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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 1909-1915 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.02.001 Phase I Trial of Weekly Docetaxel With Concurrent Three-Dimensional Conformal Radiation Therapy in the Treatment of Unfavorable Localized Adenocarcinoma of the ProstateFrom the Department of Radiation Oncology, University of Southern California Keck School of Medicine, Los Angeles, CA; Divisions of Medical Oncology and Urology and Departments of Surgery and Medicine, Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine & Dentistry of New Jersey, New Brunswick, NJ. Address reprint requests to Parvesh Kumar, MD, Department of Radiation Oncology, University of Southern California Keck School of Medicine, 1441 Eastlake Ave, NOR G356, Los Angeles, CA 90033-0804; e-mail: parveshk{at}usc.edu
PURPOSE: A phase I trial was conducted to determine the maximally tolerated dose (MTD) of concurrent weekly docetaxel and three-dimensional conformal radiation therapy (3-D CRT) in unfavorable localized adenocarcinoma of the prostate. PATIENTS AND METHODS: Patients with unfavorable localized adenocarcinoma of the prostate underwent daily 3-D CRT to a total dose of 70.2 Gy at 1.8 Gy/fraction and concurrent docetaxel given once a week for 8 to 9 weeks. The initial weekly docetaxel dose level was 5 mg/m2 and the docetaxel doses were escalated as follows: 8, 12, 16, 20, and 25 mg/m2. RESULTS: Between January 2000 and August 2002, 22 men completed the chemoradiation therapy protocol. The dose-limiting toxicity was grade 3 diarrhea, which occurred in the first two patients treated at the 25 mg/m2 docetaxel dose level. The MTD of weekly docetaxel was determined to be 20 mg/m2. The overall incidence of grade 2 diarrhea and grade 2 dysuria was 36% and 23%, respectively. Seven (32%) and 15 (68%) patients did not experience any diarrhea or dysuria, respectively. No neutropenia or thrombocytopenia was observed. One patient required intermittent urinary catherization 10 months postcompletion of therapy, which resolved without any surgical intervention. Seventeen patients remain in prostate-specific antigen remission. At a median follow-up interval of 8 months (range, 2 to 27 months), all patients are alive. CONCLUSION: Concurrent weekly docetaxel in conjunction with 3-D CRT is well tolerated with acceptable toxicity. The MTD of weekly docetaxel was determined to be 20 mg/m2 with concurrent 3-D CRT.
According to the estimates by the American Cancer Society, approximately 230,110 new cases of prostate cancer will be diagnosed and 29,900 men are expected to die of this disease in the United States in 2004. The lifetime probability of developing prostate cancer in men in the United States between 1998 and 2000 was one in six, higher than the lifetime probability of women developing breast cancer during the same time interval.1 Many of these men will present with intermediate or high-risk disease (ie, T3 or T4; prostate-specific antigen [PSA]  10 ng/mL; Gleason score 7) in whom, historically, radiation therapy (RT) has been the standard of treatment. In a recent report, Hanks et al2 updated the results of their three-dimensional conformal radiation therapy (3-D CRT) experience in 232 patients with 8 to 12 years follow-up. Biochemical failure was defined according to the American Society of Therapeutic Radiation Oncology consensus definition.3 The biochemical no evidence of disease (bNED) rates at 8 years for all patients treated with 3-D CRT (67 to 81 Gy) was 48% at 10 and 12 years of follow-up. For PSA levels between 0 and 9.9 ng/mL and prostate cancer with unfavorable features (ie, T2B/T3 and/or Gleason score 7 and/or perineural invasion), the bNED rate was 62%; for PSA levels between 10 and 19.9 ng/mL with unfavorable features, it was only 44%; and for PSA 20 ng/mL, only 14% of patients exhibited biochemical remission. Hence, anywhere from 38% to 86% of men experienced a biochemical relapse despite definitive 3-D CRT. Furthermore, attempts to enhance the therapeutic ratio by adding hormonal therapy to RT have not improved survival outcome except in two randomized trials.4-7 Given the intermediate to poor results achieved thus far with either RT alone or in combination with hormonal therapy, other strategies are needed to improve local control and survival outcome for patients presenting with intermediate- or high-risk prostate cancer. Since long-term cure rates cannot be achieved without first controlling local disease, a strategy that can enhance the local effects of RT is very appealing. One such strategy involves the use of concurrent chemotherapeutic agent(s) to sensitize the local effects of RT. This strategy has been successfully used in other malignant diseases such as rectal and anal cancers to improve survival outcomes.8-10 Chemotherapeutic radiosensitizers for prostate cancer have not been widely investigated. Ionizing radiation causes direct and indirect DNA structural damage, especially during the G2-M phases of the cell cycle, which disrupts viable cell division, eventually leading to tumor cell death. Certain drugs such as docetaxel (Taxotere; Aventis Pharmaceuticals, Bridgewater, NJ) have mechanisms of cytotoxicity that are complementary to these lethal effects of radiation. