Measurable disease, treatment

Cytotoxic chemotherapy is eventually required in most patients with metastatic breast cancer. Patients with hormone-receptor-negative tumors require chemotherapy as initial therapy of symptomatic metastases. Patients who respond initially to hormonal manipulations eventually cease to respond and go on to require chemotherapy. The median duration of response is 5 to 12 months, but some patients will have an excellent response to an initial course of chemotherapy and may live 5 to 10 years or longer without evidence of disease. In general, median survival of patients after treatment with commonly used drug combinations for metastatic breast cancer is 14 to 33 months. The median time to response has ranged from 2 to 3 months in most studies, but this period depends in large part on the site of measurable disease. The median time to appearance of response is between 3 and 6 weeks in patients whose disease is primarily in the skin and lymph nodes, 6 to 9 weeks in patients with metastatic lung involvement, 15 weeks in patients with hepatic involvement, and nearly 18 weeks in patients with bone involvement. Thus it is often the case that an immediate response to therapy is not... 

Direct costs include both medical and nonmedical expenditures for the detection, treatment, and prevention of disease. Direct medical costs reflect resources consumed in the "production" of health care, such as pharmaceutical products and services, physician visits, and hospital care. Direct nonmedical costs reflect expenditures for products and services that are not directly related to disease treatment but are still related to patient care. Examples of direct nonmedical costs include transportation to a pharmacy or physician s office and housekeeping during the illness period. Indirect costs account for changes in productivity of an individual because of illness. The monetary value of lost or altered productivity is typically used as a measure of indirect costs. Intangible costs and consequences are nonmonetary in nature and reflect the impact of disease and its treatment on the individual s social and emotional functioning and quality of life. Table 12.2 provides examples of these types of costs and consequences. 

Idiopathic thrombocytopenic purpura is an immune-mediated disease in which immunoglobulin, either as antibody directed against platelet antigens or nonspecifically bound to platelets, is present in increased quantities on platelets. This leads to increased destruction of platelets and, in many instances, megakaryocytes. Standard treatment consists of corticosteroids and splenectomy (72). When these measures fail, treatment may include androgenic steroids, administration of intravenous 7-globulin, or injection of vinca alkaloids. 

In Table 8.5, we compare the response rates for the two primary endpoints - disease deterioration and mortality for the Flindle et al. study. What is interesting is that for the mortality endpoint ARR shows less deviation from the null than in the case of disease deterioration, while the converse holds for the RR. This is often regarded as a major defect of the RR as a measure of treatment effect, in that it does... 

Wilson s disease is a copper storage disorder that is apparently due to an inherited lesion in the copper excretion mechanism. One in 200-400 persons is a carrier of the disease. Diagnosis may be made by measuring serum ceruloplasmin levels. Whereas normal serum ceruloplasmin is 200-400 mg/L, in Wilson s disease patients it is well below 200 mg/L. Liver copper in these patients (determined by biopsy) is more than 250 /xg/g, whereas normal individuals show a value of only 20-45 /xg/g. Liver function deterioration is the most prominent symptom of Wilson s disease. Treatment includes chelation therapy with penicillamine. 

CT scan to objectively measure disease response (lung and liver metastases) -after three to four cycles of treatment,... 

Elevated concentrations of plasma homocysteine (HCY) are related to an increased risk of cardiovascular disease, which exists in numerous forms in plasma, with the main form existing as a disulfide with itself, cysteine, or albumin. Therefore, the first step in the measurement involves treatment with a reducing agent, in this case dithiothreitol (DTT), to obtain HCY in its free form (Eq. 16.34). Some amino acids (e.g., L-cysteine and L-methionine) are present in human plasma at higher molar concentrations than HCY and may interfere with this assay. To avoid this possible interference, the highly selective enzymatic conversion of HCY to S-adenosyl-L-homocysteine (SAH), as shown in Eq. 16.34, is used. Both reactions (reduction and conjugation) are accomplished in 30 min at 34 °C. 

In murine models of experimental autoimmune encephalomyelitis (multiple sclerosis), diabetes mellitus type 1, and inflammatory bowel disease, treatment with 1,25-hydroxycholecalciferol (in conjunction with adequate calcium intake) has been shown to inhibit the development of disease (Froicu et al., 2003 Hypponen, 2004 Van Amerongen et al., 2004). In lupus mouse strains, however, a more complex situation is seen, with some evidence of worsening of disease (particularly with respect to measures of renal damage) with 1,25-hydroxycholecalciferol treatment (Vaisberg et al., 2000). 

Lyng H, Sundfor K, Trope C, Rofstad EK (2000) Disease control of uterine cervical cancer relationships to tumor oxygen tension, vascular density, cell density, and frequency of mitosis and apoptosis measured before treatment and during radiotherapy. Clin Cancer Res 6 1104-1112... 

Treatment response to therapy is poorly measured. Measurable disease is absent after surgical excision of many tumors. 

Overall response 1. Best response recorded in measurable disease 2. NC in non-measurable lesions will reduce a CR in measurable lesions to an overall PR 3. NC in non-measurable lesions will not reduce a PR in measurable lesions 1. Best response recorded in measurable disease from treatment start to disease progression or recurrence 2. Non-PD in non-target lesion(s) will reduce a CR in target lesion(s) to an overall PR 3. Non-PD in non-target lesion(s) will not reduce a PR in target lesion(s)... 

Assay of Enzymes In body fluids, enzyme levels aie measured to help in diagnosis and for monitoiing treatment of disease. Some enzymes or isoenzymes are predominant only in a particular tissue. When such tissues are damaged because of a disease, these enzymes or isoenzymes are Hberated and there is an increase in the level of the enzyme in the semm. Enzyme levels are deterrnined by the kinetic methods described, ie, the assays are set up so that the enzyme concentration is rate-limiting. The continuous flow analyzers, introduced in the early 1960s, solved the problem of the high workload of clinical laboratories. In this method, reaction velocity is measured rapidly the change in absorbance may be very small, but within the capabiUty of advanced kinetic analyzers. 

Mechanical removal of plaque is the most effective measure against plaque-caused diseases, dental caries, and periodontal diseases. Even before the advent of fluoride treatments, it was assumed that a clean tooth does not decay. A toothbmsh is effective in removing dental plaque and, for those individuals who optimize its use, it usually can adequately control plaque. Despite the proven efficacy of mechanical plaque removal, the amount of patient involvement is such that only about 30% of the population in developed countries and considerably less in undeveloped countries can be expected to adequately remove plaque (1). Hence, supplementary measures such as dentifrices and dental rinses are necessary. 

Historically the only melanocortin peptide to be used clinically is the parent hormone from which all these peptides are derived from namely ACTH (see above). It has also been used in the treatment infantile spasms for epilepsy, where it is administered as an intramuscular injection only over a 2-12 weeks period. Obvious side effects include weight gain, puffy face, high blood pressure and an increased risk of infection and should never be administered to patients with diabetics, renal or heart failure. ACTH is also used as a stimulation test to measure adrenal cortex activity, i.e. production of cortisol and is used to ascertain whether someone has Addison s disease. 

---