Chemotherapy of Genitourinary Cancer

Maha Hussain

Gary R. Macvicar

PROSTATE CANCER

Introduction

Prostate cancer remains the most common noncutaneous cancer diagnosis among American men with an estimated 217,730 new diagnoses in 2010. Furthermore, 32,050 men are expected to die of prostate cancer in 2010, making this malignancy the second leading cause of cancer-specific mortality in men in the United States.¹ Owing to prostate-specific antigen (PSA) screening, a stage migration has occurred, resulting in most men being diagnosed with clinically localized disease,² but whether screening improves survival remains unclear.³^,⁴ The appropriate management of patients with localized disease (Table 35-1), whether radical prostatectomy, radiation therapy, or active surveillance, remains a matter of some debate. Nonetheless, although many men are cured with primary therapy, either radiation or surgery, a significant portion will progress and develop recurrent disease. Therefore the role of systemic therapy, whether androgen deprivation therapy, chemotherapy, or immunotherapy, continues to evolve as clinical investigators try to improve outcomes for all stages of the disease.

Neoadjuvant and Adjuvant Therapy in Localized and Locally Advanced Prostate Cancer

Although the rate of disease-free and overall survival (OS) is relatively high with both radical prostatectomy and
radiation as primary therapy, special consideration must be given to the reality that a significant portion of patients experiences recurrent disease. In a pooled analysis of men following radiation, 34% experienced a biochemical recurrence at 5 years,⁵ and similarly, rates of 15% to 31% have been reported following radical prostatectomy.⁶^,⁷^,⁸ Pound et al.⁷ reported that 34% of men with a rising PSA following radical prostatectomy developed metastatic disease at a median of 8 years, and once metastases were detected, patients experienced a median survival of 5 years. Investigators have identified that patients at diagnosis who have a PSA >20 ng per ml, Gleason score 8 to 10, or a clinical stage T2c or T3 are at high risk for recurrent disease following primary therapy.⁹ Learning from results in other solid tumors that even modestly active systemic chemotherapy can have curative potential when administered in the adjuvant setting, clinical investigators have studied the role of systemic therapy in conjunction with primary therapy for early stage disease with the hopes of improving outcomes.

Table 35-1 Prostate Cancer Staging

Primary Tumor
Clinical (cT)
TX	Primary tumor not assessed
T0	No evidence of primary tumor
T1	Clinically inapparent tumor that is neither palpable nor visible by imaging
T1a	Tumor incidental histologic finding in no >5% of resected tissue
T1b	Tumor incidental histologic finding in >5% of resected tissue
T1c	Tumor identified by needle biopsy (e.g., because of elevated PSA level)
T2	Tumor confined within the prostate
T2a	Tumor involves one-half of one lobe or less
T2b	Tumor involves more than one-half of one lobe but not both lobes
T2c	Tumor involves both lobes
T3	Tumor extends through the prostate capsule
T3a	Extracapsular extension (unilateral or bilateral)
T3b	Tumor invades seminal vesicle(s)
T4	Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum bladder, levator muscles, and/or pelvic wall
Pathologic (pT)
pT2	Organ confined
pT2a	Unilateral, one-half of one side or less involved with tumor
pT2b	Unilateral, more than one-half of side but not both sides involved with tumor
pT2c	Bilateral disease
pT3	Extraprostatic extension
pT3a	Extraprostatic extension or microscopic invasion of bladder neck
pT3b	Seminal vesicle invasion
pT4	Invasion of the rectum, levator muscles, or pelvic wall
Regional lymph nodes (N)
Clinical
NX	Regional lymph nodes not assessed
N0	No regional lymph node metastases
N1	Metastasis in regional lymph nodes
Pathologic
pNx	Regional lymph nodes not assessed
pN0	No regional lymph nodes positive
pN1	Metastasis in regional lymph nodes
Metastatic disease (M)
M0	No distant metastases
M1	Distant metastases present
M1a	Nonregional lymph nodes
M1b	Bone metastases
M1c	Other site(s) with or without bone involvement
Stage grouping
	T	N	M	PSA	GS
Stage I	T1a-c	N0	M0	<10	≤6
	T2a	N0	M0	<10	≤6
	T1-2a	N0	M0	X	X
Stage IIA	T1a-c	N0	M0	<20	7
	T1a-c	N0	M0	≥10 and <20	≤6
	T2a	N0	M0	<20	≤7
	T2b	N0	M0	<20	≤7
	T2b	N0	M0	X	X
Stage IIB	T2c	N0	M0	Any	Any
	T1-T2	N0	M0	≥20	Any
	T1-T2	N0	M0	Any	≥8
Stage III	T3a-b	N0	M0	Any	Any
Stage IV	T4	N0	M0	Any	Any
	Any T	N1	M0	Any	Any
	Any T	Any N	M1	Any	Any
X, not assessed.
From Edge SB; American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.

Androgen Ablation

Several trials have evaluated the role of neoadjuvant and adjuvant hormonal therapy in combination with radical prostatectomy or radiation therapy. Although studies done in surgical settings demonstrated decreased rates of positive margins with neoadjuvant hormone therapy, they did not show a survival benefit for patients with localized or locally advanced prostate cancer.¹⁰^,¹¹ Alternatively, men with lymph node metastases at radical prostatectomy appear to benefit from adjuvant hormonal therapy. Messing et al.¹² reported a reduction in disease progression from 77% to 18% and an increase in survival from 65% to 85% at a median follow-up of 7.1 years in men with node-positive disease who received immediate androgen deprivation therapy versus delayed treatment at the time of progression. However, a retrospective analysis of the Surveillance, Epidemiology and End Results-Medicare database of men who had lymph-node positive disease at prostatectomy did not demonstrate an improvement in OS with the addition of adjuvant hormonal therapy.¹³ Although the study by Messing et al. has been criticized for not meeting its accrual goal, this latter study is limited in its conclusions because of its observational design.

