Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma ...survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer.
Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines.
A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17-121) months, survivors scored significantly lower on physical (83.7 vs. 89.8, difference (diff) = −5.80, p=.005), role (83.5 vs. 90, diff = −5.97, p=.02), cognitive (83.7 vs. 91.9, diff = −8.05, p=.001), and social functioning (86.5 vs. 95.1, diff = −8.49, p= <.001) and had a higher symptom burden of fatigue (23.0 vs. 15.5, diff = 7.48, p=.004), dyspnea (13.3 vs. 6.7, diff = 6.47 p=.02), diarrhea (7.9 vs. 4.0, diff = 3.78, p=.04), and financial impact (10.5 vs. 2.5, diff = 8.07, p=.001) than matched controls. Group differences were indicated as clinically relevant.
Compared to matched controls, long-term advanced melanoma survivors had overall worse functioning scores, more physical symptoms, and financial difficulties. These data may contribute to the development of appropriate survivorship care.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) can result in long-term survival for selected patients with colorectal peritoneal metastases (PM). Most ...patients are additionally treated with systemic chemotherapy, but timing (adjuvant vs. preoperative) varies between treatment centers. This study aimed to compare short- and long-term outcomes for patients with synchronous colorectal PM undergoing CRS + HIPEC who received preoperative or adjuvant chemotherapy.
Methods
This study enrolled patients with synchronous colorectal PM who underwent macroscopically complete or near complete CRS + HIPEC. Data were collected from a prospective database containing all patients between 2007 and 2014. Perioperative outcome and survival were compared between patients who underwent adjuvant chemotherapy (adjuvant strategy AS) and those who had preoperative chemotherapy followed by adjuvant systemic chemotherapy if possible (preoperative strategy PS).
Results
The study enrolled 91 patients, 25 (28 %) of whom received preoperative chemotherapy. The peritoneal cancer index (PCI) score was lower and the operation length shorter for the patients receiving preoperative chemotherapy (both
p
= 0.02). The complication rates were comparable between the two groups. The median survival after diagnosis was 38.6 months in the AS group, whereas median survival was not reached in the PS group (
p
< 0.01). The 3-year overall survival rates were 50 and 89 %, respectively. After correction for other significant prognostic factors, preoperative chemotherapy was independently associated with improved survival (HR 0.23; 95 % confidence interval, 0.07–0.75;
p
= 0.01).
Conclusion
Treatment with preoperative chemotherapy was associated with improved long-term survival after CRS + HIPEC compared with adjuvant chemotherapy. Ideally, a randomized controlled trial should be performed to investigate the optimal timing of systemic chemotherapy for colorectal PM patients.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Biliary tract cancer (BTC) is an uncommon cancer with an unfavorable prognosis. Since 2010, the standard of care for patients with unresectable BTC is palliative treatment with gemcitabine plus ...cisplatin, based on the landmark phase III ABC-02 trial. This current study aims to evaluate the efficacy and safety of gemcitabine and cisplatin in patients with unresectable cholangiocarcinoma and gallbladder cancer in daily practice that meet the criteria for the ABC-02 trial in comparison to patients who did not.
Patients diagnosed with unresectable BTC between 2010 and 2015 with an indication for gemcitabine and cisplatin were included. We divided these patients into three groups: (I) patients who received chemotherapy and met the criteria of the ABC-02 trial, (II) patients who received chemotherapy and did not meet these criteria and (III) patients who had an indication for chemotherapy, but received best supportive care without chemotherapy. Primary outcome was overall survival (OS) and secondary outcome was progression-free survival (PFS).
We collected data of 208 patients, of which 138 (66.3%) patients received first line chemotherapy with gemcitabine and cisplatin. Median OS of 69 patients in group I, 63 patients in group II and 65 patients in group III was 9.6 months (95%CI = 6.7-12.5), 9.5 months (95%CI = 7.7-11.3) and 7.6 months (95%CI = 5.0-10.2), respectively. Median PFS was 6.0 months (95%CI = 4.4-7.6) in group I and 5.1 months (95%CI = 3.7-6.5) in group II. Toxicity and number of dose reductions (p = .974) were comparable between the two chemotherapy groups.
