|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 26, No 18 (June 20), 2008: pp. 2973-2978 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.4105 Phase I/II Study of Biweekly Paclitaxel and Radiation in Androgen-Ablated Locally Advanced Prostate Cancer
From the Departments of Radiation Oncology, Urology, and Medicine; New York University School of Medicine, New York, NY Corresponding author: Nicholas J. Sanfilippo, MD, 160 E 34th St, Department of Radiation Oncology, New York, NY 10016; e-mail: Nicholas.sanfilippo{at}med.nyu.edu
Purpose To determine the maximum-tolerated dose (MTD) of concurrent paclitaxel and radiation therapy (RT) in patients with locally advanced prostate cancer. Materials and Methods Eligible patients had T2-4 tumors with Gleason scores greater than 7 and/or PSA levels greater than 10 ng/mL and/or had tumors with pathologic stage TxN1. Hormonal ablation was initiated 3 months before RT and was given for 9 months. RT was delivered daily (1.8 Gy) with concurrent twice-weekly paclitaxel (30 mg/m2). The whole pelvis was irradiated to 39.6 Gy. The radiation dose was escalated as follows: 63 Gy, 66.6 Gy, 70.2 Gy, and 73.8 Gy. The last RT dose level was fixed at 73.8 Gy. Results Between January 2000 and October 2006, 22 patients were enrolled. The median age was 59 years (range, 48 to 72 years); the median PSA level was 22.4 ng/mL (range, 2.8 to 113 ng/mL). The number of patients per stage was as follows: three with T1, eight with T2, 11 with T3, and five with pN1 = 5. No grade 3 toxicities occurred at 63 Gy. Grade 3 diarrhea occurred in three patients at 66.6 Gy. The protocol then was amended to treat the prostate volume first followed by the whole pelvis. No grade 3 toxicities were observed at 70.2 Gy. One patient experienced grade 3 diarrhea at 73.8 Gy. Five additional patients were treated to 73.8 Gy without grade 3 toxicity, which established the MTD for combined paclitaxel and RT at 73.8 Gy. At 38 months median follow-up (range, 9 to 87 months), 21 (95%) of 22 patients are alive. Six (27%) of 22 experienced recurrence. Conclusion Concurrent biweekly paclitaxel with RT is feasible, with an MTD of 73.8 Gy. Recovery of gonadal function occurs in the majority of patients. These results encourage testing in a phase III setting.
Prostate cancer is the most common malignancy in men in the United States and is the second leading cause of cancer-related mortality.1 Patients with prostate-specific antigen (PSA) levels greater than 10 to 20 ng/mL and/or Gleason scores  7 carry a recurrence risk of approximately 70% at 5 years.2-6 Single-modality treatment is associated with high failure rates,7 and multimodality treatments, including the combination of radiation therapy (RT) and hormonal ablation, have become the mainstay of therapy.8,9 However, a large proportion of patients with locally advanced prostate cancer still progress to hormone-refractory disease.8-10 Three-dimensional conformal radiotherapy (3D-CRT) and, more recently, intensity-modulated radiation therapy (IMRT) have allowed for dose escalation and have improved progression-free survival while limiting toxicity.11 However, local recurrence remains significant for patients with adverse features. After treatment with 75.6 Gy, Zelefsky et al12 reported positive biopsies in 30% of patients with unfavorable disease. As dose escalation continues, concurrent chemotherapy can provide radiosensitization at the primary site while addressing micrometastatic disease. Pacitaxel (Taxol, Bristol-Myers Squibb; Princeton, NJ) is a naturally occurring taxane molecule that induces accumulation of cells in the G2/M phase of the cell cycle, which is the most radiosensitive period.13,14 Clinical trials in adenocarcinoma of the esophagus, lung, and breast have demonstrated an additive effect when paclitaxel is combined with radiation.15-18 Experience from these and other cancers suggests that chemotherapy may be more effective if used earlier.7,19 This rationale, with preclinical data that supports combination therapy, also can be applied to prostate cancer.20,21 Although paclitaxel has demonstrated limited activity in hormone-refractory prostate cancer, its activity in hormone-sensitive disease is unknown.22 Because most patients are hormone sensitive at presentation, paclitaxel could reveal greater effect when used initially, both as a radiosensitizer and a cytotoxic agent. Because paclitaxel now is available as a generic drug, it is a cost-effective option in high-risk prostate cancer treatment. Inspired by our successful experience in locally advanced breast cancer, we designed a phase I/II study to determine the maximum-tolerated dose (MTD) of concurrent paclitaxel and RT in patients with locally advanced prostate cancer.14,15
