A 55-year-old Hispanic male presents with a family history of gastric cancer in one sibling and prostate cancer in an older brother. His medical history is relevant for obesity, multifactorial chronic kidney disease, and retroperitoneal inflammatory myofibroblastic tumor (IMT) treated successfully with steroids and currently under surveillance. In 2001, he was diagnosed with benign prostatic hyperplasia. Because of lower urinary tract symptoms, he underwent two transurethral resections of the prostate (TURPs) in 2001 and 2005.
Computed tomography (CT) performed in March 2015 for IMT surveillance showed a heterogeneous prostate with local invasion involving the bladder, seminal vesicles, and perirectal fat (Figure 1). His prostate-specific antigen (PSA) level was 22 ng/mL and digital rectal exam revealed a fixed prostate (cT4) not amenable to surgical resection. He underwent a third TURP in April 2015 for management of his lower urinary tract symptoms; this revealed adenocarcinoma of the prostate with Gleason score 4 + 3 = 7 (Figure 2). A staging bone scan revealed no evidence of metastatic disease. He was diagnosed with high-risk prostate cancer, and after discussion of his case in a multidisciplinary tumor board, external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT) were prescribed. The patient asked whether chemotherapy would provide any additional benefit, given his young age. He is currently receiving ADT and radiation therapy (RT).
What is the optimal upfront treatment for this patient?
B. EBRT + ADT (2–3 years)
C. EBRT + brachytherapy boost + ADT (2–3 years)
D. EBRT + ADT (2–3 years) + 6 cycles of docetaxel
Locally advanced or high-risk localized prostate cancer has a relatively poor prognosis. Patients in this category who present with prostate fixation are not candidates for radical prostatectomy. However, local control in this setting may be attempted with radiation therapy (RT). In order to improve outcomes in these patients, clinical trials have centered on adding different strategies for local and systemic control to standard EBRT. Local therapies have focused on escalating doses in RT and/or increasing RT dose in other ways (eg, through use of brachytherapy). Systemic treatments that have been explored include ADT and intravenous chemotherapy.
Add-on options currently approved for patients with prostate fixation and high-risk disease
Currently, the National Comprehensive Cancer Network guidelines for patients with prostate fixation and high-risk or very-high-risk disease include two options: EBRT + ADT (2–3 years) or EBRT + brachytherapy ± ADT (2–3 years). The addition of ADT to RT has a proven benefit in overall survival (OS) and cancer-specific survival.[3,4] Existing level 1 evidence from prospective, randomized trials demonstrates a progression-free survival (PFS) advantage for dose-escalated EBRT (DE-EBRT) relative to conventional RT.[5-10] Combination therapy with EBRT followed by a brachytherapy boost is one approach that can achieve higher doses while attempting to maintain acceptable acute and long-term toxicities for patients with prostate cancer. Recently, the ASCENDE-RT trial was presented at the 2015 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium and the American Society for Radiation Oncology Annual Meeting. ASCENDE-RT is a multicenter, randomized trial comparing DE-EBRT (78 Gy) vs EBRT (46 Gy) plus brachytherapy in intermediate- and high-risk, node-negative prostate cancer. Patients in both arms have received 12 months of ADT with a luteinizing hormone–releasing hormone agonist plus a nonsteroidal anti-androgen for at least 1 month. Preliminary results, presented in abstract form, showed a PFS benefit with the combination therapy (hazard ratio [HR], 0.473; P = .0022), but no OS improvement (P = .29) at a median follow-up of 6.5 years. Single-institution studies comparing DE-EBRT vs EBRT plus brachytherapy have reported mixed findings.[12,13] Overall, acute genitourinary and gastrointestinal toxicities were reported to be greater in the combined-RT arm, whereas long-term side effects were similar in the two cohorts. The National Cancer Data Base was recently reviewed, and the addition of brachytherapy was found to be associated with a reduced risk of death in men with intermediate-risk and high-risk prostate cancer, with or without ADT; however, this association was found to be no longer significant when EBRT plus brachytherapy was compared with very high doses of EBRT (79.2–81 Gy).
