Cytoxan:
An Active Agent in the Treatment of
Prostate Cancer

Introduction:

One of the most studied drugs for the treatment of prostate cancer (PC) is Cytoxan (cyclophosphamide). When we review the chemotherapeutic treatment of PC, it becomes apparent that the results from many of these studies were reported 10-20 years ago. To compare them to more recent studies is problematic for 3 major reasons:

1. Older studies treated patients with far advanced disease (Stage D2)
2. Many were done prior to the availability of the serum PSA assay and a patient's disease response could only be measured by X-rays or scans
3. Biologic agents that are commonly used today to support the bone marrow Procrit (erythropoietin), Neupogen (granulocyte colony stimulating factor, G-CSF) and Leukine (granulocyte-macrophage colony stimulating factor, GM-CSF) had not been invented, thus limited the dosage of Cytoxan to be significantly intensified

However, an evaluation of chemotherapy studies, both old and new, highlight the following concepts that are important for drug effectiveness:

• Dose intensity
• Drug combinations that result in synergy
• Exposure time to chemotherapy
• Bone marrow support

DOSE INTENSITY

Dose intensity, or DI, relates to how much drug is given within a particular period of time. For example, regimen A administers a drug at a dose of 1,000 mg every 2 weeks for a total of 3 months. A patient on regimen A would receive 7 treatments at 1,000 mg each for a total dose of 7,000 mg of drug, or an average of 2,333 mg per month.

If he were to receive regimen B. the same drug is given a dose of 3,000 mg every 3 weeks for the same duration. The patient on regimen B would receive 5 treatments at 3,000 mg each for a total of 15,000 mg of drug, or 5,000 mg per month. The DI, comparing the ratios of drug given per unit time between regimens A and B. indicates that regimen B has a DI that is 2.1 times greater than that of regimen A.

Chlebowski, et.al., studied the effects of DI in patients receiving a single intravenous (IV) dose of Cytoxan at 800-1,000 mg/m² every 3 weeks compared to patients receiving an oral (PO) Cytoxan dose of 200 mg/m² per day for 4 days, then drug was stopped and restarted again in 4 weeks. Approximately 50% of an oral Cytoxan dose is absorbed through the gastrointestinal tract (e.g., its oral bioavailability is only 50%). Therefore, patients receiving oral Cytoxan received a "net" dose of 100 mg/m² per day over the 4 day period. Results of this Dl study showed:

(Chlebowski RT, Hestorff, R. Sardoff L, et al, Cytoxan vs combination Adriamycin, 5-FU and Cytoxan in the treatment of metastatic prostatic cancer. Cancer 42:2546-52,1978).

In a more recent trial, Small, et.al., used escalating doses of Cytoxan (800-1,200 mg/m²) combined with Adriamycin (40 mg/m²). Patients were given G-CSF to support their bone marrow in an attempt to prevent a low white blood cell count and possible infection. The results of this study a greater than 50% reduction in PSA levels in 16/35 (46%) patients, who reportedly survived for a median duration of 23 months. Ten of 35 patients (29%) has a greater than 75% reduction in their serum PSA. The median survival for patients who did not have a PSA response was 7 months. Importantly, G-CSF support resulted in a significant decrease in white blood cells in only 33% of treatment cycles, and fever developed in only 8% of treatments. (Small EJ, Srinivas S. Egan B et al: Doxorubicin and dose-escalated cyclophosphamide with granulocyte colony-stimulating factor to treat hormone-resistant prostate cancer. J Clin Oncol 14:1617-25, 1996).