Several randomized, phase III trials have been completed in the United States and in Europe evaluating the utility of combining androgen deprivation therapy with external beam radiation in high-risk disease (Table 35-2). RTOG 85-31, RTOG 86-10, and EORTC 22863 all included patients with clinically localized, high-risk disease, or locally advanced disease, and patients were randomized to radiation alone or to radiation in combination with androgen deprivation therapy. Although the schedule of hormonal therapy differed among the three trials, they each resulted in similar improvements in survival.¹⁴^,¹⁵^,¹⁶ For patients with high-risk disease or locally advanced disease, the addition of a minimum of 3 years of adjuvant androgen
deprivation therapy is thought to result in superior outcomes based on RTOG 92-02 and EORTC 22961.¹⁷^,¹⁸ However, some have criticized all of these studies in that they were designed several years ago, during which time the characteristics of prostate cancer patients and their management have changed. Currently, a smaller fraction of patients present with locally advanced disease than is represented in a number of these trials, and patients with bulkier disease are less likely to be cured with radiation alone. However, they may benefit more from the addition of androgen deprivation therapy than patients with less burdens of disease, skewing the results of these studies. Also, the total dose of radiation in many of the studies is on the order of 65 to 70 Gy, which is less than what is recommended today on the basis of dose escalation studies in prostate cancer.¹⁹^,²⁰^,²¹ The proper timing and duration of androgen deprivation therapy as well as whether combined androgen blockade (CAB) is necessary is yet to be completely defined. Thus, until additional randomized trials demonstrate otherwise, androgen deprivation for a minimum of 3 years in conjunction with radiation is the standard of care for patients with high-risk disease.

Table 35-2 Phase III Trials Evaluating the Addition of Androgen Deprivation Therapy to External Beam Radiation

Clinical Trial	Patient Population	Treatment Arms	OS	Disease-Specific Survival
Clinically localized, high-risk disease or locally advanced disease
RTOG 85-31¹⁶	cT3 or N1	Indefinite adjuvant	49%	84%
		vs.
		EBRT alone	39%	78%
			P = .002	P = .0052
			(10 y)	(10 y)
RTOG 86-10³⁵²	Bulky cT2-T4	4 mo’s neoadjuvant + concurrent	43%	77%
		vs.
		EBRT alone	34%	64%
			P = .12	P = .01
			(10 y)	(10 y)
EORTC 22863¹⁴	cT1-2, grade 3	Concurrent + adj 3 y	78%	—
	or	vs.
	cT3-4, any grade	EBRT alone	62%	—
			P = .0002	—
			(5 y)
TROG 9601³⁵³	cT2b-4, N0, M0	3 mo’s neoadjuvant + concurrent	—	92%
		vs.
		6 mo’s neoadjuvant + concurrent	—	94%
		vs.
		EBRT alone	—	91%
			—	P = .04^a
				(5 y)
MGH³⁵⁴	cT1b-2b, N0, M0	6 mo’s neoadjuvant + concurrent	74%	—
	And	vs.
	≥1 risk factor^b	EBRT alone	61%	—
			P = .01	—
			(8 y)
Short vs. long course of androgen deprivation therapy
RTOG 92-02¹⁸	cT2c-4	Neoadjuvant + concurrent 4 mo’s	52%	84%
		vs.
		Neoadjuvant + concurrent + adj 28 mo’s	54%	89%
			P = .36	P = .004
			(10 y)	(10 y)
EORTC 22961¹⁷	cT1c-T2b N1 T2c-	Concurrent + adj 6 mo	81%	—
	T4 N0-1	vs.
	T2c-T4 N0-1	Concurrent + adj 3 y	85%	—
			P = .019	—
			(5 y)
^a6 mo’s of neoadjuvant therapy vs. 0 mo’s of neoadjuvant therapy. ^bRisk factors: PSA >10 ng per ml, Gleason score ≥7, extracapsular extension, seminal vesicle invasion on endorectal MRI.

Treatment strategies based on risk of biochemical relapse following radiation have been proposed. Patients with low-risk disease (stage T1-T2b, Gleason’s score no >6, and PSA no >10 ng per ml) do not require adjuvant hormonal therapy. Those with
intermediate-risk disease (stage T2b, Gleason’s score 7, or PSA 10 to 20 ng per ml) should receive 4 to 6 months of neoadjuvant and concurrent androgen deprivation therapy, and the high-risk population (stage T2c or greater, or Gleason’s score 8 to 10, or PSA >20 ng per ml) should be offered at least 2 years of adjuvant hormonal therapy in addition to neoadjuvant and concurrent hormonal therapy.²² In the trials discussed above, adjuvant androgen deprivation largely consisted of luteinizinghormone releasing hormone (LHRH) agonist monotherapy, but other trials that have utilized three-dimensional conformal radiation have administered a LHRH-agonist in combination with an antiandrogen.²³^,²⁴

Chemotherapy

No data exist to support the use of chemotherapy either pre- or postprostatectomy, but cooperative group studies have been conducted or are ongoing to evaluate the utility of both neoadjuvant and adjuvant chemotherapy. The Cancer and Leukemia Group B (CALGB) has an ongoing clinical trial, CALGB 90203, in which men with high-risk features are randomized to neoadjuvant leuprolide and docetaxel prior to radical prostatectomy versus radical prostatectomy alone. The Southwest Oncology Group (SWOG) conducted an adjuvant study for patients with high-risk disease following prostatectomy, SWOG 9921. Men were randomized to receive 2 years of adjuvant deprivation therapy alone or in combination with six cycles of mitoxantrone and prednisone. The study was closed prematurely after three patients in the mitoxantrone arm were noted to develop acute myelogenous leukemia,²⁵ but no survival results have been reported to date.

