By Stephen B. Strum, M.D., and Jonathan E. McDermed, Pharm.D

Dr. Strum is on the Life Extension Medical Advisory Board, and Dr. McDermed is from the Prostate Cancer Research Institute (PCRI) in Los Angeles, California. Drs. Strum and McDermed are proponents of a holistic medical strategy that combines peer-reviewed conventional scientific publications with new findings in the areas of nutrition and supportive care of the patient. Dr. Strum and his partner, Mark C. Scholz, M.D., have a medical practice (Healing Touch Oncology) in Marina del Rey, California, that cares for patients with prostate cancer (PC) or who are at high risk of having PC.

Many studies that evaluated the efficacy of various secondary treatments predated the days of PSA testing. In these studies, responses were evaluated by improvement in symptoms such as bone pain, or by reduction in tumor size on bone scans or CT scans. Based upon the limited sensitivity of scans to assess tumor response, older studies may have missed patient responses that might have been noted if PSA testing were available.

Past studies may have also underestimated the importance of drug absorption, proper drug dosing based on elimination half-life, dose intensity, and altered drug metabolism. Treatments that were labeled as ineffective in the past may conceivably turn out to be more effective when given to patients with less tumor volume and under better pharmacological conditions. In a thorough review of the literature, long-lasting responses to secondary therapies have been documented. What patient or treatment-related variables were present in such responding patients?

Dose Intensity

Dose intensity is a term used to compare relative amounts of a drug administered in a given unit of time. For example, compare the relative dose intensities of Regimens A and B. Regimen A delivers a dose intensity that averages 2000 mg a month. Regimen B delivers a dose intensity that averages 4000 mg a month.

Regimen A, with its lower, more frequently administered dose, may have less toxicity due to lower peak blood levels than Regimen B, with its higher but less frequently administered dosing. For example, Taxotere administered every 3 weeks at 70 mg/m2 has a dose intensity of approximately 93 mg/m2 a month. Taxotere administered weekly at 25 mg/m2 has a dose intensity of 100 mg/m2 a month. The latter regimen is associated with far less toxicity due to the lower but more frequent drug doses. The efficacies of these regimens have not been reported in a randomized trial. Low weekly doses of Taxotere are, in our experience, without question a more patient and friendly regimen compared to the standard, higher dose Taxotere protocol.

Exposure Time

Most chemotherapy agents kill cancer cells that are actively multiplying. PC cells generally grow slowly, which mandates that they receive a longer exposure time to the chemotherapy or other anticancer agent. Examples of ways to increase exposure time include daily oral therapy; a more frequent schedule of intravenous administration; or use of low-dose, continuous intravenous infusions administered by means of a computerized pump through a venous access device, such as a Port-a-Cath. Such protracted infusion delivery increases exposure time while decreasing the toxicity of chemotherapy. Drugs such as Cytoxan and Adriamycin have a much lower toxicity profile and a higher therapeutic index when given in this manner. We currently have a protocol in progress that employs Cytoxan, an active agent in PC, given as a continuous infusion over 120 hours. This is given in conjunction with another agent, 5-Fluorouracil, during the same period of time. This combination has shown high activity in advanced refractory breast cancer in a pilot trial. Since prostate and breast cancer are strikingly similar in so many ways, we have begun this program in advanced PC to utilize a long exposure time of drugs that are known to be active in PC. Moreover, the use of low-dose continuous chemotherapy has another advantage in lowering the toxicity of the drugs. Therefore, the therapeutic index, a measurement of efficacy and side effects, is greatly enhanced with protracted chemotherapy administration. Unfortunately, many oncologists are not familiar with the use of ambulatory infusion pumps or venous access devices such as the Port-A-Cath.

Bone Marrow Support

One of the essential factors in the successful management of the cancer patient is adequate supportive care. This involves multiple factors in the medical and surgical management of the patient, and includes psychological support as well. With the advent of agents that can stimulate the bone marrow, we now are able to give chemotherapy at higher doses by supporting and/or preventing toxicity such as low white blood cell counts, anemia, and low platelet counts.