SYNERGY

Does adding a second chemotherapy drug result in MORE than an additive effect? If so, then synergy is likely at work. Pavlick, et.al., studied 27 patients treated with high-dose ketoconazole plus hydrocortisone combined with oral Cytoxan at a dose of 100 mg/m² per day for 14 days. A new cycle was begun after 28 days. The median baseline PSA for these patients was 68 ng/ml. The median nadir PSA was 5.0 ng/ml. Study results showed a 50% or greater decline in PSA in 21/27 (78%) patients. The median duration of this response was 9 months. (Paviick AC, Pecora AL, Scheuch J. et al. Treatment of hormone refractory prostate cancer with ketoconazole, hydrocortisone and cvclochosohamide. Proc Am Soc Clin Oncol: 15:A698, 1996. )

EXPOSURE TIME

When a chemotherapeutic drug is given to treat a PC patient, how long are his tumor cells exposed to the chemotherapeutic drug? Patients with prostate cancer generally have a slow turnover of tumor cells which mandates that they receive a longer exposure time to the chemotherapy or other antineoplastic agent.

The effects of prolonged chemotherapy exposure time was reported in a study by Ihde. et.al., where oral Cytoxan was given at a dose of 100 mg/m² per day for 14 days out of each 28 day cycle. This was combined with Adriamycin at a dose of 30 mg/m² intravenous on the 1^st and 8^th day of each 28 day cycle. In this study, there was a 32% rate of partial response that lasted for a median duration of 8 months (range 2-23 months). (Ihde DC, et.al., Effective treatment of hormonally unresponsive metastatic carcinoma of the prostate with Adriamycin and cyclophosphamide. Cancer 45:1300-1310,1980 )

BONE MARROW SUPPORT

One of the key factors for successful management of the cancer patient is supportive care. This may involve multiple aspects in the medical and surgical management of the patient, and often includes psychological support as well. With the advent of agents that can stimulate the bone marrow, we now have a mean to give chemotherapy at higher doses by supporting and/or preventing toxicity such as white blood cell count suppression and anemia.

White blood cell count depression (also called granulocytopenia or neutropenia) is a major dose-limiting factor with chemotherapy agents and is the cause for the most serious side-effect of chemotherapy, infection. We have noted a remarkable improvement in the tolerance of chemotherapy given to prostate cancer patients who receive agents that stimulate bone marrow white blood cell production. In a report by Smith, et.al., high-dose Cytoxan was used in 21 prostate cancer patients in conjunction with granulocyte-macrophage colony stimulating factor, or GM-CSF. Cytoxan at a dose of 3 grams/m² was given intravenously on day 1 and subcutaneous GM-CSF 5 mcg/kg per day was begun on day 3 and continued for 1 week. Patients were given a lower dose of Cytoxan if prior pelvic radiation had been given. Results of this study showed a greater than 90% reduction in PSA levels 6/21 (29%) patients. No survival information was given in this report. (Smith DC et al. Hi-dose Cytoxan with GM-CSF in hormone-refractory prostatic carcinoma. 3rd Annual Pittsburgh Cancer Conference, November 19-20, 1992, p 12.)

Another study used the novel agent DPPE (a histamine antagonist) to potentiate chemotherapy cytotoxicity and protect bone marrow integrity, minimize gastrointestinal toxicity and prevent hair loss. In this study, 20 patients with hormone refractory prostate cancer were treated with Cytoxan 600-800 mg/m² intravenously once per week for 4 weeks. Results of this study showed at least a 50% reduction in soft tissue measurements in 5 of the 7 patients (71%) who had measurable soft tissue tumor. A greater than 50% drop in PSA was seen in 9/18 (50%) patients. Eleven of the 13 patients (85%) with bone pain had a partial or complete response. (Brandes LJ et al, DPPE in combination with Cytoxan: an active, low toxicity regimen for metastatic hormonally unresponsive prostate cancer. J Clin Oncol 13:1398-403, 1995. )

Conclusions:

Cytoxan is an extremely active chemotherapeutic agent for the treatment of prostate cancer. We need more experience in order to learn how best to give it - how large of a dose can we give and over what period of time.

We also need to explore the application of other supportive care medications such as DPPE to provide additional protection against chemotherapy-induced side effects in PC patients treated with Cytoxan.

September 1997

 

Prostate Cancer Research Institute (PCRI)

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