Previously presented as an oral presentation at the Annual Meeting of the American Society of Radiation Oncology on 3 November 2010.
Young E. Whang, UNC Lineberger Comprehensive Cancer Center, CB #7295, Chapel Hill, NC 27599-7295, USA. e-mail: email@example.com
Study Type – Therapy (phase 1)
Level of Evidence 2a
What's known on the subject? and What does the study add?
High-risk and locally advanced prostate cancers are difficult to cure with the standard regimen of radiation therapy (RT) with concurrent androgen-deprivation therapy (ADT). Multiple studies have explored the addition of docetaxel chemotherapy in attempt to improve patient outcomes. Prior Phase I studies have shown that docetaxel 20 mg/m2 is a safe dose, when given concurrently with 70 Gy of radiation. But current standard RT for prostate cancer uses higher doses, and it is unclear if concurrent chemotherapy is safe with modern RT.
This is a Phase I study that explored the addition of concurrent docetaxel chemotherapy to modern RT (intensity-modulated RT to 78 Gy) plus ADT. The study showed that weekly docetaxel at 20 mg/m2 is safe with modern RT. At a median follow-up of 2.2 years, biochemical progression-free survival was 94%. This triple-therapy regimen is safe and promising for further evaluation in prospective trials.
• To evaluate in a phase I trial, the feasibility of adding concurrent weekly docetaxel chemotherapy to high-dose intensity modulated radiation therapy (IMRT) and androgen-deprivation therapy (ADT) for treatment of high-risk prostate cancer.
PATIENTS AND METHODS
• Patients with high-risk prostate cancer were treated with a luteinising hormone-releasing hormone agonist (starting 2–3 months before IMRT and lasting 2 years), IMRT of 78 Gy to the prostate and seminal vesicles, and weekly docetaxel during RT.
• All patients had computed tomography and bone scans to exclude metastatic disease.
• A standard 3 + 3 design was used for docetaxel dose escalation. Successive patients were treated on dose levels of 10, 15, and 20 mg/m2 of weekly docetaxel.
• In all, 18 patients participated in the study: 15 (83%) had Gleason 8–10 disease; the other three had either clinical T3 disease and/or a prostate-specific antigen (PSA) level of >20 ng/mL.
• Grade 3 diarrhoea (a defined dose-limiting toxicity, DLT) occurred in one patient in each of the first two dose levels. However, when the cohorts were expanded, no further DLT was seen.
• Weekly docetaxel at 20 mg/m2 (dose level 3) was successfully given without DLT.
• No patient had grade 4 or 5 toxicity.
• At a median follow-up of 2.2 years, all patients achieved a PSA nadir of <1 ng/mL, including 13 patients who had an undetectable PSA level. The 2-year biochemical progression-free survival was 94%.
• A dose of 20 mg/m2 of weekly docetaxel given concurrently with high-dose IMRT and ADT appears safe for further study in patients with high-risk prostate cancer.
Prostate cancer is the most common malignancy in men in the USA . For patients with high-risk or locally advanced disease, outcomes are poor despite aggressive treatment. For example, in the Radiation Therapy Oncology Group (RTOG) 92-02 trial, which randomised high-risk or locally advanced patients to radiation therapy (RT) plus short-term (4 months) or long-term (28 months) concurrent androgen-deprivation therapy (ADT), 52% of patients in the more aggressive arm (RT plus 28-month ADT) had disease recurrence within 10 years . In the RTOG 85-31 trial, which consisted of patients with locally advanced or node-positive prostate cancer, the 10-year disease-free survival in those treated with RT and indefinite ADT was 31% . The high recurrence rates despite long-term ADT, suggest that some patients with high-risk or locally advanced prostate cancer may harbour castration-resistant disease even at diagnosis. There is significant interest in continued treatment intensification for these patients, who currently have suboptimal outcomes with standard therapy .
