Philip Beale

A phase 3 trial of bevacizumab in ovarian cancer.

BACKGROUND Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. METHODS We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival. RESULTS A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months. CONCLUSIONS Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).

Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies.

SummaryTemozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug’s safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100–250 mg m–2 was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m–2 day–1. Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean Tmax ~1 h) and eliminated (mean t1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m–2 day–1 for 5 days, every 28 days, is recommended for phase II studies.

Mini-review: discovery and development of platinum complexes designed to circumvent cisplatin resistance

The discovery and development of new platinum-containing anticancer drugs have represented an integral part of anticancer drug development at the Institute of Cancer Research, Sutton, over almost 20 years. As part of a collaboration with chemists at Johnson Matthey, later AnorMED, four major new classes of platinum drug have been discovered, three of which have entered clinical trial. Earlier studies led to the clinical development of the less toxic analogue carboplatin and JM216, the first orally administerable platinum drug. In recent years, the focus has been on two lead complexes designed to overcome the major mechanisms of tumour resistance to cisplatin: JM335 (trans-ammine (cyclohexylaminedichlorodihydroxo) platinum(IV)), an active trans platinum complex; and ZD0473 (cis-amminedichloro(2-methylpyridine) platinum(II)), a sterically hindered complex shown to be less reactive towards thiol-containing molecules than cisplatin. JM335 shows some circumvention of acquired cisplatin resistance in vitro and exhibits unique cellular pharmacological properties in comparison to cisplatin or its cis-isomer in terms gene-specific repair of adducts on DNA and the rate of induction of apoptosis. ZD0473 is now in phase I clinical trial. Myelosuppression is the dose-limiting toxicity at a dose of 130 mg/m2 given i.v. every 3 weeks and there has been evidence of antitumour activity. ZD0473-resistant human ovarian carcinoma cell lines have been established in vitro. Some mechanisms of resistance common to those described for cisplatin (decreased drug uptake, increased glutathione) have been observed plus, in one cell line, increased BCL2 levels and loss of the DNA mismatch repair protein MLH1.

Impact of Medical Qigong on quality of life, fatigue, mood and inflammation in cancer patients: a randomized controlled trial

Background: Substantial numbers of cancer patients use complementary medicine therapies, even without a supportive evidence base. This study aimed to evaluate in a randomized controlled trial, the use of Medical Qigong (MQ) compared with usual care to improve the quality of life (QOL) of cancer patients. Patients and methods: One hundred and sixty-two patients with a range of cancers were recruited. QOL and fatigue were measured by Functional Assessment of Cancer Therapy—General and Functional Assessment of Cancer Therapy—Fatigue, respectively, and mood status by Profile of Mood State. The inflammatory marker serum C-reactive protein (CRP) was monitored serially. Results: Regression analysis indicated that the MQ group significantly improved overall QOL (t144 = −5.761, P < 0.001), fatigue (t153 = −5.621, P < 0.001), mood disturbance (t122 =2.346, P = 0.021) and inflammation (CRP) (t99 = 2.042, P < 0.044) compared with usual care after controlling for baseline variables. Conclusions: This study indicates that MQ can improve cancer patients’ overall QOL and mood status and reduce specific side-effects of treatment. It may also produce physical benefits in the long term through reduced inflammation.

Effect of medical Qigong on cognitive function, quality of life, and a biomarker of inflammation in cancer patients: A randomized controlled trial

