Peter M Wilkinson

Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer

Trastuzumab is an effective treatment for patients with metastatic breast cancer (MBC) that overexpresses HER-2. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. A retrospective chart review was conducted of 100 patients commencing trastuzumab for metastatic breast cancer from July 1999 to December 2002, at the Christie Hospital. Seven patients were excluded; five patients developed central nervous system metastases prior to starting trastuzumab, and inadequate data were available for two. Out of the remaining 93 patients, 23 (25%) have developed BM to date. In all, 46 patients have died, and of these 18 (39%) have been diagnosed with BM prior to death. Of the 23 patients developing BM, 18 (78%) were hormone receptor negative and 18 (78%) had visceral disease. Univariate analysis showed a significant association between the development of cerebral disease and both hormone receptor status and the presence of visceral disease. In conclusion, a high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases. HER-2-positive breast cancer may have a predilection for the brain, or trastuzumab therapy may change the disease pattern by prolonging survival. New strategies to address this problem require investigation in this group of patients.

Ovarian cancer antigen CA125: a prospective clinical assessment of its role as a tumour marker.

Serum CA 125, quantified by an immunoradiometric assay employing the monoclonal antibody 0C125 was found to be elevated in 48/58 (83%) of patients with established ovarian cancer. All histological types of carcinoma were antigen positive and there was a positive correlation between the frequency and level of serum CA125 and body burden of tumour. Twenty patients undergoing chemotherapy had serial CA125 estimations following a prospective protocol. Variation in CA125 level reflected disease progression or regression in 21/23 instances. Three of 9 patients tested showed an acute elevation of CA125 in the first week following chemotherapy and this effect predicted a good response to treatment. The natural half-life of CA125 in serum was estimated at approximately 4.8 days, sufficiently short to allow changes in tumour volume to be rapidly reflected by a change in circulating antigen level. Although none of 15 patients with non-Hodgkin lymphoma demonstrated antigen levels outside the normal range, 11/27 patients with non-ovarian adenocarcinoma showed elevated CA125 levels, a specificity of 58% for this latter group. The value of CA125 in the management of ovarian malignancy is discussed.

Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: Results of a double-blind, randomised trial

BACKGROUND Early clinical trials have suggested that glutathione (GSH) offers protection from the toxic effects of cisplatin. PATIENTS AND METHODS One hundred fifty-one patients with ovarian cancer (stage I-IV) were evaluated in a clinical trial of cisplatin (CDDP) +/- glutathione (GSH). The objective was to determine whether GSH would enhance the feasibility of giving six cycles of CDDP at 100 mg/m2 without dose reduction due to toxicity. RESULTS When considering the proportion of patients receiving six courses of CDDP at any dose, GSH produced a significant advantage over control--58% versus 39%, (P = 0.04). For these patients there was a significant difference between the reduction in creatinine clearance for GSH treated patients compared with control--74% versus 62% (P = 0.006). Quality of life scores demonstrated that for patients receiving GSH there was a statistically significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath and difficulty concentrating. As an indication of overall activity, these patients were statistically significantly more able to undertake housekeeping and shopping. Clinically assessed response to treatment demonstrated a trend towards a better outcome in the GSH group (73% versus 62%) but this was not statistically significant (P = 0.25). CONCLUSIONS The results demonstrate that adding GSH to CDDP allows more cycles of CDDP treatment to be administered because less toxicity is observed and the patients quality of life is improved.

Prognostic factors in patients progressing after cisplatin based chemotherapy for malignant non-seminomatous germ cell tumours

SummaryThe aim of this study was to define prognostic parameters for survival in patients with malignant germ cell tumours progressing after platinum-based induction chemotherapy with or without surgery. A total of 164 progressing patients (testicular: 83%, extragonadal: 17%) were identified out of 795 patients treated with platinum-based induction chemotherapy for metastatic germ cell malignancy with or without surgery. ‘Progressive disease’ included patients who had progressed after a previous partial or complete remission as well as patients who failed primary therapy. Salvage chemotherapy consisted of ‘conventional’ platinum-based chemotherapy. Prognostic factors for survival were assessed by uni- and multivariate analyses. The resulting prognostic model was validated in an independent data set of 66 similar patients. For all 164 patients the median time from start of induction chemotherapy to progression was 10 months (range: 0–99). Thirty-eight (23%) patients relapsed after 2 years. The 5-year survival rate for all progressing patients was 30% (95% confidence interval 23–38%). In the univariate analysis the following factors most importantly predicted a poor prognosis: progression-free interval < 2 years: initial poor prognosis category (MRC criteria), < CR to induction chemotherapy, initial treatment early in the 1980s and treatment given at a ‘small’ centre. Three prognostic factors remained in the multivariate analysis: progression-free interval, response to induction treatment and the level of serum human chronic gonadotrophin (hCG) and alpha fetoprotein (AFP) at relapse. One hundred and twenty-four patients could be classified on the basis of these characteristics, Those patients with progression-free interval < 2 years, < CR to induction chemotherapy and high markers at relapse (AFP >100 kU l–1 or hCG >100 IU l–1) formed a poor prognosis group of 30 patients, none of whom survived after 3 years. Patients with at most two of these three risk factors formed a good prognosis group of 94 patients (76%) with a 47% (37–56%) 5-year survival. Thirty-eight patients from the good prognosis group with a progression-free interval of >2 years had a 2-year survival of 74% (60–88%) and 5-year survival of 61%. These prognostic groups were validated in the independent data set, in which 5-year survival rates in the good and poor risk groups were 51% and 0% respectively. One-third of patients progressing during or after platinum-based induction chemotherapy for metastatic germ cell malignancy may be cured by repeated ‘conventional’ platinum-based chemotherapy. Good prognosis parameters are: progression-free interval of > 2 years, CR to induction treatment and normal or low serum markers at relapse (hCG < 100 IU l–1 and AFP < 100 kU l–1). The results of high-dose salvage chemotherapy should be interpreted on the background of these prognostic factors.

