We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for ...registration-directed trials.
Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on-2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice.
A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15-17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8-10.0) and 18.7 months (95% CI: 17.5-19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand-foot syndrome (each 7%).
Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.
•This ESMO Clinical Practice Guideline provides key recommendations for managing renal cell carcinoma.•The guideline covers imaging and diagnosis, staging and risk assessment, treatment and ...follow-up.•Algorithms for the management of localised and advanced or metastatic disease are provided.•The authors comprise a multidisciplinary group of experts from different institutions and countries.•Recommendations are based on available scientific data and the authors’ collective expert opinion.
Background: A large amount of evidence suggests a possible role of interleukin-6 (IL-6) in the pathogenesis of hepatocellular carcinoma (HCC). Patients and methods: We studied both IL-6 and A1FP in ...patients with HCC, non-neoplastic liver disease or in healthy controls. Results: IL-6 titers were four-fold higher in cancer than in cirrhotic patients and 25-fold higher than in healthy controls. As for alpha1-fetoprotein (A1FP) titers, the highest levels were observed in cancer patients. Receiver operating characteristic (ROC) curves analysis demonstrated that IL-6 is significantly more discriminant than A1FP, with ‘optimal’ cut-off values of 7.9 pg/ml (sensitivity = 0.83, specificity = 0.83, efficiency = 0.83). The ROC curves used to distinguish HCC from cirrhotic patients only, showed higher discriminant power of IL-6 versus A1FP titers, with a new cut-off value of 12 pg/ml (sensitivity = 0.73, specificity = 0.87, efficiency = 0.8). Discriminant analysis on HCC and non-HCC subjects yielded sensitivity, specificity and efficiency rates of 77%, 93% and 88%, respectively. The overall efficiency of the two tests combined was 82%. Conclusions: IL-6 could be considered a promising tumor marker for HCC. In particular, the diagnostic value of the test is significantly increased when combined with A1FP.
Everolimus, an orally administered rapamycin analogue, inhibits the mammalian target of rapamycin (mTOR), a highly conserved intracellular serine–threonine kinase that is a central node in a network ...of signaling pathways controlling cellular metabolism, growth, survival, proliferation, angiogenesis, and immune function. Everolimus has demonstrated substantial clinical benefit in randomized, controlled, phase III studies leading to approval for the treatment of advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, renal angiomyolipoma and subependymal giant-cell astrocytoma associated with tuberous sclerosis complex, as well as advanced hormone-receptor-positive (HR+) and human epidermal growth factor receptor-2-negative advanced breast cancer.
We discuss clinically relevant everolimus-related adverse events from the phase III studies, including stomatitis, noninfectious pneumonitis, rash, selected metabolic abnormalities, and infections, with focus on appropriate clinical management of these events and specific considerations in patients with breast cancer.
The majority of adverse events experienced during everolimus therapy are of mild to moderate severity. The safety profile and protocols for toxicity management are well established. The class-effect adverse event profile observed with everolimus plus endocrine therapy in breast cancer is (as expected) distinct from that of endocrine therapy alone, but is similar to that observed with everolimus in other solid tumors. Information gained from the experience in other carcinomas on prompt diagnosis and treatments to optimize drug exposure, treatment outcomes, and patients' quality of life also applies to the patient population with advanced breast cancer.
As with all orally administered agents, education of both physicians and patients in the management of adverse events for patients receiving everolimus is critical to achieving optimal exposure and clinical benefit. Active monitoring for early identification of everolimus-related adverse events combined with aggressive and appropriate intervention should lead to a reduction in the severity and duration of the event.
Compressive sensing (CS) has received considerable interest in hyperspectral sensing. Recent articles have also exploited the benefits of CS in hyperspectral image classification (HSIC) in the ...compressively sensed band domain (CSBD). However, on many occasions, the requirement of full bands is not necessary for HSIC to perform well. So, a great challenge arises in determining the minimum number of compressively sensed bands (CSBs), n CSB , needed to achieve full-band performance. Practically, the value of n CSB varies with the complexity of an imaged scene. Although virtual dimensionality (VD) has been used to estimate the number of bands to be selected, n BS , it is not applicable to CSBD because a CSB is actually a mixture of n CSB bands sensed by a random sensing matrix, while VD is used to estimate n BS which is the number of single bands to be selected. As expected, n CSB will be generally smaller than n BS . To estimate an optimal value of n CSB , two feature selection approaches, filter and wrapper methods, are proposed to extract scene features that can be used to estimate the minimum value of n CSB required to maximize performance with minimum redundancy. Specifically, these methods are fully automated by leveraging optimal partitioning schemes which enable classification to further reduce storage requirements in CSBD. Finally, a set of experiments are conducted using real-world hyperspectral images to demonstrate the viability of the proposed approach.