PurposeCancer patients often experience diminished cognitive function (CF) and quality of life (QOL) due to the side effects of treatment and the disease symptoms. This study evaluates the effects of medical Qigong (MQ; combination of gentle exercise and meditation) on CF, QOL, and inflammation in cancer patients.MethodsEighty-one cancer patients recruited between October 2007 and May 2008 were randomly assigned to two groups: a control group (n = 44) who received the usual health care and an intervention group (n = 37) who participated in a 10-week MQ program. Self-reported CF was measured by the European Organization for Research and Treatment of Cancer (EORTC-CF) and the Functional Assessment of Cancer Therapy—Cognitive (FACT-Cog). The Functional Assessment of Cancer Therapy—General (FACT-G) was used to measure QOL. C-reactive protein (CRP) was assessed as a biomarker of inflammation.ResultsThe MQ group self-reported significantly improved CF (mean difference (MD) = 7.78, t51 = −2.532, p = 0.014) in the EORTC-CF and all the FACT-Cog subscales [perceived cognitive impairment (MD = 4.70, t43 = −2.254, p = 0.029), impact of perceived cognitive impairment on QOL (MD = 1.64, t45 = −2.377, p = 0.024), and perceived cognitive abilities (MD = 3.61, t45 = −2.229, p = 0.031)] compared to controls. The MQ group also reported significantly improved QOL (MD = 12.66, t45 = −5.715, p < 0.001) and had reduced CRP levels (MD = −0.72, t45 = 2.092, p = 0.042) compared to controls.ConclusionsResults suggest that MQ benefits cancer patients’ self-reported CF, QOL, and inflammation. A larger randomized controlled trial including an objective assessment of CF is planned.

Clinical trials in recurrent ovarian cancer.

The 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup was held in Vancouver, Canada, in June 2010. Representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. Group C, 1 of the 3 discussion groups, examined recurrent ovarian cancer, and we report the consensus reached regarding 4 questions. These included the following: (1) What is the role of cytoreductive surgery for recurrent ovarian cancer? (2) How do we define distinct patient populations in need of specific therapeutic approaches? (3) Should end points for trials with recurrent disease vary from those of first-line trials? (4) Is CA-125 progression alone sufficient for entry/eligibility into clinical trials?

Evaluation of nutritional and inflammatory status of advanced colorectal cancer patients and its correlation with survival.

Abstract: The purpose of this study was to evaluate novel inflammatory and nutritional prognostic factors in patients with advanced colorectal cancer (ACRC). All ACRC patients attending the clinic for palliative treatment were eligible for study. Demographics, including performance status (PS), C-reactive protein (CRP), albumin (Alb), Glasgow prognostic score (GPS), weight, weight history, body mass index (BMI), and nutritional status using the patient-generated subjective global assessment (PGSGA), were collected and correlated with survival. At a median follow-up of 29.8 mo, with a minimum follow-up of 15.7 mo, the median survival was 9.9 mo (0.8–21.8 mo). Fifteen (29%) patients were newly diagnosed (stage IV colorectal cancer), and 36 (71%) had received prior chemotherapy. Although the median BMI was 27 kg/m2 (range = 17–41 kg/m2), 28 of 50 (56%) were nutritionally at risk. In fact, 19 patients (38%) were critically in need of nutrition intervention (PGSGA score of ≥9). Thirty-three of 48 patients (69%) had an elevated CRP (>10 mg/l with a median of 21.1 mg/L), and 7 patients (15%) had both a CRP of >10 mg/l and hypoalbuminemia (< 35 g/l). A significant positive correlation was found between PGSGA score and CRP (P = 0.003; r = 0.430). Using univariate analysis, significantly worse survival was found for patients with poorer PS (P = 0.001), high GPS (P = 0.04), low Alb (P = 0.017), elevated serum alkaline phosphatase (SAP; P = 0.018), PGSGA score of > 9 (P = 0.001), and PGSGA group B/C (P = 0.02). Using the Cox proportional hazard model for multivariate survival analysis, type of treatment (hazard ratio, HR = 1.48; 95% confidence interval, CI = 1.11–1.79; P = 0.005), PS (HR = 2.37; 95% CI = 1.11–5.09; P = 0.026), GPS (HR = 2.27; 95% CI = 1.09–4.73; P = 0.028), and SAP (HR = 0.44; 95% CI = 0.18–1.07; P =0.069) remained significant predictors of survival. These preliminary data suggest that the type of treatment, PS, GPS, and SAP are important predictors of survival in ACRC.

