OVPSYCH2: A randomized controlled trial of psychological support versus standard of care following chemotherapy for ovarian cancer.

BACKGROUND: Fear of disease progression (FOP) is a rational concern for women with Ovarian Cancer (OC) and depression is also common. To date there have been no randomized trials assessing the impact of psychological intervention on depression and FOP in this patient group. PATIENTS AND METHODS: Patients with primary or recurrent OC who had recently completed chemotherapy were eligible if they scored between 5 and 19 on the PHQ-9 depression and were randomized 1:1 to Intervention (3 standardized CBT-based sessions in the 6-12 weeks post-chemotherapy) or Control (standard of care). PHQ-9, FOP-Q-SF, EORTC QLQ C30 and OV28 questionnaires were then completed every 3 months for up to 2 years. The primary endpoint was change in PHQ-9 at 3 months. Secondary endpoints were change in other scores at 3 months and all scores at later timepoints. RESULTS: 182 patients registered; 107 were randomized; 54 to Intervention and 53 to Control; mean age 59 years; 75 (70%) had completed chemotherapy for primary and 32 (30%) for relapsed OC and 67 patients completed both baseline and 3-month questionnaires. Improvement in PHQ-9 was observed for patients in both study arms at three months compared to baseline but there was no significant difference in change between Intervention and Control. A significant improvement on FOP-Q-SF scores was seen in the Intervention arm, whereas for those in the Control arm FOP-Q-SF scores deteriorated at 3 months (intervention effect = -4.4 (-7.57, -1.22), p-value = 0.008). CONCLUSIONS: CBT-based psychological support provided after chemotherapy did not significantly alter the spontaneously improving trajectory of depression scores at three months but caused a significant improvement in FOP. Our findings call for the routine implementation of FOP support for ovarian cancer patients.

How many cisplatin administration protocols does your department use?

The introduction, 30 years ago, of the co-administration of appropriate hydration and ensuring a diuresis occurs during the administration of cisplatin was important in its development, allowing clinically significant doses to be given with acceptable rates of toxicity. The clinical usage of cisplatin has increased and hydration protocols have been amended to increase patient comfort and reduce resource utilization. We suspected that this had led to unnecessary variations in practice both in clinical trials and subsequently in the clinic. Therefore, we reviewed practice in the Edinburgh Cancer Centre and discovered that 25 different hydration protocols were in use, with wide variation in dilution of cisplatin, total fluid administered, use of electrolyte (potassium and magnesium) supplementation and diuretics. These differences are a reflection of adoption of variations in hydration regimes published in pivotal clinical trials. A review of the available evidence relating to cisplatin associated hydration regimens was performed and recommendations will be made for the future design of evidence-based protocols.

Improving outcomes for limited stage small cell lung cancer patients in Scotland with concomitant chemoradiation.

AIMS: To determine whether the introduction of early concomitant chemoradiotherapy for patients with limited stage small cell lung cancer (LS-SCLC) has resulted in acceptable outcomes and toxicity in a UK practice. MATERIALS AND METHODS: The case records of all patients with LS-SCLC treated with chemoradiotherapy from July 2001 to 2004 were reviewed, and subjected to descriptive statistics and proportional hazards analysis. RESULTS: Concomitant chemoradiotherapy was delivered to 30 patients and sequential chemoradiotherapy was delivered to 36 patients. The former patients tended to be younger (mean 58.9 vs 64.1 years, P=0.01); the latter patients tended to have bulkier disease. There was no difference in performance status, but cisplatin was given more often in the former group (90% vs 44%, P<0.0001). Grade 3 acute oesophagitis occurred in less than 10% of either group and there were no cases of grade 3 or greater pneumonitis. Two-year actuarial survival for the concomitant group was 53% (95% confidence interval 36-71%) and 36% (95% confidence interval 20-52%) for the sequential group (P=0.018). Proportional hazards analysis showed an increased hazard of death with increasing performance status and age, sequential therapy and the use of cisplatin with sequential therapy. CONCLUSION: Concomitant chemoradiotherapy can be safely given in a UK population with outcomes comparable with those reported in North American series.

