By Stephen B. Strum, MD
Reprinted from PCRI Insights December 1999, vol. 2, no. 4
One of the greatest problems we face today is how to prevent the emergence of AIPC and how to treat it when it develops. AIPC is defined as disease progression evidenced by a progressively rising PSA (three consecutive rises of at least 10% each or three rises that involve an increase of 50% over the nadir PSA) or an increase in tumor mass on bone scan, X-ray, CT scan or MRI despite a castrate level of testosterone (T<20 ng/dl). In addition, understanding the endocrinology of PC is essential to accurately defining the patient’s status.
For example, if a patient’s PSA stops falling and begins to rise on ADT2 or ADT3, if the testosterone (T) level is castrate, and if the adrenal androgen precursors are not low, then AIPC is presumed present until proven otherwise. If in this setting, the levels of the adrenal androgen precursors are suppressed, an androgen receptor mutation (ARM) should be excluded. The latter is confirmed by demonstrating a response to anti-androgen withdrawal with falling PSA levels.
As shown in Figure 1, the patient’s serum LH level should be checked if T > 20 ng/dL. If LH is not completely suppressed (usually <1.0), it is reasonable to increase the dosage of the LHRH-A. If the LH level is suppressed, we measure the levels of adrenal androgen precursors DHEA-S and androstenedione. These hormones can be converted to T and may account for T levels of > 20 ng/dl. If such levels were found, we would prescribe drugs to suppress adrenal androgen precursor production such as Nizoral® (high dose ketoconazole or HDK) and hydrocortisone.
Figure 1. HDK = high dose ketoconazole;
HC = hydrocortisone;
LH = luteinizing hormone;
ARM = androgen receptor mutation
There are studies to support the concern that adrenal androgen precursors can increase in the setting of PC treatment and that this increase leads to higher T levels which in turn affect a poor clinical outcome, if the condition is not recognized. The elevation in androstenedione and T shown in Figure 2 in 10/27 men undergoing orchiectomy for PC supports our concerns.1
Defining Key Pharmacological Principles & Supportive Care
Many studies that evaluated the efficacy of various secondary treatments, including chemotherapy of AIPC, 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. In addition, past studies did not focus on pharmacological principles such as: Dose Intensity, Exposure Time, Bone Marrow Support and other Supportive Care.
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, we have found that long-lasting responses to secondary therapies have been documented. What patient or treatment-related variables were present in such responding patients?
Dose Intensity (DI)
Dose intensity or DI 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 Taxotere® regimens A and B. Regimen A delivers a dose intensity that averages 93 mg/m<sup>2</sup> per month. Regimen B delivers a dose intensity that averages 100 mg/m2 per month.
Drug dose: 70 mg/m2 (m is for meters of body surface area calculated using height and weight)
Frequency: every three weeks
Average: 280 mg/m2 in 12 weeks (or 93 mg/m2 per month)
Drug dose: 25 mg/m2
Frequency: every week
Average: 300 mg/m2 in 12 weeks or 100 mg/m2 per month
Regimen B with its more frequent lower doses has less toxicity due to lower peak blood levels than Regimen A with its higher but less frequent dosing. For example, Taxotere® dosed weekly at 25 mg/m2 is associated with far less toxicity in regard to hair loss, bone marrow suppression, and nausea. The doses of premedication (e.g. dexamethasone, Benadryl®, Tagamet®, Cytoxan®), and/or the need for premedications to suppress pulmonary side-effects of Taxotere® with the weekly regimen are significantly different than with the every-three-week regimen. The efficacies of these different regimens have not been reported in a randomized trial. Low-dose weekly Taxotere® is unquestionably a more patient friendly regimen than the higher dose standard Taxotere® protocol. Our preliminary results appear to confirm similar response rates.
In a study by Chlebowski, et al, Cytoxan® at 800-1,000 mg/m2 every three weeks intravenously (IV) as a single agent was compared to patients receiving an oral Cytoxan® dose of 200 mg/m2 per day for four days every four weeks as part of a three-drug regimen of Cytoxan®2, Adriamycin® and 5-FU (CAF). 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 for four days every four weeks. The average weekly Cytoxan® doses of these regimens would be:
In a more recent trial, Small et al used escalating doses of Cytoxan® (800-1,200 mg/m2) combined with Adriamycin® (40 mg/m2)3. Patients were given G-CSF (Neupogen®)to support their bone marrow in an attempt to prevent a low white blood cell count and possible infection. There was a greater than 50% reduction in PSA levels in 16/35 (46%) patients, who survived for a median duration of 23 months. Ten of 35 patients (29%) had a greater than 75% reduction in their serum PSA. The median survival for patients who did not have a PSA response was seven months.
Importantly, Neupogen® support resulted in a significant decrease in white blood cells in only 33% of treatment cycles, and fever developed in only 8% of treatments.
Most chemotherapy agents kill cancer cells that are actively multiplying. PC cells generally grow slowly so they must receive a longer exposure time to the chemotherapy or other anti cancer agent. Exposure time can be increased by (1) daily oral therapy, (2) a more frequent schedule of intravenous administration, or (3) use of low-dose continuous intravenous infusions administered by means of a computerized pump given 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 way.
We currently have a protocol in progress that employs Cytoxan®, given as a continuous infusion over 120 hours. In conjunction with another agent, 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 drug(s). 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®.
Two additional studies show this principle of prolonged exposure time. Pavlick et al treated 27 patients with AIPC with high dose ketoconazole (HDK) + hydrocortisone (HC) combined with oral Cytoxan® at 100 mg/m2 per day for 14 days out of each 28 day cycle.4 Twenty-one of 27 (78%) of patients had a >= 50% drop in PSA with a mean and median PSA decline of 79% and 93%, respectively. The median baseline PSA was 68 and the median nadir PSA was 5.1. The median duration of response was nine months with a range of 3-36 plus months. Cruciani evaluated 35 patients receiving an oral regimen of Emcyt® (estramustine phosphate or EMP) and etoposide (VP-16)5. Both drugs were given for 14 days of each 28 day cycle. 30/35 (85.7%) had a >= 50% drop in PSA with an actuarial median survival of 32 months for the entire group of patients.
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 such toxicities 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 a cause of infection – the most serious side effect of chemotherapy. Neupogen® or Leukine® support reduces or eliminates the number of hospitalizations for infection associated with chemotherapy and reduces other problems such as mouth and throat sores.
Anemia may also be a significant problem for AIPC patients receiving chemotherapy. Usually, a low red blood cell count is 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. Neupogen® and Procrit® are miracle drugs for the patient receiving chemotherapy. Unfortunately, they are often not used in an attempt by HMO doctors to save money or just plainly out of ignorance.
A low platelet count, also called thrombocytopenia, is another dose-limiting factor and is the cause for a serious side effect of chemotherapy, bleeding. Until recently, thrombocytopenia could delay chemotherapy and cause dosage reductions or even changes in drug therapy. Neumega® has now become available as a marrow stimulant specific for platelet production and its use will support patients with low platelet counts to prevent hemorrhagic complications.
Two studies involving marrow supportive agents in patients treated with chemotherapy for AIPC demonstrate the importance of these principles. In a report by Smith et al, high-dose Cytoxan® was used in 21 PC patients in conjunction with granulocyte-macrophage colony stimulating factor, (GM-CSF or Leukine®).6
Cytoxan® at a dose of three grams/m2 was given intravenously on day one and subcutaneous GM-CSF 5 mcg/kg per day was begun on day three and continued for one week. Patients were given a lower dose of Cytoxan® if prior pelvic radiation had been given. This study showed a greater than 90% reduction in PSA levels of 6/21 (29%) patients, but gave no survival information.
Another study used the novel agent DPPE (a histamine antagonist) to potentiate chemotherapy cytotoxicity and thereby protect bone marrow integrity, minimize gastrointestinal toxicity, and prevent hair loss7. In this study, 20 patients with AIPC were treated with Cytoxan® 600-800 mg/m2 intravenously once per week for four weeks. A 50% reduction in soft tissue measurements in five of the seven patients (71%) who had measurable soft tissue tumor was observed. 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.
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, in order to minimize side effects such as those shown in the following table.
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 can cause significant tissue damage called “extravasation injury” if they accidentally leak out of the vein into surrounding tissues. Drugs that can cause extravasation injuries are known as vesicant chemotherapy agents. Patients receiving vesicant chemotherapy through a peripheral (hand, arm or leg) vein should inspect the chemotherapy injection site for several days after each treatment.
To prevent potential extravasation injuries, vesicant chemotherapy should be given with caution to patients with poor quality veins, or patients who are to receive a drug or drugs as a protracted infusion over several days. For such patients, it may be preferable to place a central venous catheter or vascular access device, e.g. Port-A-Cath ®, prior to therapy. This not only lessens the chance for potential extravasation injury, but also provides access to a patient’s veins to draw blood and/or to give blood products, intravenous fluids or any kind of drug. If chemotherapy extravasation does occur, 70% DMSO applied topically prevents tissue injury and should be administered at least 4-6 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.
It is important to properly identify AIPC and not confuse it with an androgen receptor mutation (ARM) or with inadequate suppression of testosterone by an LHRH agonist (Lupron® or Zoladex®). Once AIPC is properly identified, it is equally important to understand essential principles in the pharmacology of the agents employed in treating and supporting patients with AIPC. As there is a need for artistry in doing a radical prostatectomy, seed implantation, external beam RT or cryosurgery, there is also artistry needed in the medical oncologic care of the PC patient, especially those with AIPC.
1. Sciarra F, Sorcini G, Di Silverio F, et al: Plasma testosterone and androstenedione after orchiectomy in prostatic adenocarcinoma. Clin Endocrinol 2:101-109, 1973.
2. 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.
3. 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.
4. Pavlick AC, Pecora AL, Scheuch J, et al: Treatment of hormone refractory prostate cancer with ketoconazole, hydrocortisone and cyclophosphamide. Proc Amer Soc Clin Oncol 15:698a, 1996.
5. Cruciani G: Phase II oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. Proc Am Soc Clin Oncol 17:329A, 1998.
6. Smith DC, Vogelzang NJ, Bahnson RR, et al. Hi-dose cyclophosphamide (CTX) with granulocyte-macrophage-colony stimulating factor (GM-CSF) in hormone-refractory prostatic carcinoma (HRPC). Third Annual Pittsburgh Cancer Conference, 1992.
7. Brandes LJ, Bracken SP, Ramsey EW, et al: N,N-diethyl-2-[4- phenylmethyl) phenoxy]ethanamine in combination with cyclophosphamide: an active, low-toxicity regimen for metastatic hormonally unresponsive prostate Oncol 13:1398-403, 1995.)