Practical treatment guide for dose individualisation in cancer chemotherapy

Dosages of anticancer drugs are usually calculated on the basis of a uniform standard, the body surface area (BSA). Although many physiological functions are proportionate to BSA, overall drug clearance is only partially related to this parameter. Consequently, following administration of equivalent drug dosages based on BSA, a wide variability in plasma drug concentrations can be found between patients, as a result of which some patients experience little toxicity while others may show severe toxic symptoms. A clear pharmacokinetic/pharmacodynamic correlation has been demonstrated for some anticancer drugs, and this relationship provides a background against which rational dose optimisation can be implemented for individual patients. The 3 strategies that can be employed for optimising dosage regimens, none based on BSA, are described and criticised. A priori adaptive dosage determination is based on the relative contribution of identifiable characteristics of patient, drug therapy and disease state that influence plasma drug concentrations; the dosage regimen is based on each patient's profile with regard to these characteristics. Although this approach is most successful with drugs whose clearance is closely tied to renal function, patient characteristics such age, obesity, serum albumin or hepatic function may be useful. The anticancer drug most closely identified with this approach is carboplatin, although dosage reduction strategies for etoposide, taxanes, anthracyclines, topotecan, oxazaphosphorines, vinca alkaloids or melphalan are advocated for patients with renal or hepatic dysfunction. The importance of pharmacogenetics for fluorouracil and mercaptopurine is also briefly discussed. The second approach consists of adaptive dosage adjustments during repetitive or continuous administration of a drug. It has been used for several years to administer methotrexate therapy and, more recently, it has been developed more fully and applied to continuous infusion of fluorouracil or etoposide. It was based, after determination of a target plasma concentration or area under the plasma drug concentration-time curve (AUC), on modification of the drug dosage during the cycle of chemotherapy or for the next cycle. Finally, the third approach of adaptive dosage adjustment with feedback control, based on population pharmacokinetics, with limited sampling strategy, may allow a feedback revision of the dosage following measurement of plasma drug concentration and comparison with the population previously studied. This approach is a theoretical strategy which has not, until now, been used prospectively in clinical oncology. For drugs such as anticancer agents with a very narrow therapeutic index, every effort should be made to minimise interpatient variability in drug exposure in order to maximise the benefit while keeping the risk of serious adverse effects at an acceptable level. This is particularly important when treatment is being given with curative intent.     

Single agent vs combination chemotherapy in the treatment of ovarian cancer

One hundred and eight patients with Stage III or IV epithelial ovarian cancers were randomly allocated to treatment with either melphalan or the combination of Actinomycin-D, 5-fluorouracil, and cyclophosphamide (ACFUCY). Those patients receiving the ACFUCY combination had a higher objective response rate and a statistically significantly lower progression rate. The ACFUCY combination gave a higher incidence of severe toxicity.     

The use of neoadjuvant intra-arterial polychemotherapy in the treatment of cancer of the genitalia

Results are submitted of employment of intraarterial superselective polychemotherapy in the treatment of malignant tumors of female genital organs in 106 patients; of these, forty individuals presented with carcinoma of the neck of the womb, 33 with tumours of the trophoblast, 18 had carcinoma of the ovaries, and 15 carcinoma of the body of the womb. A clinical analysis was done of the results obtained as were clinical-morphological correspondences (there has been studied a therapeutic pathomorphosis of the tumours) depending on the disease stage, individual schemes of polychemotherapy. The greatest benefit from the above treatment occurred in proliferative and invasive vascular mole and choriocarcinoma; patients with carcinoma of the neck and body of the womb derived less benefit, those with carcinoma of the ovaries experienced the least therapeutic effect. Intraarterial polychemotherapy permits the generative function to be preserved in trophoblast disease, the percentage of operability to be raised in carcinoma of the neck and body of the womb.     