A low white blood cell count (also called granulocytopenia or neutropenia) is a major dose-limiting factor with chemotherapy and is the cause for the most serious side effect of chemotherapy-- infection. AIPC patients who receive agents that stimulate the bone marrow to produce white blood cells tolerate this chemotherapy side effect remarkably better. Neupogen or Leukine support reduces or eliminates the number of hospitalizations for infection associated with chemotherapy, and it reduces other problems such as mouth and throat sores.

A low red blood cell count, or anemia, can also be a significant source of concern for AIPC patients receiving chemotherapy. Anemia is usually already present to some degree in AIPC patients due to their ADT. Anemia, left untreated, can cause severe weakness, shortness of breath, dizziness, mental status changes, and chest pain. The availability of Procrit to stimulate bone marrow red blood cell production can help minimize the adverse effect severe anemia can have upon the AIPC patient. The use of Procrit has largely replaced the need for blood transfusions.

A low platelet count, also called thrombocytopenia, is another dose-limiting factor with chemotherapy and is the cause for a serious side effect of chemotherapy--bleeding. Until recently, thrombocytopenia could delay chemotherapy, cause dosage reductions, or even cause changes in drug therapy. Neumega has recently become available as a marrow stimulant specific for platelet production, and its use may treat patients for low platelet counts.

Other Supportive Care

A medical oncologist should offer the most effective medications or other approaches to maximize the level of supportive care for the AIPC patient receiving chemotherapy. Other chemotherapy side effects include the following:

Unfortunately, there are no medications or approaches available that will prevent loss of hair from chemotherapy. However, hair will grow back in the weeks after therapy is stopped, and may actually begin to grow back during continued chemotherapy treatments.

Certain intravenous chemotherapy drugs, if they accidentally leak out of the vein and into surrounding tissues, can cause a significantly damaging extravasation injury. Drugs that can cause extravasation injuries are known as vesicant chemotherapy agents. To prevent potential extravasation injuries, vesicant chemotherapy should be given with caution to patients with poor-quality veins, or patients who are to receive drugs as a protracted infusion over several days. In most cases, it may be preferable in such patients for them to have a central venous catheter or access device, e.g., Port-A-Cath, placed before therapy is started. This not only avoids a potential extravasation injury, but also preserves access to a patient's veins to draw blood. If chemotherapy extravasation does occur, 70% DMSO applied topically prevents tissue injury and should be administered as soon as possible, and at least 4 to 6 times a day until the site of extravasation is fully healed. If stinging occurs with DMSO application, the patient should wipe off the remaining DMSO and apply aloe vera gel to the skin.

It is very important that a patient promptly report any unusual symptoms or side effects during chemotherapy treatment to his physician to be sure that it is not, or does not become, a major problem. Patients receiving vesicant chemotherapy through a peripheral (hand, arm, or leg) vein should inspect the chemotherapy injection site for several days after each treatment.

Concepts in AIPC Management

Due to our concern for the emergence of androgen independence in PC, the following principles are relevant until we have a better understanding of hormone sensitivity and independence.

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 > or = 50% decrease in PSA with these therapies and even longer in patients who have > or = 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).

  
  High-Response Regimens in the Treatment of
  AIPC in 1999-2000

  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., > or = 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 star (*). Two stars (**) 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).

  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.

  The PCRI has a protocol involving 5 days of continuous infusion Cytoxan at 600 mg/m² a day coupled with 5-FU at 300 mg/m² a day over 5 days. In addition, dexamethasone at 4 mg a day for 5 days is used as an anti-emetic and an anticancer agent in this regimen. The medications are given continuously using a Port-A-Cath and a computerized Cadd Pump with cycles repeated every 21 days. Neupogen and Procrit are used to protect the bone marrow. There is rationale for this based on outstanding responses in "refractory" breast cancer patients as well as responses to cytoxan shown here. The dose of 600 mg/m² a day for 5 days is equal to 3 grams per M², the same dose employed by Smith et al. Of 21 patients, 6 had a 90% reduction in PSA. Survival information is needed.

