Year: 1999
Type: article
Abstract: Increasing numbers of treatment strategies for hormone-refractory prostate cancer have been tested clinically or are underway in the clinic in the last few years.7, 19, 26, 27, 56 Encouraging results in clinical endpoints, such as improvement in pain, decrease in narcotic use, and trends toward improved survival over historical controls, have been reported in clinical trials of new agents and combinations.27, 55 The use of intermediate or surrogate endpoints, such as prostate-specific antigen (PSA) and other markers of therapeutic response, has increased as well. Lack of a consistent definition of response and lack of application of these surrogate markers have made comparison of treatment outcomes difficult. PSA has been used most consistently, whereas the utility of other markers remains under investigation. Changes in serum levels of PSA have been validated as a marker of response after surgery and radiotherapy for localized prostate cancer.28, 53, 81 and hormonal therapy for metastatic disease,43, 44, 47 and as a marker of progression after hormonal therapy and chemotherapy.59, 67, 83 PSA levels have been shown to correlate with tumor differentiation, tumor volume, and extent of disease.54 More recently, preclinical studies on the PSA-producing human prostate cancer cell line LNCaP demonstrate varying effects on PSA production, secretion, and clearance by a variety of agents, each possessing unique mechanisms of action.75, 80 PSA changes after treatment may represent a direct antitumor effect, exemplified by prostate cell death and a decline in PSA secondary to a decline in volume or burden. On the other hand, PSA changes may simply reflect a change in protein binding or cellular production not correlative with a reduction in tumor burden but more suggestive of a biologic effect of the agent. Differentiating agents, such as the retinoids and nonretinoids (phenylbutyrate, vitamin D), may increase PSA production as a marker of differentiation to a less malignant state.20, 80 Suramin is another agent that through pleiotropic mechanisms of activity alters cellular function and reduces PSA mRNA expression in vitro.71, 73 Correlation of PSA changes or response after treatment with definable and reproducible measures of antitumor response remains a clinical challenge because the majority of patients with advanced hormone-refractory prostate cancer lack measurable disease.21, 33 The radiographic evaluation of osseous metastases as a parameter of response yields little useful information unless there is progression, defined as new lesions. Even new lesions may represent a “flare phenomenon” early in the treatment sequence, confounding the response assessment. Subjective measures of clinical benefit are difficult to capture and correlate with PSA changes because of the numerous confounding variables of treatment-related toxicity, individual characterization of symptoms, and divergence in the practice of handling pain and supportive medicines. Despite these challenges, clinical trial reports of new agents and combinations provide detailed descriptions of PSA changes after treatment in tandem with descriptions of patients with measurable disease and clinical improvement of symptoms. More recently, other markers of response have been examined. The rationale behind these other markers is described in detail herein.
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,000
Funder: U.S. Public Health Service
Awards: G2058098592, G8849387423
OpenAlex ID: W2134478425