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Continued from PROSTATE CANCER: LATE STAGE

HDK in Regimens Combined with Chemotherapy

It is not clear whether HDK should be used in combination with HC versus a chemotherapy combination-in light of its synergism with Adriamycin and Velban-along with its ability to prevent MDR (multidrug resistance). There are two regimens that use HDK in combination with chemotherapy. The first regimen was a combination of Adriamycin and Ketoconazole (Sella et al., J. Clin. Oncol., 1994).

The Sella regimen with its effectiveness was employed in a multidrug regimen that we have termed the Logothetis regimen (Ellerhorst et al., Clin. Cancer Res., 1997). Dr. Christopher Logothetis has combined two most active chemotherapy regimens into one protocol of alternating regimens. Our modifications of this regimen are italicized.

• Chemotherapy Cycle length = 56 days (8 weeks)
  Adriamycin 20 mg/m2 IV day 1, 15, 29
  Ketoconazole 400 mg orally 3 times a day for days 1-7, 15-21,
  29-35
  Vinblastine 4 mg/m2 IV day 8, 22, 36
  Estramustine 140 mg orally 3 times a day for days 8-14, 22-28,
  36-42
  Rest period from day 43 to 56, then restart next cycle

    

• Supportive Medications
  Hydrocortisone, 20 mg orally in A.M. and 10 mg in P.M. (take with food)
  Coumadin dosed to maintain an INR between 1.75 and 2.25
  Neupogen 300 mcg s.q. twice a week except during the rest period
  Epogen, 10,000 units s.q. 3 times a week as needed to avert anemia
  Kytril, 0.7 mg with each dose of Velban or Adriamycin
  Decadron, 10 mg with each dose of Adriamycin

    

• Laboratory Tests
  CBC blood test on the day of each injection and day #10 of the first cycle
  Chemistry panel once a month and day #14 of the first cycle
  PSA and PAP once a month
  Prothrombin time weekly

  Information that We Also Discuss with the Patient
  Nonspecific lassitude and tiredness may occur.Hair loss to some degree is common. Temporary mouth sores and/or diarrhea is unusual but can occur.

  Adriamycin and Velban can cause low blood counts, which can increase the risk for serious infection. It is critical that weekly CBC tests are obtained to guide chemotherapy and Neupogen dosing.

  Any fever greater than 100.5 should be called to your M.D. immediately, day or night.
  Velban can cause numbness and tingling in the hands and feet.

  Velban has caused temporary malfunction of the intestines, resulting in bloating (ileus). We recommend a small dose of milk of magnesia on the day of Velban therapy.

  Ketoconazole and Estramustine can cause nausea and upset stomach, but with use of antinausea drugs this should not occur.

  Estrogen in Estramustine can cause blood clots, thus the need for Coumadin.
  Adriamycin, if it is used for more than 1 year, can occasionally cause weakening of the heart muscle.

  Adriamycin and Velban, if they are improperly injected into the skin (outside of the vein), can cause severe skin reactions and ulcers.

  Ketoconazole can cause hepatitis, thus the need to do monthly chemistry.

  Hydrocortisone can cause adrenal atrophy, so when the protocol is stopped, the hydrocortisone must be tapered off over a 4 to 8 week period.

 The results with the Logothetis regimen for AIPC indicate a median survival of 19 months. In responding patients, the median survival has not yet been reached.

Patient Guidelines for Nizoral and HC

We start Nizoral at a dose of 200 mg every 8 hours for 1 week, then increase the dose to 400 mg (2 tablets) every 8 hours thereafter. HC should be given at a dose of 20 mg with breakfast and 20 mg with dinner. If symptoms suggest HC excess (ankle swelling or diabetes in poor control), we decrease the dose to 20 mg with breakfast and 10 mg with dinner.

Stomach acid is needed to enhance Nizoral absorption. We advise patients to take Nizoral on an empty stomach since food reduces acid. As stated above, histamine-2 blockers (Zantac, Tagamet, Pepcid, and Axid) decrease Nizoral absorption by 75%. Prescription proton-pump inhibitors such as omeprazole (Prilosec) and lansoprazole (Prevacid) reduce stomach acid even more. Antacids and the prescription anti-ulcer agent sucralfate (Carafate) will also interfere with Nizoral absorption.

We recommend taking Nizoral with Coca-Cola, Pepsi, 1000 mg of chewable vitamin C, lemonade, or orange juice. In a recent study done in AIDS patients receiving acid-reducing drugs, the oral absorption (bioavailability) of Nizoral was increased by 50% by the concurrent intake of Coca-Cola or Pepsi (Chin et al., Antimicrob. Agents Chemother., 1995).

It is now possible to measure Nizoral levels in the serum using a new assay method. We recommend monitoring serum drug levels at the onset and periodically on Nizoral therapy. A blood level between 3 and 5 mcg/mL is considered therapeutic when drawn 4 hours after the usual dose of Nizoral. Serum Nizoral values can also be obtained 1 hour post Nizoral ingestion (peak level) and just before the next dose of Nizoral (trough level).

Other drugs that have the potential to interfere with Nizoral absorption by decreasing stomach acid through anticholinergic mechanisms are listed below. Drugs commonly used in PC patients appear in boldface type.

The main side effects of Nizoral are nausea and loss of appetite in approximately 10% of patients. Concurrent administration of HC may reduce the frequency of this side effect. A number of skin changes-including rash; dry, cracked lips; and an unusual "sticky skin" syndrome-have also been reported in approximately 5% of patients. This can usually respond to topical application of vitamin E. The peeling of the lips is very responsive to the use of Carmex topical ointment. Photophobia (sensitivity to light) is rarely seen in patients taking Nizoral for fungal infections, but may be more common with chronic use. Liver function tests (LFTs) include elevations in SGOT, SGPT, and/or alkaline phosphatase. These are generally mild and usually return to normal without intervention. Patients on Nizoral must have LFTs checked monthly. Although rare, a rise in serum bilirubin indicates that Nizoral must be discontinued. Intolerance of nausea, fatigue, or abnormal liver function tests is the most common reason patients stop Nizoral treatment.

Side-effects of Nizoral +HC

Potential Drug Interactions with Nizoral

Drugs that may need dose changes if Nizoral is taken concurrently

Warning: Nizoral should not be taken with alcohol. Concurrent use of Nizoral and alcohol-containing beverages may cause an "antabuse reaction" (skin flushing, rash, swollen legs, nausea, vomiting, and headache).

Continuation of PROSTATE CANCER: LATE STAGE