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Doi:10.1016/j.urology.2006.10.007

Adult Urology
Phase II Trial of Gemcitabine, Prednisone,and Zoledronic Acid in Pretreated Patientswith Hormone Refractory Prostate Cancer Giuseppe Di Lorenzo, Riccardo Autorino, Mario Giuliano, Emilio Morelli,Antonio Giordano, Giorgio Napodano, Aniello Russo, Giuseppe Benincasa,Massimino D’Armiento, Vincenzo Altieri, and Sabino De Placido To investigate the impact on biochemical and objective response and on pain improvement ofgemcitabine, prednisone, and zoledronic acid in patients with hormone-refractory prostatecancer (HRPC), previously treated with docetaxel-based regimens.
The patients were treated with gemcitabine 1000 mg/m2 every 14 days, prednisone 10 mg orallyon days 1 to 7 and 14 to 21, and zoledronic acid every 4 weeks. Changes in prostate-specificantigen levels, tumor response, and toxicity were evaluated every month. The pain response,based on pain reduction and analgesic drug reduction, was assessed during therapy.
A total of 22 men (median age 65 years) were treated. Overall, 5 patients (23%) achieved a 50%or greater reduction in prostate-specific antigen level after two cycles; a partial response wasobserved in 1 (14%) of 7 patients with measurable disease, and 3 (43%) of 7 had stable disease.
Of the 22 men, 23% had pain improvement. The most important hematologic toxicity wasneutropenia (grade 3 in 18%).
The combination of gemcitabine, prednisone, and zoledronic acid appears to be associated withbiochemical response, pain improvement, and good safety in pretreated patients withHRPC.
UROLOGY 69: 347–351, 2007. 2007 Elsevier Inc.
Prostate cancer is the most common malignancy However,duringthepast5years,thepreviousskepticism affecting men in the United States and Western has been challenged by the development of new agents Europe. In 2005, approximately 200,000 men will and combinations, thanks to an increased understanding have been diagnosed with prostate cancer and 30,000 of the biology of this form of prostate cancer and the men will have died secondary to metastatic prostate evaluation of more appropriate response criteria, such as prostate-specific antigen (PSA) levels and the quality of Metastatic prostate cancer responds to androgen de- privation for a variable period. In this respect, treatment Recently, the results of the TAX 327 and Southwest- with luteinizing hormone-releasing hormone analogues, ern Oncology Group (SWOG) 99-16 trials have shown with or without combined treatment with antiandrogens, for the first time that the taxane-based regimens not only leads to objective responses, with an interval to progres- improved QOL and PSA response in HRPC, but also sion of 20 to 25 months. Prostate cancer that grows extended the overall survival of patients undergoing despite castrate levels of testosterone and that no longer This is the first time that a chemotherapeu- responds to any form of hormonal manipulation and for tic regimen has been shown to improve survival for which nonhormonal approaches are required has been patients with HRPC, and the results represent a signifi- defined as hormone-refractory prostate cancer cant milestone in treatment. However, the efficacy of the Until recently, no chemotherapeutic approach has drug has not been universally effective, and nearly all been available for HRPC to improve overall survival.
patients have progression after docetaxel treatment.
After failure of a docetaxel regimen, what can we do? From the Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia It is possible to treat the patients with a second or Molecolare e Clinica, Università degli Studi di Napoli “Federico II”; Clinica Urologica, third-line regimen or to provide only supportive It Seconda Università degli Studi Napoli, Napoli; Urologia, Casa di Cura Villa Maria, is important to consider the clinical conditions of the Mirabella Eclano, Avellino; Clinica Urologica, Università degli Studi di Napoli “Fed-erico II”, Napoli; and UO Urologia, Ospedale San Luca, Vallo della Lucania, Italy patients and a potential therapy that can improve QOL Reprint requests: Giuseppe Di Lorenzo, M.D., Cattedra di Oncologia Medica, with a good toxicity profile would be well accepted. To Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università degli Studi date, no standard second-line chemotherapy regimen has di Napoli “Federico II”, Napoli, Italy. E-mail: giuseppedilorenzoncol@hotmail.com Submitted: March 19, 2006, accepted (with revisions): October 5, 2006 been defined and no survival benefit has been demon- strated for additional chemotherapy after failure of front- pain intensity evaluation, and analgesic consumption eval- uation. The hemoglobin, neutrophil, and platelet counts Gemcitabine is a nucleoside analog with activity were repeated every week. The PSA measurement and pain against a broad spectrum of solid Previous stud- response assessment were analyzed every 2 weeks. The clin- ies in pancreatic cancer have shown considerable im- ical laboratory test (liver and kidney function and serum provement in QOL using a gemcitabine-based calcium dosage) results were recorded every 4 weeks. CT in As a result, the term “clinical benefit response” was patients with measurable disease was repeated after twocycles (2 months).