Hormone Sensitive Metastatic Disease

Androgen deprivation therapy is the standard of care for men with overt metastatic disease, and the rationale for this approach is based on findings that prostate cancer proliferation is regulated and stimulated by the interaction of androgens with the androgen receptor (AR).

Androgen Deprivation Therapy

On the order of 80% to 90% of men with advanced prostate cancer will experience a response to androgen deprivation therapy.²⁶^,²⁷ Multiple options exist to reduce testosterone production or interrupt its action, and these include orchiectomy, LHRH agonists, LHRH antagonists, antiandrogens, and estrogens (Fig. 35.1). Additional novel hormonal agents are in various stages of development. Orchiectomy is the gold standard by which other hormonal manipulations are compared after Huggins et al.²⁸ demonstrated the efficacy of the surgical procedure with a high rate of symptomatic improvement in 1943.

Medical castration, either in the form of LHRH agonists or DES, is thought to be equivalent.²⁹^,³⁰^,³¹^,³²^,³³ However, because of an increased rate of cardiovascular and thromboembolic events, DES and other estrogens fell from favor. A concern with LHRH agonist use is a surge of testosterone production that occurs with their initiation, known as a “flare” reaction, which may result in a transient increase in symptoms, namely bone pain, ureteral obstruction, and spinal cord compression. To avoid the flare reaction, an antiandrogen can be given in conjuction with an LHRH agonist for a short duration.³⁴ LHRH antagonists have also been developed, and they have similar efficacy as LHRH agonists with a reduced incidence of a flare reaction obviating the need for concurrent antiandrogen use.³⁵ One LHRH antagonist, abarelix was withdrawn from the market because of injection site reactions and incidences of anaphylaxis. Degarelix has been shown in a randomized study to be equivalent to leuprolide in terms of suppressing testosterone production over 1 year of therapy, but degarelix appears to be able to lower testosterone and PSA levels more rapidly than leuprolide.³⁶ Because of cost, lack of long-term data with LHRH antagonists, and monthly formulation, many clinicians continue to favor LHRH agonists. However, antagonists are particularly useful in settings where concern for flare exists.

Antiandrogens provide yet another means of reducing the effect of testosterone. In the United States, only nonsteroidal antiandrogens are available, and they include flutamide, bicalutamide, and nilutamide. Normal levels of testosterone are maintained, and many men maintain potency. As monotherapy, early studies suggested that this class may be as effective as orchiectomy,³⁷ but subsequent studies indicated that they are inferior to orchiectomy in the metastatic and locally advanced settings.³⁸

Much debate has focused on the utility of adding antiandrogens to either LHRH agonists or orchiectomy, known as CAB. Several trials have addressed this issue, and although some studies show a small survival advantage with this approach,³⁰^,³⁴^,³⁹^,⁴⁰ several studies do not, including INT 0105.⁴¹ This intergroup study randomized men with metastatic disease to either orchiectomy alone or to orchiectomy with flutamide. No difference in OS was identified. However, INT 0036 randomized men with metastatic disease to leuprolide monotherapy or to leuprolide and flutamide. The men in the CAB arm were observed to have an improvement in median OS (35.6 vs. 28.3 months) over leuprolide monotherapy.³⁴ A meta-analysis evaluating the utility of adding antiandrogens to either orchiectomy or LHRH agonist reported a small improvement in 5-year survival of 2% to 3% with the use of CAB, but at the expense of additional toxicity.³⁹ Current ASCO guidelines suggest that CAB should be discussed with patients as a possible treatment option.⁴²

When to Initiate Androgen Deprivation Therapy

In the past, many men presented or developed symptoms related to metastatic disease, providing an indication for androgen deprivation therapy. However, several studies suggest that earlier initiation of hormonal therapy is better than deferred in men with metastatic disease. An early Veteran’s Administration Cooperative Urological Research Group study that randomized men to DES or to placebo demonstrated a delay in time to progression in the DES treatment arm. Furthermore, a survival advantage was noted with DES in younger men with higher grade and metastatic disease.⁴³ A trial conducted by the Medical Research Council (MRC) randomized men with locally advanced or asymptomatic metastatic disease to orchiectomy or to LHRH agonist either at diagnosis or at the time of disease progression, but the study failed to reach
target accrual. Immediate androgen deprivation therapy was associated with significantly less morbidity, but survival benefits were less clear.⁴⁴^,⁴⁵ The Eastern Cooperative Oncology Group (ECOG) randomized men with nodal metastases at radical prostatectomy to immediate androgen deprivation therapy at the time of diagnosis or to delayed therapy until the time of disease progression. They noted an advantage in time to progression and survival with immediate treatment.¹² The European Organization for Research and Treatment of Cancer (EORTC) noted a trend toward worse survival with a delay in treatment in a study that randomized men with node positive disease who did not undergo radical prostatectomy to either immediate or delayed androgen production.⁴⁶ A meta-analysis also suggested improvements in progression-free survival (PFS) at 1 and 5 years as well as a small but significant survival advantage at 10 years in men who received immediate androgen deprivation.⁴⁷

Figure 35.1 Strategies for androgen deprivation. 5αR, 5-α reductase; LH, Luteinizing hormone; T, Testosterone; DHT, Dihydrotestosterone. (From Hellerstedt BA, Pienta KJ. The current state of hormonal therapy for prostate cancer. CA Cancer J Clin. 002;52(3):154-179.)

