A Phase I Trial of Samarium-153-Lexidronam Complex for Treatment of Clinically Nonmetastatic High-Risk Prostate Cancer: First Report of a Completed Study

Int. J. Radiation Oncology Biol. Phys., Vol. 79, No. 3, pp. 732–737, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter

doi:10.1016/j.ijrobp.2009.11.011

CLINICAL INVESTIGATION

Prostate

A PHASE I TRIAL OF SAMARIUM-153-LEXIDRONAM COMPLEX FOR TREATMENT OF CLINICALLY NONMETASTATIC HIGH-RISK PROSTATE CANCER: FIRST REPORT OF A COMPLETED STUDY RICHARD K. VALICENTI, M.D.,* EDOUARD TRABULSI, M.D.,y CHARLES INTENZO, M.D.,z JOROSALI LAVARINO, B.S.,* YIHUAN XU, M.S.,x AND INNA CHERVONEVA, PH.D.x *Department Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA, and Departments of yUrology, z Radiology, and xPharmacology, Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA Purpose: We completed a Phase I trial to determine the maximum tolerated dose of samarium-153 EDTMP (153Sm) with hormonal therapy (HT) and radiation therapy (RT) in high-risk clinically nonmetastatic prostate cancer. Methods and Materials: High-risk M0 prostate cancer patients (prostate-specific antigen >20 ng/mL, Gleason score >7, or >T3) were eligible for this prospective trial of dose-escalated radioactive 153Sm-EDTMP (.25–2.0 mCi/kg) as primary or postoperative therapy. After 1 month of HT, we administered 153Sm-EDTMP followed by 4 more months of HT, 46.8 Gy to the pelvic region and 23.4 Gy to the prostate target (TD = 70.2 Gy). The primary endpoint was Grade III toxicity or higher by the National Cancer Institute Common Toxicity Criteria. Results: Twenty-nine patients enrolled (median prostate-specific antigen = 8.2 ng/mL, 27/29 (93%) T stage $T2b, 24/29 (83%) had Gleason >7) and received 153Sm-EDTMP (.25 mCi/kg, 4 patients; 0.5 mCi/kg, 4 patients; 0.75 mCi/kg, 6 patients; 1.0 mCi/kg, 6 patients; 1.5 mCi/kg, 5 patients; 2.0mCi/kg, 4 patients). Twenty-eight patients underwent all planned therapy without delays (1 patient required surgery before the start of RT). With a median follow-up time of 23 months, there were 2 patients (7 %) experiencing Grade III hematologic toxicity. There were no other Grade III or IV side effects. Conclusions: Our trial demonstrates that 2 mCi/kg 153Sm -EDTMP with HT and RT was safe and feasible in men with high-risk M0 prostate cancer. A Phase II study to test this treatment is currently underway by the Radiation Therapy Oncology Group. Ó 2011 Elsevier Inc. Prostate cancer, Hormonal therapy, Radiation therapy, Samarium-153.

prostate cancer (4–11). In particular, beta-emitting radiopharmaceuticals such as samarium-153 ethylenediaminetetramethylenephosponate (153Sm-EDTMP) and strontium-89 have been devised that selectively irradiate osteoblastic metastases, with minimal or no effect on normal tissue, by binding to hydroxyapatite. With these agents, reported palliative response rates have ranged from 55% to 80% (5, 7, 10, 11). Response duration has been reported to range from 2 to 17 weeks, with one study noting that 50% of responses lasted 16 weeks. Less than 10% of patients had National Cancer Institute Toxicity Criteria Grade III/IV bone marrow toxicity. Clinical trials testing radiopharmaceuticals to treat metastatic disease beyond palliation have been developed (12–14). Tu et al. (12) found that bone-targeted radiation therapy with one dose of strontium-89 and doxorubicin enhanced antitumor activity and improved overall survival

INTRODUCTION Prostate cancer is a common cause of cancer morbidity and mortality. It is estimated that 192,280 new cases of prostate cancer were diagnosed in 2009, and approximately 27,000 died of disease (1). Approximately 25% of men with locally advanced prostate cancer develop bony metastatic disease despite aggressive treatment with radiation therapy and hormonal therapy (2). In fact, the majority of men dying of prostate cancer have bone as the only site of metastasis (3). Complications from skeletal metastases dominate the clinical course of advanced prostate cancer and are the primary cause of death in most patients. Because of this predictable pattern of progression, the development and clinical evaluation of effective bone-targeted therapy will benefit patients. Multiple clinical trials have evaluated the palliative benefits of bone-targeted radiation therapy in advanced metastatic

Reprint requests to: Richard K. Valicenti, M.D., M.A., Department of Radiation Oncology, UC Davis School of Medicine, 4501 X Street, Ste, 0140, Sacramento, CA 95817. Tel: (916) 734-7888; Fax: (916) 703-5069; E-mail: [email protected] Supported by funding from Berlex Laboratories and Cytogen Cooperation.

