E. Wiltshaw

Carboplatin dosage: prospective evaluation of a simple formula based on renal function.

A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.

Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds

Fifty-four patients with ovarian cancer who achieved a complete or partial remission with cisplatin or carboplatin were rechallenged with the same drug or crossed over to the other platinum compound at relapse. Fifteen of 43 (35%) crossover patients and 1/11 (9%) rechallenged patients responded; the difference was not significant and there was no difference in survival between the two groups. Responders survived significantly longer than nonresponders (P = 0.001) but there was no survival difference between those who responded to a rechallenge and those who responded to crossing over to the other platinum compound. The progression-free interval between the end of initial treatment and relapse was a significant prognostic factor for response to treatment and survival; 17% (6/35) of patients who relapsed before 18 months responded as compared to 53% (10/19) who relapsed after 18 months (P = 0.006) and median survival was 221 and 486 days, respectively, for these two groups (P = 0.026).

Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer.

PURPOSE The study was undertaken to define the relationship between tumor response and carboplatin area under the curve (AUC) in patients with ovarian cancer; to study the relationship between carboplatin AUC and myelosuppression in the same population; to establish the true impact of carboplatin AUC, prior therapy, and pretreatment platelet and WBC counts on toxicity; and to define an optimal carboplatin exposure for treating patients with ovarian cancer. METHODS With the equation AUC = dose/(glomerular filtration rate [GFR]+25), carboplatin AUC (course 1) was calculated for 1,028 patients (450 previously untreated) who received single-agent carboplatin (40 to 1,000 mg/m2) for advanced ovarian cancer. GFR was measured (chromium-51-edathamil [51Cr-EDTA] or creatinine clearance) in all patients. RESULTS Regression analysis showed that carboplatin AUC, prior treatment, and Eastern Cooperative Oncology Group grade performance status (PS) are predictors of tumor response, thrombocytopenia, and leukopenia. Pretreatment platelet and WBC counts are additional predictors of thrombocytopenia and leukopenia, respectively. Although the likelihood of tumor response increased with increasing carboplatin AUC, this relationship was nonlinear. In all patient subsets, the likelihood of complete response (CR) or overall response did not increase significantly above a carboplatin AUC of 5 to 7 mg/mL x minutes. At any given carboplatin AUC, thrombocytopenia occurred more frequently than leukopenia, although both approached 100% as carboplatin AUC increased. Both thrombocytopenia and leukopenia were more frequent in pretreated than in untreated patients regardless of pretreatment count. At any carboplatin AUC, the influence of PS on likelihood of response and toxicity was profound. CONCLUSION Carboplatin dosing by AUC will lead to more predictable toxicity, and increasing carboplatin AUC above 5 to 7 mg/mL x minutes does not improve the likelihood of response but does increase myelotoxicity. Therefore, careful evaluation of high-dose carboplatin therapy in a prospective, randomized trial is needed before such treatment becomes accepted practice.

Natural history and prognosis of untreated stage I epithelial ovarian carcinoma

PURPOSE The aim of this study was to investigate the independent significance of prognostic factors in stage I invasive epithelial ovarian cancer (EOC). PATIENTS AND METHODS Between 1980 and 1994, all patients with stage I EOC (borderline tumors excluded) following surgical resection were entered onto this study. No patient received adjuvant therapy and patients were monitored as follows: years 1 to 2-physical examination and serum CA125 every 3 months and computed tomographic (CT) scan every 6 months; years 3 to 5-physical examination and serum CA125 every 6 months and CT scan yearly; years 5 to 10-annual physical examination and serum CA125, with CT scan if clinically indicated. RESULTS A total of 194 patients entered the study. The median patient age was 54 years (range, 15 to 83), and the median follow-up duration 54 months (range, 7 to 157). Five-year survival rates were as follows: stage IA, 93.7%; stage IB, 92%; and stage IC, 84%. Multivariate analysis using Coxs regression identified grade (P < .001), presence of ascites (P = .05), and surface tumor (P < .01) as independent poor prognostic factors. International Federation of Gynecology and Obstetrics (FIGO) substage did not appear to have independent prognostic significance. Intraoperative capsule rupture was not found to be prognostically significant. The impact of pre-operative rupture remains unclear. CONCLUSION This is an important series, as no patient received adjuvant therapy, and represents the natural history of surgically resected stage I EOC.

Chronic Myelomonocytic Leukaemia

Summary. The natural history and haematological features of 18 patients with a chronic form of myelomonocytic leukaemia are described. The majority were elderly and, in this series, females predominated. Haematological prodomata, such as unexplained monocytosis, leucopenia, or thrombocytopenia were common, and the clinical onset was insidious. Splenomegaly was variable but tended to increase as the disease progressed.

The clinical and histologic criteria that predict metastases from cystosarcoma phyllodes

A retrospective study of 33 patients with cystosarcoma phyllodes was done. Eight of these patients had metastases, and the clinical and histologic criteria predicting the development of metastases were examined. The most reliable predictor was the presence of stromal overgrowth; this appears to be necessary for metastasis to occur. Other useful indicators of clinical behavior were the degree of mitotic activity, nuclear pleomorphism, and infiltrating margins. Based on these data and a literature review, the authors suggest close follow‐up of patients whose primary tumors contain areas of stromal overgrowth because, in all series combined, the risk of metastatic spread in such patients was 72% within 5 years. Among these high‐risk patients, local recurrence is another indication that metastasis is likely.

Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. London Gynaecological Oncology Group

PURPOSE We have examined the role of an increase in cisplatin dose-intensity in patients with advanced epithelial ovarian cancer by means of single-agent carboplatin therapy. PATIENTS AND METHODS Two hundred twenty-seven patients were randomized to treatment and eligible for analysis. The dose of carboplatin was calculated according to the Calvert formula. One hundred seventeen patients received carboplatin at an area under the concentration time curve (AUC) of 6 for six courses, administered every 28 days, and 110 patients received carboplatin at an AUC of 12 for four courses, administered every 28 days. Patients were eligible provided they had not received prior chemotherapy or radiotherapy and had International Federation of Gynecology and Obstetrics stages II to IV or relapsed stage I epithelial ovarian cancer. RESULTS The planned total-dose increase was 33% for the patients treated with carboplatin AUC 12, but the received percentage total-dose increase was 20%. There were no differences in progression-free or overall survival between the two treatment arms; the overall survival rate at 5 years was 31% and 34% of patients treated at AUCs 6 and 12, respectively. There was significantly more toxicity associated with carboplatin AUC 12, which resulted in more treatment delays and/or dose reductions (52% v 18%; P < .001). CONCLUSION We have shown that carboplatin can be delivered at an AUC of 12 for four courses without granulocyte colony-stimulating factor support, although significant hematologic toxicity occurs. Nonhematologic toxicities were not clinically significant. Carboplatin offers an opportunity to intensify cisplatin therapy, but a greater than two-fold increase in dose-intensity probably needs to be achieved before significant effects on survival will be produced and hematologic support will be required.

ORAL NON-ABSORBED ANTIBIOTICS PREVENT INFECTION IN ACUTE NON-LYMPHOBLASTIC LEUKÆMIA

113 patients being treated for acute non-lymphoblastic leukaemia were investigated to determine the effect of suppression of body microbial flora on prevention of infection. They were randomly allocated to a control group or a group which received non-absorbed antibiotics by mouth and topical applications of cutaneous and mucosal antiseptic preparations. The group receiving oral non-absorbed antibiotics had significantly few infections, fewer deaths from infection, fewer pyrexial episodes, and consequently received less systemic antibiotic therapy than the controls.

High-dose alkylation therapy using ifosfamide infusion with mesna in the treatment of adult advanced soft-tissue sarcoma.

SummaryIn a phase II study, 42 patients with advanced soft-tissue sarcoma were treated with ifosfamide by 24-h infusion and mesna by 4-h IV bolus, repeated every 3 weeks. Ten patients received ifosfamide 5.0 g/m2, 20 had the dosage increased to 8.0 g/m2, and 12 received 8.0 g/m2 from the outset. Mesna was given in doses of 400 mg/m2 or 600 mg/m2. Of 40 patients evaluable for response, six (15%) achieved complete response and nine (23%) partial response. The overall response rate was 38%. The median duration of response was 11 months. Treatment was associated with falls in peripheral WBC and alopecia in all patients. Most experienced severe nausea and vomiting. In seven nephrotoxicity developed, and two of these died of renal failure. Renal tubular defects and cerebral effects also occured. Mesna largely prevented haemorrhagic cystitis. Ifosfamide offers a new alternative to previous chemotherapy for advanced soft-tissue sarcoma, but alterations in dose or method will be necessary to reduce toxicity.

Ovarian trials at the Royal Marsden

Following initial studies at The Institute of Cancer Research (1) and The Royal Marsden Hospital (2, 3) carboplatin (JM8) was introduced into a Phase III study ofstages III and IV ovarian epithelial cancer. A Phase II study had shown that in previously treated patients, almost all of whom had had prior chemotherapy including cisplatin, there was a response rate of 25%. The purpose of the Phase III trial was to confirm the reduced toxicity of carboplatin compared to cisplatin, to compare the efficacy of the two drugs and to further investigate the possible lack of cross resistance between the two agents. Patients and methods Patients with histologically proven FIG0 stages III and IV were selected for entry into the trial unless they had had another carcinoma in the past or renal function was poor (EDTA clearance of < 50 ml/min). Other causes of exclusion were impaired hearing or peripheral neuropathy from whatever cause. All patients were started on chemotherapy within 8 weeks of surgery. Patients were randomized to receive cisplatin 100 mg/m’ as an intravenous bolus injection after 24 hours of intravenous saline prehydration. Following injection, a further 24 hours of 3 litres of saline was given together with 20 mmol of KC1 every 8 hours. Intravenous frusemide was given if urinary output fell below 100 ml/hour. Treatment was repeated at 28 day intervals for five courses followed by a further five doses of cisplatin 2 30 mg/m plus 12 hours normal saline. Carboplatin 400 mg/m2 was administered as an intravenous infusion over 30 minutes with no special hydration and was repeated every 28 days. Since the toxicity ofcarboplatin is related to renal clearance, doses were reduced if the EDTA clearance was less than 60 ml/min. A total of ten courses was administered. In both arms of the trial, patients were assessed for response at 3 months and in unresponding cases the treatment was changed to the other drug. In responding patients or