CA-125 can be part of the tumour evaluation criteria in ovarian cancer trials: experience of the GCIG CALYPSO trial.

BACKGROUND: CA-125 as a tumour progression criterion in relapsing ovarian cancer (ROC) trials remains controversial. CALYPSO is a large randomised trial incorporating CA-125 (GCIG criteria) and symptomatic deterioration in addition to Response Evaluation Criteria in Solid Tumours (RECIST) criteria (radiological) to determine progression. METHODS: In all, 976 patients with platinum-sensitive ROC were randomised to carboplatin-paclitaxel (C-P) or carboplatin-pegylated liposomal doxorubicin (C-PLD). CT-scan and CA-125 were performed every 3 months until progression. RESULTS: In all, 832 patients (85%) progressed, with 60% experiencing a first radiological progression, 10% symptomatic progression, and 28% CA-125 progression without evidence of radiological or symptomatic progression. The benefit of C-PLD vs C-P in progression-free survival was not influenced by type of first progression (hazard ratio 0.85 (95% confidence interval (CI): 0.66-1.10) and 0.84 (95% CI: 0.72-0.98) for CA-125 and RECIST, respectively). In patients with CA-125 first progression who subsequently progressed radiologically, a delay of 2.3 months was observed between the two progression types. After CA-125 first progression, median time to new treatment was 2.0 months. In all, 81%of the patients with CA-125 or radiological first progression and 60% with symptomatic first progression received subsequent treatment. CONCLUSION: CA-125 and radiological tests performed similarly in determining progression with C-PLD or C-P. Additional follow-up with CA-125 measurements was not associated with overtreatment.

Phase II study of gemcitabine and oxaliplatin in patients with recurrent ovarian cancer: an Australian and New Zealand Gynaecological Oncology Group study.

Gemcitabine and oxaliplatin have shown single-agent activity in relapsed ovarian cancer. This combination was used to determine response rates, time-to-event efficacy measures, and toxicity in patients with recurrent ovarian cancer. Patients with prior platinum-based chemotherapy who had measurable lesions and/or elevated CA-125 levels were identified as group A (platinum-refractory/platinum-resistant patients) and group B (platinum-sensitive patients). All patients received gemcitabine 1000 mg/m(2) on days 1 and 8 and oxaliplatin 130 mg/m(2) on day 8 every 21 days for up to eight cycles. Seventy-five patients (21 in group A and 54 in group B), with a median age of 58 years (range, 37-78), were enrolled. A median of six cycles (range, 1-8) was administered. By intent-to-treat analysis, 15 patients with measurable disease achieved partial response for an overall best response rate of 20.0% (9.5% in group A and 24.1% in group B). CA-125 response was observed in 48.4% patients (30.0% in group A and 57.1% in group B). Median time to progressive disease was 7.1 months (95% CI, 5.6-9.0 months) with 5.0 months in group A and 8.3 months in group B. Median overall survival was 17.8 months (95% CI, 12.9-21.3 months) with 9.2 months for group A and 20.0 months for group B. Major grade 3/4 toxicities were neutropenia (61.3%), leukopenia (24.0%), nausea (16.0%), and vomiting (22.7%). We conclude that the combination of oxaliplatin and gemcitabine is active in patients with recurrent ovarian cancer, but the regimen is unsatisfactory for further study due to modest response and relatively high toxicity.

Phase II study of carboplatin followed by sequential gemcitabine and paclitaxel as first-line treatment for advanced ovarian cancer.

The aim of this exploratory phase II study was to evaluate sequential chemotherapy with carboplatin followed by gemcitabine-paclitaxel combination in chemonaive patients with advanced ovarian cancer. The primary objective was to evaluate time to progressive disease (TTPD); secondary objectives included the evaluation of 1- and 3-year survival, response rates, and toxicity. Following initial debulking surgery or biopsy, patients with FIGO stage IIC-IV disease received four cycles of carboplatin area under the curve (AUC) 6 (day 1) every 21 days, followed by four cycles of gemcitabine 1000 mg/m(2) (days 1 and 8) and paclitaxel 175 mg/m(2) (day 8) every 21 days. A total of 47 patients enrolled, 44 (93.6%) completed the initial four cycles, and 39 patients (82.9%) completed the planned eight cycles. The median and maximum lengths of follow-up were 31.2 and 43.7 months, respectively. Median TTPD was 13.8 months (95% CI, 11.6-21.0 months), and median survival time was 31.2 months (95% CI, 25.2-39.6 months). Survival at 1 and 3 years was 95.7% and 44.2%, respectively. Of the 43 evaluable patients, most (95.3%) of them achieved a CA-125 marker response based on Gynecologic Cancer Intergroup (GCIG) definition. The partial response rate in the seven patients with measurable disease was 46.4%. Myelosuppression was the major toxicity, with grade 3 and 4 neutropenia observed in 76.6% patients and thrombocytopenia in 12.8% patients. The sequential approach of carboplatin followed by gemcitabine-paclitaxel as first-line treatment for patients with ovarian cancer is feasible and well tolerated, and depending upon the findings from other major trials, it may merit further evaluation.