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly.11-12 This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis and thus impairment of tumor cell division. Moreover, by disrupting normal division during the M phase of the cell cycle, docetaxel can potentially radiosensitize the cytotoxic effects of RT.13-15 Both in vitro and in vivo studies have demonstrated the synergistic effects of docetaxel when combined with RT. Hennequin et al13 and Milas et al14 have shown that docetaxel significantly increases radioresponsiveness in vitro by a factor of 2.5- to three-fold. Mason et al15 conducted in vivo experiments to assess the synergistic effects of docetaxel with radiation in murine MCa-K tumors. Murine MCa-K tumors were treated with three single dose schedules (9, 15, and 21 Gy) of radiation and docetaxel or docetaxel only. Docetaxel radiosensitization, as measured by tumor growth delay, was increased by a factor of up to 2.64. Furthermore, multiple phase I and II clinical studies have shown that docetaxel, given either as a single agent or part of combination therapy, is safe and efficacious in metastatic prostate cancer.16-22 Recognizing the laboratory radioenhancement and the potential for clinical synergy between radiation and docetaxel, we initiated a phase I trial in January 2000 at Robert Wood Johnson Medical School, University of Medicine & Dentistry of New Jersey, Cancer Institute of New Jersey, New Brunswick, NJ, to determine the maximally tolerated dose (MTD) of weekly docetaxel that could be concurrently delivered with 3-D CRT in the treatment of unfavorable localized adenocarcinoma of the prostate.
Eligibility Criteria and Staging Work-Up The eligibility criteria included men with biopsy proven adenocarcinoma of the prostate and unfavorable localized disease defined as follows: T3N0M0 or T4N0M0, T1B/T1C/T2N0M0 and Gleason Score 8, or T1C/T2N0M0 with Gleason Score 5 to 7 and PSA 10 ng/mL. Other major eligibility criteria also included Karnofsky Performance Status 70, no history of prior chemotherapy or pelvic irradiation, adequate bone marrow/liver function, and no history of prior invasive malignant cancer(s) within the last 5 years except adequately treated or controlled basal cell or squamous cell carcinoma of the skin. Neoadjuvant or adjuvant hormonal therapy could be given, but concurrent hormonal therapy was not allowed. The protocol was approved by the University of Medicine and Dentistry/Robert Wood Johnson Medical School institutional review board and informed consent was obtained from all patients before entry into the protocol. All patients underwent a complete history and physical examination, PSA test and baseline and weekly CBC with differential, platelet count, comprehensive metabolic panel, and liver function tests. Radiologic work-up included a chest x-ray, bone scan, and computed tomography (CT) scan of the abdomen and pelvis. All men were serially followed at 3- to 4-month intervals with a physical examination, including a digital rectal exam and a PSA test. PSA relapse was defined according to the American Society of Therapeutic Radiation Oncology consensus definition.3
Study Design Patients were accrued in cohorts of three, beginning at the 5 mg/m2 docetaxel dose level. Chemotherapy dose escalation was done using a classic phase I design. That is, if none of the patients treated at a given dose level experienced a DLT, then the docetaxel dose was escalated to the next higher dose level in three subsequent patients. If one of the three patients experienced a DLT at a specific dose level, then three more patients were accrued to the same dose level. If none of these additional patients suffered a DLT, then the docetaxel dose was escalated to the next cohort. However, if at least one of the additional patients experienced a DLT, then the MTD had been exceeded and three more patients were to be treated at the prior dose level. Hence, the MTD was the dose level that zero of six patients or one of six patients experience a DLT; at least two of three patients or two of six patients treated with the next higher dose will have experienced a DLT. A DLT was defined as any grade 3 or 4 nonhematologic toxicity (including neurotoxicity), or grade 4 hematologic toxicity lasting for more than 7 days. Dose escalation did not occur until all three patients at the previous dose level had completed all weekly cycles of chemotherapy and the total planned dose of 3-D CRT.