Presented at the 50th Annual Meeting of the American Society of Therapeutic Radiology and Oncology, September 2008. Conflict or interest: none. Received July 22, 2009, and in revised form Nov 10, 2009. Accepted for publication Nov 16, 2009. 732

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Patient exclusion criteria

153 Smlexidronam

Clinically nonmetastatic high-risk prostate cancer

TAB 1 month

0.25 mCi/kg 0.5 mCi/kg 0.75 mCi/kg 1.0 mCi/kg 1.5 mCi/kg 2.0 mCi/kg

733

TAB 2 months

RT + TAB 2 months

Follow-Up

Fig. 1. Study schema demonstrating evaluation of dose-escalated 153 samarium-lexidronam and sequential treatments. TAB = total androgen blockade. RT = radiation therapy.

in selected patients who responded to sequential chemotherapy (12). In their study, patients with advanced metastatic androgen-independent prostate cancer who had consolidation bonetargeted radiation therapy after induction chemotherapy had improved time to progression (14 vs. 7 months, p <0.0001) and overall survival (27.7 vs. 16.8 months, p = 0.0001). The Tu study provides rationale for additional work testing bone-targeted therapy as a valuable treatment paradigm in men with advanced prostate cancer. The benefits of this treatment strategy have yet to be tested in hormone naı¨ve, clinically nonmetastatic prostate cancer patients. As the first step to study this innovative approach in this patient population, we designed and conducted a Phase I study to determine the feasibility and tolerability and initial efficacy of administering 153Sm-EDTMP sequentially with hormonal therapy (HT) and external beam radiation therapy (RT). METHODS AND MATERIALS Study design This trial was a Phase I open-label dose-escalation study designed to determine the maximal tolerated dose (MTD) of 153Sm-EDTMP administered intravenously in a single dose after 1 month of HT and 2 months before starting RT in men with high-risk clinically nonmetastatic prostate cancer. The dose-limiting toxicity was Grade III or higher hematologic toxicity (Common Terminology Criteria for Adverse Events, version 3.0, for toxicity). Protocol treatment was according to the schema in Fig. 1. Patient cohorts were treated with 153 Sm-EDTMP doses of 0.25 0.5, 0.75, 1.0, 1.5, and 2.0 mCi/Kg. Before patients were treated with doses greater than 1.0 mCi/Kg, the toxicity was reviewed by the U.S. Food and Drug Administration before proceeding. All patients were required to sign an institutional review board–approved informed consent form before study entry.

Inclusion criteria Patients had to have histologically confirmed prostate cancer at high risk for relapse as determined by one or more following poor prognostic categories: (1) prostate specific antigen (PSA) 20–150 and Gleason score $7 (any T stage); or (2) clinical or pathologic stage $T2 and Gleason score $8 (PSA #150) or; (3) pathologically positive lymph nodes. Patients having prior radical prostatectomy within 6 months of enrollment were eligible if they fit one of these poor prognostic categories. Pretreatment serum PSA was mandatory before study entry and any treatment. It was also required that the Zubrod Performance Status was 0–1, white blood cell count >3000/mL, a platelet count >130,000/mL, and a hemoglobin level >11.5 g/dL. Prior pharmacologic HT was allowed only if the onset was less than 30 days before date of study entry and a complete blood count was done within 2 weeks.

A pretreatment PSA elevation >150 ng/mL or a prostate cancer tumor with neuroendocrine features excluded patients from the trial because of the more likely probability of micrometastatic visceral metastasis and more aggressive phenotype of neuroendocrine tumors. Other exclusion criteria included radiographic evidence of M1 disease, prior pelvic RT, prior orchiectomy, previous chemotherapy for malignancy within the past 5 years, or previous or concurrent invasive cancers other than superficial nonmelanomatous skin cancers. Major medical or psychiatric illness that would prevent completion of treatment and interfere with follow-up also excluded patients from the study.

