A randomised phase II trial of three dosing regimens of radium-223 in patients with bone metastatic castration-resistant prostate cancer.

BACKGROUND: Radium-223 prolongs overall survival and delays symptomatic skeletal events (SSEs) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. The approved radium-223 regimen is 55 kBq/kg every 4 weeks (q4w) for six cycles (standard dose). We investigated different radium-223 regimens in patients with mCRPC. PATIENTS AND METHODS: Patients were randomised 1 : 1 : 1 to radium-223 standard-dose, high-dose (88 kBq/kg q4w for six cycles) or extended-schedule arms (55 kBq/kg q4w for 12 cycles). The primary end point, SSE-free survival (SSE-FS), was compared in patients treated with a high- versus standard-dose regimen, or with a standard dose in an extended (>6 to 12 cycles) versus standard schedule (six cycles). RESULTS: A total of 391 patients were randomised; baseline characteristics were balanced between arms. On-treatment SSEs developed in 37/130 (28%), 42/130 (32%) and 48/131 (37%) patients in the standard-dose, high-dose and extended-schedule arms, respectively. There was no statistically significant difference in SSE-FS in the high- versus standard-dose arms [median 12.9 months versus 12.3 months; hazard ratio (HR) 1.06, 80% confidence interval (CI) 0.88-1.27, P = 0.70], and in the extended- versus standard-schedule arms (median 10.8 months versus 13.2 months; HR 1.26, 80% CI 0.94-1.69, P = 0.31). Overall survival in the three treatment arms was similar. As many as 370 (95%) patients received treatment (median of six cycles) in each arm. Grade ≥3 treatment-emergent adverse events (TEAEs) affected 34% of patients in the standard-dose, 48% in the high-dose and 53% in the extended-schedule arm, causing permanent discontinuation in 9%, 16% and 17% of patients, respectively. CONCLUSION: Radium-223 high-dose or extended-schedule regimens resulted in no change in SSE-FS or other efficacy end points and were associated with more grade ≥3 TEAEs. The extended-schedule regimen (beyond six doses) could not be implemented in a large proportion of patients due to disease progression. Therefore, the standard-dose schedule remains one of the standard therapies for patients with symptomatic mCRPC. TRIAL REGISTRATION: ClinicalTrials.govNCT02023697.

Resolution of paraneoplastic immune thrombocytopenia following everolimus treatment for metastatic renal cell carcinoma.

Autoimmune thrombocytopenia is an uncommon but reported paraneoplastic manifestation of renal cell carcinoma (RCC). Treatment usually involves management of the underlying malignancy; however, steroids have shown a benefit in published case reports. Here, we describe a patient with profound thrombocytopenia secondary to metastatic RCC. It was refractory to steroid and intravenous immunoglobulin, but the platelet count improved markedly following initiation of everolimus. The possible explanation includes immunomodulation, tumour lysis or a combination of both effects. This is the first reported case of everolimus used in paraneoplastic thrombocytopenia from RCC. More studies are needed for further investigation of its potential use in secondary immune thrombocytopenia from RCC and perhaps other malignancies.

Intermittent androgen deprivation is a rational standard-of-care treatment for all stages of progressive prostate cancer: results from a systematic review and meta-analysis.

BACKGROUND: The optimal hormone treatment strategy in prostate cancer is uncertain, particularly in patients with metastatic disease. We aimed to compare the relative benefits and harms of intermittent androgen deprivation (IAD) to continuous androgen deprivation (CAD) in all stages of prostate cancer. METHODS: We included eight randomised control trials (4668 patients) in our systematic review and meta-analysis. Median follow-up ranged from 29 to 118 months. Pooled hazard ratios (HRs) were calculated for overall survival (OS), cancer-specific survival, time to cancer progression and mortality unrelated to prostate cancer. The relative effect of treatment in patients with metastatic and those with non-metastatic disease was compared using pre-planned subgroup analysis. RESULTS: There was no difference in OS between patients treated with IAD and CAD (HR 1.01, 95% confidence interval (CI) 0.93-1.10); nor was there any difference in cancer-specific survival (HR 1.03; 95% CI 0.88-1.21). There was a non-significant trend towards longer time to prostate cancer progression for IAD (HR 0.93, 95% CI 0.84-1.04), raising the possibility of slower selection for castrate resistance. There was no significant difference in OS when analysis was restricted to patients with metastatic disease (HR 1.04, 95% CI 0.91-1.19) or patients without metastatic disease (HR 1.06, 95% CI 0.91-1.23) (test for subgroup differences P=0.84). Most studies found an improvement in quality of life or toxicity profile with IAD. CONCLUSIONS: IAD is non-inferior to CAD in terms of OS and cancer-specific survival, and is at least non-inferior in terms of time to progression. This meta-analysis confirms IAD as a valid standard of care for managing prostate cancer patients.

