This study was a multi-center, non-randomized phase II study. The primary endpoint was best overall response and response duration for elderly patients with AIPC. Secondary endpoints were changes in PSA levels, safety, and changes in patient reported health-related quality of life measures. At entry, patients were categorized according to extent and type of metastatic disease (bone, visceral/lymph nodes, or both) for later response assessment.

Patients were required to have histologically confirmed adenocarcinoma of the prostate progressed following primary or secondary hormonal manipulations. Disease progression was defined as at least two successive increases in serum PSA (> 20% rise from baseline value) taken at least two weeks apart or documented soft tissue or osseous progression demonstrable on imaging studies. Prior hormonal treatment (flutamide, ketoconazole, diethylstilbesterol) must have been discontinued at least four weeks prior to study treatment (6 weeks for bicalutamide). Other entry criteria included: age ≥ 65 years; Karnofsky Performance Status (KPS) ≥ 70%; castrate levels of testosterone (≤ 50 ng/ml) maintained with medical or surgical castration; no prior treatment with cytotoxic chemotherapy; peripheral neuropathy ≤ grade 1; and appropriate renal, hepatic, and hematologic function consistent with package insert for docetaxel. The Institutional Review Boards at participating institutions approved this protocol and all patients were counseled regarding the benefits, risks, and alternatives to study participation. All patients signed written informed consent forms before any study related procedures were performed.

Treatment consisted of docetaxel 60 mg/m² IV over 60 minutes every 21 days and erlotinib 150 mg orally daily for 21 days. Patients received dexamethasone 8 mg orally twice daily for 3 days beginning one day prior to the docetaxel infusion. Anti-emetics were administered as per institutional standard of care.

A complete blood count, PSA, AST, ALT, alkaline phospatase, total bilirubin, BUN, creatinine, and electrolytes were obtained at baseline and prior to each cycle of therapy. Patients were evaluated with cross sectional imaging of chest, abdomen, and pelvis and radionucleotide bone scintigraphy at baseline and after every 3 cycles. An electrocardiogram was obtained at screening.

Patients without objective progression of disease (at least stable bone scans and/or stable disease by RECIST criteria) following 9 cycles of docetaxel/erlotinib were allowed to continue on 3 weeks cycles of erlotinib therapy administered alone for up to 8 additional cycles.

For erlotinib, dose reductions to 100 mg, 50 mg, or 25 mg, were required for moderate to severe (≥ grade 3) keratitis, rash, or diarrhea. Dose interruptions of erlotinib for up to two weeks were allowed as clinically indicated for erlotinib-related toxicities. For docetaxel, a 25% dose reduction for hematologic toxicities (neutropenia and thrombocytopenia ≥ grade 3) was allowed. Alternatively, myeloid growth factor support for secondary prophylaxis of neutropenia was permitted without dose modification. Dose interruption followed by a subsequent 25% docetaxel dose reduction was required for liver enzyme abnormalities including total bilirubin > upper limit of normal (ULN), alkaline phosphatase > 5 × ULN, and alanine transferase >5 × ULN. Dose reductions were also required for neuropathy ≥ grade 2 and other toxicities ≥ grade 3. Dose delays were required if stomatitis was present on day 1. If moderate to severe (≥ grade 3) stomatitis occurred during any cycle, then subsequent docetaxel doses were reduced by 25%.

The National Cancer Institute Common Toxicity Criteria (version 2.0) was used to evaluate patient toxicity during each cycle. Adverse events were reported to authorities as required by institutional and regulatory guidelines. Every effort was made to administer the regimen at full dose, as tolerated. Standard supportive care measures were employed according to routine local practice.

At entry, patients were classified by disease site according to the presence of measurable lesions by RECIST criteria or non-measurable lesions (by bone scan only) 16. Patients were evaluated after 3 cycles with bone scans and/or cross sectional imaging as clinically indicated. For patients with measurable disease, response was assessed by standardized RECIST criteria 16. For patients with bone-only disease, response was assessed by a combination of an improvement in non-measurable lesions (on bone scan) and a reduction in PSA levels (≥ 50%) sustained for at least 21 days. Patients with at least stable disease were continued on therapy. Additional response evaluations were performed after cycles 6, 9, 13, and at study completion (following cycle 17 or at early termination).