The evidence regarding chemotherapy in other prostate cancer settings
Correct Answer: B
With regard to systemic strategies for improving cancer control, chemotherapy has been tested several times using different drug regimens. Men with high-grade (Gleason score ≥ 8) or extraprostatic disease (T3/T4 or lymph node involvement) have a risk of treatment failure as high as 70% with surgery alone.[15,16] This poor prognosis fostered interest in combining adjuvant therapy with ADT and chemotherapy, which was evaluated by the Southwest Oncology Group (SWOG) 9921 study. This trial randomly assigned 983 men with high-risk features at prostatectomy (Gleason score ≥ 8; preoperative PSA level ≥ 15 ng/mL; stage T3b, T4, or N1 disease; or Gleason score of 7 with either preoperative PSA > 10 ng/mL or a positive margin) to receive adjuvant therapy with ADT alone (goserelin and bicalutamide for 2 years) or in combination with mitoxantrone chemotherapy.
Unfortunately, this trial was closed early to further accrual after three cases of acute myelogenous leukemia were reported among the 487 men on the mitoxantrone treatment arm. The primary OS endpoint of the trial has not been reached. The authors reported the results of the ADT-alone treatment arm at a median follow-up of 4.4 years. The estimated 5-year OS was 96%, even after excluding those who received adjuvant RT, and the estimated benefit in 5-year freedom from biochemical failure was maintained (92.7% compared with 92.5% for the whole group). Thus, these data supported the consideration of adjuvant ADT in patients with high-risk prostate cancer after radical prostatectomy. However, the data do not yet provide support for the use of early chemotherapy and illustrate the potential side effects of systemic treatment with mitoxantrone. More modern adjuvant chemotherapy treatment with docetaxel is being evaluated in the STAMPEDE trial, discussed below.
For many years, unusual combinations of chemotherapy compounds were used in prostate cancer trials. The NRG Oncology RTOG (Radiation Therapy Oncology Group) 9902 trial assessed the addition of adjuvant combination chemotherapy with paclitaxel, estramustine, and oral etoposide to long-term ADT and RT in patients with high-risk prostate cancer. Only 41% of patients assigned to the experimental arm received all 4 cycles of the three drugs. Another limitation of the study was the use of low-dose RT (70.2 Gy), which is now known to be inferior to DE-EBRT. Also, the trial was designed to detect a 6% improvement in OS, from 79% to 85%, at 5 years and would have needed to include 1,400 randomized patients in order to do this. The study was closed prematurely because of a high incidence of thromboembolic events in the chemotherapy arm. The trial included 397 men; 68% of them had a Gleason score of 8–10, 34% had T3/T4 tumors, and the median PSA level was 22.6 ng/mL. The median follow-up period was 9.2 years. There were no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival.
- Upfront treatment for nonresectable high-risk prostate cancer is external beam radiotherapy (EBRT) and 2–3 years of androgen deprivation therapy (ADT).
- The addition of brachytherapy to EBRT and ADT in nonresectable high-risk disease might help achieve better local control.
- The addition of chemotherapy to EBRT and ADT in nonresectable high-risk disease might help achieve better systemic control, but this needs to be proved.
- Patients with high-risk prostate cancer have systemic disease. Standard-of-care treatment should include consultation with a medical oncologist and consideration for clinical trials testing systemic therapies whenever possible.
For more than a decade, docetaxel chemotherapy has been largely used in patients with metastatic castration-resistant prostate cancer (mCRPC), with a known benefit in quality of life and OS. More recently, the CHAARTED trial demonstrated that adding docetaxel to ADT in newly diagnosed metastatic hormone-sensitive prostate cancer improves OS compared with ADT alone. This has raised interest in the question of whether including chemotherapy earlier in the disease course could provide a benefit for prostate cancer patients.
What about chemotherapy for localized high-risk disease?
Early use of docetaxel in combination with RT and ADT in the initial curative-intent treatment of localized high-risk prostate cancer was evaluated by the RTOG 0521 trial. For the first time in decades, a chemotherapy regimen showed promise in this subset of patients. The RTOG 0521 study demonstrated improvement in OS among patients who received RT (72.0–75.6 Gy using three- dimensional conformal or intensity-modulated RT techniques) plus ADT and docetaxel compared with those who did not receive chemotherapy as part of curative-intent treatment for high-risk localized disease. The trial enrolled 563 patients with high-risk disease or node-positive disease (in contrast to the RTOG 9902 study, in which pN+ patients were ineligible). The patient population was notable for their unfavorable disease characteristics, which included Gleason score of 8–10 in 84% of participants (compared with 67.8% in RTOG 9902), cT3/cT4 disease in 27% (compared with 34.3% in RTOG 9902), and pN0 disease in only 33% of patients (pN+ patients were ineligible in RTOG 9902). The 4-year OS favored the chemotherapy arm, as reported at the 2015 ASCO Annual Meeting. However, one of the limitations of the trial is that investigators used a one-sided statistical analysis for finding an improvement in OS at 4 years of follow-up. Therefore, longer follow-up will help further clarify whether adding docetaxel provides an actual benefit for these patients.
