A randomized phase II study comparing capecitabine alone with capecitabine and oral cyclophosphamide in patients with advanced breast cancer-cyclox II.

BACKGROUND: Capecitabine and cyclophosphamide are active in patients with advanced breast cancer, have non-overlapping toxic effects and synergy pre-clinically. We explored the efficacy and toxic effect of an all-oral combination of capecitabine with cyclophosphamide versus capecitabine alone in a multicentre, randomized, phase II study. PATIENTS AND METHODS: Patients with locally advanced or metastatic breast cancer were randomized to treatment with capecitabine given continuously (666 mg/m(2) b.i.d. days 1-28) alone (C) or with oral cyclophosphamide (100 mg/m(2) days 1-14 of a 28-day cycle) (CCy) for up to six cycles. RESULTS: Eighty-two patients were randomized. There was no complete response. The proportions with partial response were 36% on C and 44% on CCy, a difference of 7.9% [95% confidence interval (CI) -13.4 to 29.1]. Significant toxic effect was uncommon: grade ≥3 diarrhoea in 4 (10%) versus 1 (3%) patients; grade ≥3 fatigue in 2 (5%) versus 5 patients (13%) and grade ≥2 hand-foot syndrome in 7 (17%) versus 11 (28%) patients receiving C versus CCy, respectively. Median progression-free survival was 3.1 months on C and 6.9 months on CCy, not significantly different statistically. There was no difference in overall survival. CONCLUSION: The difference in tumour response suggests a reasonable chance that CCy is superior to C alone.

Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent.

The antitumour action of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is mediated through tumour-selective antivascular effects and cytokine induction. This clinical phase I trial was conducted to examine its toxicity, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). A secondary objective was to assess its antitumour efficacy. DMXAA was administered every 3 weeks as a 20-min i.v. infusion. Dose escalation initially followed a modified Fibonacci schema but was also guided by PK and toxicity. A total of 63 patients received 161 courses of DMXAA over 19 dose levels ranging from 6 to 4900 mg m(-2). DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen. Rapidly reversible dose-limiting toxicities were observed at 4900 mg m(-2), including confusion, tremor, slurred speech, visual disturbance, anxiety, urinary incontinence and possible left ventricular failure. Transient prolongation of the corrected cardiac QT interval was seen in 13 patients evaluated at doses of 2000 mg m(-2) and above. A patient with metastatic cervical carcinoma achieved an unconfirmed partial response at 1100 mg m(-2), progressing after eight courses. The results of PK and PD studies are reported separately. DMXAA has antitumour activity at well-tolerated doses.

Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumours: a randomised trial. Australian and New Zealand Germ Cell Trial Group.

BACKGROUND: Most patients with metastatic germ-cell tumours are cured with chemotherapy. However, the optimum chemotherapy regimen is uncertain, and there is variation in international practice. We did a multicentre randomised trial to compare two standard chemotherapy regimens for men with good-prognosis germ-cell tumours. METHODS: Good prognosis was defined by modified Memorial Sloan-Kettering criteria. The first regimen (regimen A) was based on treatment recommendations from Indiana University and comprised three cycles of 20 mg/m2 cisplatin on days 1-5, 100 mg/m2 etoposide on days 1-5, and 30 kU bleomycin on days 1, 8, and 15, repeated every 21 days. The second regimen (regimen B) was based on the control regimen of a published randomised clinical trial and comprised four cycles of 100 mg/m2 cisplatin on day 1, 120 mg/m2 etoposide on days 1-3, and 30 kU bleomycin on day 1, repeated every 21 days. The primary outcome measure was overall survival. Analysis was by intention to treat. FINDINGS: 166 patients were randomised, 83 to each regimen. The trial was stopped when the second planned interim analysis met predefined stopping rules. The median follow-up was 33 months. Overall survival was substantially better with regimen A (three vs 13 deaths, hazard ratio 0.22 [95% CI 0.06-0.77], p=0.008). This difference was due to deaths from cancer (one vs nine), and not deaths from treatment (two vs two) and remained significant after adjustment for other prognostic factors (0.25 [0.07-0.88], p=0.03). INTERPRETATION: In men with good-prognosis germ-cell tumours, the regimen developed at Indiana University is superior to the alternative regimen studied in this trial. The lower total dose and dose-intensity of bleomycin and the lower dose-intensity of etoposide in regimen B could be responsible for the worse outcome.