The hormonal and chemotherapy of prostatic cancer

Adenocarcinoma of the prostate is one of the most common malignant tumors in adult males. Hormonal therapy is the treatment of choice for patients with systemic disease concerning 80% response rate. Androgen ablation is now the first hormonal manipulation and can be achieved either by means of bilateral orchiectomy or of LH-HR agonist therapy: both are equally effective. Total androgen blockage (association between orchiectomy or LH-RH agonist and non-steroidal anti-androgens) would be reserved for controlled clinical trials only. Estrogens had the same efficacy, but revealed the serious cardio-vascular events. Endocrine therapy does not prolong survival but provides good palliation. Palliation should be given when there is something to palliate. Prostate cancer is usually not recognized as being sensitive to cytotoxic agents. Single agent or combination chemotherapy has not been shown to have a role as first line treatment of disseminated disease and is usually used for hormone refractory disseminated disease.     

The role of chemotherapy in head and neck cancer

We studied the effect of cytoreductive chemotherapy in head and neck cancer and analyzed it in terms of efficacy, remission rates, and duration, as well effect on survival. Single-agent chemotherapy, which formerly was used as a palliative therapy in recurrent and metastatic disease, had little affect on survival. More recently, multi-agent chemotherapy trials have shown significantly higher response rates, but this success has not translated into an added survival benefit. These findings led to the introduction of multi-agent chemotherapy into the induction (neoadjuvant) clinical setting. In these clinical circumstances, better objective response rates were found, particularly in the previously untreated patient. Although this therapy has resulted in better control of local disease, the impact on survival is not yet clear. Adjuvant chemotherapy is most useful in patients who have a high risk of relapse. Therapy appears to decrease its incidence, particularly at distant sites. Finally, chemoradiation trials have shown that this treatment provides a survival advantage, but at the cost of a significant increase in toxicity.     

p53 and c-erbB-2 as markers of resistance to adjuvant chemotherapy in breast cancer

Recent literature suggests that c-erbB-2 and p53 alteration might be linked to drug resistance. This study investigates the relation of c-erbB-2 oncoprotein overexpression and p53 protein accumulation with prognosis in patients with node-positive breast cancer (NPBC) and assesses the modifying effect of these markers on response to short (1-10 courses) or prolonged (> 10 courses) adjuvant chemotherapy. This study is based on 458 patients with NPBC diagnosed from 1980 to 1986, with an average of 10 years of follow-up. Marker expression was evaluated by immunohistochemical analysis on formalin-fixed, paraffin-embedded material with antibodies to c-erbB-2 and p53. c-erbB-2 was expressed in 17.2% of the cases, and 19.1% of the tumors stained positively for p53. By multivariate analysis, women with prolonged adjuvant chemotherapy had better survival than those with a short course of chemotherapy among patients whose tumor lacked c-erbB-2 oncoprotein expression (P = .0245) or p53 protein accumulation (P = .0477). Prolonged chemotherapy, however, was associated with little or no change in survival among patients whose tumor expressed those markers. The present study adds support to the hypothesis linking c-erbB-2 and p53 expression to drug resistance.     

Possibility of the use of perfluorochemicals (fluorocarbons) as adjuvants in chemotherapy of cancer

In Fischer 344 rats weighing about 100 gr., 7 X 10(5) 9L tumor cells were implanted into right cerebral hemisphere. BCNU. Fluosol-43 (perfluorochemicals blood substitute), or combined therapy BCNU and Fluosol-43 were initiated on Day 7 postimplantation and its therapeutic effect was studied. Mean survival time of control animals was 15.23 +/- 2.84 (SD) days, the group of Fluosol-43 treated in oxygen chamber (95% Oxygen & 5% Carbon Dioxide) was 15.30 +/- 2.11 (SD) days. BCNU treatment alone prolonged the mean survival time to 20.90 +/- 3.80 (SD) days, BCNU plus Fluosol-43 in normal aeration was 21.20 +/- 2.63 (SD) days. On the other hand, BCNU plus Fluosol-43 in oxygen chamber showed a significant increase of mean survival time of 32.27 +/- 4.80 (SD) days (p less than 0.005). From these results, it was concluded that Fluosol-43 (perfluorochemicals) with oxygen might have a synergistic effect for BCNU chemotherapy.     

