A retrospective multicentre cohort study of all men diagnosed with primary mCSPC in the South East health care region of Sweden was designed. This region covers approximately 1.1 million citizens and include the oncology departments of Linköping, Jönköping and Kalmar. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Regional Ethics Review board in Linköping, Region Östergötland, Sweden (diary number 2018/3–31). Based on the retrospective and noninterventional nature of the study, and the absence of publication of individual data, the Regional Ethics Review board in Linköping, Region Östergötland, Sweden (diary number 2018/3–31) did not consider it possible or necessary to obtain written informed consent.
Inclusion criteria were as follows: Male sex, age of 18 years or older, evidence of newly diagnosed mCSPC between July 2015 and December 2017 (ICD-10 code C61.x), defied as either node positive (N+) and/or distant metastatic (M+) disease, and administration of at least one cycle of upfront docetaxel chemotherapy in addition to ADT. Exclusion criteria were recurrent disease, castrate refractory disease, and patient’s refusal to undergo ADT.
The Swedish Cancer Registry (SCR) was used to identify eligible patients (https://www.socialstyrelsen.se/statistik-och-data/register/alla-register/cancerregistret/). Reporting to the SCR is mandatory, and the registry achieves over 95% coverage for all malignant tumours. The CSAM Cytodos software system (CSAM Health AS, Oslo, Norway), a software being used for the prescription and administration of chemotherapy at all participating centres, was used to identify those treated with docetaxel.
Medical records were reviewed and data were registered in a standardised case report form where patient and tumour characteristics, baseline biochemistry, performance status according to Eastern Cooperative Oncology Group (ECOG), treatment regimens, toxicity parameters, PSA levels, relapse, and vital status were recorded. Patient and tumour characteristics were recorded according to the TMN classification (8th edition by Union for International Cancer Control [UICC] 2017), GS according to International Society of Urological Pathology (ISUP) 2014, and histology according to WHO 2004.
The patients included had received docetaxel according to any of two different regimens; either by intravenous infusion every three weeks at doses of 75mg/m² for a total of six cycles (according to the CHAARTED and STAMPEDE treatment protocols) or at a dose of 50 mg/m² in two weeks cycles for a total of nine cycles according to local guidelines. The latter was used by one site for patients whom, for any reason and at the treating oncologist’s discretion, were deemed unfit to receive the 75mg/m² regimen.
Bone marrow toxicity was evaluated by blood cell counts beside other standard biochemical parameters prior to each dose. In general, treatment response was evaluated with PSA levels at day 18–20 in every cycle and, for most patients, with X-ray computed tomography at the end of the sixth cycle (or at the ninth cycle of the 50 mg/m2 two weeks cycles).
Primary endpoint was progression free survival (PFS) at 12 months. PFS was defined as time to biochemical progression in accordance with the CHAARTED protocol, where a serologic increase of the PSA level of more than 50% above nadir, reached after initiation of ADT and with two consecutive increases at least two weeks apart, clinical progression due to increasing symptoms, or deterioration or disease progression according to RECIST 1.0 were considered progression. If PSA nadir was less than 2 µg/l, a minimum increase of more than 2 µg/l was required [10, 11]. In addition, an alternative definition of progression according to the Swedish national guidelines, which stipulate serologic increase ≥ 25% from lowest PSA value after start of latest given treatment (and a minimum absolute increase of ≥ 2 µg/l), worsening of clinical symptoms, or radiological disease progression according to RECIST 1.0, was similarly applied[15].
Secondary endpoints were PFS at 24 months, overall survival (OS), treatment intensity including dose reductions, premature termination and protocol modifications, and safety of docetaxel treatment in terms of registered bone marrow toxicity and unplanned hospitalisations under and within 30 days after the last docetaxel treatment cycle. Patients were followed until death or May 18th 2018, whatever occurred first.
Statistical analysis:
All statistical analyses were carried out in the per protocol population, defined as all patients that received at least one dose of docetaxel. Patient characteristics and tumour and treatment data were reported as number and percentage for categorical variables and median and range for continuous variables. PFS at 12 and 24 months were estimated according to the CHAARTED [11] and the Swedish national guidelines [15] definitions of progressive disease, respectively. Median PFS and OS for the whole cohort and subgroups defined by age over and under median [68], PSA over and under median [180], comorbidities, and presence or absence of distant metastases, were estimated using Kaplan-Meier survival analyses and the significance of the differences in estimates of median survival was calculated using log rank test. Cox regression analysis with 95% confidence interval was used to evaluate hazard ratios for the same subgroups. P-values below 0.05 were considered statistically significant. Analyses were performed using IBM SPSS statistics software (IBM, version 25).