Phase II trial of weekly docetaxel for patients with relapsed ovarian cancer who have previously received paclitaxel--ANZGOG 02-01.

OBJECTIVE: To determine the response rate of weekly docetaxel in women with relapsed epithelial ovarian cancer previously treated with paclitaxel and at least one line of platinum-based chemotherapy. METHODS: In this multi-center phase II trial, 37 patients with relapsed disease were enrolled and treated with weekly docetaxel at 35 mg/m for 5 out of 6 consecutive weeks. Two patient cohorts were considered, those who progressed or relapsed within 4 months (N=7) or at greater than 4 months (N=30) from the time of completing their last course of paclitaxel. RESULTS: Patients in both cohorts received a median of 2 cycles of treatment (range; 1-4). In evaluable patients, the combined overall response rate, using both CA125 and RECIST response criteria was 18.9% (7/37; 95% CI; 10-34%). The combined overall progression-free survival was 3.1 months (95% CI; 2.5-3.8), and the combined overall survival was 12.3 months (95% CI; 8.2-16.4). Treatment was generally well tolerated with the only grade 4 toxicity being skin toxicity (3%). The most common grade 3 toxicities were fatigue (14%) and watery eyes (8%) with grade 3 neutropenia observed in only 5% of patients. CONCLUSION: Weekly docetaxel is well tolerated and has activity in patients with relapsed ovarian cancer previously treated with platinum and paclitaxel.

Australasian multicentre phase II study of paclitaxel (Taxol) in relapsed ovarian cancer.

BACKGROUND: Until recently there has been no effective therapy for patients with relapsed ovarian carcinoma following standard platinum based chemotherapy. Paclitaxel has recently been approved for clinical use in this malignancy. AIMS: To evaluate the objective response rate and toxicity of paclitaxel in patients with relapsed ovarian cancer. METHODS: Paclitaxel was given on an outpatient basis as a three hour infusion every 21 days for a maximum of ten cycles to 72 patients with advanced ovarian cancer previously treated with at least one platinum containing regimen. The starting dose was either 175 mg/m2 (patients with one or two prior chemotherapy regimens) or 135 mg/m2 (three previous regimens). Premedication was given because of the documented risk of hypersensitivity reactions to paclitaxel. RESULTS: The overall response rate was 22% (95% confidence interval [CI] 13% to 34%) in the 72 patients enrolled in the study: four patients had a complete response. Three patients (4%) ceased treatment due to hypersensitivity reactions. Other significant (WHO grade 3 or 4) toxicities included neutropenia (51%), myalgia (14%), neurological (3%), alopecia (93%) and nausea and vomiting (3%). The estimated median survival of all patients was 9.8 months (95% CI: 9.1-13.0 months) with 44% alive at one year (standard error [SE] 7%). CONCLUSIONS: This study confirms that paclitaxel given as a three hour infusion has significant activity and acceptable toxicity in advanced ovarian carcinoma previously treated with platinum regimens.

Carcinoma in situ of the testis followed by an overt malignant teratoma of the testis within 12 months.

A case of bilateral metachronous testicular non-seminomatous germ cell tumour (NSGCT) is presented. The second tumour was preceded by carcinoma in situ, diagnosed at the time of the first orchidectomy. The patient was placed under active surveillance and 1 year later the second testis tumour developed. A second orchidectomy was performed and testosterone replacement begun. Carcinoma in situ of the testis is discussed.

Primary thyroid lymphoma: clinical features, treatment and outcome: a report of 8 cases.

