Craig Underhill

Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer.

PURPOSE We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin, and methotrexate (FAMTX) in previously untreated patients with advanced esophagogastric cancer. PATIENTS AND METHODS Two hundred seventy-four patients with adenocarcinoma or undifferentiated carcinoma were randomized and analyzed for survival, tumor response, toxicity, and quality of life (QL). RESULTS The overall response rate was 45% (95% confidence interval [CI], 36% to 54%) with ECF and 21% (95% CI, 13% to 29%) with FAMTX (P = .0002). Toxicity was tolerable and there were only three toxic deaths. The FAMTX regimen caused more hematologic toxicity and serious infections, but ECF caused more emesis and alopecia. The median survival duration was 8.9 months with ECF and 5.7 months with FAMTX (P = .0009); at 1 year, 36% (95% CI, 27% to 45%) of ECF and 21% (95% CI, 14% to 29%) of FAMTX patients were alive. The median failure-free survival duration was 7.4 months with ECF and 3.4 months with FAMTX (P = .00006). The global QL scores were better for ECF at 24 weeks, but the remaining QL data showed no differences between either arm of the study. Hospital-based cost analysis on a subset of patients was similar for each arm and translated into an increment cost of

Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy

975 per life-year gained. CONCLUSION The ECF regimen results in a survival and response advantage, tolerable toxicity, better QL and cost-effectiveness compared with FAMTX chemotherapy. This regimen should now be considered the standard treatment for advanced esophagogastric cancer.

Gefitinib or Placebo in Combination with Tamoxifen in Patients with Hormone Receptor-Positive Metastatic Breast Cancer: a Randomized Phase II Study

We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.

Psychosocial well-being and supportive care needs of cancer patients living in urban and rural/regional areas: a systematic review

Purpose: Increased growth factor signaling may contribute to tamoxifen resistance. This randomized phase II trial assessed tamoxifen plus placebo or the epidermal growth factor receptor inhibitor gefitinib in estrogen receptor (ER)–positive metastatic breast cancer. Experimental Design: Patients with newly metastatic disease or recurred after adjuvant tamoxifen (stratum 1), or recurred during/after adjuvant aromatase inhibitor (AI) or after failed first-line AI (stratum 2), were eligible. Primary variables were progression-free survival (PFS; stratum 1) and clinical benefit rate (CBR; stratum 2). A 5% or more improvement in response variables with gefitinib was considered to warrant further investigation. Outcome was correlated with biomarkers measured on the primary tumor. Results: In stratum 1 (n = 206), the PFS HR (gefitinib:placebo) was 0.84 (95% CI, 0.59–1.18; median PFS 10.9 versus 8.8 months). In the stratum 1 endocrine therapy–naïve subset (n = 158) the HR was 0.78 (95% CI, 0.52–1.15), and the prior endocrine-treated subgroup (n = 48) 1.47 (95% CI, 0.63–3.45). In stratum 1, CBRs were 50.5% with gefitinib and 45.5% with placebo. In stratum 2 (n = 84), CBRs were 29.2% with gefitinib and 31.4% with placebo. Biomarker analysis suggested that in stratum 1 there was greater benefit with gefitinib in patients who were ER-negative or had lower levels of ER protein. Conclusions: In stratum 1, the improved PFS with gefitinib plus tamoxifen met the protocol criteria to warrant further investigation of this strategy. In stratum 2, there was a numerical disadvantage for gefitinib; additional investigation after AI therapy is not warranted. Studies of predictive biomarkers are needed to subset appropriate patients. Clin Cancer Res; 17(5); 1147–59. ©2011 AACR.

Plasma Epstein-Barr Virus (EBV) DNA Is a Biomarker for EBV-Positive Hodgkin's Lymphoma