A protocol to determine the feasibility and safety of combining paclitaxel and RT received New York University institutional review board approval in January 2000. All patients signed an institutional review board–approved informed consent form and were recruited and treated at Tisch Hospital and Bellevue Hospital Center. Eligible patients had clinical stage T2-4 tumors with Gleason scores greater than 7 and/or PSA levels greater than 10, or they had pathologic lymph node involvement. For eligibility, an Eastern Cooperative Oncology Group perfomance status less than 2; hemoglobin greater than 11 gm/dL; white blood cell count greater than 4,000; and a platelet count greater than 100,000 were required. Patients were ineligible if there was evidence of another synchronous primary tumor or a history of prior malignancy without a disease-free interval of at least 5 years. Patients also were excluded for any of the following: evidence of distant metastasis; current treatment with ketoconazole, cimetidine, or hormone therapy for more than 3 months before enrollment; bilirubin greater than 1.5; or a history of prior chemotherapy. Pretreatment evaluation included history and physical examination, baseline PSA, bone scan, chest x-ray, computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis, complete blood cell (CBC) count, and liver and renal function tests. The overall treatment schema is listed in Table 1. Treatment was initiated with hormonal ablation (HA) by using a luteinizing hormone-releasing hormone (LHRH) agonist (leuprolide acetate or goserelin given by injection) in combination with either oral flutamide (250 mg given three times a day) or bicalutamide (50 mg a day). HA began 3 months before RT and continued for a total of 9 months.
All patients had a treatment-planning CT at the time of enrollment to define clinical and planning target volumes and adjacent organs. Pelvic images were acquired with a slice thickness of 0.25 to 0.5 cm. Computerized treatment planning was employed to deliver 3D-CRT. The clinical target volume was defined before hormonal treatment and included the prostate and bilateral seminal vesicles. A 5- to 10-mm margin around the clinical target volume then was added to define the planning target volume (PTV). A classic, four-field pelvic technique was used to deliver 1.8 Gy per fraction on 5 days per week (Monday through Friday) for a dose of 39.6 Gy to the whole pelvis, with a consecutive conformal boost that used six fields to the PTV. Custom blocking was used to protect normal tissue both for the whole pelvis and for the boost portion of the treatment. All patients were treated with megavoltage equipment (> 10 MV). RT started after 3 months of HA. The dose was escalated in cohorts of three patients; the total RT dose began at 63 Gy and then escalated to 66.6.Gy, 70.2 Gy, and 73.8 Gy. The latter dose was predetermined as the last dose level for MTD, because 73.8 Gy is the accepted standard dose for hormonally ablated prostate cancer.23 After a total dose of 66.6 Gy, the protocol was amended to allow treatment of the six-field conformal boost before the four-field pelvis. The dose to the whole pelvis remained 39.6 Gy. Toxicities were reported by using National Cancer Institute Common Toxicity Criteria, version 2. Paclitaxel began during the first week of RT and was given for 8 consecutive weeks as a 1-hour infusion at a fixed dose of 30 mg/m2 twice a week (Monday and Wednesday or Tuesday and Thursday). Premedication with dexamethasone, diphenhydramine, and cimetidine or ranitidine was routine. All patients were seen weekly during chemoradiotherapy by an attending radiation oncologist and a medical oncologist to assess toxicities. After treatment, patients were seen every 3 months for the first 2 years, and a PSA level was obtained before each visit. Follow-up then was extended to 6-month intervals. An MRI or CT of the pelvis and a bone scan were done yearly unless clinical symptoms developed that prompted intervention. Biochemical recurrence was defined as three consecutive PSA elevations, according to guidelines from the American Society for Therapeutic Radiology and Oncology. Kaplan-Meier estimates of biochemical disease-free survival were calculated.