Despite these results, in the setting of only a biochemical recurrence without either symptoms or clinical progression, the impact of androgen deprivation therapy and its timing on objective disease progression or survival is not known. However, PSA kinetics, such as PSA doubling time and PSA velocity, may point to patients at increased risk for prostate
cancer-specific mortality and identify a population who should be considered for early androgen deprivation therapy. A PSA doubling time of <12 months following radical prostatectomy and <13 months following radiation therapy has been associated with prostate cancer-specific mortality.⁴⁸^,⁴⁹ A PSA velocity of >2 ng per ml in the year prior to with radical prostatectomy or radiation has also been associated significantly with prostate cancer-specific mortality.⁵⁰^,⁵¹ Trials are needed to test PSA kinetics in a prospective fashion to further establish their validity in predicting outcomes.

Alternate Methods of Androgen Deprivation

Several side effects result from extended periods of androgen deprivation therapy. Hot flashes, decreased libido, erectile dysfunction, fatigue, osteoporosis, weight gain, decreased muscle mass, anemia, and decline in cognitive function have been associated with orchiectomy.⁵² In addition to effects on bone mineral density, the use of androgen deprivation therapy has been associated with an increase in fracture risk among men with prostate cancer.⁵³^,⁵⁴ Although some observational studies have suggested an increased risk of cardiovascular disease and diabetes mellitus with the use of androgen deprivation therapy, reports are conflicting.⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰

Because of these side effects, alternatives to traditional androgen deprivation therapy have been sought. Intermittent androgen deprivation is one such approach, typically involving CAB in a cyclical fashion as a means to control prostate cancer growth. After an initial induction period during which a maximal PSA response is attained, CAB is discontinued. PSA and testosterone are monitored, and when PSA reaches a predetermined level, CAB is reinitiated. In a large European study randomizing men to continuous versus intermittent androgen deprivation therapy, no difference in 5-year survival was noted between the two arms, 54% with intermittent therapy versus 51% with continuous therapy. However, the median time off of therapy in the intermittent therapy cohort was 52 weeks with 29% off therapy for at least 36 months. Men in the intermittent arm reported a more favorable side effect profile and sexual activity.⁶¹ A second study randomizing men to intermittent versus continuous androgen deprivation therapy noted a trend toward an improved time to disease progression with intermittent therapy (16.6 months) compared with continuous therapy (11.5 months), but this difference was not statistically significant. Similarly, no difference in OS was observed (51.4 months with intermittent therapy and 53.8 with continuous therapy). Among men in the intermittent therapy arm, 88% were off therapy for at least 50% of the time on study, and as a group, self-assessment of their overall health and sexual activity was more favorable than that of the men in the continuous therapy arm.⁶² Large phase III studies that are evaluating the role of intermittent versus continuous androgen blockade in men with a PSA relapse post-radical prostatectomy (European EC507) and in men with newly diagnosed metastatic disease (SWOG S9346, INT-0162, and NCIC PR8) are pending results. However, for men with a biochemical recurrence following radiation, intermittent androgen blockade and continuous androgen blockade are equivalent in terms of OS.⁶³ Intermittent androgen blockade is considered experimental in advanced disease pending data from phase III studies in this setting.

Other nontraditional approaches exist that may be appealing to men who wish to maintain potency. One is the use of high-dose bicalutamide, sometimes referred to as peripheral androgen blockade. Bicalutamide at 150 mg daily has been reported to be as effective as orchiectomy or CAB for patients with PSA only disease,⁶⁴ but it is inferior to castration for patients with metastatic disease.³⁸ A second potency sparing approach involves the combination of a nonsteroidal antiandrogen with finasteride, termed sequential androgen blockade. This combination results in androgen deprivation at the cellular level while leaving circulating androgen levels intact. Most men included in phase II trials with this approach have experienced a decrease in PSA,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹ but the effect of sequential androgen blockade on survival has not been tested in phase III trials. There is no level 1 evidence to support the routine use of peripheral blockade.

Secondary Hormonal Manipulations

Although most men will respond to hormonal manipulations, clinicians can anticipate that the response is temporary in most, lasting on the order of 18 to 24 months for patients with metastatic disease. Despite a rising PSA heralding progression to androgen independence, the disease often remains responsive to hormonal manipulations.

Various options exist as second-line hormone therapy, but none has been shown to be effective with regard to survival in a randomized phase III trial. The addition or removal of antiandrogens when men experience a rising PSA while on androgen deprivation therapy may be effective in lowering PSA values. Flutamide added to men who failed orchiectomy, DES, or LHRH agonist resulted in a PSA response rate of 35% with a mean duration of 24 months.⁷⁰ Alternatively, patients who received an antiandrogen either as monotherapy or as part of CAB may experience a decline in PSA with antiandrogen withdrawl. This phenomenon was first reported in 1993, and subsequent results reported PSA responses in 15% to 30% of men that lasted on the order of 3 to 6 months.⁷¹^,⁷²^,⁷³^,⁷⁴ Investigators have also reported PSA response rates of 20% to 50% with a change of one antiandrogen to another.⁷⁵^,⁷⁶