Chemotherapy Dose Adjustments
RT All acute chemoradiotherapy toxicities were graded using the Common Toxicity Criteria of the National Cancer Institute (version 2.0). Late toxicity was scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scoring scheme.
Between January 2000 and August 2002, 22 men with unfavorable localized adenocarcinoma of the prostate were enrolled to the phase I trial with characteristics summarized in Table 1. Eleven men received neoadjuvant hormonal therapy and seven are currently undergoing adjuvant hormonal therapy. One additional patient was also enrolled to the protocol, but he experienced back and chest pain during two separate test runs of the docetaxel infusion, and refused further chemotherapy. The patient then went off protocol. None of the patients required any interruption of their chemoradiotherapy therapy treatments as a result of hematologic toxicity. The median number of weekly docetaxel infusions was eight (range, six to nine). Eleven patients received eight weekly docetaxel infusions, while 10 patients underwent nine weekly chemotherapy infusions. Conformal 3-D CRT was completed in all patients. In all patients, the prostate was treated to a total dose of 70.2 Gy, except in one patient who received a dose of 66.6 Gy, as he missed his last two treatment fractions because of noncompliance. The median number of elapsed days during the radiation therapy treatments was 56 (range, 54 to 64 days). The median number of days of treatment-related interruptions was 0 (range, 0 to 8 days). Only three patients experienced treatment-related interruptions of their chemoradiotherapy treatments lasting 1 (grade 2 hematuria), 2 (grade 2 diarrhea), and 8 (7 days due to grade 3 diarrhea, and 1 day due to abdominal cramping) days.
Toxicity Twenty-two patients were enrolled to weekly docetaxel dose levels of 5, 8, 12, 16, and 20 and 25 mg/m2. No DLT was observed at weekly docetaxel dose levels between 5 mg/m2 and 20 mg/m2. One patient at the 16 mg/m2 dose level experienced transient increases in his total bilirubin level which required two 25% dose reductions of the docetaxel dose but was not considered a DLT. This patient underwent only six weekly docetaxel infusions before the chemotherapy was discontinued because of persistently elevated total bilirubin levels as per protocol guidelines. Although this was not a DLT, two more patients were accrued to the 16 mg/m2 dose level to further ensure the safety of this dose level. DLT occurred in the first two patients treated at the 25 mg/m2 docetaxel dose level, both of whom experienced grade 3 diarrhea. These two patients experienced grade 3 diarrhea at 21.6 and 37.8 Gy dose level. Subsequently, the docetaxel doses were reduced by 25%, and both patients went on to tolerate their chemoradiotherapy treatments without any further significant toxicity. Hence, three more patients were then enrolled to the 20 mg/m2 dose level, for a total of six patients, and no DLT was observed. Overall, diarrhea occurred as follows: grade 0 in seven patients, grade 1 in five patients, grade 2 in eight patients, and grade 3 in two patients. The increasing severity of the diarrhea appeared to correlate with the docetaxel dose-intensity. For example, the incidence of grade 2 diarrhea increased from 33% at 8 and 12 mg/m2 dose levels, to 40% at the 16 mg/m2 dose level, to 50% at the 20 mg/m2 docetaxel dose level (Table 2). In all cases, the diarrhea was self-limiting or responsive to medication. The diarrhea caused interruption of the chemoradiotherapy treatments in only two patients; one treated at the 16 mg/m2 and the other one treated at the 25 mg/m2 weekly docetaxel dose level.