Docetaxel is an active chemotherapeutic agent for advanced prostate cancer. Two randomised trials have shown that docetaxel-based chemotherapy improved survival in patients with metastatic castration-resistant prostate cancer [5,6], establishing its role for treatment in this setting. Docetaxel is also a known radiosensitizer, and previous studies have examined its concurrent use with RT for lung, head and neck, and cervical cancers [7–9]. Its activity in castration-resistant disease and radiosensitizing property make docetaxel a logical agent to incorporate into the treatment regimen for patients with newly diagnosed high-risk or locally advanced prostate cancer.
A prior Phase I trial reported 20 mg/m2 weekly docetaxel, as the maximum-tolerated dose (MTD) when used concurrently with RT in prostate cancer, and grade 3 diarrhoea was the dose-limiting toxicity (DLT) . This dose for docetaxel has been used in two subsequent Phase II trials [11,12]. Together, these three trials have established 20 mg/m2 weekly docetaxel as a standard dose when used concurrently with RT for prostate cancer. However, all three trials were performed using an older technique of three-dimensional (3D) conformal RT, delivering ≈70 Gy to the prostate. More recently, three randomised trials have been published showing the benefit of dose-escalated RT [13–15]; these results have changed the standard of care and a radiation dose of 70 Gy as used in the prior docetaxel trials is no longer recommended for prostate cancer treatment . While the concurrent delivery of docetaxel chemotherapy with RT appears to be a promising strategy for patients with high-risk and locally advanced prostate cancer, the safety and tolerability of 20 mg/m2 weekly docetaxel with dose-escalated RT is currently unknown.
We report results of a Phase I trial, which escalated the weekly docetaxel dose, up to 20 mg/m2, to determine the MTD of docetaxel that could be safely delivered concurrently with dose-escalated RT and long-term ADT for patients with high-risk or locally advanced prostate cancer.
PATIENTS AND METHODS
Eligible subjects were aged ≥18 years with histologically confirmed adenocarcinoma of the prostate and had locally advanced (clinical T3 or T4) or high-risk localised (Gleason 8–10 or PSA level of ≥20 ng/mL) disease. All patients had a chest X-ray, bone scan, and CT of the abdomen/pelvis to exclude nodal and distant metastasis. Other eligibility criteria included Eastern Cooperative Oncology Group performance status 0–1, no prior pelvic or prostate RT or chemotherapy for prostate cancer, adequate haematological [absolute neutrophil count ≥1500/mm3, haemoglobin ≥8.0 g/dL, platelets ≥100 000/mm3], hepatic [total bilirubin ≤1.2 mg/dL, transaminases (alanine transaminase and aspartate transaminase) ≤1.5 × the upper limit of normal (ULN), alkaline phosphatase ≤2.5 × ULN], and renal (creatinine ≤1.5 × ULN) function.
Patients were excluded if they had documented metastases, a life expectancy of <10 years secondary to comorbid illness, myocardial infarction or a significant change in anginal pattern of chest pain within 1 year prior to study entry, congestive heart failure (New York Heart Association Class ≥2), a hypersensitivity reaction to docetaxel, or a history of invasive malignancy within the last 5 years before study entry (except for carcinoma in situ or non-melanoma skin cancer).
Before treatment, all patients underwent a complete evaluation including medical history, complete physical examination, laboratory tests and imaging (described above), and 12-lead electrocardiogram. All patients provided written informed consent before participation. The protocol was approved by the Institutional Review Boards of the University of North Carolina at Chapel Hill (approval date 8 June 2005; reference number 05-1657) and Rex Hospital (approval date 23 May 2006; reference number 00000869). Patients were enrolled and treated at these two institutions. This trial conforms to the USA Food and Drug Administration (FDA) Good Clinical Practice, and is registered on Clinicaltrials.gov (NCT00225420).