Carcinosarcoma of the ovary

We report our experience in the management of patients with carcinosarcoma of the ovary, a rare but aggressive variant of ovarian cancer. Forty patients were treated at a single centre, which is the largest reported series. The median age at diagnosis was 65 years (range 45–86) and the median Karnofsky performance (KP) status was 70. Thirty-two patients (80%) presented with FIGO stage III or IV disease. Twenty-four had heterologous and 14 homologous carcinosarcoma on review of histopathology, but there was no significant difference in survival between these groups (P=0.28). Twenty-seven of the 40 patients had bulk residual disease present after surgery and this was associated with a worse prognosis (P=0.045). Chemotherapy was given to 32 patients (80%) of whom 26 (81%) received platinum-based regimens. Of these 32 patients, three (9.4%) achieved a complete response (CR), 10 (31%) a partial response (PR), five (16%) had stable disease, 10 (31%) had progressive disease and four were not assessable. Of the 19 patients who had a CR, PR or stable disease after chemotherapy or were unevaluable (stage Ic), the median survival was 29.6 months. Currently, seven patients are still alive although one has cancer. The overall censored median survival was 8.7 months after a median follow-up of 34 months, and the 1- and 5-year survival were 40 and 7.5%, respectively.

The level of haemoglobin in anaemic cancer patients correlates positively with quality of life

The aim of this study was to assess the relationship between haemoglobin level and quality-of-life in anaemic cancer patients. Patients, diagnosed with one of four cancers, were recruited if their haemoglobin level was <12 g dl−1 (female) or <13 g dl−1 (male). The condition-specific Functional Assessment of Cancer Therapy – Anaemia and the generic SF-36 were used to assess quality-of-life. Thirty-six per cent of the 179 recruited patients had breast cancer, 28% ovarian cancer, 25% lung cancer, and 11% multiple myeloma. Their mean (s.d.) haemoglobin level was 10.66 (1.04) g dl−1. Partial correlations controlling for the potentially confounding effects of age, gender, and time since diagnosis found significant positive relationships between haemoglobin and all domains of the Functional Assessment of Cancer Therapy – Anaemia, and with all but two of the SF-36 domains. On linear regression controlling for the same factors, each unit haemoglobin rise equalled an average 8.19 Functional Assessment of Cancer Therapy – Anaemia, and an average 6.88 Functional Assessment of Cancer Therapy–Fatigue, increase. Haemoglobin accounted for a similar amount of variability (8%) in SF-36 scores. In conclusion, quality-of-life has been found to be significantly positively related to haemoglobin level in anaemic cancer patients. This suggests that normalisation of haemoglobin in cancer patients is likely to increase their quality-of-life. The greater sensitivity of the condition-specific Functional Assessment of Cancer Therapy – Anaemia compared with the generic SF-36 suggests that the Functional Assessment of Cancer Therapy – Anaemia can be used alone to assess quality-of life in this patient group.

Survival benefit from high-dose therapy with autologous blood progenitor-cell transplantation in poor-prognosis non-Hodgkin's lymphoma.