Dysuria was observed as follows: grade 0 in 15 patients, grade 1 in two patients, and grade 2 in the other five patients. Unlike acute diarrheal toxicity, the severity of the dysuria and urinary frequency did not correlate with docetaxel dose (Table 2), and were self-limiting or responsive to supportive medications. Dysuria was also either self-limiting or responsive to pyridium intervention in all cases. Dysuria did not cause interruption of therapy in any patients. Six (27%) of 22 patients did not experience any diarrhea or dysuria. Urinary frequency occurred in 10 of 22 patients; grade 1 in two patients and grade 2 in eight patients, requiring flomax intervention. Twelve patients did not experience any urinary frequency or urgency above their normal threshold. Four patients developed metabolic disturbances. One patient experienced hyponatremia (ie, sodium levels between 127 to 130 mEq/L), which reversed after chemoradiation therapy, while another patient experienced slight elevation of his creatinine levels (1.5 to 1.6 mg/dL), which also reversed after all therapy. As described previously, one patient experienced transient elevation of his total bilirubin levels (1.3 mg/dL) during weeks 2, 3, 6, and 7, which required two successive 25% dose reductions of the docetaxel dosing before the chemotherapy was discontinued as per protocol after he had received 6 weekly docetaxel infusions. In two other patients, transient mild increases of ALT (two patients) and AST (one patient) levels occurred during one to two infusions of docetaxel, which subsequently returned to normal levels by the next weekly infusion. No significant hematologic toxicity (grade 2 to 4) was encountered among the 22 patients (Table 3). No thrombocytopenia or neutropenia was observed in any of the 22 patients, including any grade 1 or higher toxicity. The only hematologic toxicity was grade 1 anemia defined by the National Cancer Institute Common Toxicity Criteria as hemoglobin values between 10 g/dL and the lower level of normal institutional value (ie, 14.1 g/dL). Fourteen of the 22 patients experienced grade 1 anemia; in five of these patients, the anemia was present before the start of the chemoradiotherapy treatments. In the other nine patients, the anemia developed after the start of the therapy. The hemoglobin level never dropped below 12 g/dL among these nine patients. None of the patients required any interruption of their chemoradiotherapy treatments as a result of hematologic toxicity.
Although the follow-up interval is relatively short, no significant subacute gastrointestinal (GI) toxicities have been observed. One patient required intermittent urinary catherization 10 months postcompletion of therapy, which resolved without any surgical intervention. Five patients have experienced a biochemical relapse, three of whom are currently undergoing salvage hormonal therapy. Seven patients are currently undergoing planned adjuvant hormonal therapy. One patient has experienced distant metastases to the bone. Seventeen patients remain in PSA remission. At a median follow-up interval of 8 months (range, 2 to 27 months), all patients are alive.
