Traditionally, patients with high-risk localized prostate cancer have been an extremely challenging group to manage due to a significant likelihood of treatment failure and prostate cancer-specific mortality (PCSM). The results of multiple large, prospective, randomized trials have demonstrated that men with high-risk features who are treated in a multimodal fashion at the time of initial diagnosis have improved overall survival. Advances in local treatments such as dose-escalated radiotherapy in conjunction with androgen suppression and postprostatectomy adjuvant radiotherapy have also demonstrated benefits to this subset of patients. However, therapeutic enhancement with the addition of chemotherapy to the primary treatment regimen may help achieve optimal disease control.
Prostate cancer is the most common noncutaneous malignancy and is the second leading cause of cancer-related mortality among men in the USA [
Historically, patients with localized prostate cancer were categorized primarily based on clinical staging and whether or not they were considered surgical candidates. Thus, the term “localized” generally referred to stage T1-T2 disease which was managed with local therapy (surgery, radiotherapy) or active surveillance. “Locally advanced” disease referred to stage T3-T4 disease which was considered inoperable. However, a better understanding of the natural history of prostate cancer and advances in both the quality and quantity of available treatment options have allowed clinicians to develop more sophisticated risk stratification systems (Table
Anatomic stage/prognostic groups, high-risk localized prostate cancer.
Group | T | N | M | PSA | Gleason |
---|---|---|---|---|---|
I | T1a–c | N0 | M0 | PSA < 10 | Gleason ≤ 6 |
T2a | N0 | M0 | PSA < 10 | Gleason ≤ 6 | |
T1-2a | N0 | M0 | PSA X | Gleason X | |
IIA | T1a–c | N0 | M0 | PSA < 20 | Gleason 7 |
T1a–c | N0 | M0 | 10 ≤ PSA < 20 | Gleason ≤ 6 | |
T2a | N0 | M0 | 10 ≤ PSA < 20 | Gleason ≤ 6 | |
T2a | N0 | M0 | PSA < 20 | Gleason 7 | |
T2b | N0 | M0 | PSA < 20 | Gleason ≤ 7 | |
T2b | N0 | M0 | PSA X | Gleason X | |
Any T | N1 | M0 | Any PSA | Any Gleason | |
Any T | Any N | M1 | Any PSA | Any Gleason |
Adapted from American Joint Committee on Cancer (AJCC Cancer Staging Manual, Seventh Edition, 2010).
Current risk stratification of prostate cancer patients is based upon the likelihood of recurrence after locoregional treatment (Table
Prognostic factors for recurrence risk in localized prostate cancer.
Very low | Low | Intermediate | High | Very high (locally advanced) |
---|---|---|---|---|
T1c | T1-T2a | T2b-T2c | T3a | T3b-T4 |
Gleason | Gleason 2–6 | Gleason = 7 | Gleason 8–10 | |
PSA < 10 | PSA < 10 | PSA 10–20 | PSA > 20 | |
<3 (+) biopsy cores w/ ≤ 50% cancer per core | ||||
PSA density < 0.15 ng/mL/g |
Adapted from NCCN Clincal Practice Guidelines in Oncology Prostate Cancer V.1.2011© 2011 National Comprehensive Cancer Network, Inc.
A recent European multi-institutional study by Spahn et al. highlighted the need to further define the high-risk population in order to deliver the most appropriate therapy to each patient. In this study, 712 high-risk patients with PSA > 20 ng/mL underwent radical prostatectomy with bilateral pelvic lymph node dissection between 1987 and 2005. Patients were stratified into four subgroups based on the number of additional risk factors present (none, biopsy Gleason score ≥ 8, clinical stage 3-4, or both) to assess which risk factors improved prediction of treatment failure and PCSM. The biopsy Gleason score was the strongest predictor of progression and mortality. Among high-risk patients with PSA > 20 ng/mL, those with Gleason scores < 8 had a 10-year PCSM of 5%, while those with Gleason scores ≥ 8 had a PCSM of 35%. Importantly, this study reports that men with PSA > 20 ng/mL and a Gleason score < 8 are at minimal risk for PCSM and may represent a specific subgroup of high-risk patients that should be considered for surgery [
Similarly, a retrospective study by Walz et al. reported that the number of risk factors (T3 disease, Gleason ≥ 8, D’Amico high-risk group, PSA ≥ 20 ng/mL) present influences the 5-year biochemical recurrence risk in the postradical prostatectomy setting. The rate of favorable pathology and recurrence after surgical intervention is dependent upon the criteria used to define high-risk disease as well as the conglomeration of risk factors present in each patient [
The most current guidelines define high-risk localized prostate cancer as patients with clinical stage T3 disease, a Gleason score of 8–10 or a PSA level > 20 ng/mL (Table
Risk stratification for high-risk prostate cancer.