Malignant peritoneal mesothelioma (MPM) is a rare disease characterized by a difficult diagnosis, different types of presentation, variable course and poor prognosis.
Eighty-one patients with MPM ...observed in 14 Italian oncology institutions from 1982 to 2007 have been examined with the aim of delineating the history of MPM.
Presentation symptoms were ascites, abdominal pain, asthenia, weight loss, anorexia, abdominal mass, fever, diarrhea and vomiting in various associations. Computed tomography scan and echotomography signs were ascites, abdominal mass and peritoneal thickening. Peritoneal fluid cytology (61 cases) was positive for mesothelioma in 31 and for malignancy, not mesothelioma, in 13. Laparoscopy was carried out in 40 cases and laparotomy in 36. Thrombocytosis was present in 59 cases. Associated tumors diagnosed during the lifetime were colorectal cancer in two cases and cheek carcinoma, thyroid carcinoma, tongue carcinoma, bladder carcinoma and testicular seminoma. Thirty patients were treated with surgery and 45 with chemotherapy. The median survival time from diagnosis is 13 months. Ascites, fever and vomiting were significative variables at presentation; only vomiting holds significance in a multivariate analysis.
MPM is a disease with various types of presentation, frequently associated with thrombocytosis, sometimes with other tumors. Survival and diagnosis time can differ in various types of MPM. Prognosis is poor.
Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with ...HCC and CP class B.
A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19–21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.
Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar.
Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.
First-line sunitinib is recommended in metastatic renal cell carcinoma (mRCC), but it is frequently associated with relevant toxicities and subsequent dose reductions. Alternative schedules, such as ...2-week-on treatment and 1-week-off (2/1 schedule), might improve tolerability. We evaluated the safety and outcomes of this schedule in a large multicenter analysis.
Retrospective, multicenter analysis of mRCC patients treated with first-line sunitinib on a 2/1 schedule. Data of 249 patients were reviewed: 208 cases who started sunitinib on the 4/2 schedule (full dosage: 188/208, 90.4%) and thereafter switched to the 2/1 schedule for toxicity (group 4/2→2/1) and 41 patients who started first-line sunitinib with the 2/1 schedule because of suboptimal clinical conditions (group 2/1). A total of 211 consecutive patients treated with the 4/2 schedule in another institution served as external controls. Safety was the primary end point. Treatment duration (TD), progression-free survival (PFS) and overall survival (OS) were also analyzed.
In group 4/2→2/1, the overall incidence of grade ≥3 toxicities was significantly reduced (from 45.7% to 8.2%, P < 0.001) after the switch to 2/1 schedule. This advantage was maintained also in the 106/188 cases (56.4%) who maintained the full dosage. Fatigue, hypertension, hand–foot syndrome and thrombocytopenia were less frequent. The incidence of grade ≥3 adverse events in the negatively selected group 2/1 (only 73.2% starting at full dose) was 26.8%, similar to what observed in the external control group (29.4%). Median TD was 28.2 months in the 4/2→2/1 group (total time spent with both schedules), 7.8 months in the 2/1 group and 9.7 months in external controls. Median PFS was 30.2, 10.4 and 9.7 months, respectively. Median OS was not reached, 23.2 and 27.8 months, respectively.
mRCC patients who moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed during the initial 4/2 schedule.
In a comparison of tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin inhibitor (mTORi) in patients with metastatic clear-cell renal cell carcinoma who received a 1st-line TKI for at ...least 6 months, the TKI-TKI sequence was favored over the TKI-mTORi. Long-term 2nd-line responders were more likely to have received a second TKI and to have been long-term responders to a 1st-line TKI.
Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1).
Retrospective multicenter study (2004–2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). End points: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM).
Sequence effect in the overall cohort was in favor of the TKI–TKI sequence over the TKI–mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI–TKI superiority was attributed in large part to the 11–22 month (TD1) subgroup of patients which displayed significantly better outcomes HR ≈ 0.5; median PFS (months): 9.4 (5.9–12.2) versus 3.9 (3.0–5.5), P = 0.003; TTF(months): 8.0 (5.5–11.0) versus 3.6 (3.0–4.6), P = 0.009. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI.
m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.
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