PURPOSE To compare standard and intensive treatment strategies for patients with high-grade non-Hodgkins lymphoma (NHL) of poor prognosis, defined by the international prognostic index. PATIENTS AND METHODS Thirty-four patients received standard chemotherapy with 11 weeks of doxorubicin, cyclophosphamide, vincristine, bleomycin, etoposide, prednisolone, and methotrexate (VAPEC-B), and 33 received intensive treatment with 7 weeks of VAPEC-B, three cycles of ifosfamide/cytarabine, then high-dose busulfan/cyclophosphamide followed by autologous blood progenitor-cell (BPC) transplantation. RESULTS Twelve of 33 patients in the intensive group and 26 of 34 patients in the standard group have died. The median follow-up time for the surviving patients is 31 months and 68 months, respectively. At 2 years, the actuarial estimates of event-free survival (EFS) were 61% versus 35% (P = .01) and of overall survival, 64% versus 35% (P = .01). A significant reduction in the event rate (progression or death) was maintained after adjustment for age and the number of risk factors. The estimated risk of experiencing an event was 0.37 (95% confidence interval [CI], 0.16 to 0.84) in the intensive group compared with the standard group. CONCLUSION Patients with poor prognostic features who received high-dose therapy and BPC rescue had a superior EFS. The survival differences observed in this study justify a formal comparison in a randomized study.

A Medical Research Council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma

The UK Medical Research Council conducted this trial of carboplatin chemotherapy in advanced seminoma to compare single agent carboplatin with a standard combination of etoposide with cisplatin. The use of single agent carboplatin was expected to be associated with reduced toxicity. A total of 130 patients with advanced seminoma were randomly assigned to treatment with either single agent carboplatin (C) at a dose of 400 mg/m2 to be corrected for glomerular filtration rate outside the range 81–120 ml min–1 and to be administered on day 1 of a 21 day cycle to a total of 4 cycles or to etoposide + platinum (EP). The trial was designed as an equivalence study aiming to exclude a reduction in the 3-year progression-free survival in patients allocated to carboplatin of between 10 and 15%, requiring initially a target accrual of 250 patients (90% power significance level 5% (one-sided)). The trial closed after 130 patients had been randomized following recommendation by an independent data monitoring committee. At a median follow-up time of 4.5 years, 81% of patients had been followed up for at least 3 years and 19 patients have died. The estimated PFS rate (95% Confidence Intervals (CI)) at 3 years was 71% (60–82%) in patients allocated C and 81% (71–90%) in those allocated EP; the 95% CI for the difference in 3 year PFS was –6% to +19%. The hazard ratio of 0.64 (95% CI 0.32–1.28) favoured EP but the difference was not statistically significant (log rank chi-squared = 1.59 P = 0.21). The 3-year survival rate was 84% (75–92%) in those allocated C, and 89% (81–96%) in those allocated EP. The hazard ratio for survival was 0.85 with 95% CI, 0.35–2.10, log rank chi-squared = 0.12, P = 0.73. The trial has not demonstrated statistically significant differences in the major survival endpoints comparing single agent carboplatin with a combination of etoposide + cisplatin. This cannot be taken as an indication of equivalence since the limited size of this trial rendered it unable to exclude a 19% lower progression-free survival and survival in those treated with single agent carboplatin which would be important clinically. Standard initial chemotherapy for advanced seminoma should be based on cisplatin combinations and the role of carboplatin awaits the outcome of further studies.

A randomised clinical trial to contrast radiotherapy with radiotherapy and methotrexate given synchronously in head and neck cancer.

Three hundred and thirteen patients with squamous cell cancer of the head and neck were entered in a randomised clinical trial to determine whether the addition of methotrexate during the course of irradiation improved the rate of primary control and subsequent survival. The overall primary control (P = 0.016) and survival (P = 0.075) for the patients receiving methotrexate was better than the patients treated by radiotherapy alone. The improvement in primary control (P = 0.0019) and survival (P = 0.0089) in patients with oropharyngeal cancers who had methotrexate in addition to radiotherapy is statistically significant. The treatment was well tolerated and there has been no increase of late morbidity.

Prolongation of ifosfamide elimination half-life in obese patients due to altered drug distribution

SummaryThe pharmacokinetics of intravenous ifosfamide were determined in 16 patients with carcinoma of the bronchus. In all 25% (4) of these patients were obese (i.e. >20% over their ideal body weight). The terminal elimination half-life (t1/2 β) was found to be higher in the obese group than in the control group (6.36 h, range 5.77–7.45 h) vs 4.95 h, range 1.82–6.48 h( (P< 0.05). This prolongation of the elimination half-life was due to an increased volume of distribution (Vdβ) in the obese group (42.81 l, range 35.49–51.90 l) vs 33.70 l range (17.76–50.62 l) (P<0.05). There was therefore no significant difference in total plasma clearance between the obese and normal groups. No correlation of ifosfamide plasma half-life was observed with total body weight (TBW) or ideal body weight (IBW). However, a significant positive correlation was observed between the percentage of IBW and plasma half-life. A strong positive correlation was observed between IBW and the plasma clearance of ifosfamide. The Vdβ correlated with both TBW and the percentage of IBW, but not with IBW itself. When Vdβ was normalised for IBW, there was a strong positive correlation with the percentage of IBW, suggesting that ifosfamide distribution into the TBW is higher than that into the IBW.