Few investigators have tested the novel concept of combining concurrent chemotherapy with RT in localized adenocarcinoma of the prostate.23 To our knowledge, this is the first trial which has investigated the use of concurrent docetaxel and RT for localized adenocarcinoma of the prostate. Our trial showed that the MTD of weekly docetaxel is 20 mg/m2 when delivered with concurrent 3-D CRT to 70.2 Gy at 1.8 Gy/fx given once daily. The radiation volume in our trial consisted of the whole pelvis, which was treated to 45 Gy followed by a boost to the prostate to 25.2 Gy using 3-D CRT. Since the DLT (ie, diarrhea) occurred during the whole pelvic portion of the RT treatment, one could surmise that even higher doses of docetaxel could have been safely delivered if we had not used whole pelvic irradiation. However, the recent results of Radiation Therapy Oncology Group trial 9413 validate our rationale for using whole pelvic RT in patients with high-risk prostate cancer.24 In this four arm randomized trial of men with high-risk prostate cancer, treatment with whole pelvic RT (in conjunction with neoadjuvant and concurrent hormonal therapy) resulted in 4-year progression-free survival of 61%, which was significantly better than other arms that used either more limited field volume confined to the prostate only or different schedules of hormonal therapy (range, 45% to 49%; P = .005). A few other studies have also evaluated combining chemotherapy with RT in prostate cancer.24-26 Zelefsky et al25 recently report their results in 27 patients treated with 3-D CRT to the prostate only (75.6 Gy) with neoadjuvant and concurrent estramustine phosphate and vinblastine (EV). Twenty-three (85%) of 27 patients completed the entire course of therapy. Two patients developed grade 3 hematologic toxicity and two patients developed grade 3 hepatotoxicity necessitating discontinuation of the chemotherapy and withdrawal from the treatment program. The 2-year actuarial likelihood of late grade 2 GI toxicity was 20%. The 2-year actuarial likelihood of late grade 2 and 3 genitourinary toxicities were 25% and 12%, respectively. Although these investigators concluded that neoadjuvant and concomitant EV with 3-D CRT is feasible for patients with high-risk prostate cancer, the incidence of late GI and genitourinary toxicities appeared to be increased compared with 3-D CRT alone or in combination with hormonal therapy. Ben-Josef et al26 also investigated the tolerability and feasibility of two 21-day neoadjuvant cycles of oral estramustine (10 mg/kg/d) and oral etoposide (50 mg/m2/d) followed by concurrent oral estramustine (10 mg/kg/d) and 3-D CRT to 70.2 Gy at 1.8 Gy/fx in 18 patients with locally advanced prostate cancer. Fourteen (78%) of 18 patients completed the entire course of therapy. Two patients required discontinuation of the neoadjuvant chemotherapy because of the development of grade 3 deep vein thrombosis and grade 4 myocardial infarction. Acute major toxicities included alopecia (100%), anemia (69%), leukopenia (37%), and thrombocytopenia (19%). Additionally, Khil et al27 reported their outcome with EV and RT for patients with locally advanced T2 to T4 prostate cancer. In this study, 65 patients were treated with concurrent EV (estramustine phosphate at 450 mg/m2 orally daily and vinblastine at 3 mg/m2 IV weekly) in combination with conventional external-beam RT (whole pelvis treatment to 45 Gy followed by a prostate boost to doses of 20 to 25 Gy). One grade 3 leukopenia and one grade 3 small bowel toxicity were observed, which required hospitalization in each case. In addition, one patient required a diverting colostomy for grade 4 radiation proctitis. In fact, the myelosuppression from the multiagent EV chemotherapy was so high that the last 19 patients were treated with only estramustine phosphate and concurrent 3-D CRT, as vinblastine was omitted from the treatment regimen. Although direct comparisons between our study and other trials is hampered by the difference in the design of the protocols (ie, phase I v