Between January 2000 and October 2006, 22 patients were enrolled. Patient characteristics are listed in Table 2. The median age was 59 years (range, 48 to 72 years) and the median PSA level was 22.4 (range, 2.8 to 113). Clinical T stages were as follows: T1 (n = 3), T2 (n = 8), and T3 (n = 11). Five patients had pN1 disease stage. Gleason scores ranged from 6 to 9, and 18 (82%) of 22 patients had tumors with Gleason scores of 7 or 8. Three of 22 patients reported erectile dysfunction at presentation. On the basis of the intent-to-treat rule, the single patient who was noncompliant with the first two doses of chemotherapy was included in the analysis. All others patients received the prescribed treatment, including 9 months of the LHRH agonist and the antiandrogen. At the time of this report, the median follow-up was 38 months (range, 9 to 87 months).
Acute and Late Toxicity of Concurrent 3D-CRT and Biweekly Paclitaxel Toxicities of the combined modality regimen are listed in Table 3. Grades 1 to 2 toxicities were observed at all dose levels. The most common adverse events were grades 1 to 2 diarrhea and fatigue, which affected 53% and 37% of patients, respectively. Grades 1 to 2 urinary frequency and proctitis were also common, which affected 32% of patients each. No grade 3 toxicities were observed at the 63 Gy dose level. Grade 3 diarrhea was observed in three patients at the dose level of 66.6 Gy. One patient developed diarrhea with acute abdominal pain at 18 Gy and was admitted to a local hospital with a diagnosis of peritonitis. After treatment with 5 days of antibiotics and intravenous fluids, the patient was discharged and resumed treatment with RT and paclitaxel at a reduced dose (15 mg/m2), and the patient completed therapy without further interruption. A second patient developed grade 3 diarrhea after 32.4 Gy and interrupted treatment for 5 weeks. Radiation then was resumed without paclitaxel, and the patient completed treatment without interruption. A third patient developed grade 3 diarrhea at 30.6 Gy that resolved with loperamide. He continued therapy without modification. Because of the common incidence of gastrointestinal toxicity, the protocol was amended to first treat the boost volume (prostate and seminal vesicles) followed by treatment of the whole pelvis to 39.6 Gy. This sequencing resulted in a better treatment tolerance. No grade 3 events were observed at the 70.2 Gy level. At the 73.8 Gy level, one patient experienced grade 3 diarrhea after receiving 19.8 Gy to the boost volume; this resolved within 1 week with loperamide. The patient resumed RT with a reduced dose of paclitaxel (22.5 mg/m2) and received 73.8 Gy without further toxicity. Five additional patients were treated to 73.8 Gy without grade 3 toxicity. As planned, no further dose escalation was explored. Dosimetry to PTV and to normal structures is summarized in Table 4. Mean doses to the rectum, bladder, and small bowel were within 2 Gy. Average maximum doses and V40(%) for normal structures were, predictably, slightly higher in patients treated with delayed pelvic RT, because these patients were treated with higher total doses, as planned by the dose-escalation design of the study.
Six patients (23%) experienced grades 1 to 2 late toxicities (observed at > 1 year post-treatment). Two patients experienced grade 1 radiation cystitis 2 years after chemoradiotherapy (on doses 63 and 66.6 Gy, respectively). One patient developed Peyronie's disease 18 months after receiving 66.6 Gy. Two patients experienced grade 1 urinary frequency and diarrhea after doses of 70.2 Gy and 73.8 Gy respectively. No grades 3 or 4 late toxicities were observed.