BCL-2 family protein expression and platinum drug resistance in ovarian carcinoma

The expression of the BCL-2 family proteins, BCL-2, BAX, BCLXL and BAK have been determined in a panel of 12 human ovarian carcinoma cell lines encompassing a wide range in sensitivity to cisplatin. Whereas BAX, BCLXL and BAK levels did not correlate with sensitivity, there was a statistically significant inverse correlation (r = –0.81;P = 0.002) between growth inhibition by cisplatin and BCL-2 levels. In sublines possessing acquired resistance to various platinum-based drugs or across a panel of human ovarian carcinoma xenografts, there was no consistent pattern of BCL-2 expression. Two relatively sensitive lines (A2780 and CH1) have been stably transfected with bcl-2 and bclXL respectively and two relatively resistant lines (A2780cisR and SKOV-3) stably transfected with bax. Overexpression of BCL-2 in A2780 cells led to resistance to cisplatin compared to the vector control when assayed at 48 h post-drug incubation but a significant increase in sensitivity at 96 h. Relative rates of apoptosis at 48- and 96-h post-cisplatin exposure mirrored the growth inhibition. There was no significant difference in sensitivity of the pair of lines by clonogenic assay. No significant changes in chemosensitivity to a variety of DNA-damaging or tubulin-interactive agents were observed in the remaining transfected lines. Taken together, these results suggest that, in human ovarian carcinoma cells, high BCL-2 levels (either naturally occurring or through gene transfection) confers a trend towards sensitivity not resistance to platinum drugs.

Nutritional Assessment in Cancer: Comparing the Mini-Nutritional Assessment (MNA) With the Scored Patient-Generated Subjective Global Assessment (PGSGA)

Abstract: The evaluation of nutritional status in cancer patients is often neglected in spite of the fact that poor nutritional status may adversely affect prognosis and treatment tolerance. In day-to-day oncology practice, a sensitive but simply applied nutritional assessment tool is needed to identify at-risk patients. Several tools exist; however, none has been universally accepted. The aim of this study was to compare two potential tools, the Mini-Nutritional Assessment (MNA) and the scored Patient Generated Subjective Global Assessment (PGSGA). The MNA is more simply applied and does not require a trained dietitian. The PGSGA has been previously validated in cancer patients. One hundred fifty-seven newly diagnosed cancer patients were assessed using both tools. Of these, 126 were reassessed at 4-6 wk, and 104 were reassessed at Weeks 8-12 after initial assessment. A significant negative correlation was found between the tools at all three time periods (at baseline r = -0.76; P < 0.001). Taking the PGSGA as the most accepted nutritional assessment tool, at baseline the MNA demonstrated a sensitivity of 97% and specificity of 54%. At 4-6 wk MNA sensitivity was 79% and specificity was 69%. At 8-12 wk MNA sensitivity was 93% and specificity was 82%. When comparing the tools in elderly patients alone (>65 yr), similar results were obtained. Both tools were able to correctly classify patients as malnourished, although the MNA lacks specificity. Therefore, the PGSGA should be the tool of choice for nutritional assessment in cancer patients.

A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug.

An excretion balance and pharmacokinetic study was conducted in cancer patients with solid tumors who received a single oral dose of capecitabine of 2000 mg including 50 μ Ci of 14C-radiolabelled capecitabine. Blood, urine and fecal samples were collected until radioactive counts had fallen to below 50 dpm/mL in urine, and levels of intact drug and its metabolites were measured in plasma and urine by LC/MS-MS (mass spectrometry) and 19F-NMR (nuclear magnetic resonance) respectively. Based on the results of the 6 eligible patients enrolled, the dose was almost completely recovered in the urine (mean 95.5%, range 86–104% based on radioactivity measurements) over a period of 7 days after drug administration. Of this, 84% (range 71–95) was recovered in the first 12 hours. Over this time period, 2.64% (0.69–7.0) was collected in the feces. Over a collection period of 24–48h, a total of 84.2% (range 80–95) was recovered in the urine as the sum of the parent drug and measured metabolites (5′-DFCR, 5′-DFUR, 5-FU, FUH2, FUPA, FBAL). Based on the radioactivity measurements of drug-related material, absorption is rapid (tmax 0.25–1.5 hours) followed by a rapid biphasic decline. The parent drug is rapidly converted to 5-FU, which is present in low levels due to the rapid metabolism to FBAL, which has the longest half-life. There is a good correlation between the levels of radioactivity in the plasma and the levels of intact drug and the metabolites, suggesting that these represent the most abundant metabolites of capecitabine. The absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine.