Ovarian cancer presents at advanced stage in around 75% of women, and despite improvements in treatments such as chemotherapy, the 5-year survival from the disease in women diagnosed between 1996 and 1999 in England and Wales was only 36%. Over 80% of patients with advanced ovarian cancer will relapse and despite a good chance of remission from further chemotherapy, they will usually die from their disease. Sequential treatment strategies are employed to maximise quality and length of life but patients eventually become resistant to cytotoxic agents. The expansion in understanding of the molecular biology that characterises cancer cells has led to the rapid development of new agents to target important pathways but the heterogeneity of ovarian cancer biology means that there is no predominant defect. This review attempts to discuss progress to date in tackling a more general target applicable to ovary cancer—angiogenesis.
ovary cancer; VEGF inhibitors; anti-angiogenesis; tyrosine kinase inhibitors; vascular disruptive agents; metronomic chemotherapy
αv integrins are involved in angiogenesis and melanoma tumourigenesis. Intetumumab (CNTO 95) is a fully human anti-αv-integrin monoclonal antibody.
In a multicentre, randomised, phase II study, stage IV melanoma patients were randomised 1 : 1 : 1 : 1 to 1000 mg m−2 dacarbazine+placebo (n=32), 1000 mg m−2 dacarbazine+10 mg kg−1 intetumumab (n=32), 10 mg kg−1 intetumumab (n=33), or 5 mg kg−1 intetumumab (n=32) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events, and pharmacokinetics.
No statistically significant differences in efficacy were observed between groups. In the dacarbazine+placebo, dacarbazine+intetumumab, 10 mg kg−1 intetumumab, and 5 mg kg−1 intetumumab groups, median PFS was 1.8, 2.5, 1.4, and 1.4 months; median OS was 8, 11, 15, and 9.8 months; and ORR of complete+partial response was 10, 3, 6, and 0%. Nonlinear intetumumab pharmacokinetics and potential intetumumab–dacarbazine interactions were observed. Transient, asymptomatic, nonrecurring, grade 1–2, uveitic reactions that resolved spontaneously or with topical steroids were seen in 22–30% of intetumumab-treated patients. Low-grade infusion-reaction symptoms (headache, fatigue, nausea, vomiting, fever, chills) were observed, as expected, in 16–73% of dacarbazine-treated patients. No intetumumab-related myelosuppression, laboratory/electrocardiogram abnormalities, or deaths occurred.
With its favourable safety profile and a nonsignificant trend towards improved OS, intetumumab merits further investigation in advanced melanoma.
intetumumab; melanoma; αv integrins; dacarbazine; CNTO 95
The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study.
In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m−2 dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37% median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0).
Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.
melanoma; sorafenib; dacarbazine; combination therapy; biomarker
Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment.
Patients and methods:
Patients with advanced cancer received olaparib (20–200 mg PO) on days 1–7 with dacarbazine (600–800 mg m−2 IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells.
The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m−2 dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma.
This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses.
chemotherapy; dacarbazine; melanoma; PARP; resistance
Optimum efficacy is the primary goal for any cancer therapy, and entails controlling tumour growth and prolonging survival as far as possible. The prognosis for patients with metastatic renal cell carcinoma (mRCC) has greatly improved with the introduction of targeted therapies. This review examines the development and efficacy of targeted agents for the management of mRCC, the challenges offered by their rapid emergence, and discusses how mRCC treatment may evolve in the future. Improvements in progression-free survival and overall survival rates, observed with targeted agents, indicate that it may now be possible to change mRCC from a rapidly fatal and largely untreatable condition into a chronic disease. The major challenges to further advances in targeted therapy for mRCC include overcoming drug resistance, identifying the most effective sequence or combination of targeted agents, optimising clinical trial design and managing the cost of treatment.
chronic disease; combinatorial therapy; renal cell carcinoma; sequential therapy; sunitinib malate; targeted agents
There is clinical evidence to suggest that tumour necrosis factor-α (TNF-α) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC.
Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population.
Acceptable safety was reported for the first three patients (infliximab 5 mg kg−1) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg−1 were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand–foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS6 31%); median PFS and overall survival were 6 and 14 months, respectively.
Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC.
renal cell carcinoma; sorafenib; infliximab
Bevacizumab plus interferon-α2a (IFN) prolongs progression-free survival to >10 months, which is comparable with sunitinib as first-line treatment of metastatic renal cell carcinoma (RCC). The two regimens have different tolerability profiles; therefore, costs for managing adverse events may be an important factor in selecting therapy.