Patients received docetaxel starting on the same week as RT, for a total of eight weekly doses. Docetaxel dose escalation was done using a classic phase I design. Patients were accrued in cohorts of three beginning at the first dose level (10 mg/m2). DLT was defined as grade 3–4 non-haematological or grade 4 haematological toxicity, using the Common Terminology Criteria for Adverse Events, Version 3.0. If none of the three patients had a DLT, then the docetaxel dose was escalated to the next higher dose level for the subsequent three patients. If one of the first three patients had a DLT at a specific dose level, then three more patients were accrued to the same dose level. If none of these additional three patients had DLT, then the docetaxel dose was escalated to the next level. However, if two of the initial six patients at any dose level had DLT, then the MTD had been exceeded. The MTD is defined as the dose of docetaxel such that ≤20% of patients have DLT. Dose escalation did not occur until all patients at the previous level had completed a toxicity assessment at week 10 (2 weeks after completion of chemoradiation).
Dose levels for docetaxel were: Level 1, 10 mg/m2; Level 2, 15 mg/m2; Level 3, 20 mg/m2. No dose escalation for RT or ADT was performed.
ADMINISTRATION OF STUDY THERAPY
ADT consisted of leuprolide (or an alternative LHRH agonist), starting 2 to 3 months before chemoradiation, and continued for a total of 24 months.
Docetaxel was given i.v. over 60 min weekly for 8 weeks, given during the course of RT. Patients received oral dexamethasone (4 mg × three doses) premedication, starting the night before each docetaxel administration. Docetaxel dose was reduced for myelosuppression or liver function test abnormalities. Certain toxicities (e.g. grade 3–4 diarrhoea) also required treatment interruption until resolution. If recovery took ≥3 weeks, patients were taken off protocol therapy. Patients who required more than two dose modifications were removed from the study.
Intensity-modulated RT (IMRT) was used for all patients. A treatment planning CT with bladder contrast was taken within 2 weeks of the initiation of RT, from which the clinical target volume of prostate and 1 cm of proximal seminal vesicles was defined. The planning target volume was the clinical target volume plus a 6-mm margin with exception of the posterior margin, which excluded the rectum. A total dose of 78 Gy in 39 fractions was delivered to the planning target volume. Radiation to the entire pelvis was not given.
Dose-volume histograms of the bladder, rectum and femoral heads were computed and dose constraints were specified per protocol. For the bladder, ≤25% of the bladder was to receive 65 Gy and ≤50% to receive 40 Gy. No more than 10 mL of the rectum was to receive 78 Gy, <17% to receive 65 Gy, and <35% receive <40 Gy. For the femoral heads, ≤25% of the each femoral head was to receive <45 Gy. Dose to the bowel was limited to <50 Gy per institutional standard practice.
Image guidance using CT on rails or B-mode Acquisition and Targeting ultrasound was used for all patients.
Physical examination, toxicity assessment and complete blood count were obtained weekly during chemoradiation treatment and at week 10 (2 weeks after finishing chemoradiation). Toxicity was scored using the Common Terminology Criteria for Adverse Events, Version 3.0. In addition, on weeks 1, 4, and 7, a complete metabolic panel including liver function tests was obtained. Serum PSA level was checked every 3 months during the follow-up period.
Biochemical progression-free survival (PFS) was measured from the date of study enrollment to death from any cause or biochemical failure using the Phoenix definition . Survival curves were estimated using the Kaplan–Meier technique.
Between December 2005 and January 2010, 18 men with high-risk or locally advanced prostate cancer were enrolled. The median (range) age was 62 (45–77) years (Table 1). The median (range) follow-up was 2.2 (1.0–3.9) years. All 18 patients completed their RT and 16 completed all planned chemotherapy doses.
Table 1. The clinical and patients' characteristics
Patients on this trial had high-risk localised (Gleason 8–10 or PSA level of ≥20 ng/mL) prostate cancer, or T3 disease.