PurposeThe aim of this study was to describe what is known about levels of morbidity and the experience and needs of people with cancer, and their informal caregivers, living in rural areas.MethodsA search of online databases for English language papers describing or assessing the prevalence of psychosocial morbidity or needs in a population of rural or regional cancer patients was employed. The following were excluded: intervention studies, discussion of service delivery, effectiveness of support groups or support via videoconferencing, concentrated on medical outcomes or survival rates, reported differences in the uptake of cancer screening or concentrated on health attitudes or treatment decision making.ResultsThere were 37 studies in the review, including 25 quantitative studies (all surveys), 11 of which included a control group of urban patients and 12 qualitative studies. Until recently, most studies had methodological shortcomings. Only two prospective studies were identified, most studies focused on breast cancer and few addressed psychological morbidity. The majority of controlled studies reported worse outcomes for rural patients, who appear to have higher needs in the domains of physical/daily living. This may reflect more limited access to resources, a more self-sufficient lifestyle and personal characteristics, for example, being more stoical and less likely to ask for help. The need to travel for treatment caused many practical, emotional and financial problems for patients and burdened them with additional worry concerning family and work commitments. Some patients reported benefits in sharing experiences with others also forced to stay away from home, but most agreed that staying at home was preferable.ConclusionThis review highlights that whilst we are beginning to get some insight into the needs of people with cancer in rural areas, much is still unknown. Population-based, prospective studies including people with heterogenous cancers from rural and urban settings are needed.

Treatment of Invasive Thymoma With Single-Agent Ifosfamide

Purpose: Latent Epstein-Barr virus (EBV) genomes are found in the malignant cells of approximately one-third of Hodgkins lymphoma (HL) cases. Detection and quantitation of EBV viral DNA could potentially be used as a biomarker of disease activity. Experimental Design: Initially, EBV-DNA viral load was prospectively monitored from peripheral blood mononuclear cells (PBMC) in patients with HL. Subsequently, we analyzed viral load in plasma from a second cohort of patients. A total of 58 patients with HL (31 newly diagnosed, 6 relapsed, and 21 in long-term remission) were tested. Using real-time PCR, 43 PBMC and 52 plasma samples were analyzed. Results: EBV-DNA was detectable in the plasma of all EBV-positive patients with HL prior to therapy. However, viral DNA was undetectable following therapy in responding patients (P = 0.0156), EBV-positive HL patients in long-term remission (P = 0.0011), and in all patients with EBV-negative HL (P = 0.0238). Conversely, there was no association seen for the EBV-DNA load measured from PBMC in patients with active EBV-positive HL patients as compared with EBV-negative HL, or patients in long-term remission. EBV-DNA load in matched plasma/PBMC samples were not correlated. Conclusions: We show that free plasma EBV-DNA has excellent sensitivity and specificity, and can be used as a noninvasive biomarker for EBV-positive HL and that serial monitoring could predict response to therapy. Additional prospective studies are required to further evaluate the use of free plasma EBV-DNA as a biomarker for monitoring response to treatment in patients with EBV-positive HL.

Mapping oncology services in regional and rural Australia.

PURPOSE To evaluate single-agent ifosfamide in the treatment of invasive thymoma. PATIENTS AND METHODS Fifteen patients (eight male and seven female) with histologically confirmed invasive thymoma were treated. The median age was 48 years (range, 23 to 76 years). Four patients had stage III disease, seven patients had stage IVa disease, and four patients had stage IVb disease. The most common histologic type was lymphoepithelial. Seven patients had received prior treatment, including one patient who received chemotherapy. Ifosfamide 1.5 g/m(2) was given on days 1 to 5, with mesna as a uroprotector. RESULTS Thirteen patients were assessable for response. Five complete responses (38.5%; 95% confidence interval [CI], 17.7% to 64.5%) and one partial response (7.7%; 95% CI, 1.4% to 33.3%) were seen. The median duration of complete response was 66+ months (range, 25 to 87 months), and the estimated survival rate 5 years after ifosfamide treatment was 57% (SE, 32% to 79%). The most frequent toxicities were nausea, vomiting, and leucopenia, but these were well tolerated. CONCLUSION Single-agent ifosfamide possesses significant activity against invasive thymoma and is comparable to currently used combination regimens. The inclusion of ifosfamide in combination therapy, particularly in place of cyclophosphamide in regimens such as cisplatin, doxorubicin, and cyclophosphamide, needs to be evaluated.

Enhancement of Platelet Recovery After Myelosuppressive Chemotherapy by Recombinant Human Megakaryocyte Growth and Development Factor in Patients With Advanced Cancer

