http://jco.ascopubs.org/cgi/content/full/26/15/2423
Journal of Clinical Oncology, Vol 26, No 15 (May 20), 2008: pp. 2423-2424
DOI: 10.1200/JCO.2007.14.7819

CELEBRATING 25 YEARS OF JCO
Chemotherapy for Advanced Prostate Cancer: 25 Years Later
Christopher J. Logothetis, Randall Millikan

The University of Texas M.D. Anderson Cancer Center, Houston, TX

When the article entitled "Doxorubicin, Mitomycin-C, and 5-Fluorouracil
(DMF) in the Treatment of Metastatic Hormonal Refractory Adenocarcinoma of
the Prostate, With a Note on the Staging of Metastatic Prostate Cancer"1
was published in the Journal of Clinical Oncology, there was great
skepticism that chemotherapy had any role in the treatment of advanced
prostate cancer. This was largely based on three justifiable concerns:

  1. Elderly prostate cancer patients would neither desire nor tolerate
the rigors of chemotherapy.
  2. Prostate cancer was inherently resistant to chemotherapy based on
its low proliferation rate.
  3. Efficacy of chemotherapy could not be assessed based on the lack of
measurable disease or other objective measures of patient benefit.

Twenty-five years later, the perception that patients with advanced
prostate cancer are either unwilling or too infirm to receive chemotherapy
is known to be false. Indeed, the strong impression of some early
investigators that chemotherapy could effectively palliate cancer-related
symptoms such as pain and asthenia was subsequently definitively
demonstrated by Slack and Murphy2 and Tannock et al.3

Recently reported data from large randomized studies confirm that a
significant proportion of patients with far-advanced disease are able to
tolerate chemotherapy, and those that are symptomatic are palliated
significantly.

Finally, randomized trials have demonstrated a survival benefit from
docetaxel-based therapy, and thus chemotherapy is now established as a
palliative useful tool that modestly alters the natural history of
castrate-resistant metastatic prostate cancer.4,5 In addition,
investigators have made advances in understanding and reducing the
severity of the adverse effects of sustained androgen ablation, including
use of antiandrogens without testicular suppression, intermittent androgen
suppression, and bone-preserving bisphosphonates.

These advances allow more patients to tolerate therapy at the time of
progression to a castrate-resistant state. Increased awareness of prostate
cancer and the emergence of patient advocacy groups demanding care have
combined with the advances in the therapeutic armamentarium to overcome
the reluctance to use chemotherapy for patients with advanced prostate
cancer.

While the general perception that castrate-resistant prostate cancer is
inherently chemotherapy-resistant has been largely overcome, it remains
true that the prolongation of survival in patients with advanced prostate
cancer is modest and effective treatment combinations have yet to be
developed.

Furthermore, and in contrast with other common solid tumors such as breast
and bladder cancer, we have no evidence of improved efficacy with the
earlier application of chemotherapy in prostate cancer.6-10

Optimization of chemotherapy combinations in the setting of advanced
cancer followed by the methodical integration in earlier disease settings
has been the hallmark of successful therapy development in solid tumors.
These milestones have yet to be achieved in prostate cancer. The absence
of reported benefit may be a result of the relative paucity of completed
large randomized studies. While there are still yet unpublished, ongoing
large randomized studies, the published data on early use of chemotherapy
is disappointing. Tumor regression observed in the preoperative setting
has been a reliable surrogate for chemotherapy efficacy in other solid
tumors. The experience to date with preoperative chemotherapy demonstrates
little tumor regression11 in early prostate cancer. If the predictive
value of tumor regression also holds true for prostate cancer, then a
unique therapy development paradigm will need to be developed. Thus, while
advanced, castrate-resistant disease has shown some response to
chemotherapy, cumulative experience continues to reinforce the notion that
early prostate cancer is refractory to the cytotoxic paradigm.

Introduction of the serum prostate-specific antigen (PSA) to monitor
disease progression has transformed the care of patents with early
prostate cancer. However, serum PSA concentration has not been accepted as
a surrogate for patient benefit, and the practice of using PSA
concentration to guide clinical decisions in advanced prostate cancer
threatens our ability to conduct trials based on more meaningful end
points such as objective progression or survival.

Although PSA has raised patient awareness, improved detection, and
provided a tool for monitoring progression of early-stage prostate cancer,
it has not translated into improved efficiency of clinical studies in
patients with advanced prostate cancer. Thus, we still have challenges to
define objective criteria for outcomes that reliably correlate with
survival.

Our sense that the distribution of visceral metastases and volume of bone
involvement are related to therapy response and patient survival is now
amply confirmed and accounted for by morphologic variants that reflect the
biologic heterogeneity of prostate cancer.12-16 Furthermore, it is
reasonable to implicate the bone microenvironment in progression of those
prostate cancers with clinical presentations dominated by bone-forming
metastases. Several lines of clinical and experimental observations have
generated interest in developing strategies to prevent or treat bone
metastases.16-17

Despite this, the further characterization of patient populations based on
the distribution of metastases and the incorporation of markers of bone
remodeling into studies has not gained the expected interest. Although the
benefit of this approach is not established, recent clinical studies
suggest that markers of bone remodeling may be important for
prognostication and, at the least, will more fully characterize patients
into relevant categories of risk.

Future therapy advances in prostate cancer may hinge on developing a new
therapy paradigm. For those patients with bone metastases, an integrated
strategy of chemotherapy and bone-targeting therapy may be required. To
effectively test such a strategy requires development of markers to
predict and monitor bone metastases. The approach may differ from that
applied to patients with visceral metastases, where the more conventional
solid tumor therapy paradigm may apply and where the underlying biology is
very different. Optimal integration of systemic therapy with control of
the primary may be required for selected high-risk patients.18,19

The treatment paradigm used as a framework to develop effective therapy
for prostate cancer may be analogous to that successfully used for
leukemia. Critical to the successes achieved in leukemia have been the
link between the underlying biology, clinical presentation, and response
to therapy. Access to relevant tissue facilitated the development of a
clinically relevant classification that overcame the challenge of
heterogeneity and allows for the effective monitoring of therapeutic
consequences.

Fortunately, our understanding of prostate cancer biology has improved
over the last decade, providing a framework in which to develop treatment
strategies and to identify markers. Ideally, candidate markers will
reflect clinically relevant milestones of prostate cancer progression:
progression within the primary site, risk for metastases, and progression
within the bone environment. Access to such markers will facilitate
development of rational treatment strategies that will likely incorporate
chemotherapy.

The goal of our efforts should be to develop a balanced approach of
parallel screening of new therapeutic agents and combinations of agents
with the development of markers that will be used to characterize and
monitor the prostate cancer.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS
Manuscript writing: Christopher J. Logothetis, Randall Millikan
Final approval of manuscript: Christopher J. Logothetis, Randall Millikan

REFERENCES [see web page]