Source | High-risk definition |
---|---|
D’Amico et al. [ | Stage T2c or PSA > 20 ng/mL or Gleason |
RTOG 9902, 0521 [ | Any T stage, PSA 20–100 ng/mL, Gleason |
NCCN (v1.2011) [ | Stage ≥ T3 and/or PSA > 20 ng/mL and/or Gleason 8–10* |
Adapted from Nat Rev Urol 2010 Nature Publishing Group [
Traditionally, single modality regimens for treating high-risk patients have resulted in poor treatment responses and high failure rates [
Technological advances in existing treatment modalities and the combination of local and hormonal therapies have led to considerable progress in disease control and survival outcomes. Radiotherapy has been and will continue to be a key component in the treatment of prostate cancer and much effort has been dedicated to increasing its therapeutic efficacy with new techniques to deliver radiation. The advent of three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) have allowed radiation oncologists to achieve safe dose escalation while limiting local tissue toxicities classically associated with EBRT, such as genitourinary and bowel complications. Several independent studies have confirmed that dose escalation is associated with improved biochemical outcomes in addition to a lower risk of radiation-associated late side effects [
Recently, both volumetric-modulated arc therapy (VMAT) and helical tomotherapy techniques have been evaluated as novel ways to deliver radiotherapy. Several preliminary studies have evaluated the dosimetric feasibility of treating a broad spectrum of prostate cancer with VMAT, including localized, locally advanced and postoperative disease [
Arguably, combination therapy with radiation and long-term androgen deprivation therapy (ADT) has been one of the most important modifications to modern clinical practice for prostate cancer. The rationale of the combined approach is that the addition of ADT is believed to slow progression of the tumor by eliminating the hormonal stimulus that drives cancer cell proliferation [
Several prospective studies have demonstrated that the combination of radiotherapy and long-term androgen suppression improves disease control and survival, compared with either treatment alone for men with adverse risk factors. A prospective phase III trial, EORTC 22863, enrolled 415 men randomized to either radiotherapy alone or radiotherapy plus three years of LHRH analog (goserelin) to assess the additive effect long-term ADT in locally advanced patients. The study reported an increase in both disease-free and overall survival in the combination therapy group. Furthermore, the 10-year results of this study found no increase in cardiovascular toxicity in addition to the survival benefit [
The optimal duration of ADT has been a controversial topic, and several studies have examined whether or not the long-term side effects of ADT outweigh the clinical benefits. It is understood that the incidence of side effects correlates with the duration of ADT treatment. Long-term complications associated with ADT are both real and severe, ranging from osteoporosis with risk of pathologic fracture, metabolic dysfunction including development of diabetes as well as cardiovascular disease with potential for fatal myocardial infarction [
In summary, the current standard of care for high-risk and locally advanced disease is EBRT in conjunction with long-term ADT; specifically, a 3D-CRT or IMRT radiation therapy technique to a dose of 75–80 Gy in conjunction with long-term ADT in a neoadjuvant, concurrent, or adjuvant setting for approximately 2-3 years. Generally, high-risk patients are usually not considered for treatment with brachytherapy; however, certain clinical scenarios may warrant the use of brachytherapy boost in combination with EBRT, with consideration of short-term ADT [
Like radiotherapy, as technology (i.e., laparoscopic, robotic) continues to improve, some of the issues with surgical management for high-risk patients are no longer valid. For example, with the advent of robotic surgery some experienced urologists now consider stage T3a prostate cancer as an operable disease. Men with clinically localized tumors without fixation that can be completely excised may be candidates for radical prostatectomy (RP) with pelvic lymph node dissection if they have a reasonable life expectancy. Lau et al., reported a post-RP overall survival of 67% at 10 years among patients with adverse prognostic features (Gleason score ≥ 8), suggesting that radical prostatectomy may be a viable alternative for patients who are not candidates for radiotherapy or whom prefer surgery [
Additionally, two recent studies have shown that surgical intervention in the high-risk cohort may result in superior clinical and survival outcomes. A 2010 retrospective study by Zelefsky et al., reported that high-risk patients undergoing RP had a lower risk of metastatic progression and PCSM compared to patients receiving IMRT (≥81 Gy) [
A significant number of patients will still require postoperative radiotherapy following radical prostatectomy for certain pathologic high-risk features. Recently, three separate studies have demonstrated that adjuvant radiotherapy following radical prostatectomy improves disease control (biochemical progression-free survival), and Thompson et al. reported a marked overall survival benefit for high-risk patients following radical prostatectomy [
Although long-term ADT plus radiotherapy is currently the standard care for high-risk patients, many high-risk prostate malignancies still recur. Importantly, a proportion of these high-risk prostate tumors will become refractory to hormonal therapies which place the patient at risk of developing recurrent or metastatic disease [
Two prospective phase III trials for men with metastatic castration-refractory prostate cancer helped to establish docetaxel and prednisone as the preferred chemotherapy regimen. SWOG 9916, a prospective trial randomizing 674 men with castration-refractory disease, compared survival outcomes and toxicity profiles in a head-to-head comparison of a docetaxel plus estramustine versus mitoxantrone. The docetaxel-containing regimen demonstrated a significant increase in overall survival of nearly two months; however, there was also an increase in side effects, including neutropenic fever and cardiovascular events [
These studies in metastatic castration-refractory patients helped lay the groundwork for early use of docetaxel and other agents as part of the primary treatment for high-risk and locally advanced prostate cancer patients (Table
Summary of randomized control trials involving chemotherapy for high-risk localized prostate cancer.