Intra-arterial infusion chemotherapy for advanced endometrial cancer before surgical treatment

Nine cases of advanced uterine body cancer (stage III: 8, stage IVa: 1) were treated by intra-arterial infusion chemotherapy before curative operation. This treatment produced primary tumors smaller than half sizes in eight cases. Necrotic changes were found in over two-thirds of the lesions in six cases. This chemotherapy enabled us to operate curatively in seven cases. After the operations, we performed various types of treatment including intra-arterial infusion chemotherapy. No evidences of disease have been found in four cases, but there is no significant difference between the groups receiving and not receiving the intra-arterial infusion chemotherapy (n = 16) in terms of survival rate of stage III. Further study of the prognosis is necessary.     

Intra-arterial infusion chemotherapy for advanced uterine cancer before surgical treatment

We reported a case of an abrupt hypotension and hypoxemia which lasted more than 60 min due to emboli of tumor at the orifice of the pulmonary artery during operation. Although the emboli were removed under the cardiopulmonary bypass (CPB) and later the patient regained good respiratory and hemodynamic conditions, he had a disturbance of consciousness after the operation. We began oxygen hyperbaric therapy (OHP) from the 6th postoperative day under spontaneous ventilation. His consciousness improved quickly after the beginning of OHP. We conclude that OHP and CPB might be useful to treat the postoperative disturbance of consciousness due to hypotension and hypoxemia during operation.     

Behavioral intervention in cancer treatment: Controlling aversion reactions to chemotherapy.

During the protracted course of cancer chemotherapy, approximately 25% of patients develop aversion reactions to treatment by becoming nauseated and/or vomiting before their chemotherapy treatments. This phenomenon has been conceptualized as a result of respondent conditioning. Since commonly used antiemetic drugs do not reliably control anticipatory nausea/emesis, behavioral techniques of control have been studied. They include hypnosis used in conjunction with guided-relaxation imagery, progressive muscle relaxation with guided imagery, and systematic desensitization. (67 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pancreatic cancer: treatment with neutron irradiation alone and with chemotherapy

PURPOSE: To evaluate neutron irradiation alone and with chemotherapy to treat inoperable pancreatic cancer. MATERIALS AND METHODS: Between 1977 and 1994, 173 patients (60 men, 113 women, aged 43-77 years [mean, 59 years]) with unresectable adenocarcinoma of the exocrine pancreas were treated, 106 with neutron irradiation alone and 67 with concomitant chemotherapy (fluorouracil [5-FU]). At follow-up, which was performed at 2-month intervals until death (range, 4-64 months), clinical status was recorded, noting the presence of overt metastasis and the onset of any major complications. Actuarial (Kaplan-Meier) survival tables were computed for both groups. RESULTS: For neutron irradiation alone and neutron irradiation plus chemotherapy, median survival times were 6 months and 9 months, respectively; actuarial survival rates at 3 years were 0 and 7%, respectively; major reactions (grade 3 or higher [scale of the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer]) occurred in 19 (18%) and 17 (25%) patients, respectively; and severe complications (grade 4) occurred in five (5%) and four (6%) patients, respectively. Most deaths were due to metastatic disease rather than to failure of local control. CONCLUSIONS: Neutron irradiation obliterated pancreatic adenocarcinoma at the primary site but has no effect on long-term survival. With more effective concomitant chemotherapy to prevent metastasis, local control of pancreatic cancer with neutron irradiation could lead to increased long-term survival.     

