemic treatment in synchronous metastatic esophagogastric cancer patients: A real-world evidence study.

The optimal first-line palliative systemic treatment strategy for metastatic esophagogastric cancer is not well defined. The aim of our study was to explore real-world use of first-line systemic treatment in esophagogastric cancer and assess the effect of treatment strategy on overall survival (OS), time to failure (TTF) of first-line treatment and toxicity. We selected synchronous metastatic esophagogastric cancer patients treated with systemic therapy (2010-2016) from the nationwide Netherlands Cancer Registry (n = 2,204). Systemic treatment strategies were divided into monotherapy, doublet and triplet chemotherapy, and trastuzumab-containing regimens. Data on OS were available for all patients, on TTF for patients diagnosed from 2010 to 2015 (n = 1,700), and on toxicity for patients diagnosed from 2010 to 2014 (n = 1,221). OS and TTF were analyzed using multivariable Cox regression, with adjustment for relevant tumor and patient characteristics. Up to 45 different systemic treatment regimens were found to be administered, with a median TTF of 4.6 and OS of 7.5 months. Most patients (45%) were treated with doublet chemotherapy; 34% received triplets, 10% monotherapy and 10% a trastuzumab-containing regimen. The highest median OS was found in patients receiving a trastuzumab-containing regimen (11.9 months). Triplet chemotherapy showed equal survival rates compared to doublets (OS: HR 0.92, 95%CI 0.83-1.02; TTF: HR 0.92, 95%CI 0.82-1.04) but significantly more grade 3-5 toxicity than doublets (33% vs. 21%, respectively). In conclusion, heterogeneity of first-line palliative systemic treatment in metastatic esophagogastric cancer patients is striking. Based on our data, doublet chemotherapy is the preferred treatment strategy because of similar survival and less toxicity compared to triplets.

Effect of a Skills Training for Oncologists and a Patient Communication Aid on Shared Decision Making About Palliative Systemic Treatment: A Randomized Clinical Trial.

BACKGROUND: Palliative systematic treatment offers uncertain and often limited benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). This trial examined the independent and combined effect of an oncologist training and a patient communication aid on SDM. METHODS: In this multicenter randomized controlled trial with four parallel arms (2016-2018), oncologists (n = 31) were randomized to receive SDM communication skills training or not. The training consisted of a reader, two group sessions, a booster session, and a consultation room tool (10 hours). Patients (n = 194) with advanced cancer were randomized to receive a patient communication aid or not. The aid consisted of education on SDM, a question prompt list, and a value clarification exercise. The primary outcome was observed SDM as rated by blinded observers from audio-recorded consultations. Secondary outcomes included patient-reported SDM, patient and oncologist satisfaction, patients' decisional conflict, patient quality of life 3 months after consultation, consultation duration, and the decision made. RESULTS: The oncologist training had a large positive effect on observed SDM (Cohen's d = 1.12) and on patient-reported SDM (d = 0.73). The patient communication aid did not improve SDM. The combination of interventions did not add to the effect of training oncologists only. The interventions affected neither patient nor oncologist satisfaction with the consultation nor patients' decisional conflict, quality of life, consultation duration, or the decision made. CONCLUSION: Training medical oncologists in SDM about palliative systemic treatment improves both observed and patient-reported SDM. A patient communication aid does not. The incorporation of skills training in (continuing) educational programs for medical oncologists is likely to stimulate the widely advocated uptake of shared decision making in clinical practice. TRIAL REGISTRATION: Netherlands Trial Registry NTR 5489. IMPLICATIONS FOR PRACTICE: Treatment for advanced cancer offers uncertain and often small benefits, and the burden can be high. Hence, treatment decisions require shared decision making (SDM). SDM is increasingly advocated for ethical reasons and for its beneficial effect on patient outcomes. Few initiatives to stimulate SDM are evaluated in robust designs. This randomized controlled trial shows that training medical oncologists improves both observed and patient-reported SDM in clinical encounters (n = 194). A preconsultation communication aid for patients did not add to the effect of training oncologists. SDM training effectively changes oncologists' practice and should be implemented in (continuing) educational programs.