Post-Treatment Outcome
Testosterone levels were followed for assessment of gonadal function after chemoradiotherapy and HA. Three (13%) of 23 patients were hypogonadal (total testosterone < 260 ng/dL) 12, 18, and 59 months, respectively, after completion of HA in the absence of further HA. The remaining patients regained gonadal function, and the median time to testosterone recovery was 6 months after completion of HA (range, 2 to 11 months). Seventeen (89%) of 19 patients who defined themselves as sexually potent before starting treatment regained potency after treatment, although two required treatment with sildenafil or intercavernosal injections. Among the 19 patients who reported potency before treatment, both patients who failed to recover potency were hypogonadal.
Concurrent chemoradiotherapy has become standard treatment in many locally advanced tumors.24-28 However, few investigators have tested this strategy in locally advanced prostate cancer.29-32 To our knowledge, this is the first study that examined concurrent paclitaxel and RT in the setting of androgen ablation. We found concurrent biweekly paclitaxel (30 mg/m2) and RT to be feasible and safe, and we established an MTD of 73.8 Gy for the combination therapy. Diarrhea was the only grade 3 toxicity; in three of four instances, it occurred during whole-pelvic RT at doses of 18 to 32.4 Gy. The design of this trial required treatment of the whole pelvis followed by a boost to the prostate and seminal vesicles. This is based on the results of the Radiation Therapy Oncology group 9413 trial, which demonstrated improved progression-free survival in high-risk patients when the whole pelvis was treated compared with more limited treatment volumes.33 Our study also was offered to patients with positive lymph nodes, which supported the need for whole-pelvic RT. However, the change in the sequence of treatment of the radiation fields, with the larger pelvic field treated after the boost field to the prostate and seminal vesicles, improved the tolerance of chemoradiotherapy. Grade 3 events occurred at low doses (< 34.2 Gy) when the whole pelvis was treated first. Because dosimetry in the two groups was similar, the observed toxicity can be explained by larger organ volume irradiation during the initial 2 to 4 weeks of therapy, which caused abrupt onset of severe diarrhea. Conversely, an initial smaller volume of bowel in the field, as achieved by treating the boost volume first, resulted in a more gradual development of diarrhea that was amenable to medical management. The study was designed before IMRT had become a common method to reduce GI toxicity through improved bowel sparing.34 Because of the acceptable toxicity encountered with 3D-CRT, it is expected that a similar regimen with IMRT would be even more tolerable. Previous studies of concurrent pelvic chemoradiotherapy generally have shown more severe toxicity. Khil et al31 tested concurrent etramustine phosphate 450 mg/m2 given orally and vinblastine 3 mg/m2 given intravenously weekly with conventional external beam RT in 65 patients with T2-4 disease.31 A four-field technique was used both for the whole pelvis to 45 Gy and for the prostate boost to an additional 20 to 25 Gy. Myelosuppression was the dominant toxicity, and the protocol was amended to omit vinblastine in the final 19 patients. Gastrointestinal toxicities also occurred, with one grade 3 small bowel complication and one grade 4 radiation proctitis occurrence that required colostomy. Zelefsky et al30 investigated neoadjuvant and concurrent etramustine phosphate plus vinblastine with RT in a phase II study of 27 patients, in which patients were treated with 3D-CRT to a limited prostate volume to 75.6 Gy. Grade 3 hematologic toxicity occurred in two patients (7%), and grade 3 hepatotoxicity occurred in two patients (7%). Three patients (11%) developed acute grade 3 urinary toxicities; overall, only 85% of patients completed therapy. Two patients experienced late grade 3 urethral strictures. The 2-year incidence of late grades 2 to 3 urinary toxicities were 25% and 12%, respectively. Seven patients (30%) relapsed (median follow-up, 26 months). The same regimen was also tested by Ben-Josef et al32: after induction chemotherapy with estramustine and etopiside, chemoradiotherapy followed and consisted of concurrent oral estramustine with 3D-CRT to 70.2 Gy. The whole pelvis was treated to 45 Gy in this study. Grade 3 toxicities included two instances of leukopenia and one of deep vein thrombosis. One patient