AIM: To assess the clinical findings and response to treatment of patients with primary thyroid lymphoma. METHODS: Patients with primary thyroid lymphoma were identified by reviewing the diagnoses of all patients with thyroid malignancies diagnosed at Christchurch Hospital between 1980-91. The records of patients with primary thyroid lymphoma were abstracted. RESULTS: During the 12 year period eight patients (6 females, 2 males) with primary thyroid lymphoma were diagnosed and treated. The median age was 78 years (range 18-90 yr). All patients presented with recent thyroid masses and obstructive symptoms were prominent. Two patients were initially referred with endocrine dysfunction--one thyrotoxic and one hypothyroid. Six patients had nonHodgkin lymphoma and two Hodgkin's disease, with all having stage IA disease. Two patients were treated by thyroidectomy, and in the remaining six patients the thyroid lymphoma masses regressed following radiotherapy with the two youngest patients also receiving chemotherapy. At follow up all five elderly patients have since died--two of disseminated lymphoma, two of concurrent cancers and one of vascular disease, and the three younger patients remain in remission after 4.5, 6.5 and 10.5 years. CONCLUSION: Primary thyroid lymphoma usually presents with obstructive symptoms, but there may be associated thyroid dysfunction. Thyroid lymphoma masses respond well to radiotherapy.

Second malignant neoplasms in patients with Hodgkin's disease.

AIM: To determine the incidence of second malignant neoplasms in patients treated for Hodgkin's disease. METHODS: The records were reviewed of all patients receiving primary treatment for Hodgkin's disease at the Oncology Service, Christchurch Hospital from 1969 to 1992. Second malignant neoplasms presenting at least six months after the diagnosis of Hodgkin's disease were noted and the cumulative risk estimated. RESULTS: Twenty-two second malignant neoplasms developed in 20 of the 209 patients. The risk was 5.6 +/- 3.8% (CI) at five years, 11.4 +/- 6.2% at ten years, and 21.7 +/- 11.2% at 15 years and continued to increase thereafter. Thirteen patients have died of their second malignancy, including two of a third malignancy, while four have been followed for less than one year. Three leukaemias (CML, 1; acute non lymphocytic leukaemia, 2), three lymphomas and 16 solid tumours developed. The risk was greater after six or more cycles of MOPP-like chemotherapy and after radiation doses exceeding 30 Gray. The risk was less after laparotomy and splenectomy (p = 0.0205). CONCLUSIONS: In view of the significant risk of a second neoplasm in survivors of Hodgkin's disease follow up should continue beyond ten years, after which time second malignancies were more likely than recurrence. Efforts should continue to minimise the carcinogenicity of therapy while preserving efficacy.

Fasting plasma lipid measurements following cisplatin chemotherapy in patients with germ cell tumors.

PURPOSE: Elevated total serum cholesterol levels have been reported recently in a group of patients with metastatic testicular cancer after treatment with cisplatin combination chemotherapy. We have studied the lipid profile of a similar group of patients in an attempt to confirm this observation. PATIENTS AND METHODS: Fasting plasma lipid concentrations were measured in 47 patients with advanced germ cell tumors who were previously treated with a cisplatin combination chemotherapy. The values obtained for mean total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein A1, and apolipoprotein B concentrations were compared with those obtained from a control group of 59 patients with germ cell tumors who were not treated with chemotherapy and with data from the New Zealand male population. Median time from the completion of chemotherapy to lipid measurement in the treated group was 50 months (range, 2 to 138 months). The median total dose of cisplatin given was 720 mg (range, 300 to 1,625 mg). RESULTS: Mean total plasma cholesterol concentrations in the cisplatin group (5.87 mol/L) and the control group (5.70 mmol/L) did not differ significantly (P > .4). There was no significant difference for any of the variables between the chemotherapy and control groups and those of the New Zealand male population. There was a trend toward higher mean triglyceride concentrations in the chemotherapy group, but this did not reach significance. CONCLUSIONS: We have not demonstrated an elevation in total plasma cholesterol after cisplatin chemotherapy as has been reported by previous investigators. Our results suggest that in these patients, cisplatin-containing combination chemotherapy is not associated with a significant adverse effect on plasma lipid profile.

The management of small cell lung cancer in Christchurch 1979-89.

The management of 215 consecutive patients with small cell lung cancer referred to the oncology service at Christchurch Hospital, 1979-89, was reviewed. After staging, 118 patients were treated with combination chemotherapy (cyclophosphamide, vincristine and doxorubicin), with (87) or without (31) thoracic irradiation. Patients with other medical problems were treated with alternative chemotherapy (34) or irradiation alone (54). Nine received symptomatic care alone. Eighty-five (40%) had limited disease, with no extrathoracic metastases beyond supraclavicular nodes. The response rate to treatment was 66%. Median survival for the whole group was 33 weeks, 51 weeks for those with limited and 26 weeks for extensive disease. The cumulative risk of developing cerebral metastases was 40% at one year. Patients surviving 26 weeks spent one third of their time as hospital inpatients or outpatients. Twenty-two patients survive, five progression free for 4-8 years, including two who had initial surgical resection. The study supports the policy of reserving intensive staging for fit patients who appear to have limited disease and for those entered into clinical trials. Fit patients with limited disease warrant treatment with combination chemotherapy and thoracic irradiation.