One of the first three patients at dose level I (10 mg/m2 docetaxel) developed grade 3 diarrhoea, which resolved after holding one dose of chemotherapy. This patient received seven of the planned eight weekly doses. In the expansion cohort of three more patients, one developed a grade 3 elevation in liver function tests, which resolved while the two doses of chemotherapy were held (completed six of eight cycles). The increase in liver function tests in this patient was not clearly related to the study treatment and was most probably related to concomitant medication. However, to further ensure the safety of this dose level, three more patients were added and no further DLT was seen.
At dose level II (15 mg/m2 docetaxel), one of the first three patients developed grade 3 diarrhoea that resolved before the next weekly dose of chemotherapy. Although this patient was able to complete all protocol chemotherapy treatment, he was assigned to have DLT and an additional three patients were treated at dose level II. No DLT was seen in the expansion cohort for dose level II. None of three patients treated at dose level III (20 mg/m2) developed DLT.
Overall, diarrhoea occurred in seven patients (five grade 1, two grade 3; Table 2). Lymphopenia developed in 11 patients (one grade 1, five grade 2, five grade 3). Other toxicities included: grade 2 acute urinary symptoms, fatigue and hypersensitivity reactions. No patient developed grade 4 or 5 toxicity.
Table 2. Acute toxicities by docetaxel dose levels
Docetaxel dose level, mg/m2
No. of patients
Other Grade II/III toxicity
No. of patients
No. of patients
No. of patients
Toxicity graded using the Common Terminology Criteria for Adverse Events, Version 3.0. *Unclear relationship to study treatment. No., number; LFT, liver function tests; GU, genitourinary.
All patients in this study achieved a post-treatment PSA of ≤1 ng/mL, including 13 patients who had an undetectable PSA (<0.1 ng/mL). The median nadir PSA for all patients was undetectable. In three other patients, PSA level has decreased to <1 ng/mL but nadir has not been reached. Three patients have had a biochemical recurrence: two treated on dose level I (recurrences occurred at 2.4 and 3.5 years from study entry) and one dose level III (recurrence at 1.3 years). Another patient died from extensive-stage small cell lung cancer at 3.4 years. The 2-year PFS was 94 (95% CI 65–99)% (Fig. 1).
In the subgroup of eight patients with an initial PSA level of >20 ng/mL, three achieved an undetectable PSA nadir and three others have not reached nadir (Table 3). One patient in this group with an initial PSA level of 114 ng/mL had biochemical recurrence at 1.3 years while on ADT.
Table 3. PSA nadir and disease control outcomes
Initial PSA level, ng/mL
Nadir PSA level, ng/mL
NED, no evident disease.
Patients with initial PSA level of >20 ng/mL
NED (nadir not yet reached)
NED (nadir not yet reached)
NED (nadir not yet reached)
Patients with initial PSA level of <20 ng/mL
NED (died from lung cancer)
The effective treatment of patients with high-risk or locally advanced prostate cancer poses a significant challenge. The mainstay of treatment typically involves external-beam RT with long-term ADT, which is based on results of multiple randomised trials [2,3,18,19]. However, more than half of patients ultimately have disease recurrence which may be due to (i) persistent local disease and/or (ii) existence of micrometastatic disease at initial diagnosis. To improve local control, dose-escalated RT (≈78 Gy) can be given, and has a proven benefit over conventional-dose RT (≈70 Gy) in three randomised trials [13–15]. To treat potential micrometastatic disease, an earlier use of chemotherapy in the curative treatment setting may have a benefit. When used concurrently with RT, chemotherapy can also have a sensitizing effect and further help improve local control. Concurrent chemoradiation therapy is an established approach to treat many aggressive cancers [20–23].