introduced as a primary endpoint to evaluate the efficacy The primary endpoints were the assessment of response (bio- of gemcitabine, and the drug is now considered as the chemical, objective, and pain responses). The secondary end- reference treatment for advanced pancreatic cancer. The points included toxicity and survival. The PSA response was clinical benefit response is defined as a composite assess- defined as a reduction from baseline of greater than 50% on two consecutive measurements taken at least 2 weeks apart. Pro- The third-generation bisphosphonates zoledronic acid gression was defined as a greater than 25% increase in PSA was found to potentially suppress the proliferation of level in two consecutive measurements taken at least 2 weeks prostate cancer. It has recently been shown to increase apart. For patients with bi-dimensionally measurable disease, a apoptosis of cell lines in vitro and to significantly inhibit complete response was defined as the resolution of bi-dimen- the growth of osteoblastic and osteolytic metastases in sionally measurable masses and a partial response was defined as vivo. In an international, multicenter, randomized trial of 422 men with HRPC and bony metastases, treatment The pain response was measured using a self-administered with zoledronic acid for 15 months led to a statistically numerical rating scale (part of the Brief Pain The significant reduction in skeletal-related events (SREs), Brief Pain Inventory pain assessment uses an 11-point scale (0 including fractures. In addition, a significant delay oc- to 10), with 0 representing no pain and 10 representing pain as curred in the onset of the first Currently, severe. The “worst pain,” “least pain,” “average pain of last zoledronic acid is approved by the U.S. Food and Drug days,” and “pain right now” values were recorded every 2 weeks.
Administration for the prevention of SREs in HRPC and Analgesic use was self-recorded daily and assigned oral mor- should be used as the standard treatment in this setting.
phine equivalents before analysis. Analgesic scores were re-corded by the investigator on the basis of the type of pain We conducted a study to evaluate the impact of gem- medication administered (0, none; 1, minor analgesics; 2, tran- citabine, prednisone, and zoledronic acid on PSA re- quilizers and antidepressants; 3, mild narcotic; and 4, strong sponse, tumor response, pain response, and toxicity pro- narcotic) and were a modification of a Radiation Therapy file in patients with HRPC, previously treated with Oncology Group analgesic The primary assessment of pain was the difference in the “worst pain” value every 2 weeks.
Pain improvement was characterized by a greater than 50% reduction in analgesic consumption, coupled with a greaterthan 50% decrease in the worst pain value. Pain deterioration Patients with HRPC who had been previously treated with was defined as any increase of the initial worst pain by more docetaxel chemotherapy (docetaxel 75 mg/m2 every 3 weeks) than 50% of the value before treatment, coupled with in- were eligible. The eligibility criteria included disease progres- creased, or at least stable, analgesic consumption.
sion (biochemical and/or objective) with previous chemother- Toxicity was assessed every week using the National Cancer apy, the presence of pain, and the use of analgesics. Continued Institute Toxicity Scale. If the platelet or neutrophil counts use of a luteinizing hormone-releasing hormone agonist was decreased to less than 75,000 or 1000 ␮L, respectively, chemo- required for those who had not undergone bilateral orchiec- therapy was discontinued until the counts had increased to tomy. No previous chemotherapy, prednisone, or radiotherapy greater than these levels. Granulocyte colony-stimulating factor was allowed within 21 days of study entry.
use was permitted. Treatment was also interrupted for nonhe- Biochemical progression, after a previous line of chemother- matologic toxicity worse than grade 3.