Anticancer activity of combination targeted therapy using cetuximab plus vemurafenib for refractory BRAF (V600E)-mutant metastatic colorectal carcinoma.

Mismatch-repair-deficient colorectal cancers often contain kinase-activating V600E BRAF mutations, but no clinical utility has yet been demonstrated in this setting for monotherapy using oral braf kinase inhibitors such as vemurafenib or dabrafenib. Recent studies have indicated that tumour resistance to braf inhibition is mediated by upregulated epidermal growth factor receptor (egfr) signalling, disruption of which is a routine treatment strategy in KRAS wild-type colorectal cancer. In this report, we describe the clinical course of a heavily pretreated patient who elected to receive off-label dual-targeted braf- and egfr-inhibitory therapy with good tolerance and apparent clinical benefit.

Has discovery-based cancer research been a bust?

The completion of the human genome sequence sparked optimism about prospects for new anticancer drug development, but clinical progress over the last decade has proven slower than expected. Here it is proposed that unrealistically high expectations of first-generation discovery-based diagnostics have contributed to this problem. Hypothesis-based single-molecule tests (e.g., mutation screening of KRAS, EGFR, BRAF or KIT genes) continue to change clinical practice incrementally, whereas first-generation multiplex assays--such as gene expression profiling and proteomics--have identified few high-impact therapeutic targets despite numerous correlations with prognosis. To move forward, second-generation multiplex diagnostics should be based not on statistical patterns/associations alone, but on clinically interpretable ('high-signal-to-noise') data such as change-of-function mutations, gene amplifications, recurrent chromosomal anomalies, and abnormal phosphorylation profiles of ERK or mTOR signaling cascades.

Death in The New York Times: the price of fame is a faster flame.

BACKGROUND: Occupational factors have long been linked to patterns of mortality. AIM: Based on the premiss that an obituary in The New York Times (NYT) tends to imply success in one's vocation, we used NYT obituary data to elucidate the relationships between career success, terminal disease frequency and longevity. DESIGN: One thousand consecutive obituaries published in NYT over the period 2009-11 were analysed in terms of gender, occupation and terminal disease, as attributed. METHODS: The frequency of disease for each occupational category was determined, and the mean age of death was calculated for each disease and occupational subgroup. RESULTS: Male obituaries outnumbered female (813 vs. 186), and the mean age of death was higher for males than females (80.4 ± 0.4 vs. 78.8 ± 1.1 years). Younger ages of death were evident in sports players (77.4 years), performers (77.1) and creative workers (78.5), whereas older deaths were seen in military (84.7), business (83.3) and political (82.1) workers. Younger deaths were more often associated with accidents (66.2 years), infection (68.6) and organ-specified cancers (73.0). 'Old age' was more often the cited cause of death for philanthropists, academics and doctors, and less often for sportsmen, performers and creatives. Cancer deaths occurred most often in performers and creatives, with lung cancer commonest among performers and least common in professionals. CONCLUSION: Fame and achievement in performance-related careers may be earned at the cost of a shorter life expectancy. In such careers, smoking and other risk behaviours may be either causes or effects of success and/or early death.

Coexisting ductal carcinoma in situ independently predicts lower tumor aggressiveness in node-positive luminal breast cancer.