Additional evidence for the addition of docetaxel and/or zoledronic acid to standard of care (SOC) in the treatment of hormone-naive prostate cancer is provided by the STAMPEDE trial. The hypothesis of this trial was that early use of active strategies (docetaxel and/or zoledronic acid) in addition to standard of care (SOC) might yield a larger absolute benefit in OS compared with delayed use. This ongoing randomized trial has a complex multi-arm, multi-stage design. There are currently six arms: SOC (ADT ± RT), SOC + zoledronic acid, SOC + docetaxel, SOC + celecoxib, SOC + zoledronic acid + docetaxel, and SOC + zoledronic acid + celecoxib. The trial includes newly diagnosed patients with metastatic, node-positive disease or those with at least two of the following: stage T3/T4 disease, PSA level ≥ 40 ng/mL, Gleason score of 8–10. The primary outcome of the trial is OS. Initial findings were recently reported; these demonstrated no significant difference in OS for patients treated with zoledronic acid. The docetaxel data, however, showed a significant difference in failure-free survival (FFS) (HR, 0.62 [95% confidence interval (CI), 0.54–0.70]; P < . 0010) and an absolute improvement in OS of 10 months for the whole treatment group (67 months vs 77 months in the docetaxel arm; HR, 0.76 [95% CI, 0.63–0.91]; P < .003). The authors concluded that docetaxel should be considered for routine use in suitable men with newly diagnosed metastatic disease and considered for selected men with high-risk nonmetastatic disease, in view of the substantial prolongation of FFS.
Both the RTOG 0521 trial and the STAMPEDE trial highlight the fact that better drugs, such as docetaxel, may finally lead to tolerable and efficient adjuvant treatment for men with nonmetastatic high-risk prostate cancer. Before this strategy can be considered SOC, however, updated results demonstrating a clear benefit in survival will be needed.
Other important aspects of this treatment strategy to consider are the acute toxicity and long-term side effects of chemotherapy. A report from Princess Margaret Hospital compared the outcomes of men with mCRPC treated with docetaxel in and out of clinical trials. In this single-institution analysis, men with mCRPC who received docetaxel in clinical trials tended to be younger, have better baseline performance status, experience fewer and less severe adverse events, and have increased survival compared with patients with mCRPC treated off-protocol. These data support the conclusion of Dr. Tannock at the 2015 ASCO Annual Meeting that “chemo delayed is toxicity delayed,” and that at present, adding docetaxel upfront to curative-intent ADT and RT is not warranted. However, it could also be argued that men with overt metastatic disease and high-volume osseous lesions are at high risk for myelosuppression after cytotoxic chemotherapy and usually have poorer performance status; in such cases, early administration may be safer.
In conclusion, the recommended treatment in this case is EBRT + ADT for 2 to 3 years (Answer B). We believe that the decision to add brachytherapy (Answer C) should be individualized for each patient, given that adding brachytherapy provides a benefit in PFS but no OS benefit, as seen in the ASCENDE-RT trial. Currently, the addition of chemotherapy in high-risk patients treated with RT and ADT (Answer D) is not SOC. EBRT as the sole treatment modality (Answer A) should be reserved for those with contraindications for hormonal treatment.
Financial Disclosure: Dr. Glodé serves as a consultant to Janssen Pharmaceutica. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Acknowledgements: The authors would like to thank the Aramont Foundation and Canales de Ayuda A.C. for their support in research activities in urologic oncology at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán.
E. David Crawford, MD, serves as Series Editor for Clinical Quandaries. Dr. Crawford is Professor of Surgery, Urology, and Radiation Oncology, and Head of the Section of Urologic Oncology at the University of Colorado School of Medicine; Chairman of the Prostate Conditions Education Council; and a member of ONCOLOGY's Editorial Board.
If you have a case that you feel has particular educational value, illustrating important points in diagnosis or treatment, you may send the concept to Dr. Crawford at firstname.lastname@example.org for consideration for a future installment of Clinical Quandaries.
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