Protocol treatment Samarium-153 EDTMP was administered as a single dose after 1 month of HT by a physician licensed in the use of radioisotopes (CI). All patients received initially 5 months of neoadjuvant HT, consisting of an LHRH analogue (leuprolide or goserelin) and nonsteroidal antiandrogen (flutamide 250 mg three times daily or bicalutamide 50 mg daily). Total androgen suppression began 3 months before initiation of RT. Radiation therapy consisted of pelvic field irradiation to the regional lymphatics to a dose of 46.8 Gy and prostatic boost to a total dose of 70.2 Gy. Daily tumor doses were given 1.8 Gy per day, 5 days per week for 7–8 weeks. Field arrangements were the four-field technique for the regional lymphatic volume and four or six three-dimensional field technique for the prostate boost volume.

Protocol assessments Before study entry, the mandatory laboratory studies (obtained within 4 weeks before study entry) included completely blood count, alanine aminotransferase (ALT), alkaline phosphatase, blood urea nitrogen (BUN), creatinine, testosterone, and PSA. Pelvic lymph node assessment (within 6 months before study entry) by one of the following procedures was obtained: pelvic CT or MRI, ProstaScint (Cytogen Corporation, Princeton, NJ), or pelvic lymph node dissection or sampling (either via laparotomy or laparoscopically). A bone scan was also required. Acute hematologic effects were evaluated weekly until 12 weeks after administration of 153 Sm-EDTMP. Hematologic toxicity was scored using the National Cancer Institute Common Toxicity Criteria. All patients were seen weekly during RT. Any observations regarding reactions were recorded and included attention to the following adverse effects involving skin reactions, small bowel or rectal irritation manifesting as abdominal cramping, diarrhea, rectal urgency, or hematochezia. Bladder effects included urinary frequency, dysuria, hematuria, urinary tract infections, and incontinence. Serum ALT, alkaline phosphatase, bilirubin, BUN, creatinine, and testosterone levels were obtained every month during oral antiandrogen therapy. Complete blood counts were evaluated 4–6 weeks after completion of RT and every 3 months thereafter in the first year after RT. History and physical exam, weight, performance status, CBC with differential, PSA, and testosterone assessments were conducted every 6 months for the next 2 years, and annually thereafter.

Statistical analysis We used a two-stage accrual design at each 153Sm-EDTMP dose level, with the initial 3 patients at each dose. If none experienced a dose-limiting toxicity, we proceeded to the next dose; if one had toxicity, three more were accrued at that dose. If at any time there were two or more dose-limiting toxicities (in the 3–6 subjects) on a given dose, we would terminate accrual. Patients were not treated at a higher dose until the 3 or 6 patients had completed toxicity

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Table 1. Patient characteristics Characteristic

Value (n = 29)

Age Race African American White Total Gleason score 7 8 9 10 T stage T1 T2 T3 Median PSA (range)

68 (51–84) 3 (10%) 26 (90%) 5 (17%) 14 (48%) 9 (31%) 1 (3%) 2 (7%) 16 (55%) 11 (38%) 8.2 ng/mL (0.2–69)

Abbreviation: PSA = prostate-specific antigen. evaluation period at the current dose. With this plan, a dose with a 50% or greater probability of causing a dose-limiting toxicity had a 12.5% chance of satisfying the conditions of dose escalation after the first three subjects and at least a 50% chance of stopping at three. With the two stages (3–6) together, there was at most a 17.2% chance of escalation. The MTD was the last dose studied or the previous dose, based on clinical judgment of the degree of toxicity seen at the last dose. While waiting for the 3 or 6 subjects accrued according to plan to complete their toxicity evaluation period, additional subjects were accrued at the current dose. The additional patients were not counted toward the formal plan of stopping at two or more toxicity occurrences but would contribute to the determination as to the MTD. All estimates of rates of toxicity were made using the exact method (15, 16). Secondary endpoint included the PSA response below 0.2 ng/mL with a noncastrate testosterone level.