Comparison of methods of assessment of renal function in patients with cancer treated with cisplatin, carboplatin or methotrexate.

In patients with cancer treated with cisplatin, carboplatin or methotrexate creatinine clearance calculated using the Cockcroft-Gault formula was compared with measured clearance and with the glomerular filtration rate. In 106 patients the average squared difference for calculated and 24 hour urine creatinine clearance was 0.288, n = 606; and for calculated creatinine clearance and glomerular filtration rate (measured using diethylenetriaminepenta-acetic acid, DTPA), 0.212, n = 34. On 35 of 606 occasions (6%) in 18 patients (17%), the calculated clearance overestimated the 24-hour urine creatinine clearance when it was less than 1 mL/s. In all but one patient, this was explained by factors leading to renal impairment (seven patients) or overestimation of clearance (ascites in two patients) or by an isolated low value of 24-hour urine creatinine clearance (eight patients). Declining renal function with increasing total dose of cisplatin was detected by both calculated and 24-hour urine creatinine clearance in patients with germ cell tumours. Derivation of an equation to predict creatinine clearance showed a linear association with plasma creatinine concentration, patient age, weight and gender. Variability in cancer patients was similar to that in the original Cockcroft-Gault study. Calculation of creatinine clearance can be used in cancer patients to monitor treatment with renally-eliminated chemotherapy agents.

Carboplatin is ototoxic.

For assessment of the ototoxic potential of carboplatin [cis-diammine-1,1-cyclobutane dicarboxylate platinum(II); CBDCA], pure-tone audiograms were evaluated in 27 patients receiving a total of 119 doses of carboplatin in the range of 300-400 mg/m2. Pure-tone audiometry (PTA) was done immediately prior to and 4 weeks after the administration of 80 doses (67%). Defining carboplatin ototoxicity as an increase of greater than or equal to 30 dB in auditory thresholds that was unexplainable by other causes, we identified 5 examples (19%). Hearing loss tended to be cumulative with increasing dose and was always maximal at 8,000 Hz. Two patients had an increase in auditory thresholds at 1,000 Hz, but this only amounted to 10 dB in each case. Patients developing ototoxicity tended to be older. Sex, the pre-treatment creatinine clearance, the pretreatment audiogram, the number of doses, and the cumulative dose did not emerge as being reliable predictors of subsequent ototoxicity. We conclude that although carboplatin is ototoxic, clinically significant deafness does not occur with conventional dosing and routine audiometric monitoring is therefore unnecessary. However, we suggest that caution should be exercised when carboplatin is given either at higher doses or for longer periods when there is concomitant use of other potentially ototoxic agents or when there is significant pre-existing auditory impairment.

A risk factor for relapse in Hodgkin's disease: female gender?

A retrospective study of 163 patients with Hodgkin's disease treated between 1969 and 1987 was performed to identify adverse prognostic factors. One hundred and thirty-five patients (83 per cent) attained a complete remission and 42 (31 per cent) of these have relapsed (median follow-up--43 months). Using multivariate analysis, no independent factors predicted for the event of relapse. However, analysis of disease-free survival revealed that females fared significantly worse than males (p less than 0.05) and this was independent of other prognostic variables. Female sex has not been recognized as an independent prognostic factor predictive of inferior survival and inferior disease-free survival.

Surveillance for stage I non-seminomatous germ cell tumours of the testis: the optimal protocol has not yet been defined.

Forty-six patients with clinical stage I testicular non-seminomatous germ cell tumours were followed up according to a protocol of active surveillance between 1979 and 1987. The median follow-up time was 40+ months. Thirteen patients (28%) relapsed, predominantly in retroperitoneum and/or lung. Ten of these relapses (76%) occurred within 8 months of orchiectomy. Relapses occurred in 7/35 T1 tumours and 5/10 T2 to T4 tumours. No correlation was detected between the histological type and relapse rate. Three late relapses were diagnosed at 23, 29 and 36 months. Eleven of the relapsed patients remain in prolonged complete remission after PVB chemotherapy +/- surgery; one patient, who initially refused treatment at the time of relapse, has died. Another relapsed with predominant elements of rhabdomyosarcoma intermingled with malignant teratoma in a bone metastasis. He had a partial response to PVB chemotherapy but subsequently died. Thirty-four patients (74%) did not undergo lymphography (LG) and had a higher relapse rate (11/34) than those who had LG (2/12); this was not a statistically significant difference in this small series. The policy of active surveillance is not yet the "state of the art" and should be under constant scrutiny with respect to safety and practice.