Phase I study of the cytotoxic agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is a new DNA-intercalating drug with a dual mode of cytotoxic action that is thought to involve topoisomerases I and II. On the basis of novelty of action and promising preclinical activity against solid tumours in mice, DACA was selected for clinical trial under the auspices of the Cancer Research Campaign, United Kingdom. We report the phase I findings of a 3-h infusion regimen, repeated 3-weekly, of escalating doses through 18-1000 mg/m2 given to 31 patients with solid malignancies. A maximum tolerated dose (MTD) of 750 mg/m2 was identified, with 3 of 6 cycles being abandoned at 1000 mg/m2. Dose-limiting toxicity took the form of infusional arm pain, in some cases associated with facial discomfort, that was of rapid onset and subsided quickly on the cessation of infusion. The mechanism is unclear but is modulated to some extent by the rate of drug delivery, and it was unaffected in this study by concurrent anti-inflammatory or opiate medication. No host or tumour anti-proliferative activity was observed at these doses, and only minimal toxicity of any other kind was evident. Animal data suggest that the MTD achieved with this schedule may be sub-therapeutic in humans. It is therefore important that efforts be continued to explore methods of giving higher doses of DACA.

Late results of surveillance of clinical stage I nonseminoma germ cell testicular tumours: 17 years' experience in a national study in New Zealand.

OBJECTIVE: To re-evaluate a national prospective study in New Zealand after 17 years to define whether orchidectomy alone and surveillance for nonseminoma germ cell testicular tumour (NSGCTT) is a sound policy and matches the results achieved by other treatment protocols. PATIENTS AND METHODS: Between 1980 and 1997, 248 men with stage I NSGCTT, from six New Zealand centres, were managed by orchidectomy alone and surveillance, with treatment of relapses using combination chemotherapy. RESULTS: Seventy of the 248 patients (28%) relapsed; 42 of 92 (46%) with vascular and/or lymphatic invasion (VLI) in the primary tumour relapsed, whereas only 26 of 151 (17%) without this feature relapsed (P<0.001). VLI was the only identifiable risk factor for relapse in this series. Only one relapse occurred >28 months after orchidectomy. Despite poor compliance in some patients (12%) their survival was not prejudiced. Three patients died from disease despite chemotherapy at relapse. At 17 years and a median follow-up of 53 months, 242 of the 248 men are disease-free and the disease-specific survival rate is 98%. CONCLUSIONS: This study shows that orchidectomy alone and treatment of relapses produces excellent long-term results without the adverse effects associated with retroperitoneal node dissection or elective chemotherapy for high-risk cases.

Do men undergoing sterilizing cancer treatments have a fertile future?

This study was designed to assess the effect of cancer treatments on the natural and assisted reproductive potential of men. A cohort of men with cancer, in whom radiotherapy and/or chemotherapy was planned, were invited to participate. Twenty-two pre- and post-treatment semen samples were analysed. The reproductive potential of participants was assessed with respect to the current range of fertility treatment options available. Abnormal sperm concentrations were found in 27% of patients pre-treatment compared to 68% post-treatment following a mean latency of 20 months from treatment. Fifty-nine percent of patients experienced a clinically significant decrease in sperm, concentration following radiotherapy and/or chemotherapy; 23% developed azoospermia following treatment. Eighty-two percent of patients with testicular malignancy had oligo- or azoospermia post-treatment. Only one patient had a clinically significant reduction in the percentage of motile spermatozoa post-treatment. Cryopreservation of semen prior to treatment improved the fertility prospects of 55% of patients. Intracytoplasmic sperm injection (ICSI) enhanced the fertility prospects of a further 14%. In the absence of, or after depletion of, cryopreserved semen, ICSI could enhance the fertility prospects of 45% of patients. Fertilization has been achieved by ICSI using spermatozoa retrieved by testicular biopsy from an azoospermic testicular cancer survivor 8 years after chemotherapy. It was concluded that chemotherapy and/or radiotherapy may depress semen concentration to the extent of rendering a man infertile. The severity of the reduction in sperm concentration following treatment is unpredictable but likely to be most severe in those with testicular malignancy and those treated with radiotherapy or alkylating chemotherapy agents. Not all men are keen to undergo an appraisal of their post-treatment fertility potential, for reasons which are unclear. Improving awareness and education of patients concerning the effects of both cancer and cancer treatments on reproductive potential is essential. With the advent of ICSI, it is possible to offer a very reasonable chance of conception in all men with cancer who present for cryopreservation of semen prior to treatment in whom spermatozoa (even in very low concentrations) are present in the ejaculate.