Serial measurements of PSA were obtained at baseline and before every cycle. Criteria for response for declines in PSA were based on the guidelines from the PSA working group 17.

Patient reported quality of life outcomes were measured with the FACT-P questionnaire at baseline (day 1 prior to study treatment) and before every treatment cycle. Patients were also asked to complete the FACT-P at the early termination visit, if applicable.

The primary outcome variable was response for each patient as classified by measurable or non-measurable disease. Secondary end points included toxicity, patient reported quality of life, and survival. The study was powered to both estimate the true percent of responders with a tolerance of +/- 23%, based on an exact 95% confidence interval, and to test the null hypothesis of a 5% response versus >5% response with 90% power with a significance level of 0.05. Confidence intervals for the proportion responders were computed using exact binominal confidence intervals. Changes in mean FACT-P scores from baseline to cycle 3 and baseline to end-of-study visit were computed with two-sided Student's t-tests. The Kaplan-Meier curve and mean survival were calculated with S-Plus (version 5; Insightful).

Between November 2002 and July 2005, 22 patients entered the study at three sites. Patient baseline characteristics are summarized in Table 1. Patient characteristics included a median age of 73.5 years (range 65–80 years) and median performance status of 90 (range 70–100). Primary therapy included radical prostatectomy alone in 6 patients, radiotherapy alone in 2 patients, primary androgen-deprivation therapy (ADT) in 7 patients, and combined prostatectomy and local radiotherapy in 7 patients. The median duration of ADT was 60 months (range 8–132 months) and most patients progressed after a median of 2 secondary hormonal agents (range 0–5). The median pre-treatment PSA was 218 ng/ml. Fourteen had metastatic disease in bone only, 2 patients had soft tissue disease only, and 6 patients had both bone and soft tissue disease.

All patients entered in the trial were evaluable by PSA criteria (Table 2). Of the 22 patients enrolled, 5 had ≥ 50% decline in PSA (23%, 95% CI 8–45%). None of 8 patients with measurable disease had objective response by RECIST criteria and 1 of 20 patients had a clinical response by composite of bone and PSA criteria (5%, 95% CI 0.1–25%).

With a median duration of follow-up of 19.0 months, a median overall survival of 24.6 months was observed (Figure 1). Five patients remain alive. There were no deaths during the active treatment phase of the trial, but 14 patients died in follow-up. Three patients were lost to follow-up.

Common treatment-related toxicities, expressed on a per patient basis, are summarized in Table 3. Anemia was the most common hematologic toxicity observed as mild (grade 1 or 2) in 8 patients and moderate (grade 3 or 4) in 1 patient. Neutropenia was observed as mild (grade 1 or 2) in 3 patients and moderate (grade 3 or 4) 9 patients. There were two episodes of neutropenic fever. The most common non-hematologic toxicities were rash (usually grade 1) in 21 patients and fatigue which was mild (grade 1 or 2) in 17 patients and moderate (grade 3 or 4) in 7 patients. Gastrointenstinal toxicities were also common including taste alteration, nausea, mucositis, and diarrhea (all generally grade 1 or 2). Significant (grade 3 or 4) non-hematologic toxicities (other than fatigue) were rare and included anorexia (3 patients) and diarrhea (2 patients). Other common, mild (grade 1 or 2) toxicities included mucositis, rash, elevated transaminases (AST or ALT), dizziness, hypertension, and ocular irritation.

Patients were asked to complete the FACT-P questionnaire before treatment at cycle 1 (baseline), cycle 3, and at the end-of-study visit (occurring variably before cycles 3 through 17). The mean ± SD FACT-P scores observed at baseline, cycle 3, and end-of-study were112 ± 11 (22 patients); 112 ± 14 (18 patients), 106 ± 17 (20 patients), respectively. No significant differences were observed in pair-wise comparisons between mean FACT-P at baseline and cycle 3 and baseline and end-of-study (p > 0.05).