High grade nonHodgkin's lymphoma: management with moderate dose combination chemotherapy.

We have reviewed the management of high grade nonHodgkin's lymphoma in a regional cancer centre over an eight year period. Forty-seven patients were referred with diffuse histiocytic, diffuse undifferentiated and lymphoblastic lymphomas or true histiocytic neoplasms. Twenty-six were treated with doxorubicin, cyclophosphamide, vincristine and prednisone (ACOP). The overall complete remission rate was 73%, 83% for stage I and II disease and 62% for stages III and IV. Kaplan-Meier analysis shows 49% surviving at a median follow up time of 23 months (range 1-108 months) with 11 of the 13 survivors continuously disease free. Toxicity was not severe except for one treatment-related death. Most were treated as outpatients. Patients 70 years of age or older were treated less intensively and only 3 of 14 survive. We conclude that treatment with ACOP is simple and effective in the management of high grade nonHodgkin's lymphoma. Currently our protocol includes the same agents, but at higher dosage, with the addition of methotrexate; we believe this should be tested against the recent more intensive, multiagent alternating regimens in a prospective, randomised clinical trial.

B cell lymphoma presenting as carcinoma of the lung.

A patient presented with superior vena caval obstruction caused by a tumour which resembled carcinoma of the lung both clinically and histologically. However, immunologic and cytogenetic analyses carried out on the mediastinal biopsy and on pleural fluid revealed that the tumour was of B cell origin, Burkitt-like in sub-type, and had the t(8;14) translocation. The nature of many poorly differentiated tumours may be more clearly identified with the help of immunological and cytogenetic analyses.

Cis-platinum and distal renal tubule toxicity.

Glomerular filtration rate (GFR) and plasma electrolyte concentrations were evaluated prospectively in 22 consecutive patients treated with serial courses of cisplatinum combination chemotherapy. In addition, renal distal tubular function was assessed in the first 12 by measurement of overnight urinary concentration after intranasal desamino-d-arginine vasopressin inhalation and by a standard short urinary acidification test following the administration of oral ammonium chloride. Cumulative and dose-related hypomagnesaemia was observed in all patients but was unassociated with clinical symptoms. No significant fall in GFR was seen in the group as a whole but four of the 12 patients studied more comprehensively developed impairment of urinary concentrating and acidifying abilities, independent of any change in GFR. This indicates a selective effect on the renal distal tubule.

Sources of proteins in human bile.

The proteins of 46 human bile specimens, collected by several different routes have been studied by crossed immunoelectrophoresis, by rocket immunoelectrophoresis and by radioimmunoassay. The results were analysed by plotting the variation in the bile: plasma ratio of particular proteins against molecular weight and by examination of the correlation between the concentrations of different proteins in the biles of different patients. Our results show that the majority of human bile proteins derive from plasma although bile specific proteins are always present. The majority of plasma proteins appear to enter bile by a 'sieving' mechanism which results in an inverse relationship between the bile: plasma ratio and the molecular weight. In addition there was a very high degree of correlation between the biliary concentrations of alpha 2-macroglobulin, IgG, haptoglobin, haemopexin, albumin, prealbumin, and orosomucoid. A number of other proteins namely thyroxine binding globulin, GC globulin and alpha 2HS-glycoprotein appeared in bile at concentrations greater than those expected if entry is by the sieving mechanism. These three proteins, however, are of rather low molecular weight and the reason for the lack of correlation appears to be individual variation in the 'pore size', presumably reflecting variation in the porosity of tight junction between hepatocytes. Although the majority of human bile proteins would appear to enter bile by a molecular weight-dependent pathway, four proteins, namely secretory IgA, IgM, haemoglobin and caeruloplasmin, showed significant deviation from the predicted relationship and probably enter bile at least partly by transport across cells. The concentration of beta 2-glycoprotein I was also much greater than expected from its molecular weight. The reason for this is not yet clear but may well reflect a very efficient and specific transport mechanism.