Study (reference) | Chemo sequencing | Chemo regimen | Study arms | Number of patients | High-risk criteria | ||
Stage | Gleason | PSA | |||||
RTOG 9902 [ | Adjuvant | paclitaxel estramustinee toposide (TEE) | ADT + RT versus ADT + RT + TEE | 397 | any T | ≥7 | 20–100 |
≥ T2 | 8–10 | <100 | |||||
RTOG 0521 [ | Adjuvant | Docetaxel | ADT + RT versus ADT + RT + docetaxel | 612 | any T | ≥9 | ≤150 |
≥ T2 | 8 | <20 | |||||
any T | 7-8 | ≥20–150 | |||||
Kumar et al. [ | Concurrent | Docetaxel | RT + docetaxel | 22 | T3-T4 | ||
T1b-T2 | ≥8 | ||||||
T1c-T2 | 5–7 | ≥10 | |||||
AGUSG 03-10 [ | Concurrent | Docetaxel | RT + docetaxel +/− ADT | 20 | ≥T3 | 8–10 | |
7 | >10 | ||||||
Sanfilippo et al. [ | Concurrent | Paclitaxel | ADT + RT versus ADT + RT + paclitaxel | 22 | TxN1 | >7 | >10 |
Hussain et al. [ | Neoadjuvant | Docetaxel estramustine | docetaxel, EMP +/− RP, RT | 21 | ≥T2b | 8–10 | ≥15 |
Hirano et al. [ | Neoadjuvant/ concurrent | Estramustine | ADT + RT versus ADT + RT + EMP | 39 | ≥T3 | 8–10 | >20 |
SWOG S9921 [ | Neoadjuvant | Mitoxantrone | RP + ADT versus RP + ADT + MTX | 983 | pT3b-T4 | ≥8 | |
7 | >15 | ||||||
CALGB 90203 [ | Neoadjuvant | Estramustine docetaxel | RP versus EMP and docetaxel + RP | recruiting | T1-T3a, NX, M0 |
ADT: androgen deprivation therapy; RT: radiotherapy; TEE: paclitaxel, estramustine, etoposide; EMP: estramustine phosphate; RP: radical prostatectomy; MTX: mitoxantrone.