Overall survival from breast cancer in women pregnant or lactating at or after diagnosis. Auckland Breast Cancer Study Group.

The effect of concurrent or subsequent pregnancy or lactation has been studied in women with breast cancer to determine if these variables influence prognosis. Information was collected from 382 women potentially capable of bearing children, aged less than 45 years, in the Auckland Breast Cancer Study Group data file, a consecutive series of women diagnosed with breast cancer from 1976 to 1985, with a median follow-up of 10.2 years. The prevalence of both pregnancy at diagnosis and lactation at diagnosis was 2.6%. The incidence of pregnancy subsequent to diagnosis was 3.9%. Women pregnant at the time of breast cancer diagnosis had significantly more advanced disease than non-pregnant patients, and there was a similar trend for women lactating at diagnosis. Overall survival in these women was poor compared with the non-pregnant and non-lactating groups; only 2 of 10 pregnant patients and 0 of 10 lactating patients survived more than 12 years. The adverse outcome for women lactating at diagnosis of their breast cancer persisted despite allowance for nodal status, tumour size and age. However, survival was similar between pregnant and non-pregnant patients when these variables were taken into account. No significant differences in survival were found between those women who had pregnancies subsequent to diagnosis of breast cancer and breast cancer patients who did not become pregnant.

Survival of women with node negative breast cancer in the Auckland region.

AIMS: To assess the effect of prognostic factors on overall survival from node negative breast cancer. METHODS: Information was collected on 1138 node negative breast cancer patients in the Auckland region, diagnosed between 1976 and 1985. Prognostic variables investigated included oestrogen (ER) and progesterone (PR) receptor status, tumour grade, tumour size, body mass index, lactation history and parity. The effects of these variables on overall survival were assessed separately in pre and postmenopausal groups. RESULTS: Over a median follow up time of 10.2 years, improved survival was seen in premenopausal women with PR+ status (p = 0.0007), ER+ status (p = 0.03), positive lactational history (p = 0.03) and low tumour grade (p = 0.04). In postmenopausal women, only ER+ status (p = 0.01) and PR+ status (p = 0.02) were associated with improved survival. Multivariate analysis suggested that positive PR status combined with tumour size provided the best prognostic discrimination in premenopausal women, whereas ER status was the dominant prognostic variable in postmenopausal patients. CONCLUSIONS: For premenopausal node negative women, progesterone receptor status, considered either alone, or together with tumour size, provides the best prognostic prediction of survival. By comparison, oestrogen receptor status is the most important predictor of overall survival in postmenopausal women.

Bilateral germ cell testicular tumors in New Zealand: experience in Auckland and Christchurch 1978-1994.

PURPOSE: The incidence of germ cell testicular tumors (GCTTs) is increasing world wide, and with effective treatment, the majority of patients are being cured. Thus, the clinical and social impact of a second testicular tumor is becoming more important. The frequency, cumulative risk, and relative risk of developing a second testicular cancer in New Zealand have been documented and compared with other reports. PATIENTS AND METHODS: The records of 741 men presenting with germ cell testicular cancer in Auckland and Christchurch between 1978 and 1994 have been reviewed, and these data have been compared with data from other published studies. Cumulative risk was assessed by the Kaplan-Meier method. RESULTS: Over 2% of the study population developed a second germ cell testicular cancer. The cumulative risk was 5.2% over 15 years. The relative risk of developing a contralateral testicular tumor is 27.5 times higher than age-matched New Zealand peers. These results match the only comparable report in the literature. Five of the 16 bilateral tumors (31%) were synchronous, which is a higher incidence than in any other reported series. There was no concordance of histology in the first and second tumors. Prior exposure to cisplatin combination chemotherapy did not prevent the development of a second tumor. CONCLUSION: Men who are cured of a germ cell testicular cancer have a greatly increased risk of developing a second testicular cancer. Such patients should be informed of this risk and ideally kept under long-term surveillance.

Adjuvant chemotherapy for non-metastatic osteosarcoma of the extremities in two New Zealand cancer centres.