phase II pilot studies), the various sequencing strategies for combining chemotherapy with radiation therapy (ie, concurrent v neoadjuvant/concurrent approach) and the different chemotherapeutic agents, relative assessment of the tolerability of these different chemoradiotherapy regimens is still worthwhile. Overall, weekly docetaxel with 3-D CRT was well tolerated in our trial. Generally, myelosuppression (ie, leukopenia and thrombocytopenia) was more frequent in these other studies25-27 as compared to our trial. For example, in comparison to the Ben-Josef study, the rates of leukopenia (37% v 0%) and thrombocytopenia (19% v 0%) were much lower in our trial. Of course, the lack of myelosuppression can be explained by the different chemotherapeutic agents (EV v docetaxel), their dosing schedules and toxicity profiles, and the design of the trials (phase II v phase I). Additionally, severe acute GI toxicity was more common, for example, in the Khil series (ie, grade 3 small bowel toxicity in one patient, grade 4 radiation proctitis requiring colostomy in another patient, and a grade 2 proctitis rate of 39%) compared with our series in which proctitis and small bowel toxicity were not observed. This may be attributed to our use of 3-D CRT, the treatment of patients with a full bladder, and the use of low residue diet before the initiating of therapy. Though our regimen was well tolerated, further confirmation of the feasibility and toxicity of concurrent docetaxel at 20 mg/m2 with 3-D CRT is still necessary, recognizing that the majority of patients treated in the current phase I trial were not treated at the MTD level. Traditionally, the recommended administration schedule of docetaxel has been once every 3 weeks. Picus and Schultz16 investigated every-3-week docetaxel schedule at 75 mg/m2 in 35 chemotherapy-naïve patients with hormone refractory prostate cancer (HRPC) and found that hematologic toxicity occurred in 43% of patients. Friedland et al17 conducted a similar phase II study of single-agent docetaxel at 75 mg/m2 every 3 weeks in 21 men with hormone refractory disease. Again, hematologic toxicities were predominant, with grade 3/4 neutropenia occurring in 71% of patients. Other phase I18-19 and phase II20 trials in HRPC using every-3-week dosing of docetaxel combined with estramustine have shown similar toxicity profiles as compared with trials using single-agent docetaxel therapy. In two phase I trials in HRPC18-19 using concurrent daily estramustine combined with escalating doses of docetaxel, the DLT was myelosuppression and the MTD of docetaxel was determined to be 70 mg/m2 every 3 weeks. In a phase II Cancer and Leukemia Group B trial conducted by Savarese et al20 using 70 mg/m2 docetaxel every 3 weeks combined with oral estramustine and low-dose daily hydrocortisone in HRPC, the predominant toxicity was grade 3/4 neutropenia, which occurred in 56% of patients. Data on the weekly administration schedule of docetaxel, compared with the every-3-week schedule, suggest it to be at least as equally efficacious with potentially fewer toxicities.21-22 For example, Berry et al21 conducted a multi-institution phase II study of weekly docetaxel (36 mg/m2/wk x 6 weeks, then 2 week rest) in 60 heavily pretreated HRPC patients and found infrequent myelosuppression. Therapy was well tolerated and the incidence of grade 3/4 neutropenia was just 3% of patients. Grade 3/4 asthenia and diarrhea were each reported in 10% of patients. A nearly identical study was conducted by Beer et al22 in 25 men who had not received prior chemotherapy. Patients received treatment with single-agent docetaxel at 36 mg/m2 weekly for 6 consecutive weeks of an 8-week cycle. Therapy was well tolerated, with 25% of patients experiencing grade 3/4 hematologic toxicity, and 36% of patients experiencing grade 3 nonhematologic toxicity. The lack of myelosuppression and the ease of tolerability of chemotherapy in our trial can be partially explained by the dose-intensity and the weekly dosing schedule of docetaxel. No thrombocytopenia