Patient Satisfaction and Quality of Life Before and After Treatment of Pancreatic and Periampullary Cancer: A Prospective Multicenter Study.

BACKGROUND: This study sought to assess patient satisfaction and quality of life (QoL) before and after treatment of pancreatic and periampullary cancer. METHODS: We conducted a prospective multicenter study of patients treated for pancreatic and periampullary cancer. General patient satisfaction was measured using the EORTC satisfaction with care questionnaire (IN-PATSAT32) at baseline and 3 months after treatment initiation, with a 10-point change on the Likert scale considered clinically meaningful. QoL was measured using the EORTC Core Quality of Life Questionnaire (QLQ-C30). The influence of treatment (curative and palliative) on patient satisfaction and QoL was determined. RESULTS: Of 100 patients, 71 completed follow-up questionnaires. General satisfaction with care decreased from 74.3 before treatment to 61.9 after treatment (P<.001), whereas global QoL increased from 68.4 to 71.4 (P=.39). Clinically meaningful reductions were also observed for the reported interpersonal skills of doctors (from 73.4 to 63.3) and exchange of information within the care team (from 63.5 to 52.5). Satisfaction scores were lower for patients treated with curative intent than for those treated with palliative intent regarding interpersonal skills of doctors (P=.01), information provision by doctors (P=.004), information provision by nurses (P=.02), availability of nurses (P=.004), exchange of information within the care team (P=.01), and hospital access (P=.02). In multivariable analysis, clinicopathologic or QoL factors were not independently associated with general patient satisfaction. CONCLUSIONS: Satisfaction with care, but not QoL, decreased after pancreatic cancer treatment. Improvements in communication and interpersonal skills are needed to maintain patient satisfaction after treatment.

Relationship Between Quality of Life and Survival in Patients With Pancreatic and Periampullary Cancer: A Multicenter Cohort Analysis.

BACKGROUND: A relationship between quality of life (QoL) and survival has been shown for several types of cancer, mostly in clinical trials with highly selected patient groups. The relationship between QoL and survival for patients with pancreatic or periampullary cancer is unclear. METHODS: This study analyzed QoL data from a prospective multicenter patient-reported outcome registry in patients with pancreatic or periampullary carcinoma registered in the nationwide Netherlands Cancer Registry (2015-2018). Baseline and delta QoL, between baseline and 3-month follow-up, were assessed with the Happiness, EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30), and QLQ-PAN26 questionnaires. The relationship between QoL and survival was assessed using Cox regression models, and additional prognostic value of separate items was assessed using Nagelkerke R2 (explained variance). RESULTS: For the baseline and delta analyses, 233 and 148 patients were available, respectively. Most were diagnosed with pancreatic adenocarcinoma (n=194; 83.3%) and had stage III disease (n=77; 33.0%), with a median overall survival of 13.6 months. Multivariate analysis using baseline scores indicated several scales to be of prognostic value for the total cohort (ie, happiness today, role functioning, diarrhea, pancreatic pain, and body image; hazard ratios all P<.05) and for patients without resection (ie, overall satisfaction with life, physical and cognitive functioning, QLQ-C30 summary score, fatigue, pain, constipation, diarrhea, and body image; hazard ratios all P<.05). Except for diarrhea, all QoL items accounted for >5% of the additional explained variance and were of added prognostic value. Multivariate analysis using delta QoL revealed that only constipation was of prognostic value for the total cohort, whereas no association with survival was found for subgroups with or without resection. CONCLUSIONS: In a multicenter cohort of patients with pancreatic or periampullary carcinoma, QoL scores predicted survival regardless of patient, tumor, and treatment characteristics. QoL scores may thus be used for shared decision-making regarding disease management and treatment choice.

Implementation of contemporary chemotherapy for patients with metastatic pancreatic ductal adenocarcinoma: a population-based analysis.