Primary breast invasive ductal carcinoma coexisting with ductal carcinoma in situ (IDC-DCIS) is characterized by lower proliferation rate and metastatic propensity than size-matched pure IDC. IDC-DCIS is also more often ER-positive, PR-positive and/or HER2-positive. This analysis aims to clarify whether the presence of coexisting DCIS in IDC affects tumor aggressiveness in various biological subtypes of breast cancer, respectively. Tumor data obtained from 1,355 consecutive female patients undergoing upfront surgery for primary breast cancer were analyzed retrospectively; 196 patients with pure DCIS were excluded. Based on evidence that immunohistochemistry (IHC) provides a reasonable approximation of molecular phenotypes, the tumor samples were divided into 4 groups: (1) luminal A (ER and/or PR-positive, HER2-negative, Ki67 ≤ 12), (2) luminal B (ER and/or PR-positive, HER2-negative, Ki67 > 12), (3) HER2 (HER2-positive) and (4) basal-like (triple-negative) disease. Ki67 expression and nodal involvement of IDC with or without DCIS in these groups were compared. The number of patients with luminal A, luminal B, HER2 and basal-like breast cancer were 396, 265, 258 and 117, respectively. Ki-67 was lower in IDC-DCIS than in size-adjusted pure IDC of both luminal A and luminal B subtypes (P = 0.15 and <0.005, respectively). In HER2 or basal-like tumors, there were no significant difference between pure IDC and IDC-DCIS. The presence of coexisting DCIS in IDC predicts lower biological aggressiveness in luminal cancers but not in the conventionally more aggressive HER2-positive and triple-negative subtypes.

Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy.

BACKGROUND: This phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Patients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers. RESULTS: Seventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen. CONCLUSIONS: Bosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population.

Impact of income and education on drug purchasing decisions in Hong Kong Chinese cancer patients: a pilot study.

BACKGROUND: The affordability of diagnostic, preventive and therapeutic interventions is a global concern, particularly in the developing world. To clarify the educational and financial factors that influence purchasing decisions, we conducted a survey of Hong Kong cancer patients across a broad social spectrum. METHODS: A questionnaire was designed to assess the effect of costs on purchasing decisions relating to six drug-related variables: efficacy, tolerability, convenience, safety, peer pressure, and uncertainty. Validation of the original 31-part survey resulted in a final set of 22 core questions that was administered to 51 consecutive oncology patients who were characterized in terms of varying household income and educational level. RESULTS: Most respondents (87.6%) were Hong Kong-born or mainland Chinese. There was a strong correlation between household income and education. Demand for drug tolerability and safety was high and cost-inelastic across all educational and income groups. An unexpected finding was that patients from low-income/education households were keen to purchase costly medications (whether Western, or Chinese herbs) of reputed high efficacy, whereas patients from middle-income/-education backgrounds were more negatively influenced by considerations of cost. Only the most affluent and well-educated patients valued overall survival above disease-free survival when making drug purchasing decisions; this cohort was also the least influenced by peer pressure, and the most willing to pay extra for drugs offering more convenience alone. CONCLUSION: Low-income/education Asian patients had paradoxically high expectations of costly drug interventions. Although larger studies addressing this issue are needed to confirm these conclusions, public education initiatives aimed at protecting low-income/education patients from exploitation or disappointment may be desirable.

Presence of an in situ component is associated with reduced biological aggressiveness of size-matched invasive breast cancer.

BACKGROUND: The metastatic propensity of invasive ductal carcinoma (IDC) of the breast correlates with axillary node involvement and with expression of the proliferation antigen Ki-67, whereas ductal carcinoma in situ (DCIS) is non-metastasising. To clarify whether concomitant DCIS affects IDC prognosis, we compared Ki-67 expression and node status of size-matched IDC subgroups either with DCIS (IDC-DCIS) or without DCIS (pure IDC). METHODS: We analysed data from 1355 breast cancer patients. End points were defined by the association of IDC (with or without DCIS) with grade, nodal status, Ki-67, and ER/HER2. RESULTS: Size-matched IDC-DCIS was more likely than pure IDC to be screen detected (P=0.03), to occur in pre-menopausal women (P=0.002), and to be either ER-positive (P=0.002) or HER2-positive (P<0.0005), but less likely to be treated with breast-conserving surgery (P=0.004). Grade and Ki-67 were lower in IDC-DCIS than in pure IDC (P=0.02), and declined as the DCIS enlarged (P<0.01). Node involvement and lymphovascular invasion in IDC-DCIS increased with the size ratio of IDC to DCIS (P<0.01). A 60-month cancer-specific survival favoured IDC-DCIS over size-matched pure IDC (97.4 vs 96.0%). CONCLUSION: IDC co-existing with DCIS is characterised by lower proliferation and metastatic potential than size-matched pure IDC, especially if the ratio of DCIS to IDC size is high. We submit that IDC-DCIS is biologically distinct from pure IDC, and propose an incremental molecular pathogenesis of IDC-DCIS evolution involving an intermediate DCIS precursor that remains dependent for replication on upstream mitogens.

Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma.

BACKGROUND: Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population. METHODS: Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg(-1) on day 1 and capecitabine 800 mg m(-2) twice daily on days 1-14 every 3 weeks as first-line therapy. RESULTS: A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand-foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score < or =3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients. CONCLUSION: The bevacizumab-capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.

Treatment outcomes in anaplastic thyroid carcinoma: survival improvement in young patients with localized disease treated by combination of surgery and radiotherapy.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a notoriously aggressive malignancy associated with a highly lethal clinical course despite therapeutic intervention. Our present study attempts to identify factors that could potentially improve therapeutic strategies by analyzing the clinicopathological features, treatment and outcome of ATC patients managed over the past four decades at our institution. METHODS: Fifty patients with biopsy-proven ATC during the period 1966 to 2006 were studied. All patients were managed with surgery, radiotherapy, chemotherapy and/or chemoradiation. Survival was calculated by the Kaplan-Meier method. Potential factors affecting survival were compared by the log rank test. RESULTS: Most patients (88%) presented with a neck mass; 17 patients (34%) also had cervical lymphadenopathy. Distant metastases were clinically present in 9 (18%). Median survival was 97 days, whereas the 1- and 3-year survival was 14% and 8%, respectively. On univariate analysis, patients aged

Review article: current management of metastatic colorectal cancer - the evolving impact of targeted drug therapies.

BACKGROUND: The field of colorectal cancer chemotherapy has been transformed by the advent of molecule-specific drugs. Combined use of such drugs enhances tumour response rates, but controlled data quantifying the relative efficacy and cost-effectiveness of different drug combinations on overall survival remain scarce. AIM: To conduct an overview of published clinical trials in advanced colorectal cancer, with the objective of framing provisional approaches to current management. METHODS: An NCBI/PubMed search was performed using the strings, 'colorectal cancer' ('metastatic' or 'advanced' or 'palliative') and ('chemotherapy' or 'drug therapy' or 'targeted' or 'target-specific' or 'molecularly-targeted'). RESULTS: Combinations of target-specific drugs (with or without the DNA-alkylating agent oxaliplatin) have substantially enhanced colorectal cancer time to progression over the last decade and have also expedited surgical resection of liver metastases. Disease-free survival, overall survival and quality of life are favourably influenced. CONCLUSIONS: Target-specific drugs improve palliative efficacy in the setting of advanced colorectal cancer. However, key issues persist as to the cost-effectiveness of these newer drug treatments, and further controlled trials are needed to resolve this important debate.

Tumor resensitization to erlotinib following brief substitution of cetuximab.

Targeted inhibition of epidermal growth factor receptors (EGFR) is becoming a standard anticancer treatment in defined clinical scenarios. EGFR inhibition may be achieved either by small-molecule orally bioavailable tyrosine kinase inhibitors, such as gefitinib or erlotinib, or else by large-molecule receptor antibodies, such as cetuximab or panitumumab. Here, we describe a case of pancreatic cancer in which the small-molecule EGFR antagonist erlotinib was used before and after the EGFR antibody cetuximab, with unexpected potentiation of both toxic and therapeutic sequelae.

A case of mixed adult Wilms' tumour and angiosarcoma responsive to carboplatin, etoposide and vincristine (CEO).

Here we report an unusual case of mixed Wilms' tumour and angiosarcoma in a 38-year-old female patient who presented with haematuria and right lower back pain. A computed tomographic (CT) scan confirmed a massive renal tumour associated with extensive retroperitoneal lymph node involvement, bony metastases and a right hip fracture. She was initially managed with palliative nephrectomy, which was followed by rapid postoperative deterioration. Histopathology revealed differentiated adult Wilms' tumour with renal angiosarcoma, whereas the pathology of the para-aortic lymph node and bone metastasis revealed angiosarcoma only. In view of her cachexia and cytopaenia, emergency chemotherapy was initiated using a modified regimen of carboplatin, etoposide and vincristine (CEO) in preference to the more traditional but less well-tolerated VAC (vincristine, actinomycin D, cyclophosphamide). Four cycles of this protocol yielded a dramatic response on re-staging CT scan. This case suggests that highly angiogenic tumours such as angiosarcoma may be effectively palliated using agents usually reserved for refractory Wilms' tumour, and supports the view that adult Wilms' tumour is more sensitive to such agents.