  The Servadio regimen combines weekly Cytoxan with weekly 5-FU in combination with DES and orchiectomy. It has been used for 11 years in Israel, with an outstanding cumulative survival rate of 55.5%.

  It would seem prudent to advise patients to consider such regimens using combinations rather than to employ single-agent therapy. This might lead to significantly longer response times than the results we are currently getting. The above regimen, however, is difficult to truly evaluate without knowing the extent of bone disease in the treated group. If you recall the Labrie et al. data on ADT2 in the 1 to 5 bone lesion group, they had an 8-year median survival rate of 58%. Therefore, if the patients receiving the Servadio regimen were heavily weighted in the 1 to 5 bone lesion category, their responses would be in keeping with those of Labrie et al. and would raise the issue of whether the chemotherapy portion of the Servadio regimen added to the response. Cytoxan has also been used in combination with HDK by Pavlick et al. (see chemotherapy table). Their response to this combination is shown below.

  Oral Cytoxan given for 14 out of each 28 days is an effective regimen, especially if combined with other active agents like Adriamycin (as shown above). The median duration of response (MDR) in this study was 8 months. Cytoxan has also been administered with a histamine antagonist, DPPE.

  The latter agent is under study. The preliminary findings are shown below.

  Emcyt Combinations: Emcyt + VP-16, Emcyt + Taxol, Emcyt + Taxotere

  The use of Emcyt has been problematic for us due to the salt retention, increased risk of thrombosis necessitating routine anticoagulation, and the moderate frequent complaints of nausea and anorexia it causes. However, there are impressive response rates with various Emcyt combinations. A few are shown here.

  Taxotere

  Emcyt has also been combined with Taxotere (docetaxel). Taxotere is most often administered as an every-3-week regimen. The recent work of Natale using weekly Taxotere has led us to employ this patient-friendly regimen. Presented are the data from the work of Petrylak et al. on every 3-week Taxotere and that of Natale et al. using weekly Taxotere.

  Taxotere is synergistic with Cytoxan, 5-FU, and Mitomycin C. There is virtually no bone marrow suppression using weekly Taxotere at the dose we employ (25 mg/m2/week). We also are finding this regimen to have minimal, if any, tendency to cause nausea or vomiting and to cause only slight hair thinning (which is reversible). Taxotere's mechanism of action may involve inactivation of BCL-2 via phosphorylation. Since 65% of AIPC specimens overexpress Bcl-2 (which inhibits apoptosis), this may be a critical area of Taxtotere action. In vitro, Taxotere has 100-fold greater potency than Taxol in inactivating Bcl-2 phosphorylation.

  
  5-FU + Interferon a-2a

  5-FU--by continuous infusion given in combination with subcutaneously administered Interferon- alpha--resulted in a 43% response rate with a median survival time of 18 months. This is shown here.

  
  Mitoxantrone + Prednisone

  The study of Tannock et al. indicated a median survival time of 12 months with or without the addition of prednisone. Patients receiving Mitoxantrone and Adriamycin need to have baseline ejection fractions done and interval ejection fractions to prevent the development of significant cardiomyopathy. The use of Coenzyme Q10, selenium, and vitamin E in such patients may have some protective value. The data from the two major Mitoxantrone studies are shown below. There are many investigational trials using Mitoxantrone combinations.

  The above regimens are used to treat adenocarcinoma of the prostate. Two regimens that we have used successfully to treat small-cell prostate cancer (SCPC) are shown below. SCPC is characterized by elevations in neuroendocrine markers such as CGA, NSE, and, not uncommonly, CEA. The PSA may not be expressed significantly, bone lesions are often lytic and not blastic, and liver and lung lesions are not uncommonly detected by CT scanning.