First-line gemcitabine and cisplatin is an effective and safe treatment for patients with unresectable BTC who do not meet the eligibility criteria for the ABC-02 trial. Median OS, PFS and treatment side effects were comparable between the patients who received chemotherapy (group I vs. group II).
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival ...is largely unknown.
Using data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR), we analyzed the association between severe toxicity and overall survival (OS) in 1,250 patients with advanced melanoma who were treated with immune checkpoint inhibitors (ICI) in first line between 2012 and 2017. Furthermore, we analyzed whether toxicity management affected survival in these patients.
A total of 1,250 patients were included, of whom 589 received anti-PD1 monotherapy, 576 ipilimumab, and 85 combination therapy. A total of 312 patients (25%) developed severe (grade ≥3) toxicity. Patients experiencing severe ICI toxicity had a significantly prolonged survival with a median OS of 23 months compared with 15 months for patients without severe toxicity hazard ratio (HR
) = 0.77; 95% confidence interval (CI), 0.63-0.93. Among patients experiencing severe toxicity, survival was significantly decreased in patients who received anti-TNF ± steroids for steroid-refractory toxicity compared with patients who were managed with steroids only (HR
= 1.61; 95% CI, 1.03-2.51), with a median OS of 17 and 27 months, respectively.
Patients experiencing severe ICI toxicity have a prolonged OS. However, this survival advantage is abrogated when anti-TNF is administered for steroid-refractory toxicity. Further prospective studies are needed to assess the effect of different immunosuppressive regimens on checkpoint inhibitor efficacy.
.
Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction ...therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control.
In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour cT stage cT4a or cT4b, extramural vascular invasion, clinical nodal cN stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1–14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15–21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin folinic acid 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3–14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete.
Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5–5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8–27·6) in the experimental group versus 30·4% (26·1–34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60–0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 18% of 460 patients in the experimental group and 41 9% of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 9% of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression).
The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer.
Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer.
Patients with a clinical T1-3 N0 M0 rectal adenocarcinoma below 10 cm ...from the anal verge will receive neoadjuvant chemoradiation therapy (25 fractions of 2 Gy with concurrent capecitabine). Transanal Endoscopic Microsurgery (TEM) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response.Primary objective is to determine the number of patients with a (near) complete pathological response after chemoradiation therapy and TEM. Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality. A three-step analysis will be performed after 20, 33 and 55 patients to ensure the feasibility of this treatment protocol.
The CARTS-study is one of the first prospective multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision. The CARTS study is registered at clinicaltrials.gov (NCT01273051).
The pharmacokinetic behaviour of anticancer drugs may be altered with aging due to (for example) differences in body composition and decreased hepatic and renal function. To address this issue for ...paclitaxel, we studied the pharmacokinetics of the drug in eight elderly women (⩾70 years) with metastatic breast cancer (median age (range), 77 years (70–84 years)) and a control group of 15 patients aged <70 years (median age (range), 54 years (22—69 years)). Paclitaxel was administered as a 1-h intravenous (i.v.) infusion at a dose of 80 (elderly) or 100 mg/m
2 (<70 years), and serial blood samples were obtained at baseline, and up to 24 h after the end of infusion. Paclitaxel concentration–time profiles were fitted to a linear three-compartment model without any demonstration of saturable behaviour. The clearance of unbound paclitaxel was 124±35.0 (elderly) versus 247±55.4 l/h/m
2 (<70 years) (
P=0.002), and was inversely related to the patient's age (
R
2=0.857;
P<0.00001). Total plasma clearance of the formulation vehicle Cremophor EL (CrEL) was 150±60.7 (elderly) versus 115±39.2 ml/h/m
2 (<70 years) (
P=0.04). These data indicate an approximately 50% change in total body clearance of unbound paclitaxel and a concomitant significant increase in systemic exposure with age, most likely as a result of altered CrEL disposition. The clinical relevance of these observations with respect to toxicity profiles and antitumour efficacy requires further evaluation.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