apy, was defined as a greater than 25% PSA increase between The treatment was administered until disease progression two independent measurements performed with a 2-week inter- (biochemical or objective progression) and pain had increased.
val. Second-line chemotherapy (mitoxantrone, vinorelbine, or If the PSA level increased but pain had improved, the patients other chemotherapeutic agents) and other bisphosphonates (eg, pamidronate, clodronate) were permitted. Previous zoledronicacid was not permitted. Patients were also required to have The sample size was determined from the overall biochemical adequate major organ function, including normal creatinine response rate. According to Simon’s two-stage minimal design, clearance. All patients were required to provide written in- assuming that the expected response rate would be at least 25% formed consent before enrollment in the trial.
and the minimal acceptable response rate was 10%, a sample of Gemcitabine (1000 mg/m2 intravenously) was administered 22 patients would be required in the first step. If a minimum of on days 1 and 14 every 28 days, prednisone (10 mg orally) was three responses was observed, 40 patients would be accrued.
administered on days 1 to 7 and 14 to 21, and zoledronic acid Thus, if at least eight responses occurred, the probability of (4 mg) was administered every 28 days in a 15-minute infusion.
accepting a treatment with a real response rate of less than 10% Patients underwent a physical examination, Karnofsky per- formance status assessment, determination of biochemical pa- Overall survival was estimated using the Kaplan-Meier prod- rameters (including basal PSA), bone scan, total body CT, * Among 4 patients with visceral lesions, treated to four cycles.
PSA ϭ prostate-specific antigen; LDH ϭ lactate dehydrogenase.
Data expressed as median, with range in parentheses.
Evaluation performed before each cycle (every two administra-tions of gemcitabine).
From March 2004 to July 2005, 22 patients enrolled in * Worst pain value from Brief Pain Inventory.
the study. We stopped the trial after 22 patients (firststep) because of the difficulty in enrolling patients withthose eligibility criteria. Today, zoledronic acid is often category and a decrease in analgesic consumption, reduc- used in first-line treatment of symptomatic patients with ing their use of strong narcotics by 50%. sum- marizes the results of the responding patients. Of the 5 The baseline characteristics of the 22 patients are patients with a PSA decrease of greater than 50%, 1 had described in All patients were pretreated with a already received mitoxantrone as a second-line therapy.
docetaxel regimen. Also, 11 patients (50%) received Two SREs (9%) occurred. Both were pathologic fac- second-line chemotherapy (9 received mitoxantrone and tures (vertebral) and required radiotherapy to the bone 2 vinorelbine). Of the 22 patients, 9 (41%) had a bio- chemical response to docetaxel; 3 (33%) of the 9 who Of the 7 patients with measurable metastatic disease, 1 received mitoxantrone as second-line therapy had a PSA had partial response, 3 had stable disease, and 3 had response. All patients completed two cycles, 7 patients disease progression after two cycles. A partial response completed four cycles, and 2 completed six cycles.
was found in the lung. After four cycles, 1 patient had As shown in of the 22 patients evaluated for stable measurable disease and continued therapy for six PSA response, 5 (23%) had a greater than 50% decrease in PSA level, and 2 patients (9%) had a PSA reduction The grade 1 to 4 toxicities are summarized in of less of 50% after two cycles. The same 5 patients had Grade 1 and 2 neutropenia and anemia was reported in 5 a pain response, with a positive response in the pain (23%) and 3 (14%) patients, respectively. Grade 3 neu- Table 4. Treatment-related toxicities for all cycles of 8, and 15 of a 28-day cycle. The response was determined by the PSA level (a complete response was normalizationof the PSA level and a partial response was a greater than 50% decrease). Of 43 patients, 3 (relative risk 7%) had a PSA response, and 7 (16%) had stable disease for a median duration of 7.1 months (range 6.1 to 11.7). One patient had objective regression of lymph node metasta- ses. Patients reported a considerably impaired health sta- tus/QOL and severe fatigue at baseline, with no change during treatment. Pain, which was evaluated using the Quality of Life Questionnaire-C30 questionnaire, wassevere at baseline but had decreased at the end of cycles1, 2, 3, and 4. Patient-rated pain and the use of analgesicsas a combined endpoint yielded palliation for at least 8 tropenia occurred in 4 patients (18%) and was reversible weeks in 14 patients (32%). Of these 14 patients, 9 had with administration of granulocyte colony-stimulating at least stable disease and 5 indicated a benefit despite factor. Grade 3 and 4 thrombocytopenia developed in 2 progressive disease. Hematologic toxicity of gemcitabine (9%) and 1 (4.5%) patients, respectively; it was revers- led to a dose reduction in 48% of all cycles. Gemcitabine ible after treatment interruption for 1 week and did not in the dose and schedule used in this trial had a beneficial require a dose reduction. One patient reported grade 3 effect on pain in patients with HRPC despite its limited diarrhea. No treatment-related deaths occurred.