or neutropenia were observed in our trial. The only observed hematologic toxicity was grade 1 anemia, which occurred in 14 of 22 patients. However, in five of these patients, the anemia was present before the start of the chemoradiotherapy treatments. Of note, the hemoglobin levels never dropped below 12 g/dL among the other nine patients who developed anemia after the start of therapy. Additionally, weekly docetaxel with concurrent 3-D CRT in our trial was easily tolerated. Nineteen patients in our trial did not require any interruptions of their chemoradiotherapy treatments. Only three patients experienced an interruption of their treatments. In two of these patients, the interruptions were only for 1 and 2 days; in only one patient, the interruption was somewhat prolonged (7 days) as a result of grade 3 diarrhea. Multiple phase I trials have been conducted to assess the combination of single-agent weekly docetaxel chemotherapy and RT in patients with non–small-cell lung cancer (NSCLC) and/or upper aerodigestive malignancies.28-29 Not surprisingly, the DLT of docetaxel in conjunction with chest RT has been esophagitis. Koukourakis et al28 investigated the radiosensitizing effects of weekly docetaxel (20 to 40 mg/m2/wk) and concomitant accelerated RT (60 to 64 Gy) in 30 patients with locally advanced NSCLC. DLTs (esophagitis, asthenia, and anorexia) occurred at the 40 mg/m2 weekly docetaxel dose level and the recommended phase II weekly docetaxel dose was 30 mg/m2. Mauer et al29 studied different schedules (once every 3 weeks, once every 2 weeks, or weekly) of concurrent docetaxel and thoracic RT (60 Gy in 6 weeks) in patients with NSCLC (n = 20) or esophageal carcinoma (n = 9). DLT consisted of grade 3 esophagitis and the MTD of weekly docetaxel was determined to be 20 mg/m2/wk. Not unexpectedly, the MTD of weekly docetaxel and concurrent pelvic/prostate RT in our trial is in the same range as the MTD of docetaxel in NSCLC or esophageal cancer with concurrent chest RT. In summary, our phase I trial showed that the combination of concurrent weekly docetaxel and 3-D CRT is well tolerated with acceptable toxicity. The MTD of weekly docetaxel was determined to be 20 mg/m2 with concurrent 3-D CRT. A phase II trial will be soon initiated to test the feasibility and efficacy of weekly docetaxel at 20 mg/m2 and concurrent RT in men with high-risk localized adenocarcinoma of the prostate.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Robert DiPaola, Aventis Pharma Ltd. Performed contract work within the last 2 years: Robert DiPaola, Aventis Pharma Ltd; Parvesh Kumar, Aventis Pharma Ltd. Received more than $2,000 a year from a company for either of the last 2 years: Robert DiPaola, Aventis Pharma Ltd; Parvesh Kumar, Aventis Pharma Ltd.
Supported partially by a grant from Aventis Pharmaceuticals. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Jemal A, Tiwari RC, Murray T, et al: Cancer statistics, 2004. CA Cancer J Clin 54:8-29, 2004 2. Hanks GE, Hanlon AL, Epstein B, et al: Dose response in prostate cancer with 8–12 years follow-up. Int J Radiat Oncol Biol Phys 54:427-435, 2002[CrossRef][Medline] 3. Consensus statement: Guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 37:1035-1041, 1997[CrossRef][Medline] 4. Pilepich MV, Winter K, John MJ, et al: Phase II Radiation Therapy Oncology Group (RTOG) trial 86–10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50:1243-1252, 2001[CrossRef][Medline] 5. Pilpepich MV, Winter K, Lawton C, et al: Phase III trial of androgen suppression adjuvant to definitive radiotherapy. Long term results of RTOG study 85–31. Proc Am Soc Clin Oncol 22:381, 2003 (abstr 1530)
6. Hanks GE, Pajak TF, Porter A, et al: Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92–02. J Clin Oncol 21:3972-3978, 2003