The adrenal glands are another source for circulating androgens. Hormonal therapy significantly reduces circulating testosterone but does not affect adrenal androgens such as dehydroepiandrosterone and androsteindione.⁷⁷ Suppression of this source in addition to gonadal production has been investigated with the use of cytochrome P450 enzyme inhibitors, namely ketoconazole. An early study of ketoconazole reported a response rate of 62% in this population with a median response time of 3.5 months.⁷⁸ A larger study involving 260 men reported a PSA response rate of 27% and a time to PSA progression of 8.6 months but no survival advantage with the simultaneous initiation of antiandrogen withdrawal and ketoconazole.⁷⁹

Hormonal Agents in Development

Androgen deprivation therapy aims to inhibit the function of the androgen receptor, and surgical or medical castration accomplishes this by decreasing the levels of circulating androgen. PSA, an androgen-regulated gene product, subsequently declines with effective hormonal therapy. However, this effect is typically temporary, as the disease will progress and PSA will rise, suggesting that tumor progression may be secondary to a restoration of androgen receptor function.⁸⁰ Multiple mechanisms of restoring androgen receptor function have been proposed, including the local production of androgens within tumors.⁸¹ Despite castrate serum testosterone levels, prostatic androgen concentrations have been reported to be 10% to 25% of levels found in untreated men, and these levels are sufficient to promote androgen receptor signaling.⁸²^,⁸³ These androgens may result from intratumoral conversion of serum adrenal androgens to testosterone or by intratumoral synthesis of androgens from substrates such as cholesterol or progesterone.⁸⁴ Thus in some men with castration-resistant prostate cancer, intracrine mechanisms rather than classic endocrine mechanisms may be driving disease progression.

Abiraterone is a novel hormonal agent that has been studied in men with metastatic castration-resistant prostate cancer (mCRPC) who are chemotherapy naïve. This oral agent is a small molecule inhibitor of both 17,20-lyase and 17-α-hydroxylase that reduces testicular, adrenal gland, and prostatic androgen production. In initial phase I and II studies in chemotherapy naïve men, PSA response rates of 55% to 67% have been reported⁸⁵^,⁸⁶ and a partial response rate by RECIST criteria of 37.5% in men with measurable disease.⁸⁵ In the post-docetaxel setting, PSA response rates of 36% to 51% were observed in phase II studies.⁸⁷^,⁸⁸ Notably, in both populations, responses occurred in a portion of men who had previously been treated with ketoconazole.⁸⁶^,⁸⁷ An industry-sponsored phase III study randomizing men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate who are chemotherapy naïve to either abiraterone or placebo has completed accrual, and results are pending. However, an identical trial in men who had progressed on docetaxel resulted in an improvement in median OS from 10.9 months with placebo to 14.8 with abiraterone (P < .0001).

TAK-700 is another 17,20-lyase inhibitor that has shown activity in this population as well,⁸⁹ and two industry-sponsored phase III studies with TAK-700 in men with mCRPC who are chemotherapy naïve or who have progressed despite docetaxel are planned.

MDV3100 is a novel androgen receptor antagonist with encouraging early results. This oral agent has been demonstrated in preclinical models to have higher affinity for the androgen receptor than bicalutamide and to have activity in bicalutamide resistant models. The drug impairs nuclear translocation of the androgen receptor, inhibits its binding to DNA and coactivators, and induces apoptosis. In an initial phase I/II study, 62% of men who were chemotherapy naïve experienced a PSA response with MDV3100.⁹⁰ An industry sponsored phase III study of this agent in chemotherapy naïve mCRPC population is ongoing. A similar study in men previously treated with docetaxel has completed accrual, and results are pending.

Castration-Resistant Prostate Cancer

When men experience an elevation in PSA or progression of metastatic disease despite serum testosterone suppression into the castrate range, the disease is considered castration resistant. Several chemotherapeutic agents have been studied in this setting in the past with minimal efficacy, leading many to conclude that chemotherapy does not have a crucial role in the management of patients with mCRPC. This opinion began to change with the demonstration of a palliative effect and an improvement in quality of life in symptomatic, mCRPC patients treated with mitoxantrone. This was followed by a survival advantage with docetaxel-based therapy that is considered the standard first-line regimen in the castration resistant setting (Table 35-3).

Mitoxantrone and Prednisone

Two phase III studies were conducted that evaluated mitoxantrone in castration-resistant prostate cancer.⁹¹^,⁹² One was reported by Tannock et al. with a primary endpoint of pain relief and the other by the CALGB with OS as the primary endpoint. In both trials, men were randomized to either steroids alone or to steroids and mitoxantrone, and neither study reported a survival advantage with the addition of mitoxantrone. However, in the Tannock study, men who received mitoxantrone were more likely to experience symptomatic improvement and for a longer period than with prednisone alone.⁹² For several years, mitoxantrone in combination with a steroid was the standard first-line regimen for mCRPC.