OBJECTIVE To map clinical oncology services in regional and rural Australia. DESIGN AND SETTING A self-administered survey was sent to 161 regional hospitals administering chemotherapy (RHAC) in Australia. RHAC were categorised by state, Hospital Peer Group and the Australian Standard Geographical Classification (ASGC) Remoteness Areas classification. MAIN OUTCOME MEASURE(S) Survey data provided percentage and aggregate figures about availability of medical, radiation and surgical oncologists, chemotherapy nurses, breast cancer nurses, palliative care physicians and allied health professionals according to remoteness and state. Chemotherapy prescribing practices, adherence to occupational health and safety guidelines and availability of multidisciplinary clinics were also explored. RESULTS A 98% survey completion rate was achieved. Significant deficiencies in service provision were identified in RHAC. Only 21% of RHAC reported a resident medical oncology service, 7% had a radiation oncology unit, and 6% had a resident surgical oncologist. Only 24% of RHAC reported a dedicated palliative care specialist and 39% identified a dedicated oncology counselling service. Other issues included administration of chemotherapy by nurses outside a recognised facility or by nurses without recognised oncology training, limited availability of funded breast care nurses and lack of multidisciplinary clinics. CONCLUSION Survey data highlight marked cancer service deficiencies in rural and regional Australia. It is not unreasonable to conclude that these deficiencies might contribute to poorer outcomes for cancer patients living in these areas. The results suggest the need for short- and long-term measures to improve access to best-practice cancer services for patients living in regional, rural and remote areas of Australia.

A Multicenter Phase II Trial of Thalidomide and Celecoxib for Patients with Relapsed and Refractory Multiple Myeloma

PURPOSE To explore the influence of dose and schedule on the ability of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) to abrogate thrombocytopenia after multiple cycles of chemotherapy and to mobilize peripheral-blood progenitor cells (PBPC). PATIENTS AND METHODS In this open-label study, 68 patients with advanced cancer were randomized to receive PEG-rHuMGDF subcutaneously at different doses and durations before administration of carboplatin 600 mg/m(2), cyclophosphamide 1,200 mg/m(2), and filgrastim 5 microgram/kg/d. PEG-rHuMGDF was not given after the first cycle of chemotherapy but was given after the second and subsequent cycles. Chemotherapy was given every 28 days for up to six cycles. RESULTS In patients who received the same dose of chemotherapy for at least two cycles, the platelet nadir was significantly higher (47.5 x 10(9)/L v 35.5 x 10(9)/L; P =.003) and duration of grade 3 or 4 thrombocytopenia significantly shorter (0 v 3 days; P =.004) when PEG-rHuMGDF was administered after chemotherapy. There was no evidence of an effect of PEG-rHuMGDF when it was given before chemotherapy. Platelet recovery after the first cycle of chemotherapy was no different for different PEG-rHuMGDF regimens, and there was no difference between patients treated with PEG-rHuMGDF and historical controls treated with identical chemotherapy. There was a modest dose-related increase in progenitor cell levels after administration of PEG-rHuMGDF alone. Peak levels of PBPC occurred later in cycle 2 than in cycle 1 but were not different in magnitude. CONCLUSION PEG-rHuMGDF abrogated severe thrombocytopenia after dose-intensive chemotherapy. However, it had only a modest effect on progenitor cell levels and did not enhance progenitor cell mobilization after chemotherapy and filgrastim.

Phase I study of tremelimumab (CP-675 206) plus PF-3512676 (CPG 7909) in patients with melanoma or advanced solid tumours

Preclinical data indicates that cyclooxygenase-2 (COX-2) inhibition impairs plasma cell growth and potentially synergizes with thalidomide. We performed a trial in previously treated patients with myeloma using thalidomide up to a maximum dose of 800 mg/d with celecoxib (400 mg bid). Outcomes were compared with a prior trial of thalidomide. Sixty-six patients with median age of 67 (range, 43-85) received a median dose of thalidomide and celecoxib of 400 and 800 mg/d, respectively, with median durations of treatment of 27 and 13 weeks, respectively. The most common toxicities associated with premature discontinuation of celecoxib (n = 30 of 53, 57%) were fluid retention and deterioration of renal function. Overall response rate (RR) was 42% and with 20 months median follow-up; the actuarial median progression-free survival and overall survival were 6.8 and 21.4 months, respectively. Unlike our prior study, age >65 years was not predictive of inferior RR due to improvement in RR in older patients with the combination (37% versus 15%, P = 0.08). The RR was superior in patients who received a total dose of celecoxib exceeding 40 g in the first 8 weeks of therapy (62% versus 30%, P = 0.021). Progression-free survival and overall survival were also improved. Other predictors for inferior progression-free survival were age >65 years (P = 0.016) and elevated β2-microglobulin (P = 0.017). This study provides evidence that the addition of high-dose celecoxib adds to the antimyeloma activity of thalidomide but this comes with unacceptable toxicity. Future studies should use newer COX-2 inhibitors with thalidomide, or their respective derivatives.