Dominant negative knockout of p53 abolishes ErbB2-dependent apoptosis and permits growth acceleration in human breast cancer cells.

We previously reported that the ErbB2 oncoprotein prolongs and amplifies growth factor signalling by impairing ligand-dependent downregulation of hetero-oligomerised epidermal growth factor receptors. Here we show that treatment of A431 cells with different epidermal growth factor receptor ligands can cause growth inhibition to an extent paralleling ErbB2 tyrosine phosphorylation. To determine whether such growth inhibition signifies an interaction between the cell cycle machinery and ErbB2-dependent alterations of cell signalling kinetics, we used MCF7 breast cancer cells (which express wild-type p53) to create transient and stable ErbB2 transfectants (MCF7-B2). Compared with parental cells, MCF7-B2 cells are characterised by upregulation of p53, p21(WAF) and Myc, downregulation of Bcl2, and apoptosis. In contrast, MCF7-B2 cells co-transfected with dominant negative p53 (MCF7-B2/Delta p53) exhibit reduced apoptosis and enhanced growth relative to both parental MCF7-B2 and control cells. These data imply that wild-type p53 limits survival of ErbB2-overexpressing breast cancer cells, and suggest that signals of varying length and/or intensity may evoke different cell outcomes depending upon the integrity of cell cycle control genes. We submit that acquisition of cell cycle control defects may play a permissive role in ErbB2 upregulation, and that the ErbB2 overexpression phenotype may in turn select for the survival of cells with p53 mutations or other tumour suppressor gene defects.

Association of ErbB2 Ser1113 phosphorylation with epidermal growth factor receptor co-expression and poor prognosis in human breast cancer.

The carboxyterminal domain of the epidermal growth factor receptor (EGFR)--a putative binding site for the ubiquitin ligase Cbl--is the site of serine phosphorylation events which are essential for ligand-dependent EGFR desensitization and degradation. Using a monoclonal antibody (aPS1113) which selectively recognizes the homologous phosphorylated domain in the ErbB2 oncoprotein, we show here that wild-type ErbB2 becomes Ser1113-phosphorylated following treatment of 3T3 cells with growth factors or tyrosine phosphatase inhibitors. In EGFR-overexpressing A431 cells, ligand-inducible aPS1113 immunoreactivity declines more rapidly than other detectable phosphorylation events and is followed by EGFR downregulation. Analysis of 65 ErbB2-expressing primary breast cancers reveals a highly significant relationship between Ser1113 phosphorylation and EGFR overexpression (p < 0.0001) as well as an association with poor prognosis (p = 0.005). We submit that ErbB2 Ser1113 phosphorylation status represents a novel and informative biomarker of cancer cell biology and tumor behavior.

Multisite phosphotyping of the ErbB-2 oncoprotein in human breast cancer.

BACKGROUND: Overexpression of the ErbB-2 (HER2/neu) receptor tyrosine kinase is one of the most common molecular changes in human cancer, but the functional significance of this phenotype remains uncertain. METHODS AND RESULTS: Using phosphorylation-specific antibodies recognizing different ErbB-2 functional states, we assessed the phosphorylation status of ErbB-2 in 102 human breast cancer specimens. Quantitative ErbB-2 immunoblotting intensity correlated directly with that of immunohistochemistry (r = 0.84). Widely varying phosphorylation profiles were evident in 65 ErbB-2-positive carcinomas, suggesting different ErbB-2 functions in different tumors. In a subset of patients for whom clinical data were obtainable, mortality trends were strongly associated with the quantitative signal intensities of ErbB-2 phosphoantibodies (P < or =.02), but not with those of conventional antibodies to ErbB-2 (P = .147), epidermal growth factor receptor (P = .44), or phosphotyrosine (P = .94). CONCLUSION: Although requiring corroboration in larger prospective clinical studies, these findings suggest that immunophenotyping using phosphorylation-specific antibodies may enable more accurate prediction of cancer behavior than is currently obtainable using conventional reagents.