Table 35-3 Standard Chemotherapy Regimens for Prostate Cancer

Regimen	Dose	Schedule	Treatment Interval
Mitoxantrone and prednisone⁹²	Mitoxantrone 12 mg/m² Prednisone 5 mg	IV day 1 PO bid days 1-21	21 d
Docetaxel and prednisone⁹⁵	Docetaxel 75 mg/m² Prednisone 5 mg Decadron 8 mg	IV day 1 PO bid days 1-21 PO 12 hr, 3 hr, and 1 hr prior to docetaxel	21 d
Cabazitaxel and prednisone (Salvage therapy)⁹⁸	Cabazitaxel 25 mg/m² Prednisone 10 mg	IV day 1 PO daily days 1-21	21 d

Docetaxel-Based Chemotherapy

Docetaxel is a cytotoxic agent targeting cellular microtubules, which are crucial for cellular processes occurring during interphase and mitosis. The drug binds to tubulin, stabilizes microtubule formation, and inhibits depolymerization.⁹³ In two phase III studies, docetaxel-based chemotherapy was shown to be superior to mitoxantrone and prednisone. SWOG 9916 demonstrated a median survival of 18 months with the combination of docetaxel and estramustine versus 15 months with mitoxantrone and prednisone, a difference that was statistically significant.⁹⁴ TAX 327 also showed superiority of docetaxel over mitoxantrone. Docetaxel, when given 75 mg per m² every 3 weeks, demonstrated a significant improvement in median survival from 16.5 months with mitoxantrone versus 18.9 months with docetaxel. A third arm utilized docetaxel 30 mg per m² given weekly for 5 weeks of 6-week cycles, but the median survival of 17.4 months did not reach statistical significance. However, an improved pain response was noted in both docetaxel arms.⁹⁵ These studies are the first to report a survival advantage with any therapy in castration-resistant prostate cancer, thus establishing docetaxel as the first-line regimen in this setting. Because of lack of obvious advantage with docetaxel and estramustine combination, the 3-week docetaxel and prednisone regimen is the standard of care. Several phase III trials have combined novel agents with docetaxel and prednisone including bevacizumab (CALGB 90401),⁹⁶ DN-101 (ASCENT-2),⁹⁷ sunitinib, but no combination to date has demonstrated a survival advantage over docetaxel and prednisone.

Second-Line Chemotherapy

Until recently mitoxantrone and prednisone have been the de facto second-line therapy post-docetaxel failure. However, cabazitaxel, a semisynthetic taxane derivative, has demonstrated a survival superiority over mitoxantrone in men who had progressed despite docetaxel-based therapy based on a randomized phase III trial. The median survival (15.1 vs. 12.7 months) and PFS (2.8 vs. 1.4 months) were both significantly longer in the cabazitaxel arm as compared with than in the mitoxantrone arm. However, grade 3 or higher febrile neutropenia (7.5% vs. 1.3%) and diarrhea (6.2% vs. 0.3%) were more frequent with cabazitaxel, and more treatment-related deaths were reported with cabazitaxel (4.9% vs. 1.9%). The treatment-related deaths among the men receiving cabazitaxel were primarily related to infectious complications and renal failure.⁹⁸ Patients should be monitored closely for toxicity, particularly for neutropenia and diarrhea, while receiving cabazitaxel, and appropriate supportive care should be provided, including primary prophylaxis with growth factor support for patients at high risk for neutropenic complications.

Immunotherapy

Immune-based strategies to treat prostate cancer have been explored in that a number of tumor-specific antigens, such as prostatic acid phosphatase, PSA, and prostate-specific membrane antigen, are expressed by prostate cancer cells and may serve as therapeutic targets. Sipuleucel-T is an autologous dendritic cell therapeutic vaccine and is the most notable example of immunotherapy for prostate cancer thus far. Treatment requires first isolating mononuclear cells from patients by leucapheresis, then exposing the cells ex vivo to a fusion protein of prostatic acid phosphatase and granulocyte-macrophage colony stimulating factor (GM-CSF), and finally reinfusing activated cells into patients. In initial randomized phase III trials, the primary endpoint of PFS was not met, but improvements in OS were noted among men who received sipuleucel-T.⁹⁹^,¹⁰⁰ This led to the design of a larger, phase III study in which the primary endpoint was OS. In this randomized, double-blind, controlled trial, 512 men were randomized to sipuleucel-T or control, given every 2 weeks for three infusions. The median survival for men receiving sipuleucel-T was 25.8 versus 21.7 months for the control group, translating to a 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.61 to 0.98; P = .03). However, no difference in either PSA response rate or time to disease progression was noted between the two arms.¹⁰¹ When considering sipuleucel-T, one must keep in mind the patient population of this study. The men were either asymptomatic or minimally symptomatic from their disease, had an ECOG performance status (PS) of 2 or better, a life expectancy of at least 6 months, no visceral metastases, and no history of a pathologic fracture or spinal cord compression. Although 18% had received prior chemotherapy, participants must not have received chemotherapy within 3 months of enrollment or more than two prior regimens. Thus, sipuleucel-T should be reserved for men with favorable disease characteristics.

In addition to dendritic cell vaccines, other immune therapies in development include monoclonal antibodies and recombinant vaccines. Cytotoxic T lymphocyte antigen-4 (CTLA4) is a molecule that can bind to T cells and inhibit their stimulation, restricting their response to self-antigens. Ipilimumab is a humanized, monoclonal anti-CTLA4 antibody that binds to the CTLA-4 receptor on T cells, augmenting their response by prohibiting the binding of CTLA4. Pilot studies have demonstrated the feasibility of administering ipilimumab to men with castrate-resistant prostate cancer, either alone or with GM-CSF.¹⁰²^,¹⁰³ Initial results of a study combining ipilimumab with radiation of bony metastases demonstrated a PSA response rate of 22%, but autoimmune reactions were also noted.¹⁰⁴^,¹⁰⁵

GVAX is a cellular vaccine that utilizes exogenous wholetumor cells that are engineered to secrete GM-CSF. An initial phase I/II study with GVAX reported PSA stabilization in 19% of patients, and two randomized trials have been reported. Both phase III studies were in men with mCRPC, comparing GVAX to docetaxel or evaluating the utility of adding GVAX to docetaxel. The studies were halted early after the data safety monitoring committee determined that GVAX was unlikely to improve survival.¹⁰⁶^,¹⁰⁷