BACKGROUND: Adjuvant chemotherapy significantly improves survival of patients with non-metastatic osteosarcoma but most of the data come from trials conducted in major international cancer centres. AIM: To review the efficacy and toxicity of an adjuvant chemotherapy regimen used in two regional cancer centres in New Zealand. METHODS: Retrospective review of patients treated for non-metastatic high-grade osteosarcoma of the extremities. The regimen (POMA) consists of high-dose-methotrexate 8 g/m2 and vincristine 1.5 mg/m2 (maximum 2 mg) on days 1 and 8 followed by folinic acid then doxorubicin 50 mg/m2 and cisplatin 100 mg/m2 on day 15. This cycle was repeated every 35 days. Following amputation patients received six cycles while in selected patients two cycles were planned prior to limb salvage surgery followed by a further four cycles. Actuarial survival was calculated using the Kaplan-Meier method. RESULTS: Twenty patients were treated with POMA between 1986 and 1993. Amputation was performed in 16 patients and limb-salvage surgery in four. Sixteen patients (80%) remain alive with no evidence of disease at a median follow-up of 40 months. Thirteen patients (65%) have been continuously disease-free. Actuarial survival at five years is 70%. Seven patients relapsed, six in lungs, of whom four underwent pulmonary metastasectomy; three of these remain free of disease 31, 35 and 40 months later. There was no local relapse. The toxicity of POMA is significant but tolerable. CONCLUSION: The results obtained at two regional cancer centres in New Zealand using POMA compare favourably to those achieved in clinical trials performed at major international cancer centres.

Late seminomatous relapse of a mixed germ cell tumor of the testis on intensive surveillance.

We report a case of a pure seminomatous relapse in the retroperitoneum 6 years after orchiectomy for an apparent stage I mixed germ cell tumor of the testis. The 4 cm. metastatic mass was not imaged on computerized tomography, tumor markers were negative and confounding symptoms made diagnosis difficult. The propensity for seminomatous tumors to relapse later than nonseminomatous tumors has profound implications for intensive surveillance programs for apparent stage I disease in mixed germ cell tumors. These programs often involve routine computerized tomography only for the first 2 years and rely on physical examination, simple radiology and serum tumor markers thereafter. Such programs may fail to detect pure seminomatous relapse and delay the onset of curative treatment.

Treatment of breast cancer in the Auckland region 1976-85.

AIM: A descriptive study of the treatment of breast cancer in Auckland between the years 1976 to 1985. METHODS: A database was constructed utilising information from all new breast cancer cases recorded in the Auckland region from September 1976 to September 1985. Details of treatment were obtained at the time of diagnosis and the database was updated every 9 months. Patient survival was measured and changes in the pattern of treatment were assessed. RESULTS: After a median follow up of 9 years 41% of patients were alive without evidence of breast cancer, 9% were alive with recurrence and 50% had died, 38% having died of breast cancer. Survival of node positive patients at 5 years of follow up who received adjuvant tamoxifen or adjuvant chemotherapy was 57 (SE 4)% and 63 (4)% respectively. The proportion of less than mastectomy surgical procedures increased over the study period, and local recurrence in these patients was reduced by postoperative radiotherapy. CONCLUSIONS: Between 1976 and 1985 there was an increasing rate of conservative surgery for breast cancer in Auckland. Overall survival of patients was comparable to that reported in international studies, with increasing use of adjuvant endocrine therapy but a decline in adjuvant chemotherapy over the duration of the study.

Phase II trial of procarbazine, vincristine and lomustine (POC) chemotherapy in metastatic cutaneous malignant melanoma.

40 patients with symptomatic metastatic melanoma were treated with procarbazine, vincristine and lomustine (POC). 4 patients had received chemotherapy previously. Responses were seen in 8 patients (20%), 4 of whom had a complete remission. All responding patients had some tumour shrinkage after one cycle. The median duration of response was 27 weeks, with 2 patients remaining in complete remission at 6 and 6.5 years. The median survival for the whole group was 22 weeks, whilst that of the responding patients was 35 weeks. Using conventional anti-emetics, the principal toxicities were nausea and vomiting, severe in 15% of cycles. Other nonhaematological toxicity was uncommon. Neutropenia (WHO grade 3 or 4) occurred in 11% of cycles and thrombocytopenia in 8%. The response rate of metastatic melanoma to POC chemotherapy was similar to other cytotoxic regimens though toxicity, other than nausea and vomiting, was minimal. The rapid response allows patients with unresponsive disease to be identified early, avoiding continuing toxicity.

Palliation of biliary obstruction in patients with advanced breast cancer using endoscopic stents.

