Radiotherapy and Concurrent Metronomic Chemotherapy in Hormone-refractory Prostate Carcinoma: A Phase I Study

Patients and Methods

Study characteristics. The study was conceived as a prospective dose-escalation study. All patients consecutively followed at our Radiotherapy Unit matching the inclusion criteria were enrolled. The trial was approved by the Institutional Review Board (# 01-2011).

Study objectives. The primary study end-point was the definition of the maximum tolerated dose (MTD) of RT combined with a fixed dose of metronomic chemotherapy. Secondary objectives of the study were the overall response rate (ORR) and progression-free survival.

Radiotherapy dose escalation. Patients were sequentially assigned to a specific dose level as detailed in Table I. RT dose escalation was based primarily on acute and subacute toxicity because late toxicity can occur months or years later. Acute-subacute toxicities were defined as those that occurred within six months from treatment. Toxicities registered at least six months after RT were defined as late toxicities. Dose-limiting toxicities (DLTs) were defined as any treatment-related non-hematological adverse effects rated as grade 3 or more, any hematological toxicity rated as grade 4 or more by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v.4.03) (15). If no DLT was not observed in any of the three patients at a given dose level, the trial proceeded to the next dose level, provided that at least three months of follow-up had occurred following RT for the third patient of the cohort. If a DLT occurred in one of the three patients at a given dose level, treatment of up to three additional patients at this dose level was required. If a DLT occurred in more than one patient of the three-patient cohort, dose escalation would stop, and the dose level below that would be considered as the MTD. If a DLT occurred in two or more patients of the expanded six-patient cohort, dose escalation would stop and the dose level below that would be considered as the MTD. If a DLT occurred in fewer than two patients of the expanded six-patient cohort, the trial proceeded to the next dose level. A 70-Gy total RT dose was selected at study initiation as the highest dose level to be evaluated considering the use of hypofractionated treatment. Late toxicities were continuously monitored even if patients showed disease progression.

Inclusion criteria. The following inclusion criteria were used: histological diagnosis of prostate adenocarcinoma, HRPC as evidenced by two consecutive (one-month interval) increases in PSA level in spite of a testosterone level in the castrate range and no distant metastases. When on an anti-androgen, withdrawal was attempted before inclusion and only patients who demonstrated progression after discontinuing this class of agent with at least a 50% increase in the PSA or objective evidence of increasing disease, were included. There was no limitation in the number of prior hormonal manipulations. Chest radiographs, computed tomography (CT) of the abdomen and pelvis, bone scan, PSA level and an electrocardiogram were performed at baseline. Other inclusion criteria were age >18 years, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, adequate bone marrow function defined as follows: neutrophil count >1,500/μl, platelets > 100,000 ml, hemoglobin >9 g/dl, creatinine <1.8 mg/dl, total bilirubin <3mg/dl, lactate dehydrogenase (LDH) <3 normal value, aspartate aminotransferase (AST) <3 normal value, alanine aminotransferase (ALT) <3 normal value, alkaline phosphatase <3 normal value. Previous treatment with prostatic surgery was accepted.

Exclusion criteria. The following exclusion criteria were used: ECOG performance status >3; previous pelvic RT; presence of medical conditions which contraindicated radiation therapy: connective system disorders, acute diverticulitis, ulcerative colitis, pelvic inflammatory disease; comorbidities that in the opinion of the referring physician constituted a risk to clinical trial participation.

End-points and statistical analysis. Toxicity was evaluated by CTCAE v.4.03. Biochemical response and PFS were calculated based on the Prostate-Specific Antigen Working Group recommendations for outcome guidelines in Phase II trial (Table II) (16). The survival curves were calculated with the Kaplan-Meier method. Statistical analysis was performed with SYSTAT, version 11.0 (SPSS, Chicago, IL, USA).

Radiotherapy. Treatment was simulated and performed with the patient in supine position. Patients were instructed to achieve stable conditions of bladder and rectal filling. Before CT simulation and each therapy fraction patients were invited to empty the bladder two hours prior to the procedure and drink 2 glasses of water right after; empty the bowel over the two hours prior to the procedure. As immobilization systems, a vac-lock and a lower-limb support were used. RT was planned based on CT simulation performed after oral administration of contrast with 5-mm slice intervals. The clinical target volume 1 (CTV1) included the prostate and seminal vesicles in patients with tumors not previously resected and local recurrence plus prostatic bed in patients previously treated by radical prostatectomy. CTV2 was defined as CTV1 plus pelvic lymph nodes (presacral, obturator, internal iliac and external iliac chains). The planning target volume 1 (PTV1) and the PTV2 were defined by adding an 8 mm margin (6 mm posteriorly) to CTV1 and CTV2, respectively. Intensity-modulated radiotherapy (IMRT) plans were generated using the Plato inverse treatment planning system (Plato B.V., Veeuendaal, the Netherlands). A class solution based on five co-planar beams consisting of different gantry angles (36°, 108°, 180°, 252°, 324°) was selected. In treatment plan calculation, the International Commission on Radiation Units and Measurements (ICRU) 62 recommendations were followed and QUANTEC dose-volume constraints (17) were respected. A daily online correction protocol of isocenter position was applied using portal imaging with set-up correction in case of deviations >0.3 cm in any direction (18). All stages of the treatment planning process were subjected to a systematic independent check procedure, as previously described (19). A dose of 45 Gy to the PTV2 (1.8 Gy/fraction) was prescribed to all patients. The following doses were prescribed to PTV1: level one: 60.0 Gy in 25 fractions (25 fractions of 2.4 Gy); level two: 65 Gy (25 fractions of 2.6 Gy); Level three: 70 Gy (25 fractions of 2.6 Gy followed by a fraction of 5 Gy delivered to the prostate or site of recurrence only).

Concurrent chemotherapy. Chemotherapy started one month before the start of RT, and was discontinued one month after the end of RT. Patients received cyclophosphamide (50 mg every morning) and dexamethasone (1 mg every evening), orally.

Follow-up. A first clinical examination was performed 20 days following the end of RT for a complete evaluation of acute toxicity. Thereafter, patients were followed-up bi-monthly assessing treatment toxicity and prostate carcinoma control, based on history, physical examination, and PSA levels. Bone scans were obtained for the assessment of bone pain.