Recombinant vaccines utilizing poxviral vectors are also in development. PROSTVAC-VF is such a vaccine, consisting of fowlpox and vaccinia vectors that encode PSA. Also contained in its design is a triad of costimulatory molecules, ICAM-1, B7.1, and LFA-3, known as TRICOM. An initial randomized phase II trial in men with minimally symptomatic mCRPC was designed with PFS as its primary endpoint. The study
did not meet its primary endpoint, but an improvement in median survival from 16.6 months with placebo to 25.1 months with PROSTVAC-VF was noted.¹⁰⁸ ECOG recently activated a phase II study with PROSTVAC in which men with mCRPC are randomized to 3 months of PROSTVAC vaccinations followed by docetaxel and prednisone or to immediate chemotherapy.

Management of Bone Metastases

Bone metastases are common in men with prostate cancer, occurring in over 80% of patients and are the cause of significant morbidity, including pathologic fractures in 25% and spinal cord compressions in 8%, and pain.¹⁰⁹^,¹¹⁰ Complex signaling interactions among prostate cancer cells, osteoclasts, and osteoblasts occur within the microenvironment of bone metastases, and bisphosphonates have been investigated as a means to interrupt this process. The utility of zoledronic acid, a third-generation bisphosphonate, in advanced prostate cancer was demonstrated in a large, double-blinded, randomized controlled trial.¹⁰⁹ In this study, 4 mg of zoledronic acid every 3 weeks resulted in a lower rate of skeletal metastases (38% vs. 49%) and a longer time to the first skeletal event (488 vs. 321 days) when compared with placebo. Although pain increased in both the treatment and control arms, the bone pain was consistently lower in the treatment arm, but this difference was not statistically significant.¹¹¹ In a separate study of zoledronic acid versus placebo in men with bone metastases, zoledronic acid was more likely to be associated with clinically meaningful reductions in pain, and a third of men in the zoledronic acid arm experienced a favorable pain response.¹¹² Zoledronic acid is approved by the Food and Drug Administration (FDA) for prostate cancer patients with skeletal metastases who have progressed despite one course of androgen deprivation therapy. Complications with long-term use of zoledronic acid have been reported, including renal insufficiency and osteonecrosis of the jaw,¹¹³^,¹¹⁴ and care should be taken to monitor creatinine clearance during treatment and to discuss the need for dental work in those with poor dentition prior to initiating therapy.

Denosumab, a fully human monoclonal antibody to receptor activator of NF-χB ligand (RANKL), has also been shown to reduce skeletal complications in men with bone metastases. The rationale for its use is also based on an understanding of bone metastasis biology. Growth factors secreted by tumor cells into the bone microenvironment induce stromal cells and osteoblasts to secrete RANKL, which is a key factor of osteoclast formation and activation. Denosumab has been shown to increase bone mineral density and reduce the vertebral fracture rates in men with nonmetastatic prostate cancer who were receiving androgen deprivation therapy.¹¹⁵ It has also been directly compared with zoledronic acid in men with mCRPC in a randomized, double-blind, active controlled phase III study. The primary endpoint was time to first on-study skeletal related event, and the median time to a first skeletal-related event was 20.7 months with denosumab arm versus 17.1 months with zoledronic acid, a difference that was statistically significant. Rates of hypocalcemia, osteonecrosis of the jaw, and renal toxicity did not differ between the two arms.¹¹⁶ Based in part on these results, the FDA approved denosumab for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

BLADDER CANCER

Introduction

Bladder cancer is the fifth most common malignancy overall in the United States. In 2010, it is estimated that there will be 70,530 newly diagnosed cases and 14,680 bladder cancer-related deaths.¹ Bladder cancer is largely a disease of the elderly with a median age at diagnosis of 65 years, and approximately 80% of those diagnosed are over the age of 60. On the order of 75% of patients present with superficial disease, and these patients are managed primarily by urologists with cystoscopy and transurethral resection (TUR). Intravesicular therapy may also be given depending on grade, presence of carcinoma in situ (CIS), and depth of invasion. The remaining patients, approximately 25%, have muscle invasive disease on a biopsy specimen, and 10% to 25% of these tumors will occur in association with relapsed superficial bladder cancer.¹¹⁷^,¹¹⁸ Patients with muscle invasive and advanced stage disease comprise most patients with bladder cancer who will be treated by medical oncologists (Table 35-4).

Management of Locally Invasive Disease

Surgery

The historical standard approach for the treatment of muscle-invasive bladder cancer is radical cystectomy and bilateral pelvic lymphadenectomy. Long-term survival following surgery has been evaluated in multiple surgical series,¹¹⁹^,¹²⁰^,¹²¹ and the 5-year survival for patients with pathologically organ-confined bladder cancer (pT2) is 68%, whereas those with extravesicular extension or lymph node involvement have a 25% to 30% 5-year survival rate.¹²⁰ Analysis of subsets of patients with muscle-invasive disease has determined that both extravesicular disease and node-positive disease are predictive of decreased survival.¹²¹ The suboptimal outcomes seen with surgical resection have provided the rationale for investigating multimodality approaches to the management of invasive bladder cancer patients. Learning from the positive outcomes with the utilization of adjuvant or neoadjuvant chemotherapy for various other solid tumors, similar trials evaluating perioperative chemotherapy for invasive bladder cancer have been conducted.