Sm-EDTMP. Thus, 29 patients were included in the analysis, with 10 (35%) having had a radical prostatectomy. Patient demographic information is shown in Table 1. Twenty-four (83%) had Gleason score 8 or higher tumors, and 27 (93%) had T2 or T3 prostate cancer. At least four patients were treated at each dose level of 153Sm-EDTMP. Safety and tolerability With a median follow-up time of 23 (range, 5–57) months, two patients (6.8%) experienced Grade III hematologic toxicity (Table 2). Except for one case of Grade III dermatitis, there were no other Grade III or IV side effects. Thus, we were able to identify the MTD as 2.0 mCi/Kg of 153 Sm-EDTMP. As Fig. 2a–2c indicates, platelet counts reached a nadir between 3 and 6 weeks following 153Sm-EDTMP administration, with recovery approaching baseline values around 12 weeks. There was a significant dose–response relationship in the mean nadir platelet count at 4 weeks after 153SmEDTMP administration (p = 0.023). Platelet count was 189  103/mL (95% confidence level [CL], 140–240  103/mL) after #0.5 mCi/kg (level 1 and 2, 7 patients), 99/mL (95% CL, 60–138  103/mL) after medium dose (level 3 and 4, 11 patients), and 128/mL (95% CL, 82–173  103/mL) after high dose (level 5 and 6, 8 patients). The hemoglobin levels and white blood cell count tended to drift downward within 12 weeks of 153Sm-EDTMP administration. At last follow-up, 26 of the 29 patients had platelet counts within 25  10 3 /mL of baseline (Fig. 3a–3c), whereas the white blood cell count was lower than baseline in 27 patients. The hemoglobin levels were within 2. 0 g/ dL in 26 of the 29 patients at last follow-up. Only one patient required erythropoietin for support.

RESULTS Patient characteristics From March 15, 2003, to February 15, 2008, 30 men agreed to participate on the trial by signing informed consent. One man was excluded because he refused to receive

Efficacy In this Phase I trial, treatment efficacy was a secondary endpoint. This endpoint was the PSA response below 0.2 ng/mL with a noncastrate testosterone level (Figure 4). At a median

Table 2. Toxicity Parameter Hemoglobin* Plateletsy WBCsz

Toxicity grade

Level 1 (n = 4)

Level 2 (n = 4)

Level 3 (n = 6)

Level 4 (n = 6)

Level 5 (n = 5)

Level 6 (n = 4)

0–2 3 4 0–2 3 4 0–2 3 4

3 (75) 1 (25) 0 4 (100) 0 0 4 (100) 0 0

4 (100) 0 0 4 (100) 0 0 4 (100) 0 0

6 (100) 0 0 5 (83) 1 (17)£ 0 5 (83) 1 (17)£ 0

6 (100) 0 0 6 (100) 0 0 6 (100) 0 0

5 (100) 0 0 5 (100) 0 0 5 (100) 0 0

4 (100) 0 0 4 (100) 0 0 4 (100) 0 0

Abbreviation: WBCs = white blood cells. Data in parentheses are percentages. * Hemoglobin: Grade 0–2, $8.0 g/dL; Grade 3, 6.5–7.9 g/dL; Grade 4, <6.5 g/dL. y Platelets: Grade 0–2, $50,000/mL; Grade 3, 10,000–49,000/mL; Grade 4, <10,000/mL. z WBCs: Grade 0–2, $2,000/mL; Grade 3, 1,000–1,900/mL; Grade 4, <1000/mL. £ these two records belonged to same patient.

Radiotherapy field in choroid plexus carcinoma. d R. K. VALICENTI et al.

(a)

9 8 7 6 5 4 3 2 1 0

14 12

level 1 level 2 level 3 level 4 level 5

WBC (1000/mcl)

WBC (1000/mcl)

(a) 10

735

level 6

10

6 4 2 0

0

5

10

Baseline Last Followup Lower Limit

8

15

0

10

20 Case NO

30

40

Week

(b)

HGB (g/dl)

15

level 1

14

level 2 level 3

13

level 4 level 5

12

level 6

11 10

HGB (g/dl)

(b) 16

0

5

10

20 18 16 14 12 10 8 6 4 2 0

Baseline Last Followup Lower Limit

0

10

20 Case NO

30

40

15

(c) 600

Week

(c) PLT (1000/mcl)

370 level 1

320

level 2

270

level 3

220

level 4

170

level 5

400

Baseline Last Followup Lower Limit

300 200 100 0

0

10

20 Case NO

30

40

level 6

120 70

PLT (1000/mcl)

500

Fig. 3. (a) White blood cell count (WBC), (b) hemoglobin (HGB), and (c) platelets recovery at last follow-up. 0

5

10

15

Week

Fig. 2. Plots of (a) white blood cell count (WBC), (b) hemoglobin (HGB), and (c) platelets (PLT) during 12 weeks after samarium153 treatment.

follow-up of 23 months, no patient has developed clinical progression or died. There were 18 patients assessed for PSA response and who also had received 153Sm-EDTMP as high as 1.5 mCi/Kg. These patients were followed for at least 8 months and evaluated every 1–3 months by obtaining a PSA and testosterone levels. Three patients were placed back on HT because of a sharply rising PSA. Fourteen patients had noncastrate levels of testosterone (>50 ng/dL), and all had PSA levels below or at 0.5 ng/mL. Of these 18 patients, 12 (66%) had a PSA level <0.2 ng/mL at last follow-up.