  Conclusions

  The chemotherapy of PC has changed significantly in the last 5 years. We are defining AIPC more precisely, detecting AIPC earlier, and treating patients at a lower tumor burden when the chance of a significant response is still possible. There remains, however, a need to educate patients and physicians about these and other fundamental issues in the care of the patient with AIPC. The coming years will see combinations of synergistic drugs, the employment of agents that affect angiogenesis, oncogenes, and growth factors as ways to eradicate the tumor cell population. The ability to control PC may be within our reach.

  
  Further Information

  Chemotherapy Options for Advanced Prostate Cancer

  By Mark A. Moyad, M.P.H., and Kenneth J. Pienta, M.D., University of Michigan Comprehensive Cancer Center

  Note: All of this information and in more detail is found in the upcoming book The ABCs of Advanced Prostate Cancer (Sleeping Bear Press, (800) 487-2323). The percentages that are shown are the percent of individuals who respond or who are affected by the treatment.

  
  The National Comprehensive Cancer Center Endorsed Chemotherapies

  Estramustine and Etoposide PSA response = 39-58% Side effects: Nausea (decreases with decreasing estramustine dose), hair loss, decrease in white blood cells (about 25%), and blockage of the veins in the legs (less than 5%).

  Paclitaxel (Taxol) and Extramustine PSA response = 53% Side effects: Nausea, breast enlargement, fluid buildup, and a decrease in white blood cells (21%).

  Ketoconazule and Doxorubicin (Adriamycin) Is also given with hydrocortisone PSA response = 55% Side effects: Remote possibility of sudden cardiac death--two patients have died-- and inflammation of some areas of the body.

  Mitroxantrone and Prednisone PSA response = 33% Side effects: A mild case of nausea.

  Estramustine and Vinblastine PSA response = 54-61% Side effects: Nausea (20%), decrease in white blood cells (12%), constipation (20%), and temporary neuropathy (12%).

  
  Newer Combinations and Options

  Paclitaxel, Extramustine, and Etoposide PSA response = 53% Side effects: Nausea, hair loss, fatigue, and a decrease in one type of white blood cell

  Doxorubicin/Ketoconazole alternating with Vinblastine/Estramustine Is also used with hydrocortisone PSA response = 67% Side effects: Swelling or edema (49%), blockage of the veins in the legs (18%), cardiac problems (4%), and a decrease in one type of white blood cell (less than 2%)

  Cytoxan, Diethylstilbestrol (DES), and Prednisone PSA response = 39% Side effects: Minimal

  
  Secondary Hormonal Therapy
  (Newer Options)

  Low-dose DES PSA response = 43% Side effects: Nipple sensitivity (90%), blockage of the veins in the legs (5%), and breast enlargement (14%)

  High-dose Casodex PSA response = 23% Side effects: Hot flashes (40%), nipple sensitivity (5%), nausea (10%), itching (5%), and breast enlargement (5%)

  
  PC-SPES in the Treatment of Prostate Cancer*

  PC-SPES is a new herbal therapy for treating PC at various stages. PC-SPES consists of a combination of eight herbal extracts, and has been in development for 10 years. The minimum dose is one 320-mg capsule 3 times a day. Most PC patients take about 9 capsules a day. Up to 12 capsules a day for 1 to 2 months have been used by advanced PC patients.

  (Refer to the PC-SPES Prostate Cancer protocol for information about a natural herbal therapy.)

  A few statistically insignificant cases of thrombosis have been reported in users of PC-SPES. Anyone taking PC-SPES should carefully follow the Foundation's Thrombosis Prevention protocol. (Refer to the Cancer: Early-Stage Prostate protocol for additional suggestions).

  For referrals to doctors experienced in using combined hormone blockade, cryo-ablation therapy, seed implantation, etc., call The Educational Center for Prostate Patients at (516) 997-1777 or PAACT at (616) 453-1477, or access the Web site of the Prostate Cancer Research Institute www.prostate-cancer.org. Hytrin, Cardura, Lupron, Zoladex, Casodex, and Eulexin are drugs that can be prescribed by your doctor.