Neoadjuvant Chemotherapy

The goal of neoadjuvant chemotherapy is to improve survival via the “eradication” of micrometastatic disease. There are several potential advantages to this approach including downstaging disease and possibly facilitating bladder-sparing strategies. Thus because patients have an intact bladder, oncologists are able to monitor for response during treatment, which has prognostic value.¹²² Patients may also tolerate chemotherapy better before surgery, after which their PS may be impaired by postoperative issues or complications. One of the concerns with this
approach is the possibility of chemoresistant disease that may progress during neoadjuvant treatment, therefore resulting in a progression to a nonoperable stage because of delaying definitive local therapy. In addition, some patients may be exposed to unnecessary therapy based on inaccurate clinical staging.

Table 35-4 Bladder Cancer Staging

Primary tumor (T)
Tx	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Ta	Noninvasive papillary tumor
Tis	CIS: flat tumor
T1	Tumor invades subepithelial connective tissue
T2	Tumor invades muscularis propria
pT2a	Tumor invades superficial muscularis propria (inner half)
pT2b	Tumor invades deep muscularis propria (outer half)
T3	Tumor invades perivesical tissue
pT3a	Microscopically
pT3b	Macroscopically (extravesical mass)
T4	Tumor invades any of the following: prostate, seminal vesicles, uterus, vagina, pelvic wall, or abdominal wall
T4a	Tumor invades prostatic stroma, uterus, or vagina
T4b	Tumor invades pelvic wall or abdominal wall
Regional lymph nodes (N)
NX	Regional lymph nodes not assessed
N0	No regional lymph node metastases
N1	Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node)
N2	Multiple regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node)
N3	Lymph node metastasis to the common iliac lymph nodes
Metastatic disease (M)
M0	No distant metastases
M1	Distant metastases present
Stage grouping
Stage 0a	Ta	N0	M0
Stage 0is	Tis	N0	M0
Stage I	T1	N0	M0
Stage II	T2a	N0	M0
	T2b	N0	M0
Stage III	T3a	N0	M0
	T3b	N0	M0
	T4a	N0	M0
Stage IV	T4b	N0	M0
	Any T	N1-3	M0
	Any T	Any N	M1
From Edge SB; American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.

Several randomized clinical trials have been performed to evaluate the use of neoadjuvant platinum-based regimens,¹²³^,¹²⁴^,¹²⁵^,¹²⁶^,¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰^,¹³¹^,¹³² and most of these trials failed to demonstrate a survival advantage. However, these studies have many shortcomings. Most include a small number of patients and are underpowered to evaluate the efficacy of neoadjuvant therapy, and many use single agent chemotherapy, which is known to be less efficacious than combination regimens. Some allowed patients to receive either radiation or cystectomy for local therapy, and these two modalities that have not been directly compared. Nonetheless, two trials as well as a meta-analysis show a survival advantage with neoadjuvant chemotherapy.¹²³^,¹²⁶^,¹³³

A multi-institutional trial by the International Collaboration of Trialists randomized 976 patients (T2-4N0M0) to either local therapy alone or to three cycles of cisplatin, methotrexate, and vinblastine followed by local therapy.¹²³ Local therapy consisted of either cystectomy or radiation therapy at the treating physician’s discretion, and a portion of patients received both radiation and surgical resection. The first report after a median follow-up of 4 years showed a trend toward improved survival with an absolute survival difference of 5.5% (P = .075). The survival was 55.5% in the chemotherapy arm versus 50% survival in the local therapy only arm. After a median follow-up of 7 years, a significant survival advantage was shown for neoadjuvant chemotherapy with a 6% improvement in OS (P = .048).¹³⁴

The SWOG conducted a phase III neoadjuvant trial that randomized 317 patients (T2-4aN0M0) over 11 years to either radical cystectomy alone or to three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) followed by radical cystectomy.¹²⁶ Median survival in the surgery arm was 46 months and in the combination-therapy arm was 77 months. When analyzed using a two-sided stratified log-rank test, this trend failed to reach statistical significance (P = .06). However, when analyzed according to the original protocol design using a one-sided stratified log-rank test, this survival difference was found to be significant (P = .04). Significantly, more patients in the combination-therapy group had no residual disease at the time of cystectomy (38% vs. 15% P < .001), and 85% of those patients who were pT0 at cystectomy were alive for 5 years. In patients who received neoadjuvant MVAC, the toxicity profile was acceptable with no associated toxic deaths reported, and compared with the surgery alone arm, they did not experience an increase in postoperative complications, demonstrating the feasibility of this approach.

The Advanced Bladder Cancer (ABC) Meta-analysis Collaboration reported an updated meta-analysis of data from 3,005 patients from 11 trials with T2-4a transitional cell carcinoma.¹³³ Although no benefit for neoadjuvant chemotherapy was observed in patients treated with cisplatin alone, a significant survival benefit was seen for patients treated with neoadjuvant platinum-based combination chemotherapy (HR = 0.86, 95% CI, 0.77 to 0.95, P = .003), equivalent to a 5% absolute improvement in survival at 5 years. A significant disease-free survival benefit associated with platinum-based combination chemotherapy was also observed (HR = 0.78 95% CI, 0.71 to 0.86, P < .0001), equivalent to a 9% absolute improvement at 5 years. This meta-analysis provides additional supportive evidence of significant benefit for neoadjuvant cisplatin-based combination chemotherapy. Based on this evidence, neoadjuvant chemotherapy should be offered to patients with muscle-invasive disease. Future trials will be needed to address the optimum regimen and to determine if noncisplatin containing combination regimens will provide survival advantage for patients unable to receive cisplatin-based therapy.

Only gold members can continue reading. Log In or Register to continue