DISCUSSION 153

The use of Sm-EDTMP in conjunction with HT and RT has never been evaluated in high-risk clinically localized

prostate cancer. The majority of men with high-risk prostate cancer develop progressive disease within 5 years of combined HT and RT, indicating that subclinical metastases may be present at the time of initial diagnosis (17, 18). In these high-risk patients, there may be a therapeutic benefit of combining HT with RT and other adjuvant systematic treatments (19). To this end, we successfully carried out a Phase I study to determine the MTD of 153Sm-EDTMP administered sequentially with neoadjuvant HT and RT in men at high risk for subclinical bone metastases. The dose-limiting toxicity was Grade 3 or higher hematologic toxicity according to common toxicity criteria (CTC). This regimen was found to be well tolerated and feasible. There were only two Grade III hematological events, with all patients recovering from declines in their blood counts. The tolerability of 153Sm-EDTMP given with external beam RT and HT supports the development of a Phase II study in the treatment of high risk prostate cancer. The doses of 153Sm-EDTMP assessed ranged from 0.25 to 2.0 mCi/kg. These doses were selected because they have

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TESTOS (ng/dl)

(a) 1000 900 800 700 600 500 400 300 200 100 0

Level 1 Level 2 Level 3 Level 4 Level 5

0

10

20

30

40

50

60

PSA (ng/dl)

(b)1000 TESTOS (ng/dl)

900 800 700

Level 1

600

Level 2

500

Level 3

400

Level 4

300

Level 5

200 100 0

0

0.1

0.2

0.3

0.4

0.5

PSA (ng/dl)

Fig. 4. Testosterone (TESTOS) vs. prostate-specific antigen (PSA) at last follow-up. This is subset of patient with a PSA less than 0.5 ng/dL at last follow-up.

been shown effective in advanced metastatic patients (5–11). Twenty-nine patients enrolled and completed acute toxicity evaluation. We were able to administer safely doses as high as 2.0 mCi/kg of 153Sm-EDTMP with HT and RT. Four patients have received the 2.0 mCi/kg of 153Sm-EDTMP without experiencing Grade 3 or higher hematological toxicity. All patients tolerated prostatic external beam irradiation without any delays or untoward complications. Thus, the MTD of 153 Sm-EDTMP is 2.0 mCi/kg. This dose of 153Sm-EDTMP is estimated to be approximately equivalent to an effective bone surface radiation dose of 50.0 Gy (10).

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Similar to other published data, 153Sm-EDTMP causes transient and reversible hematologic toxicity in most patients (5, 10, 11). In patients who receive a 1.0 mCi/Kg dose, there is typically a 40%–50% reduction in white blood cells and platelets, with a nadir at 3–5 weeks, which generally returns to pretreatment levels by 8 weeks (5). At doses as high as 2.0 mCi/Kg, we found that the pattern of count decline and recovery were in line with these parameters. In our study, the doses of 153Sm-EDTMP were selected on the basis of results from previously published Phase III studies in patients with metastatic prostate cancer (5, 6). At a 1.0mCi/Kg dose, 64% of patients reported pain relief at 4 weeks for a median duration of 16 weeks. The starting dose for the first cohort of patients was 0.25 mCi/Kg given intravenously. This dose was 8 times less than the highest dose that was administered to patients with metastatic cancer in several Phase III studies (10). In previously published studies, the antitumor effects of 153Sm-EDTMP have been demonstrated at doses of 0.5 and 1.0 mCi/Kg (9, 10). Although not a primary endpoint of our study, we found that there was suggestion of antitumor effects by PSA nadirs sustainable below 0.2 ng/mL after testosterone recovery. Given the diversity of our patient population and varying 153Sm-EDTMP doses, this response is not readily comparable to historical controls. This study had several limitations, including short followup, small number of patients at each dose level, and diversity of primary treatment (postoperative RT and primary RT). In particular, given the lack of long-term PSA data and pretreatment with HT in all patients, the duration of tumor control was not accurately assessed in this study and should be interpreted cautiously. CONCLUSIONS This Phase I trial demonstrates that 153Sm-EDTMP is well tolerated when administered with RT and HT for high-risk clinically nonmetastatic prostate cancer. Furthermore, the safety profile justifies the prospective evaluation of this agent regarding efficacy in men with nonmetastatic prostate cancer.

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