7. Bolla M, Gonzales D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337:295-300, 1997 8. Gastrointestinal Tumor Study Group. Survival after postoperative combination treatment of rectal cancer. N Engl J Med 315:1294-1295, 1986[Medline] 9. Tveit KM, Guldvog I, Hagen S, et al: Randomized controlled trial of postoperative radiotherapy and short-term time-scheduled 5-fluorouracil against surgery alone in the treatment of Dukes’ B and C rectal cancer. Br J Surg 84:1130-1135, 1997[CrossRef][Medline] 10. Nigro ND: Multimodisciplinary management of cancer of the anus. World J Surg 11:446-451, 1987[CrossRef][Medline] 11. Diaz JF, Andreu JM: Assembly of purified GDP-tubulin into microtubules induced by taxol and taxotere: Reversibility, ligrand stoichiometry, and competition. Biochemistry 32:2747-2755, 1993[CrossRef][Medline]
12. Ringel I, Horwitz SB: Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst 83:288-291, 1991
13. Hennequin C, Giocanti N, Favaudon V: Interaction of Ionizing Radiation with Paclitaxel (Taxol) and Docetaxel (Taxotere) in HeLa and SQ20B Cells. Cancer Res 56:1842-1850, 1996 14. Milas L, Milas MM, Mason KA: Combination of taxanes with radiation: Preclinical studies. Semin Radiat Oncol 9:12-26, 1999[Medline]
15. Mason KA, Hunter NR, Milas M, et al: Docetaxel enhances tumor radioresponse in vivo. Clin Cancer Res 3:2431-2438, 1997 16. Picus J, Shultz M: Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory cancer: Preliminary results. Semin Oncol 29:14-18, 1999 (suppl 17) 17. Friedland D, Cohen J, Miller R, et al: A phase II trial of docetaxel in hormone-refractory prostate cancer: Correlation of antitumor effect to phosphorylation of bcl-2. Semin Oncol 26:19-23, 1999 (5 suppl 7)
18. Kreis W, Budman DR, Fetten J, et al: Phase I trial of the combination of daily estramustine phosphate and intermittent docetaxel in patients with metastatic hormone refractory prostate carcinoma. Ann Oncol 10:33-38, 1999
19. Petrylak DP, Macarthur RB, O'Connor J, et al: Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 17:958-967, 1999
20. Savarese DM, Halabi S, Hars V, et al: Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: A final report of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol 19:2509-2516, 2001 21. Berry W, Dakhil S, Regich M, et al: Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol 28:8-15, 2001 (4 suppl 15)[CrossRef]
22. Beer T, Pierce WC, Lowe BA, et al: Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Ann Oncol 12:1273-1279, 2001 23. DiPaola R, Kumar P, Hait W, et al: State-of-the-art prostate cancer treatment and research. A report from The Cancer Institute of New Jersey. N J Med 98:23-33, 2001 24. Roach M 3rd, Lu JD, Lawton C, et al: A Phase III Trial Comparing Whole-Pelvic (WP) to Prostate Only (PO) Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression (TAS): Preliminary Analysis of RTOG 9413. Int J Radiat Oncol Biol Phys 51:3, 2001 (abstr 5)
25. Zelefsky MJ, Kelly WK, Scher H, et al: Results of a Phase II study using estramustine phosphate and vinblastine in combination with high-dose three-dimensional conformal radiotherapy for patients with locally advanced prostate cancer. J Clin Oncol 18:1936-1941, 2000 26. Ben-Josef E, Porter AT, Han S, et al: Neoadjuvant estramustine and etoposide followed by concurrent estramustine and definitive radiotherapy for locally advanced prostate cancer: Feasibility and preliminary results. Int J Radiat Oncol Biol Phys 49:699-703, 2001[CrossRef][Medline] 27. Khil MS, Kim JH, Bricker LJ, et al: Tumor control of locally advanced prostate cancer following combined estramustine, vinblastine, and radiation therapy. Cancer J Sci Am 3:289-296, 1997[Medline] 28. Koukourakis MI, Kourousis C, Kamilaki M, et al: Weekly docetaxel and concomitant boost radiotherapy for non-small-cell lung cancer. A phase I/II dose escalation trial. Eur J Cancer 34:838-844, 1998
29. Mauer AM, Masters GA, Haraf DH, et al: Phase I study of docetaxel with concomitant thoracic radiation therapy. J Clin Oncol 16:159-164, 1998 Submitted February 3, 2003; accepted March 2, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3 weeks until the laboratory values normalized, and the docetaxel was to be reinitiated at a 25% reduced dose. Furthermore, if patients developed an elevation of alkaline phosphatase (