Endoscopic insertion of a biliary endoprosthesis was successful in eight patients with extrahepatic biliary obstruction caused by breast cancer metastases. The serum bilirubin level was significantly reduced in seven patients and in four this was accompanied by marked symptomatic improvement. Endoprostheses required replacement after a median of 8 (range 3-127) weeks. Two patients responding to systemic anticancer therapy survived 27 and 43 months. Endoscopically placed stents offer effective palliation of extrahepatic biliary obstruction caused by metastatic breast cancer and long-term survival may be possible.

Results of the surveillance policy of stage I non-seminomatous germ cell testicular tumours.

A series of 115 patients with clinical Stage I non-seminomatous germ cell testicular tumours were managed with orchiectomy and close surveillance (median follow-up 36 months, range 3-119); 34 (29.5%) relapsed, 21 within 6 months, 29 within a year and the latest at 28 months. At relapse all patients were treated with platinum or analogue-based drug combinations, supplemented in 7 by retroperitoneal node dissection; 30 patients achieved durable remissions and 2 have had further relapses successfully treated. Two died; both had malignant teratoma intermediate with primary stage T1 and vascular and/or lymphatic invasion of primary tumour. At a median follow-up time of 36 months, the survivors (98.3%) demonstrate no evidence of disease, these results matching the outcome of other methods of management. Vascular and/or lymphatic invasion was associated with an enhanced relapse rate but specific histology, T stage of the primary and pre-orchiectomy serum alpha-fetoprotein status did not appear to favour relapse. The first sign of relapse was tumour marker alone in 10 patients, radiological features alone in 12, or both in 10 patients. However, in 2 cases the relapse was first detected clinically. Furthermore, pre-orchiectomy and relapse marker status did not correlate well. These points emphasise the importance of all aspects of follow-up, none of which can be safely omitted.

Ondansetron reduces chemotherapy induced nausea and vomiting refractory to standard antiemetics.

Ondansetron, a selective 5HT3 (serotonin) antagonist, was used in patients refractory to standard antiemetics. Seventy-five patients receiving chemotherapy without cisplatin were given ondansetron 4 mg IV and 4 mg orally immediately prior to chemotherapy, then 8 mg orally after six and 12 hours, followed by 8 mg orally eight hourly during days 2-5. Complete control of vomiting occurred in 52 patients (69%) on the first day and 45 patients (60%) on days 2-5. Sixty patients (80%) preferred ondansetron to their previous antiemetics. The efficacy of ondansetron was maintained over multiple chemotherapy cycles. Ondansetron was also given to 16 patients receiving cisplatin chemotherapy. They received 8 mg IV immediately prior to chemotherapy followed by an infusion of 1 mg/hr for 8 hr, with 8 mg orally at the end of the infusion and then 8 mg orally eight hourly during days 2-6. Some control of vomiting (less than = 5 vomits) was achieved in eight patients (50%) on the first day and in 14 patients (87%) on subsequent days. Eight patients (50%) preferred ondansetron to their previous antiemetics. Adverse events with ondansetron were frequent but mild, with constipation and headache being most common. Ondansetron is highly effective in patients refractory to standard antiemetics, especially after noncisplatin chemotherapy.

A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer.

One hundred forty-one patients with advanced breast cancer who had not received prior chemotherapy were randomly assigned to receive doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 every 3 weeks. These doses were selected to produce equivalent toxicities. All patients were assessed for toxicity, and 138 patients were assessable for response. After a median of five treatment cycles, 47% (32 of 68) of doxorubicin-treated patients achieved a partial or complete response. Response duration and survival were 10 and 12 months for doxorubicin and 8 and 10 months for epirubicin, respectively. Noncardiac toxicities were similar for both drugs. Of 41 patients receiving doxorubicin who had serial left ventricular ejection fraction assessments, seven sustained a fall of 10% or more, and one patient developed congestive cardiac failure at a cumulative doxorubicin dose of 489 mg/m2. Of 39 patients receiving epirubicin who had serial cardiac assessments, five sustained left ventricular ejection fraction falls of 10% or more and two patients developed congestive cardiac failure at cumulative doses of 178 mg/m2 and 833 mg/m2. These data indicate that an epirubicin dose of 90 mg/m2 produces toxicity equivalent to doxorubicin 60 mg/m2 but does not improve response rates, response duration, or survival in advanced breast cancer.