Costs of managing adverse events affecting patients with metastatic RCC eligible for treatment with bevacizumab plus IFN or sunitinib were evaluated using a linear decision analytical model. Management costs were calculated from the published incidence of adverse events and health-care costs for treating adverse events in the United Kingdom, Germany, France and Italy.
Adverse event management costs were higher for sunitinib than for bevacizumab plus IFN. The average cost per patient for the management of grade 3–4 adverse events was markedly lower with bevacizumab plus IFN compared with sunitinib in the United Kingdom (€1475 vs €804), Germany (€1785 vs €1367), France (€2590 vs €1618) and Italy (€891 vs €402). The main cost drivers were lymphopaenia, neutropaenia, thrombocytopaenia, leucopaenia and fatigue/asthaenia for sunitinib; and proteinuria, fatigue/asthaenia, bleeding, anaemia and gastrointestinal perforation for bevacizumab plus IFN.
The costs of managing adverse events are lower for bevacizumab plus IFN than for sunitinib. The potential for cost savings should be considered when selecting treatments for RCC.
adverse events; bevacizumab; cost; management; sunitinib
A prospective study of 50 patients of trauma was carried out at a tertiary level trauma center in Mumbai. The aim was to study the hypermetabolic response to trauma and the effect of early enteral feeding and nutritional supplementation in blunting this response in these patients.
Early enteral feeding was started within 72 h in most patients. The caloric requirement was calculated as per the body weight and a 150: 1 ratio of nonprotein calories to protein was maintained. A 24-h urinary nitrogen loss was estimated and nitrogen balance was calculated on days 1, 3 and 7.
The correlation between the injury severity and the severity of catabolism was also analysed. Urinary nitrogen loss and nitrogen balance were used as parameters to evaluate the hypermetabolic response.
Early (within 72 h) enteral nutritional support blunts this hypermetabolic response to some extent in these trauma patients.
Enteral nutrition; nitrogen; nutrition assessment
The safety and maximum tolerated dose (MTD) of erlotinib with docetaxel/carboplatin were assessed in patients with ovarian cancer. Chemonaive patients received intravenous docetaxel (75 mg m−2) and carboplatin (area under the curve 5) on day 1 of a 3-week cycle, and oral erlotinib at 50 (cohort 1), 100 (cohort 2a) or 75 mg day−1 (cohort 2b) for up to six cycles. Dose-limiting toxicities were determined in cycle 1. Forty-five patients (median age 59 years) received treatment. Dose-limiting toxicities occurred in 1/5/5 patients (cohorts 1/2a/2b). The MTD of erlotinib in this regimen was determined to be 75 mg day−1 (cohort 2b; the erlotinib dose was escalated to 100 mg day−1 in 11 out of 19 patients from cycle 2 onwards). Neutropaenia was the predominant grade 3/4 haematological toxicity (85/100/95% respectively). Common non-haematological toxicities were diarrhoea, fatigue, nausea and rash. There were five complete and seven partial responses in 23 evaluable patients (52% response rate). Docetaxel/carboplatin had no measurable effect on erlotinib pharmacokinetics. In subsequent single-agent maintenance, erlotinib was given at 100–150 mg day−1, with manageable toxicity, until tumour progression. Further investigation of erlotinib in epithelial ovarian carcinoma may be warranted, particularly as maintenance therapy.
docetaxel; carboplatin; erlotinib; HER1/EGFR; gynaecological; cancer
The objective of this study was to determine the objective response rate in patients with platinum-sensitive and platinum-resistant recurrent ovarian cancer to treatment with trabectedin (Yondelis®) administered as a 3-h infusion weekly for 3 weeks of a 4-week cycle. We carried out a multicentre Phase II trial of trabectedin in patients with advanced recurrent ovarian cancer. Trabectedin (0.58 mg m−2) was administered via a central line, after premedication with dexamethasone, to 147 patients as a 3-h infusion weekly for 3 weeks followed by 1-week rest. Major eligibility criteria included measurable relapsed advanced ovarian cancer and not more than two prior platinum-containing regimens. Patients were stratified according to the treatment-free interval (TFI) between having either platinum-sensitive (⩾6 months TFI) or platinum-resistant disease (<6 months TFI)/platinum-refractory disease (progression during first line therapy). In the platinum-sensitive cohort, 62 evaluable patients with measurable disease had an overall response rate (ORR) of 29.0% (95% CI: 18.2–41.9%) and median progression-free survival (PFS) was 5.1 months (95% CI: 2.8–6.2). Four patients with measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) criteria had no follow-up scans at the end of treatment. In the platinum-resistant/refractory cohort, 79 patients were evaluable with an ORR of 6.3% (95% CI: 2.1–14.2%). Median PFS was 2.0 months (95% CI: 1.7–3.5 months). Two patients with measurable disease per RECIST criteria had no follow-up scans at the end of treatment. The most frequent (⩾2% of patients) drug-related treatment-emergent grade 3/4 adverse events were reversible liver alanine transferase elevation (10%), neutropaenia (8%), nausea, vomiting, and fatigue (5% each). Trabectedin is an active treatment, with documented responses in patients with platinum sensitive advanced relapsed ovarian cancer, and has a manageable toxicity profile.
