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Symptomatology Means Large Tumor Volume

There is an inverse correlation with diminished survival in patients who are more symptomatic from their PC than those with fewer symptoms. The symptom complex is a manifestation of tumor burden. It is also expressed in the stage of disease and may explain why patients with 1 to 5 bone metastases do so much better than those with greater numbers of bone lesions. Therefore, consider initiating treatment if there is a persistent increase in PSA. This can be confirmed by three consecutive increases of the PSA obtained in the same medical center or office using the same PSA methodology. Late treatment, when symptoms are prevalent, is more difficult. In such circumstances, the treatment is compromised by a debilitated patient who is less tolerant of the therapy and who has a large tumor burden that has had a chance to mutate to resistant clones. Earlier treatment, when the patient is asymptomatic, has a greater chance of a durable remission with a higher quality of survival. This is true of all cancer therapy. The relationship of tumor volume as seen in the number of bone lesions vs. survival in patients receiving ADT is shown below from the work of Labrie et al. (Clin. Invest. Med., 1993).

Use Multiple Biomarkers to More Clearly Define Response

Tumor biomarkers are the barometers that reflect the success or failure of therapy. A definite upward trend in the PSA level, for example, should dictate a treatment change, whereas a flat PSA graph or downward trend would suggest that the treatment remain unchanged. Other tumor markers, such as prostatic acid phosphatase (PAP), alkaline phosphatase, chromogranin A (CGA), neuron-specific enolase (NSE), or carcino-embryonic antigen (CEA), if initially abnormal, should be followed as well.

Steineck et al. showed the value of monitoring response to AIPC treatment by using more than one tumor marker. In a retrospective study, he demonstrated that the overall survival of AIPC patients was longer if both PSA and PAP levels declined on therapy than if only PSA or PAP declined. The shortest survival was seen in patients in whom neither marker declined.

Even if other tumor markers are not abnormal when a particular therapy is started, it is reasonable to monitor their levels periodically on treatment, especially if disease progression occurs. It is also better to follow trends in PSA in combination with other markers than to use the results from a single test.

Drug Absorption, Dosing, and Toxicity May Mean the Difference between Response and Progression

Many of the drugs currently in use do not have a long half-life in the body and are commonly given every 8 or 12 hours. Patient compliance to these dosing intervals is important to the success of such treatment. Nizoral and estramustine phosphate (Emcyt), for example, require an empty stomach for complete absorption. Nizoral also requires a sufficient amount of stomach acid to facilitate absorption. Many patients are not compliant and miss multiple doses of drug. This results in blood levels that are not therapeutic. Patients who understand the proper dosing and the toxicity of the medications they are taking will respond far better than those who are ignorant of this information. Nizoral blood levels are commercially available and are not expensive. It is recommended that patients on Nizoral obtain a blood level reading 4 hours after their last dose of drug to see if a therapeutic level is attained. This should be at least > 2.0 mcg/ml.

Synergistic Drug Combinations Are More Effective AntiCancer Therapies

Treatments employing synergistic combinations of more than one chemotherapy agent or chemotherapy combined with second-line hormonal therapy result in higher rates of anticancer response. It has been demonstrated that the duration of response and overall survival are significantly longer in patients who have > 50% decrease in PSA with these therapies and even longer in patients who have > 80% decrease in PSA. Combination treatments that fulfill these criteria for response, and that do so in at least 50% of the patients treated for a minimum average response time of 6 months, are considered "high-response regimens." These regimens will be discussed later. It is important for patients to understand the definitions of response, percentage of responders, and durability of response.

Additional Factors to Consider When Choosing a Treatment

The approach to the patient with PC that has progressed during ADT is complicated. A number of important variables in each patient history and previous pattern of response must be addressed. These include: 

• Age and general health of the patient.
  Patients with progressive disease after ADT who are elderly, frail, or have other significant medical problems do not tolerate many of the therapies for advanced PC compared to younger patients or patients in otherwise good health. This is not an absolute statement but a general observation.
• Amount of disease as reflected by PSA level.
  Patients who have extensive disease with large tumor burdens have a lower chance of a complete response. In addition, the duration of response, in general, is not as long in these patients. This is true for primary hormonal blockade and also secondary therapies. A high PSA does not preclude a major response to treatment, however.
• Potential response to "secondary" hormonal treatments.
  The term "secondary" hormone therapy includes nonchemotherapy treatments that may be effective in patients progressing after ADT as well as some patients with AIPC. Secondary "hormonal" treatments include anti-androgen withdrawal alone or coupled with high-dose ketoconazole (Nizoral) or aminoglutethimide (Cytadren) plus hydrocortisone, estrogens, or progestins. We are learning that the effectiveness of such therapies may relate to the nonhormonal effects of drugs such as Nizoral and estrogens. In other words, agents that previously were believed to work only via a hormonal mechanism are now being shown to have other biologic effects independent of the hormonal axis. Examples of such effects include direct cytotoxicity against the PC cell, cell differentiation, and down-regulation of oncogenes that protect the tumor cell from apoptosis (programmed cell death).

The following table is a synopsis of the high- response regimens found in the peer-reviewed literature. PSA response criteria are generally the same, i.e., > 50% drop in PSA from baseline is considered a PSA response. To be considered a high-response regimen, the required PSA response rate is approximately 50%. Following this table are specific comments about individual regimens. This section is constantly evolving and is by no means a definitive treatise on the chemotherapy of PC. Some of the regimens in the table have one diamond (+). Two diamonds (++) indicate longer median survival times than others. This is done with reluctance, since studies were not similarly stratified by extent of disease or prior treatment(s).

Synopsis Table

Adriamycin and Cytoxan Regimens

Adriamycin is definitely an active agent in PC. The Sella and Logothetis regimens have already been discussed. The combination of adriamycin plus 5-FU after Koch et al. involves a 24-hour infusion of adriamycin to lessen the cardiac toxicity from this agent. The Adriamycin + Cytoxan regimen after Small et al. is shown below. The use of Cytoxan, a high-response agent in PC, with dose escalation is used in this regimen to take advantage of the principle of dose intensity. Notice the similarity of responses of this regimen with that of Chlebowski et al., with median survivals of 23 months vs. 18.6 months.