Electropermeabilization in bladder cancer chemotherapy

PURPOSE: Electropermeabilization has been used for the introduction of genes into cells. Using this technique, we introduced the cytotoxic drug bleomycin (BLM) into cells and examined whether the technique might be useful for the treatment of bladder cancer. MATERIALS AND METHODS: For electropermeabilization in vitro, we used YTS-1 cells, a human transitional cell carcinoma line. Aliquots of cell suspension were mixed with a solution of BLM and immediately exposed to electric pulses. A high-power pulse generator was used to supply square-shaped pulses of 1250 V/cm (100 micros, eight pulses). After a 2-h post-shock incubation, cells were washed and incubated for one further hour. Then the concentration of BLM in the cells was measured using a bioassay. For electropermeabilization of tissue, we used normal male Wistar rats. The bladder was exposed and 10 mg/kg BLM was injected into the caudal vein. A series of eight pulses with a time constant of 100 micros at an electric field intensity of 1000 V/cm was applied. The bladder, liver and lungs were extracted 1 h later and prepared for quantification of the BLM concentration using the bioassay. RESULTS: Electrotreated cells contained significantly higher concentrations of BLM than nonelectrotreated cells. The concentration of BLM 1 h after electrotreatment in bladder tissue was 2.7 times higher than that in nonelectrotreated bladder tissue. CONCLUSION: The electropermeabilization technique has the potential to serve as a new and effective modality for the treatment of bladder cancer.     

Circadian chemotherapy in cancer patients

Continuous infusion of 5-FU at night was performed for four patients: three had liver metastasis (one with gastric cancer and two with rectal cancer) and one had local recurrence of rectal cancer. The chemotherapy schedule was 400 mg/m2/day 5-FU intraarterial or intravenous infusion from 6:00 p.m. to 6:00 a.m. for five days repeated every 3 weeks. There were one complete response, two partial responses and one with no change. It is expected that the chemotherapy of 5-FU at night will result in a high efficacy and lower toxicity.     

Cytoreductive surgery plus combined chemotherapy for the treatment of advanced ovarian cancer

OBJECTIVE: To evaluate the impact of cytoreductive surgery plus combined chemotherapy on advanced ovarian cancer. METHODS: From Jan. 1980 to Dec. 1992, 76 patients admitted to our hospital for primary treatment, were eligible for retrospective evaluation. 26 patients with stage II and 50 with stage II. All patients with ovarian cancer were given cytoreductive surgery followed by systemic and intraabdominal chemotherapy. Regimens were CAP (Cyclophosphamide, Adriamycin, Cisplatin), AP (Adriamycin, cisplatin) or CE (Carboplatin, Epi-adriamycin). RESULTS: In 52 patients no residual tumor was found in 24 patients there were residual lesions less than 2cm in diameter. Postoperative chemotherapy ranged from 1 to 12 courses. The overall 5-year-survival rate was 33.6%, with 34.9% for stage II and 29.5% for stage II (P > 0.1). The 5-year-survival rates of cases with and without residual tumor were 16.5% and 37.6% respectively, the rates of those cases receiving less or more than 8 courses of chemotherapy were 20.0% and 60.1% respectively. CONCLUSION: The prognosis of ovarian cancer following cytoreductive surgery is influenced by residual tumor, and the number of courses of chemotherapy.     

The use of the alpha-glucosidase inhibitor acarbose for the treatment of type-2 diabetes mellitus in secondary sulfanilamide resistance

Efficacy was studied of acarbose in patients with type II diabetes mellitus during the development of secondary sulfamide resistance. 63 patients were evaluated. Studies were made involving glycemia on an empty stomach, postprandial glycemia and 24-h glucosuria in order that we might learn about the above drug's efficacy. High confidence level decrease in postprandial glycemia was recorded as was significant reduction in diurnal glucosuria.     

The treatment of metastatic melanoma with chemotherapy and biologics

The majority of adults over the age of 65 y develop osteoarthritis (OA), a joint disease characterized by degeneration of articular cartilage and subchondral sclerosis. Early in the disease, the articular cartilage surface begins to change histologically from a smooth to a rough or fibrillated appearance. A prerequisite for any chondroprotective pharmacological intervention is detection of OA in its preclinical phase. Current diagnostic imaging modalities, such as radiographs or (nuclear) magnetic resonance imaging, either cannot directly image the cartilage surface or lack sufficient resolution to detect surface fibrillations. We have developed an ultrasonic technique that can be used to characterize these surface fibrillations directly. We present our in vitro results with validation by laser-based confocal microscopic imaging.