also experienced a grade 4 myocardial infarction. During a median follow-up of 20 months, 3 (17%) of 18 patients experienced relapse. Taxane-based chemoradiotherapy has been evaluated in numerous tumor sites.15,35-37 For prostate cancer, Kumar et al29 conducted a phase I study of concurrent weekly docetaxel and 3D-CRT in high-risk patients. Pelvic RT was delivered through a boost field to the prostate and to a pelvic field with the superior border of the portal at the low to mid sacroiliac joint, which was a smaller volume than that treated in our series. (We used the classical upper border at L5/S1 interspace.) The dose to the seminal vesicles was often limited to 59.4 Gy, whereas, in our series, bilateral seminal vesicles received the full dose. The only grade 3 toxicity was diarrhea, which occurred during whole-pelvic irradiation at 21.6 Gy and 37.8 Gy (docetaxel dose, 25 mg/m2). Grades 1 to 2 effects were also similar, with 40% and 45% gastrointestinal and urinary toxicity, respectively, compared with 53% and 32%, respectively, in our series. Late toxicities were rare, as only one late urinary stricture occurred. Although our results are preliminary, the absence of grades 3 to 4 late toxicity is encouraging. The majority of patients (89%) reported a recovered potency, although two required medical therapy to achieve adequate sexual function. However, the data was based only on subjective reporting. A more structured assessment of sexual function before and after combined treatment, ideally in a larger cohort of patients, would be necessary to reach reliable conclusions. Biochemical control in our series (73%) was comparable to the 77% reported by Kumar et al29 with RT and docetaxel, but the median follow-up in our series was longer (38 months v 8 months). Docetaxel binds tubulin with slightly higher affinity than paclitaxel and targets centromere formation, which causes cell damage in the S, G2, and M phases of the cell cycle, and treatment with docetaxel confers an improved survival in patients with hormone-refractory prostate cancer.38,39 Conversely, paclitaxel's action mainly is restricted to the G2 and M phases of the cell cycle, which are the most radiosensitive phases of the cell cycle.40 It is likely that both agents cause comparable radiosensitization, but the generic status of paclitaxel makes it a more convenient agent for chemoradiotherapy in hormone-naive patients. A course of HA also was used systematically in our study but in only seven of 22 patients in Kumar's series.29 Although HA has increased survival in locally advanced prostate cancer,8,9 it is associated with delayed hematologic and cardiovascular toxicities.41 D'Amico42 recently reported an increased incidence of fatal myocardial infarction in patients older than 65 years who were treated with androgen suppressive therapy for 6 months. Three patients (13%) in our series had persistently low testosterone levels after 9 months of HA. The median time to testosterone recovery in our series was 6 months, which is consistent with previous reports after comparable durations of HA.43 Other investigators have used 36 months of HA in high-risk patients,8 which can result in a prolonged time to testosterone recovery and in a greater likelihood of complications.44 Concurrent chemoradiotherapy may provide an added advantage of limiting the duration of HA, thus reducing its complications. In summary, our study illustrated that RT with concurrent biweekly paclitaxel and androgen blockade is feasible and results in acceptable acute toxicity. Because of the high-risk features of patients in this series and the poor outcomes associated with RT and HA, the data presented encourage further investigation of this approach, particularly in combination with IMRT to further reduce toxicity.
The authors indicated no potential conflicts of interest.
Conception and design: Samir S. Taneja, Abraham Chachoua, Silvia C. Formenti Provision of study materials or patients: Nicholas J. Sanfilippo, Samir S. Taneja, Abraham Chachoua, Herbert Lepor, Silvia C. Formenti Collection and assembly of data: Nicholas J. Sanfilippo, Silvia C. Formenti Data analysis and interpretation: Nicholas J. Sanfilippo, Samir S. Taneja, Abraham Chachoua, Herbert Lepor, Silvia C. Formenti Manuscript writing: Nicholas J. Sanfilippo, Silvia C. Formenti Final approval of manuscript: Nicholas J. Sanfilippo, Silvia C. Formenti
We thank Beverly Smith for nursing support, Chiara Magnolfi for data management support, and Jason H. Lee for statistical support.