trabectedin; ovarian cancer; overall response rate; platinum-sensitive; platinum-resistant; progression-free survival
Temozolomide is an alkylating agent with activity in the treatment of melanoma metastatic to the brain. Lomustine is a nitrosurea that crosses the blood brain barrier and there is evidence to suggest that temozolomide may reverse resistance to lomustine. A multicentre phase I/II study was conducted to assess the maximum-tolerated dose (MTD), safety and efficacy of the combination of temozolomide and lomustine in melanoma metastatic to the brain. Increasing doses of temozolomide and lomustine were administered in phase I of the study to determine the MTD. Patients were treated at the MTD in phase II of the study to six cycles, disease progression or unacceptable toxicity. Twenty-six patients were enrolled in the study. In phase I of the study, the MTD was defined as temozolomide 150 mg m−2 days 1–5 every 28 days and lomustine 60 mg m–2 on day 5 every 56 days. Dose-limiting neutropaenia and thrombocytopaenia were observed at higher doses. Twenty patients were treated at this dose in phase II of the study. No responses to therapy were observed. Median survival from starting chemotherapy was 2 months. The combination of temozolomide and lomustine in patients with brain metastases from melanoma does not demonstrate activity. The further evaluation of this combination therefore is not warranted.
cerebral metastases; melanoma; chemotherapy; lomustine; temozolomide
Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCα), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.
protein kinase C; melanoma; midostaurin
The effects of sorafenib – an oral multikinase inhibitor targeting the tumour and tumour vasculature – were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with ⩾25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with ⩾25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had ⩾25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had ⩾25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.
Sorafenib; multikinase inhibitor; advanced melanoma; V600E BRAF; randomised discontinuation trial
Vascular endothelial growth factor (VEGF) is overexpressed in around 80% of patients with clear cell carcinoma of the kidney owing to the inactivation of von Hippel Lindau gene activity. VEGF stimulates angiogenesis and acts as an autocrine growth factor. A number of different agents are now available which target VEGF and its signalling pathways. A significant body of evidence has accumulated demonstrating that antagonism of VEGF and its downstream pathways is clinically useful in a significant proportion of patients with metastatic clear cell carcinoma of the kidney. Enough data is now available to recommend that patients with metastatic clear cell carcinoma of the kidney should at some point during the course of their disease be offered entry into a clinical trial enabling exposure to a targeted inhibitor of VEGF or its signalling pathways. Assuming early clinical trial data is substantiated by ongoing registration studies, efforts should be made to minimise the time taken between licensing and general availability of these active agents.
renal cell carcinoma; VEGF; vascular endothelial growth factor; sorafenib; sunitinib
Platinum-based combination chemotherapy has been proven to be superior to single-agent platinum in the treatment of relapsed ovarian cancer after a treatment-free interval of more than 6 months. A response rate of 41% was previously reported by our group using a combination of epirubicin, cisplatin and 5-FU in patients who relapsed within 12 months, we therefore assessed a similar, but more convenient combination of epirubicin, carboplatin and capecitabine in this phase-I/II trial. In total, 18 patients with recurrent epithelial ovarian carcinoma, who had not received more than two lines of chemotherapy and the treatment-free interval exceeded 6 months were treated with carboplatin AUC5, epirubicin 50 mg m−2 and capecitabine at several dose levels on continuous 21 day cycles and 14 of 21 day cycles. Patients were assessed for toxicity and by CT and CA-125 for response. The overall response rate was 61.1%, with three complete and eight partial responses. Grade 3/4 haematological toxicity was seen in 10 out of 18 patients and caused dose reductions and treatment delays. The combination of epirubicin, carboplatin and capecitabine showed good activity but caused excessive toxicity. A phase-II trial using carboplatin and capecitabine is underway.
