Chapter 091. Benign and Malignant Diseases of the Prostate (Part 10)

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Metastatic Disease: Castrate Castration-resistant disease can manifest in many ways. For some it is a rise in PSA with no change in radiographs and no new symptoms. In others it is a rising PSA and progression in bone with or without symptoms of disease. Still others will show soft tissue disease with or without osseous metastases, and others have visceral spread. The prognosis, which is highly variable, can be predicted using nomograms designed for the castration-resistant disease state. The important point is that despite the failure of first-line hormone treatment, the majority of these tumors remain sensitive to second- and...

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Chapter 091. Benign and Malignant Diseases of the Prostate (Part 10) Metastatic Disease: Castrate Castration-resistant disease can manifest in many ways. For some it is a rise in PSA with no change in radiographs and no new symptoms. In others it is a rising PSA and progression in bone with or without symptoms of disease. Still others will show soft tissue disease with or without osseous metastases, and others have visceral spread. The prognosis, which is highly variable, can be predicted using nomograms designed for the castration-resistant disease state. The important point is that despite the failure of first-line hormone treatment, the majority of these tumors remain sensitive to second- and third-line hormonal treatments. Castration resistance does not indicate that the tumor is "hormone-refractory." The rising PSA is an indication of continued signaling through the androgen receptor axis.
The manifestations of disease in this patient group hinder the assessment of drugs and treatment standards because traditional measures of outcome such as tumor regression do not apply. Bone scans can be inaccurate for assessing changes in osseous disease, and no PSA-based outcome is a true surrogate for survival benefit. It is essential to define therapeutic objectives before initiating treatment, as there are defined standards of care for different disease manifestations. Therapeutic objectives need not be defined by survival only as useful endpoints also include relief of symptoms and delay of metastases or new symptoms of disease. The management of patients with castrate metastatic disease requires first that the castrate status be documented. Patients receiving an antiandrogen alone, whose serum testosterone levels are elevated, should be treated first with a GnRH analogue or orchiectomy and observed for response. Patients on an antiandrogen in combination with a GnRH analogue should have the antiandrogen discontinued, as ~20% will respond to the selective discontinuation of the antiandrogen. Any withdrawal response occurs within weeks of stopping flutamide but may take 8–12 weeks with nilutamide and bicalutamide because of their long terminal half-lives. At the time of progression, a different antiandrogen can be given, as some tumors are not cross-resistant. An additional consideration in this setting is that significant androgen production persists in the adrenal gland and that one of the adaptive/selective changes, which occurs in the tumor itself, is the upregulation of
adrenal synthetic enzymes, leading to autocrine signaling. High-dose ketoconazole, which inhibits adrenal androgen synthesis, is also often effective in these cases. Other hormones that may be active include estrogens, progestins, and glucocorticoids. Cytotoxic agents are considered when hormones are no longer effective, or the tempo of the illness suggests a more aggressive approach is needed. Mitoxantrone was the first cytotoxic agent approved to provide palliation of pain secondary to castrate metastatic disease. The results established the important principle that systemic chemotherapy can provide palliation of pain in the absence of a survival benefit. In this trial, mitoxantrone-treated patients had a greater reduction in pain, less use of narcotics, and less fatigue. In 2004, docetaxel was established as the first-line standard cytotoxic drug for patients in this state, based on a trial showing that q3w docetaxel was superior to weekly therapy and to mitoxantrone. The results were confirmed in a second trial of estramustine/docetaxel vs. mitoxantrone. The addition of estramustine produced significant toxicity with no apparent improvement in survival and has been dropped from these regimens. Docetaxel and other microtubule targeted agents produce PSA declines in 50% of patients, measurable disease regression in 25%, and both an improvement in preexisting and prevention of future cancer-related pain.
Management of pain is a critical part of therapy. Optimal palliation requires assessing whether the symptoms and metastases are focal or diffuse and whether disease threatens the spinal cord, the cauda equina, or the base of the skull. Neurologic symptoms require emergency evaluation because loss of function may be permanent if not addressed quickly. Single sites of pain and areas of neurologic involvement are best treated with external beam radiation. As the disease is often diffuse, palliation at one site often is followed by the emergence of symptoms in a separate site that had not received radiation. Given the bone-dominant pattern of prostate cancer spread, two bone- 89 153 seeking radioisotopes, Sr (Metastron) and Sm-EDTMP (Quadramet), are approved for palliation of pain, although they have no effect on PSA or survival. Fewer patients treated with one of these isotopes developed new areas of pain or required additional radiation therapy compared to patients receiving external beam radiation therapy alone. Additionally, patients randomly assigned to a combination 89 of Sr and doxorubicin after induction chemotherapy had fewer skeletal events and longer survival than patients treated with doxorubicin alone. Confirmatory studies are ongoing. Addition of the bisphosphonate zoledronate to "standard therapy" in patients with castration-resistant disease resulted in fewer skeletal events relative to placebo. The skeletal events included microfractures, new pain, and need for radiation therapy. Bisphosphonates have a dual role: to protect
against the bone loss associated with androgen depletion and to prevent skeletal events.