A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer.

Experimental evidence from several sources has identified a link between mismatch repair deficiency and cytotoxic drug resistance. Selection for cisplatin resistance in the human ovarian cancer cell line A2780, results in loss of expression of the mismatch repair protein hMLH1 in most (90%) of the resultant cisplatin-resistant cell lines. Here we demonstrate that the cisplatin sensitive parental cell line displays methylation of the promoter of only one hMLH1 allele, but that the resistant cell lines all exhibit hyper-methylation of the promoters of both hMLH1 alleles. Full methylation of all sites tested was found to be invariably associated with loss of hMLH1 expression, whereas a partial increase in methylation appears compatible with either loss or maintenance of expression. In addition treatment of two of the resistant cell lines with 5-azacytidine, a known inhibitor of methylation, results in re-expression of hMLH1. Clonogenic assays demonstrate that the 5-azacytidine treated cells show increased sensitivity to cisplatin. Furthermore, 12.5% (3/ 24) of ovarian tumours show hypermethylation of the hMLH1 promoter. Expression of hMLH1 is absent in the tumours that are hypermethylated, while all the unmethylated tumours still express the protein. This analysis suggests that methylation of the hMLH1 promoter may be a common mechanism for loss of hMLH1 expression, and possibly for cisplatin-resistance, in ovarian cancer.

Reduced MLH1 expression in breast tumors after primary chemotherapy predicts disease-free survival.

PURPOSE: Loss of function or expression of the mismatch repair protein MLH1 and the tumor suppressor protein p53 have been implicated in acquired resistance to anticancer drugs. We have compared the expression of MLH1 and p53 in tumors from women with clinically node-positive breast cancer before and after primary (neoadjuvant) chemotherapy. Further, we have assessed the value of these markers as predictors of response to therapy by correlation with disease-free survival. PATIENTS AND METHODS: Immunohistochemistry scores of MLH1 and p53 expression were made on 36 tru-cut prechemotherapy biopsies and 29 paired postchemotherapy tumor samples. The significance of the change in scores and their correlation with disease-free survival were evaluated by the Wilcoxon signed rank sum test and Cox proportional hazards regression analysis, respectively. RESULTS: Primary chemotherapy results in a significant reduction in the percent of cells expressing MLH1 (P =.010). This change in MLH1 expression after chemotherapy is strongly associated with poor disease-free survival (P =.0025). Expression of p53 was not significantly altered by chemotherapy. Neither MLH1 nor p53 expression before chemotherapy predicted disease-free survival or tumor response to chemotherapy. Low MLH1 expression after chemotherapy was an independent predictor of poor disease-free survival on multivariate Cox analysis when considered with other clinicopathologic prognostic factors. CONCLUSION: Tumor cells that have reduced MLH1 expression seem to have a survival advantage during combined chemotherapy of locally advanced breast cancers, which supports the hypothesis that loss of MLH1 has a role in drug resistance. MLH1 expression after chemotherapy is an independent predictive factor for poor disease-free survival and may, therefore, define a group of patients with drug-resistant breast cancer.

A cautionary lesson on the use of targeted methods for EGFR mutation analysis: a case report.

Epidermal growth factor receptor (EGFR) mutation analysis is recommended for lung cancer patients prior to the prescription of first-line EGFR tyrosine kinase inhibitors in order to predict response to treatment. There are many methods available to identify mutations in the EGFR gene; a large number of clinical laboratories use the therascreen EGFR RGQ PCR kit (Qiagen). We report a case where this kit detected an exon 19 deletion, predicting sensitivity to tyrosine kinase inhibitors (TKIs), which on further analysis was found to be a 2 bp indel (c.2239_2240delinsCC, p.(Leu747Pro)). Two of four published cases with this mutation were found to be associated with resistance to EGFR TKI. The sample was also tested using two other commercial kits, one of which indicated a deletion. This is a rare mutation making the erroneous detection of a deletion unlikely; however, it is important that clinical laboratories are aware of the potential failings of two commercial kits for EGFR mutation analysis.