activity in terms of PSA response and considerable, es- After disease progression with this regimen, the pa- pecially hematologic, In contrast to the previ- tients received supportive care. The median survival was ous trial, in our study, gemcitabine was administered every 2 weeks with prednisone and at this dosage the drughad a good toxicity profile.
Recently, Qin et evaluated the efficacy and tox- icity of combined chemotherapy with gemcitabine and Advanced or metastatic prostate cancer is incurable. An- cisplatin for HRPC. Fifteen patients with advanced drogen ablation is the standard first-line therapy for pa- HRPC were enrolled in the study. Gemcitabine 1000 tients with advanced or metastatic prostate cancer. How- mg/m2 were administered by intravenous drip on days 1 ever, although 80% will initially respond to androgen and 8, cisplatin 100 mg/m2 was administered by intrave- withdrawal, the median duration of the response is ap- nous drip on day 1, or cisplatin 30 mg/m2 was adminis- proximately 20 to 25 months. Once a patient developsmetastatic hormone-resistant disease, the median sur- tered by intravenous drip on days 1 to 5 within each 28-day cycle. The results showed that the PSA values in The results from two recent Phase III randomized 10 patients decreased to normal (less than 4 ng/L), those clinical trial have propelled docetaxel-based chemother- in 4 patients decreased by more than 50%, and in 1 apy into the forefront of treatment options for these patient did not change. After chemotherapy, 9 patients patients as the new standard of No effective had a release from pain, only 2 had pain of grade 1, and second-line treatment has been recognized after do- 1 had grade 2 pain. The median survival time was 14.7 cetaxel failure. We conducted a study to evaluate the months. The toxicity from chemotherapy was tolerable impact on PSA response, tumor response, pain improve- and included nausea/vomiting, leukopenia, anemia, and ment, and toxicity profile of a regimen with gemcitabine, prednisone, and zoledronic acid in pretreated patients Considering that some of the patients were highly pretreated, our results were promising and are interesting Of our 22 patients, 23% had a positive response in the because they open a discussion about a second line of pain category. Of the 22 patients evaluated for PSA level, therapy for HRPC. However, although gemcitabine may 23% had a greater than 50% decrease in PSA level. All have activity against HRPC, as shown by our trial, it patients with a PSA response of greater than 50% had might not be as great as reported in our study because of pain improvement. In 3 patients, the pain was stable. Our several limitations, including that the improvement in pain and the decline in PSA could have resulted from the To our knowledge, our study represents the first study addition of an increased dose of prednisone. Also of gemcitabine as second-line therapy for HRPC. Two zoledronic acid has been shown to reduce bone pain, as previous studies have been published that used gemcit- abine as first-line therapy for In a Phase II As previously noted, no agents have been approved for trial, Morant et treated 43 patients with gemcitabine second-line treatment of HRPC. However, the interest in at a dose of 1200 mg/m2 for 2 hours (later decreased to this field is growing, many oncologists have begun to 1000 mg/m2 because of hematologic toxicity) on days 1, treat patients after a first line of therapy, and different trials are ongoing. In this respect, preclinical data have 2. Scher HI, Steineck G, and Kelly WK: Hormone refractory (D3) demonstrated that satraplatin, an oral platinum analog, is prostate cancer: refining the concept. Urology 46: 142–148, 1995.
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