capecitabine; carboplatin; epirubicin; ovarian cancer; relapse
BGC9331 is a rationally designed, specific nonpolyglutamatable thymidylate synthase (TS) inhibitor that is active in gynaecological malignancies. In the light of the sensitivity of human ovarian tumour cell lines to BGC9331 and non-cross resistance to platinum drugs, we studied the combination BGC9331/carboplatin (BCA) in a phase I (PI) pharmacokinetic (PK) and pharmacodynamic (PD) study in platinum pretreated gynaecological malignancies. Patients were ⩾18 years or over, with a histologically confirmed gynaecological malignancy, radiological evidence of relapse, and a platinum treatment free interval of at least 6 months. Up to three prior lines of chemotherapy were permitted. Carboplatin (AUC5) and BGC9331 were administered on day 1, and BGC9331 was also given on day 8 of a 21-day cycle. In total, 14 patients were enrolled, and treated with BGC9331 at four dose levels, 40, 65, 85 and 100 mg m−2. The principal grade 3 and 4 haematological toxicity was neutropaenia. The principal nonhaematological toxicities were lethargy and nausea. Dose-limiting toxicities were seen in two patients at 100 mg m−2 BGC9331 (grade 4 neutropaenia >7 days, and grade 4 fatigue >7 days). Plasma BGC9331 was measured by an ELISA that was adapted for use in humans. Carboplatin was assayed by flameless atomic absorption spectrometry. There was no PK interaction between the two drugs. Plasma deoxyuridine was elevated indicating TS inhibition to at least day 12. Antitumour activity was observed in four out of 14 (28%) of patients. In conclusion, the combination of BGC9331 and carboplatin is well tolerated with no significant PK interaction between the two drugs. There is evidence of TS inhibition with the combination. We have demonstrated antitumour activity in platinum pretreated gynaecological malignancy. Further exploration of this combination in this disease is warranted.
renal cell carcinoma; capecitabine; gemcitabine; chemotherapy
melanoma; palliative radiotherapy; brain metastases; prognosis; prognostic index
feasibility; carboplatin; sequential paclitaxel; gemcitabine ovarian cancer
interleukin-2; metastatic renal cell carcinoma; subcutaneous administration; continuous intravenous infusion; safety; efficacy
Standard chemotherapy for advanced epithelial ovarian cancer is a combination of platinum-paclitaxel. One strategy to improve the outcome for patients is to add other agents to standard therapy. Doxil is active in relapsed disease and has a response rate of 25% in platinum-resistant relapsed disease. A dose finding study of doxil-carboplatin-paclitaxel was therefore undertaken in women receiving first-line therapy. Thirty-one women with epithelial ovarian cancer or mixed Mullerian tumours of the ovary were enrolled. The doses of carboplatin, paclitaxel and doxil were as follows: carboplatin AUC 5 and 6; paclitaxel, 135 and 175 mg m−2; doxil 20, 30, 40 and 50 mg m−2. Schedules examined included treatment cycles of 21 and 28 days, and an alternating schedule of carboplatin-paclitaxel (q 21) with doxil being administered every other course (q 42). The dose-limiting toxicities were found to be neutropenia, stomatitis and palmar plantar syndrome and the maximum tolerated dose was defined as; carboplatin AUC 5, paclitaxel 175 mg m−2 and doxil 30 mg m−2 q 21. Reducing the paclitaxel dose to 135 mg m−2 did not allow the doxil dose to be increased. Delivering doxil on alternate cycles at doses of 40 and 50 mg m−2 also resulted in dose-limiting toxicities. The recommended doses for phase II/III trials are carboplatin AUC 6, paclitaxel 175 mg m−2, doxil 30 mg m−2 q 28 or carboplatin AUC 5, paclitaxel 175 mg m−2, doxil 20 mg m−2 q 21. Grade 3/4 haematologic toxicity was common at the recommended phase II doses but was short lived and not clinically important and non-haematologic toxicities were generally mild and consisted of nausea, paraesthesiae, stomatitis and palmar plantar syndrome.
British Journal of Cancer (2002) 86, 1379–1384. DOI: 10.1038/sj/bjc/6600250 www.bjcancer.com
© 2002 Cancer Research UK
ovarian cancer; liposomal doxorubicin; carboplatin; paclitaxel