Three years of erlotinib in routine practice for non-small cell lung cancer in South East Scotland.

We present a review of 111 patients who were treated over an initial 3-year period with erlotinib. The median treatment time was 68 days and 59% of patients had stopped treatment within the first 3 months. However, 20 patients were on erlotinib for more than 12 months. Performance status and smoking history were the significant prognostic factors. The overall 3-year survival in patients who had never smoked was 26%.

A feasibility study of roquinimex (Linomide) and alpha interferon in patients with advanced malignant melanoma or renal carcinoma.

Thirty-one patients with advanced renal carcinoma or malignant melanoma were treated in the first feasibility study of alpha-interferon (Roferon) and the new oral immunomodulating agent, Linomide. Linomide 5 mg or 10 mg p.o. daily was given for 2 weeks; alpha-interferon was then added at 3 MU s.c. three times weekly, escalating in each patient by 3 MU per week, if tolerable, up to 12 MJ. The combination was poorly tolerated with nausea, vomiting, somnolence and myalgia commonly reported. Adverse events accounted for treatment withdrawal in ten patients and contributed to withdrawal in four other patients. Treatment with Linomide alone in the first 2 weeks led to a significant increase in white blood cells, neutrophils and platelets. When alpha-interferon was added, the platelet count decreased significantly over the following 6 weeks. Nineteen patients had white cell phenotype and function measured. After 2 weeks of 5 mg Linomide, a transient but significant decrease in the absolute number of activated T-helper cells (CD4+DR+) was observed. No changes in natural killer (NK) cell number or activity were observed. Twenty-two patients were evaluable for response. One with metastatic renal cell carcinoma had a complete response and six had stable disease. This study does not support the use of the combination because significant toxicity was seen without the anticipated immunological benefits.

Bolus/infusional 5-fluorouracil and folinic acid. A report on two prospective, consecutive phase II studies with 5-fluorouracil dose escalation.

We have used a relatively new trial methodology, the group sequential design, to prospectively evaluate two dose levels of bolus/infusional 5-fluorouracil (5-FU) and folinic acid in 192 consecutive-patients with advanced colorectal carcinoma. On day 1, all patients received 200 mg m(-2) of folinic acid infusion over 2 h. Cohort A (n = 102 patients) received 500 mg m(-2) 5-FU by i.v. 15-min infusion followed by an infusion of 500 mg m(-2) 5-FU over 22 h. Treatment was repeated on day 2 and further cycles given 2-weekly. After sequential analysis excluded a response rate of over 40%, cohort B (n = 90 patients) received an increased dose of 600 mg m(-2) 5-FU bolus and infusion. Patients had received no prior 5-FU therapy and the two cohorts had similar demographic features. In 179 evaluable patients, the overall response rate was 18% (95% CI 12-24%) with CR of 6% and PR of 12%, with no difference between the two cohorts. Overall median survival was 34 weeks (95% CI 30-39) with no significant difference between cohorts (median survival 32 and 37 weeks in cohort A and B respectively; P = 0.27). On multivariate analysis, poor performance status, elevated initial WBC and alkaline phosphatase and low serum albumin were associated with reduced survival (P < 0.05), and initial raised WBC showed an association with reduced likelihood of response (P = 0.002). Overall toxicity was low with CTC grade 3 mucositis, diarrhoea, nausea or vomiting in < or = 6% of patients and no treatment-related deaths. Significant (grade 3 or above) leucopenia was more common in cohort B than in cohort A (9% and 1% respectively); there were more dose reductions, and the median administered dose intensity was lower in cohort B than in cohort A (89% and 97% respectively; P = 0.006). In this group of relatively unselected patients, we have confirmed a relatively low objective response rate and median survival of 7.8 months with this regimen. There was no significant difference in outcome between the two dose levels but the higher dose of 5-FU was associated with more dose reductions and greater toxicity.