Background: Positive results of randomized trials led to the introduction of FOLFIRINOX in 2012 and gemcitabine with nab-paclitaxel in 2015 for patients with metastatic pancreatic ductal adenocarcinoma. It is unknown to which extent these new chemotherapeutic regimens have been implemented in clinical practice and what the impact has been on overall survival.Material and methods: Patients diagnosed with metastatic pancreatic ductal adenocarcinoma between 2007-2016 were included from the population-based Netherlands Cancer Registry. Multilevel logistic regression and Cox regression analyses, adjusting for patient, tumor, and hospital characteristics, were used to analyze variation of chemotherapy use.Results: In total, 8726 patients were included. The use of chemotherapy increased from 31% in 2007-2011 to 37% in 2012-2016 (p < .001). Variation in the use of any chemotherapy between centers decreased (adjusted range 2007-2011: 12-67%, 2012-2016: 20-54%) whereas overall survival increased from 5.6 months to 6.4 months (p < .001) for patients treated with chemotherapy. Use of FOLFIRINOX and gemcitabine with nab-paclitaxel varied widely in 2015-2016, but both showed a more favorable overall survival compared to gemcitabine monotherapy (median 8.0 vs. 7.0 vs. 3.8 months, respectively). In the period 2015-2016, FOLFIRINOX was used in 60%, gemcitabine with nab-paclitaxel in 9.7% and gemcitabine monotherapy in 25% of patients receiving chemotherapy.Conclusion: Nationwide variation in the use of chemotherapy decreased after the implementation of FOLFIRINOX and gemcitabine with nab-paclitaxel. Still a considerable proportion of patients receives gemcitabine monotherapy. Overall survival did improve, but not clinically relevant. These results emphasize the need for a structured implementation of new chemotherapeutic regimens.

Increased assessment of HER2 in metastatic gastroesophageal cancer patients: a nationwide population-based cohort study.

BACKGROUND: Addition of trastuzumab to first-line palliative chemotherapy in gastroesophageal cancer patients with HER2 overexpression has shown to improve survival. Real-world data on HER2 assessment and administration of trastuzumab are lacking. The aim of this study was to assess HER2 testing, trastuzumab administration, and overall survival (OS) in a nationwide cohort of metastatic gastroesophageal cancer patients. METHODS: Data of patients with synchronous metastatic gastroesophageal adenocarcinoma diagnosed in 2010-2016 that received palliative systemic treatment (n = 2846) were collected from the Netherlands Cancer Registry and Dutch Pathology Registry. The ToGA trial criteria were used to determine HER2 overexpression. Proportions of HER2 tested patients were analyzed between hospital volume categories using Chi-square tests, and over time using trend analysis. OS was tested using the Kaplan Meier method with log rank test. RESULTS: HER2 assessment increased annually, from 18% in 2010 to 88% in 2016 (P < 0.01). Median OS increased from 6.9 (2010-2013) to 7.9 months (2014-2016; P < 0.05). Between the hospitals, the proportion of tested patients varied between 29-100%, and was higher in high-volume hospitals (P < 0.01). Overall, 77% of the HER2 positive patients received trastuzumab. Median OS was higher in patients with positive (8.8 months) and negative (7.4 months) HER2 status, compared to non-tested patients (5.6 months; P < 0.05). CONCLUSION: Increased determination of HER2 and administration of trastuzumab have changed daily practice management of metastatic gastroesophageal cancer patients receiving palliative systemic therapy, and possibly contributed to their improved survival. Further increase in awareness of HER2 testing and trastuzumab administration may improve quality of care and patient outcomes.

The risk of not receiving adjuvant chemotherapy after resection of pancreatic ductal adenocarcinoma: a nationwide analysis.