Supported in part by the New York University Department of Radiation Oncology and Bristol-Myers Squibb. The study was investigator-initiated and partially supported by Bristol-Myers Squibb through a grant covering data management, administrative support, and regulatory costs. Presented at the 49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 27-November 1, 2007, Los Angeles, CA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Penson DF, Chan JM: Prostate cancer. J Urol 177:2020-2029, 2007[CrossRef][Medline] 2. Green GA, Hanlon AL, Al-Saleem T, et al: A Gleason score of 7 predicts a worse outcome for prostate carcinoma patients treated with radiotherapy. Cancer 83:971-976, 1998[CrossRef][Medline] 3. Lowe BA, Lieberman SF: Disease recurrence and progression in untreated pathologic stage T3 prostate cancer: Selecting the patient for adjuvant therapy. J Urol 158:1452-1456, 1997[CrossRef][Medline] 4. Epstein JI, Pound CR, Partin AW, et al: Disease progression following radical prostatectomy in men with Gleason score 7 tumor. J Urol 160:97-100, 1998; discussion 101[CrossRef][Medline] 5. D'Amico AV, Whittington R, Malkowicz SB, et al: A multivariate analysis of clinical and pathological factors that predict for prostate specific antigen failure after radical prostatectomy for prostate cancer. J Urol 154:131-138, 1995[CrossRef][Medline] 6. Kupelian P, Katcher J, Levin H, et al: Correlation of clinical and pathologic factors with rising prostate-specific antigen profiles after radical prostatectomy alone for clinically localized prostate cancer. Urology 48:249-260, 1996[CrossRef][Medline] 7. Oh WK, Kantoff PW: Treatment of locally advanced prostate cancer: Is chemotherapy the next step? J Clin Oncol 17:3664-3675, 1999 8. Bolla M, Gonzalez 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 9. Pilepich MV, Krall JM, al-Sarraf M, et al: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: A randomized comparative trial of the Radiation Therapy Oncology Group. Urology 45:616-623, 1995[CrossRef][Medline] 10. Tyrrell CJ: Controversies in the management of advanced prostate cancer. Br J Cancer 79:146-155, 1999[CrossRef][Medline] 11. Pollack A, Zagars GK, Starkschall G, et al: Prostate cancer radiation dose response: Results of the M.D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 53:1097-1105, 2002[CrossRef][Medline] 12. Zelefsky MJ, Fuks Z, Hunt M, et al: High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol 166:876-881, 2001[CrossRef][Medline] 13. Shu CH, Yang WK, Shih YL, et al: Cell cycle G2/M arrest and activation of cyclin-dependent kinases associated with low-dose paclitaxel-induced sub-G1 apoptosis. Apoptosis 2:463-470, 1997[CrossRef][Medline] 14. Formenti SC, Symmans WF, Volm M, et al: Concurrent paclitaxel and radiation therapy for breast cancer. Semin Radiat Oncol 9:34-42, 1999[Medline] 15. Formenti SC, Volm M, Skinner KA, et al: Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: A phase I/II trial. J Clin Oncol 21:864-870, 2003 16. Wright CD: Multimodality therapy of esophageal cancer. Chest 116:461S–462S, 1999[CrossRef][Medline] 17. Steinberg L, Hassan M, Olmsted L, et al: A phase I trial of radiotherapy and simultaneous 24-hour paclitaxel in patients with locally advanced head and neck squamous cell carcinoma. Semin Oncol 24:S19-51-S19-56, 1997 (suppl 19) 18. Akerley W, Choy H: Single-agent paclitaxel and radiation for non-small cell lung cancer. Semin Radiat Oncol 9:85-89, 1999[Medline] 19. Lucas A, Petrylak DP: The case for early chemotherapy for the treatment of metastatic disease. J Urol 176:S72–S75, 2006[CrossRef][Medline] 20. Lokeshwar BL, Ferrell SM, Block NL: Enhancement of radiation response of prostatic carcinoma by