There is emerging data on combining RT with an earlier use of chemotherapy in attempt to improve outcomes in these patients. In a Phase I trial by Kumar et al. , patients received 3D-conformal RT to a total dose of 70.2 Gy. Concurrent ADT was not allowed. The DLT was grade 3 diarrhoea and the MTD for docetaxel was 20 mg/m2. Based on these data, Perrotti et al. (20 patients)  and Bolla et al. (50 patients)  conducted Phase II trials using 20 mg/m2 docetaxel with conventional-dose RT, to confirm the tolerability of this treatment regimen. In the Bolla et al. trial , there was a relatively high rate of all-grade toxicities: 37 patients (74%) had diarrhoea, seven proctitis, 13 dysuria and one anal ulcer. These three trials have established a weekly docetaxel dose of 20 mg/m2 as a standard for further clinical trials when used with concurrent RT. However, because these previous studies used conventional-dose RT and most were treated with the 3D-conformal technique, both of which are no longer recommended for prostate cancer treatment today , the safety of concurrent docetaxel with long-term ADT and dose-escalated modern RT (IMRT) is unknown.
We performed a Phase I trial to define the MTD and DLT of docetaxel in patients treated with 78 Gy of radiation delivered using IMRT, with concurrent weekly docetaxel and long-term ADT. As 20 mg/m2 weekly docetaxel has been established by three prior Phase I and II trials as the MTD, our goal was to confirm the safety of this dose when used concurrently with dose-escalated RT, so that this treatment strategy can be further pursued with modern RT standards. This is the first study to combine docetaxel with dose-escalated RT. We confirmed that 20 mg/m2 of docetaxel is tolerable in this treatment regimen. Similar to the previous trials, grade 3 diarrhoea was the DLT, and occurred in two patients. All patients in the present study completed RT and all but two completed the protocol-prescribed eight chemotherapy doses. Other toxicities, including acute urinary symptoms and fatigue, were comparable with those reported by previous studies [10,11].
While not the primary endpoints of the present study, the PSA response and PFS rates were promising. Multiple studies have shown the prognostic value of the PSA nadir after RT for long-term disease control and survival outcomes [24–27]. In a secondary analysis of the Trans-Tasman Radiation Oncology Group 96.01 trial, the PSA nadir was significantly different among patients in the three treatment arms. The median nadir was 1.05 ng/mL in men treated with RT alone, 0.3 ng/mL in those who received radiation with 3-month ADT, and 0.2 ng/mL for RT plus 6-month ADT. This trend suggests that more effective treatment regimens may be associated with a lower PSA nadir. In patients who received RT with ADT, a PSA nadir of ≤0.4 ng/mL was significantly associated with improved biochemical failure-free survival, distant failure-free survival and prostate cancer-specific survival . The 5-year biochemical failure-free survival was ≈70% for patients with nadir of ≤0.4 ng/mL compared with ≈20% for those with a higher nadir. In the present study, the median PSA nadir was undetectable. The 2-year biochemical PFS was 94%, with one patient developing disease progression at 1.3 years and two others with longer follow-up.
Radiation dose and delivery technology have changed since the three prior Phase I and II trials of concurrent docetaxel with RT. The significance of the present study is confirmation of the safety of 20 mg/m2 weekly docetaxel, when used concurrently with dose-escalated modern RT and long-term ADT, allowing this regimen to be used in further clinical trials. As dose-escalated RT is now considered the standard of care for high-risk prostate cancer treatment, the finding that this can be delivered safely in the setting of concurrent docetaxel chemotherapy is of clinical importance.
In the treatment of patients with high-risk and locally advanced prostate cancer, concurrent docetaxel chemotherapy with RT has the potential to improve the currently suboptimal outcomes. The present results show the safety and tolerability of using modern dose-escalated RT with concurrent docetaxel, and contribute to the emerging and promising evidence supporting further clinical studies to examine the efficacy of this treatment regimen.
The authors would like to thank Gayle Grigson for assistance with patient care, Cathy Watkins and Juanita Cuffee for assistance with data management, Madlyn Ferraro for help with coordinating the study, and Laura Hendrix for manuscript preparation.
CONFLICT OF INTEREST
None declared. This trial was sponsored by Sanofi-Aventis. The sponsor had no involvement in the trial design, data collection, analysis or manuscript preparation.