BACKGROUND: The relation between type of postoperative complication and not receiving chemotherapy after resection of pancreatic ductal adenocarcinoma (PDAC) is unclear. The aim was to investigate which patient factors and postoperative complications were associated with not receiving adjuvant chemotherapy. METHODS: Patients who underwent resection (2014-2017) for PDAC were identified from the nationwide mandatory Dutch Pancreatic Cancer Audit. The association between patient-, tumor-, center-, treatment characteristics, and the risk of not receiving adjuvant chemotherapy was analyzed with multivariable logistic regression. RESULTS: Overall, of 1306 patients, 24% (n = 312) developed postoperative Clavien Dindo ≥3 complications. In-hospital mortality was 3.5% (n = 46). Some 433 patients (33%) did not receive adjuvant chemotherapy. Independent predictors (all p < 0.050) for not receiving adjuvant chemotherapy were older age (odds ratio (OR) 0.96), higher ECOG performance status (OR 0.57), postoperative complications (OR 0.32), especially grade B/C pancreatic fistula (OR 0.51) and post-pancreatectomy hemorrhage (OR 0.36), poor tumor differentiation grade (OR 0.62), and annual center volume of <40 pancreatoduodenectomies (OR 0.51). CONCLUSIONS: This study demonstrated that a third of patients do not receive chemotherapy after resection of PDAC. Next to higher age, worse performance status and lower annual surgical volume, this is mostly related to surgical complications, especially postoperative pancreatic fistula and post-pancreatectomy hemorrhage.

Training for Medical Oncologists on Shared Decision-Making About Palliative Chemotherapy: A Randomized Controlled Trial.

BACKGROUND: Systemic treatment for advanced cancer offers uncertain and sometimes limited benefit, while the burden can be high. This study examines the effect of shared decision-making (SDM) training for medical oncologists on observed SDM in standardized patient assessments. MATERIALS AND METHODS: A randomized controlled trial comparing training with standard practice was conducted. Medical oncologists and oncologists-in-training (n = 31) participated in a video-recorded, standardized patient assessment at baseline (T0) and after 4 months (T1, after training). The training was based on a four-stage SDM model and consisted of a reader, two group sessions (3.5 hours each), a booster session (1.5 hours), and a consultation card. The primary outcome was observed SDM as assessed with the Observing Patient Involvement scale (OPTION12) coded by observers blinded for arm. Secondary outcomes were observed SDM per stage, communication skills, and oncologists' satisfaction with communication. RESULTS: The training had a significant and large effect on observed SDM in the simulated consultations (Cohen's f = 0.62) and improved observed SDM behavior in all four SDM stages (f = 0.39-0.72). The training improved oncologists' information provision skills (f = 0.77), skills related to anticipating/responding to emotions (f = 0.42), and their satisfaction with the consultation (f = 0.53). CONCLUSION: Training medical oncologists in SDM about palliative systemic treatment improves their performance in simulated consultations. The next step is to examine the effect of such training on SDM in clinical practice and on patient outcomes. IMPLICATIONS FOR PRACTICE: Systemic treatment for advanced cancer offers uncertain and sometimes limited benefit, while the burden can be high. Hence, applying the premises of shared decision-making (SDM) is recommended. SDM is increasingly advocated based on the ethical imperative to provide patient-centered care and the increasing evidence for beneficial patient outcomes. Few studies examined the effectiveness of SDM training in robust designs. This randomized controlled trial demonstrated that SDM training (10 hours) improves oncologists' performance in consultations with standardized patients. The next step is to examine the effect of training on oncologists' performance and patient outcomes in clinical practice.

Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parallel-group, phase II-III, randomised, superiority study (CAIRO6)

BACKGROUND: Upfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes. METHODS: This open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0-10 or 11-20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician's discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates. DISCUSSION: This is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM. TRIAL REGISTRATION: Clinicaltrials.gov/ NCT02758951 , NTR/ NTR6301 , ISRCTN/ ISRCTN15977568 , EudraCT/ 2016-001865-99 .

DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.

BACKGROUND: Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], and c.1236G>A [rs56038477, E412E, in haplotype B3]) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care. METHODS: In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete. FINDINGS: Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 [39%] of 85 patients) than in wild-type patients (231 [23%] of 1018 patients; p=0·0013). The RR for severe fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63-2·73) for genotype-guided dosing compared with 2·87 (2·14-3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10-8·80) in c.1679T>G carriers, 2·00 (1·19-3·34) compared with 3·11 (2·25-4·28) for c.2846A>T carriers, and 1·69 (1·18-2·42) compared with 1·72 (1·22-2·42) for c.1236G>A carriers. INTERPRETATION: Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care. FUNDING: Dutch Cancer Society.