taxol: Therapeutic potential for late-stage malignancy. Anticancer Res 15:93-98, 1995[Medline] 21. Haldar S, Chintapalli J, Croce CM: Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res 56:1253-1255, 1996 22. Roth BJ, Yeap BY, Wilding G, et al: Taxol in advanced, hormone-refractory carcinoma of the prostate: A phase II trial of the Eastern Cooperative Oncology Group. Cancer 72:2457-2460, 1993[CrossRef][Medline] 23. Kupelian PA, Mohan DS, Lyons J, et al: Higher than standard radiation doses ( 24. Dillman RO, Seagren SL, Propert KJ, et al: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 323:940-945, 1990[Abstract] 25. Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340:1154-1161, 1999 26. Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340:1144-1153, 1999 27. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340:1137-1143, 1999 28. Herskovic A, Martz K, al-Sarraf M, et al: Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326:1593-1598, 1992[Abstract] 29. Kumar P, Perrotti M, Weiss R, et al: Phase I trial of weekly docetaxel with concurrent three-dimensional conformal radiation therapy in the treatment of unfavorable localized adenocarcinoma of the prostate. J Clin Oncol 22:1909-1915, 2004 30. Zelefsky MJ, Kelly WK, Scher HI, 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 31. 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] 32. 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] 33. Roach M III, DeSilvio M, Lawton C, et al: Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 21:1904-1911, 2003 34. Nutting CM, Convery DJ, Cosgrove VP, et al: Reduction of small and large bowel irradiation using an optimized intensity-modulated pelvic radiotherapy technique in patients with prostate cancer. Int J Radiat Oncol Biol Phys 48:649-656, 2000[CrossRef][Medline] 35. Solomon B, Ball DL, Richardson G, et al: Phase I/II study of concurrent twice-weekly paclitaxel and weekly cisplatin with radiation therapy for stage III non-small cell lung cancer. Lung Cancer 41:353-361, 2003[CrossRef][Medline] 36. Nichols RC Jr, Sweetser MG, Mahmood SK, et al: Radiation therapy and concomitant paclitaxel/carboplatin chemotherapy for muscle invasive transitional cell carcinoma of the bladder: A well-tolerated combination. Int J Cancer 90:281-286, 2000[CrossRef][Medline] 37. Willey CD, Murphy BA, Netterville JL, et al: A Phase II multi-institutional trial of chemoradiation using weekly docetaxel and erythropoietin for high-risk postoperative head and neck cancer patients. Int J Radiat Oncol Biol Phys 67:1323-1331, 2007[Medline] 38. Stein CA: Mechanisms of action of taxanes in prostate cancer. Semin Oncol 26:3-7, 1999 (suppl 17)[Medline] 39. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004 40. Haldar S, Basu A, Croce CM: Bcl2 is the guardian of microtubule integrity. Cancer Res 57:229-233, 1997 41. Holzbeierlein JM, Castle E, Thrasher JB: Complications of androgen deprivation therapy: Prevention and treatment. Oncology (Williston Park) 18:303-309, discussion 310, 315, 319-321, 2004[Medline] 42. D'Amico AV, Denham JW, Crook J, et al: Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol 25:2420-2425, 2007 43. Nejat RJ, Rashid HH, Bagiella E, et al: A prospective analysis of time to normalization of serum testosterone after withdrawal of androgen deprivation therapy. J Urol 164:1891-1894, 2000[CrossRef][Medline] 44. Kaku H, Saika T, Tsushima T, et al: Time course of serum testosterone and luteinizing hormone levels after cessation of long-term luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer. Prostate 66:439-444, 2006[CrossRef][Medline] Submitted September 13, 2007; accepted March 3, 2008.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