A critical phase III multicenter study by Rosenthal et al. highlighted the severe toxicities that may occur with multichemotherapy multimodal regimens. A total of 397 high-risk non-metastatic patients (PSA 20–100 ng/mL and Gleason score ≥ 7 or stage
Kumar et al. conducted a phase I trial of concurrent weekly docetaxel with 3D-CRT in order to discern to maximal tolerated dose (MTD) of weekly docetaxel for patients with unfavorable localized prostate cancer. The 22 patients who were enrolled in the concurrent docetaxel and 3D-CRT regimen met inclusion criteria of: (1) T3-T4 disease (2) T1b-T2 disease and Gleason score ≥ 8 or (3) T1c-T2 disease with Gleason score 5–7 and PSA ≥ 10. The MTD of weekly docetaxel was determined to be 20 mg/m2 in conjunction with 3D-CRT, in general, this regimen was considered to be well tolerated without any excessive or objectionable toxicity. Other relevant findings from the study include the side effect of grade 3 diarrhea which was the dose-limiting toxicity; however, no hematologic adverse side effects were noted [
Sanfilippo et al. conducted a prospective phase I/II study of biweekly paclitaxel and concurrent radiotherapy in order to determine the maximum tolerated dose of paclitaxel in androgen-ablated locally advanced prostate cancer. Paclitaxel, a taxane molecule, has a similar mechanism of action to docetaxel which leads to the accumulation of cells in G2/M phase having both cytotoxic as well as radiosensitizing effects [
Examining the efficacy of chemotherapy in the neoadjuvant setting in combination with ADT and radiotherapy is becoming an area of increasing interest. Hussain et al. evaluated the safety of neoadjuvant docetaxel and estramustine chemotherapy alone in 21 patients with high-risk cancer defined as clinical stage T2b or greater, PSA > 15 ng/mL and/or a Gleason score of 8–10. Induction chemotherapy with docetaxel and estramustine was reported to be a well-tolerated and a feasible regimen for the high-risk cohort. Patients did experience grade 3 and 4 toxicities in the form of neutropenia in nine patients and deep vein thrombosis in two patients. Furthermore, the efficacy of this regimen in comparison to ADT remains unclear and its use in conjunction with other modalities was not evaluated [
Recently, the role of chemotherapy in conjunction with radical prostatectomy has also been examined. Similarly to RTOG 99-02, which has halted due to prohibitive toxicities, SWOG 9921, a randomized phase III trial, prematurely closed the chemotherapy plus ADT arm due to the development of acute myelogenous leukemias. In this study, 983 patients with high-risk features were randomized to receive adjuvant ADT with or without mitoxantrone in the postradical prostatectomy setting. This study underlined the importance of prospective trials to assess potential safety issues for patients. In this particular case, the risk of secondary malignancies associated with a mitoxantrone-containing adjuvant chemotherapy regimen was an unexpected problem [
The need to improve high-risk disease management has prompted the development of novel agents, several of which may be genuine contenders to impact disease outcomes in the future. Initial studies in castration-refractory disease have been useful in order to characterize the efficacy and safety of these potential therapeutic agents.
Sipuleucel-T (APC8015), a cancer vaccine, is an active cellular immunotherapy that stimulates a prostate cancer-specific T-cell immune response against prostatic acid phosphatase (PAP), an antigen expressed by approximately 95% of prostate cancer cells [
While prostate cancer patients often initially derive benefit from ADT, a proportion of these patients will develop castration-refractory prostate cancer characterized by progression of disease despite castrate levels of circulating testosterone. The persistence of ligand-mediated androgen receptor signaling implicates extragonadal (prostate, adrenal, intratumoral) androgen production as a potential mechanism of resistance to ADT rather than an androgen-independent mechanism. Abiraterone acetate suppresses extragonadal androgen biosynthesis via inhibition of CYP17 (cytochrome P-450c17), an enzyme that has been shown to be over expressed in castration-refractory disease. In a recent 2011 phase III multicenter trial, de Bono and colleagues evaluated the efficacy of abiraterone in castration-refractory patients with progression after docetaxel treatment. Patients were randomized to receive prednisone with either abiraterone or placebo and there was a median follow-up time of 12.8 months among the 1195 enrolled patients. A clear survival benefit was reported in the abiraterone-prednisone group, with a 35.4% reduction in the risk of death compared to the placebo cohort (hazard ratio, 0.65) which translated into an increase in overall survival of 3.9 months (14.8 versus 13.9 months). Secondary end points including PSA progression, progression-free survival and PSA response rate also favored the patients whom received abiraterone. Of note, while both treatment cohorts received prednisone as part of the treatment regimen, steroid-related toxicities and side effects were more frequent among patients receiving the androgen biosynthesis inhibitor. However, the general consensus regarding this study is that abiraterone acetate plus prednisone is effective in prolonging overall survival with minimal increase in additional toxicities for patients with metastatic castration-refractory prostate cancer with progression after chemotherapy [
A new therapy, MDV3100, targets androgen receptor-mediated treatment resistance with a distinct mechanism of action to that of abiraterone. While the concept of androgen-receptor antagonism is not a novel concept, MDV3100 is notable for its extremely high receptor-binding affinity, ability to induce tumor cell apoptosis and pure androgen receptor antagonism [
While considerable progress has been made in the treatment of high-risk prostate cancer, there is a clear need to continue prospective randomized clinical trials in order to optimize treatments. Combination therapies involving radiotherapy, androgen deprivation therapy, surgery and chemotherapy have yielded varied success. Importantly, the combination of long-term ADT and radiotherapy and has been particularly successful and chemotherapy may have the potential further improve outcomes. As we continue to appreciate the additive and synergistic effects of multimodality therapy, we must also acknowledge the potential for additive toxicities.