Molecular profiling of advanced solid tumours. The impact of experimental molecular-matched therapies on cancer patient outcomes in early-phase trials: the MAST study.

INTRODUCTION: Molecular-matched therapies have revolutionized cancer treatment. We evaluated the improvement in clinical outcomes of applying an in-house customized Next Generation Sequencing panel in a single institution. METHODS: Patients with advanced solid tumors were molecularly selected to receive a molecular-matched treatment into early phase clinical trials versus best investigators choice, according to the evaluation of a multidisciplinary molecular tumor board. The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1). RESULTS: Of a total of 231 molecularly screened patients, 87 were eligible for analysis. Patients who received matched therapy had a higher median PFS2 (6.47 months; 95% CI, 2.24-14.43) compared to those who received standard therapy (2.76 months; 95% CI, 2.14-3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008). DISCUSSION: We demonstrate the pivotal role of the institutional molecular tumor board in evaluating the results of a customized NGS panel. This process optimizes the selection of available therapies, improving disease control. Prospective randomized trials are needed to confirm this approach and open the door to expanded drug access.

Multimodality Treatment of Pediatric and Adult Patients With Ewing Sarcoma: A Single-institution Experience.

INTRODUCTION: The treatment of Ewing Sarcoma family of tumors is multimodal, both in children and adults. Axial location and metastases are classic prognostic factors. However, the worse prognosis in older patients is more controversial. METHODS: Retrospective analysis was performed of pediatric and adult patients treated with the 2001 SEOP protocol: 6 cycles of VIDE chemotherapy (CT). If no progression was observed, local (surgery and/or radiotherapy) and consolidation treatments were performed adjusted to prognosis: 8 cycles of VAC in standard-risk patients or 1 cycle of VAC and high-dose CT and autologous transplant in the case of increased risk.We analyzed induction CT toxicity, type of consolidation treatment, and disease-free (DFS) and overall (OS) survival by the Kaplan-Meier method, with a log-rank analysis of prognostic factors with regard to OS. RESULTS: Thirty-six patients were analyzed (2003 to 2011). Sixty percent were male, with a median age of 16 years (range, 7 to 57 y). The most frequent location was axial (43%), followed by extremities (34%), extraosseous (18%), and ribs (9%). Fifty-four percent of patients had metastases, of which, 58% were pulmonary.The median follow-up period was 36 months (5 to 101 mo). Median DFS was 25 months (16 to 34 mo) and median OS 29 months (19 to 40 mo), with a 3-year OS of 40%. Median OS from progression was 7 months (0.4 to 15 mo). Age <15 years and normal lactate dehydrogenase levels were associated with prolonged OS. CONCLUSIONS: Induction CT with the VIDE regimen was feasible in most patients, with a low risk for early progression. Hematological toxicity was substantial but manageable. Adult patients had a worse prognosis. Survival after progression was dismal.

Feasibility and safety of a modified outpatient regimen with intravenous/intraperitoneal chemotherapy for optimally debulked stage III ovarian cancer.

OBJECTIVE: Intraperitoneal (i.p.) chemotherapy improves survival in optimally debulked ovarian cancer patients. However, the need for inpatient administration and the perceived higher toxicity rates compared with standard intravenous chemotherapy have limited its widespread application. Several modified outpatient schemes, such as the Spanish Ovarian Cancer Research Group (GEICO) regimen, have been tested and have reported overall better tolerance with an improvement in completion treatment rates. The aim of our study was to assess the toxicity of the GEICO regimen in patients treated at our institution. METHODS: We reviewed clinical records of stage III ovarian cancer patients with optimally debulked primary cytoreduction surgery that were treated from June 2009 to April 2013 with the GEICO regimen. Patients received intravenous paclitaxel (175 mg/m2) for 3 hours on day 1, i.p. cisplatin (100 mg/m2) on day 2, and i.p. paclitaxel (60 mg/m2) on day 8 every 21 days for a maximum of 6 cycles. RESULTS: Twenty-one patients were identified. In 67% of the patients, i.p. port placement was performed at the primary surgery. The most common grade 3-to-4 toxicities seen were abdominal pain (14.3%) and neurotoxicity (9.5%). Eighteen patients (85.7%) completed the 6 cycles. Three patients stopped chemotherapy because of treatment-related toxicity. There were no serious port-related complications. With a median follow-up of 46 months, median progression-free survival was 23 months (95% confidence interval [11.8-34.6]). Nine patients (42.9%) have relapsed; most relapses were multifocal and extraperitoneal. CONCLUSION: The administration of the GEICO outpatient modified regimen was feasible with a good safety profile. It seems to show less toxicity than previously reported IP chemotherapy regimens. In our institution, port-related complications were infrequent and easily managed. However, further studies are warranted to establish the optimal i.p. regimen in a prospective manner and to validate it in a larger phase 3 trial.

Long-term and short-term prognostic value of the prognostic nutritional index in cancer: a narrative review.

OBJECTIVE: To perform a narrative review of the prognostic value of prognostic nutritional index (PNI) in cancers. BACKGROUND: Prognostic estimation greatly determines the treatment approach in various cancers. The PNI, calculated using the serum albumin level and total lymphocyte count, is a useful indicator to assess nutritional and immunological conditions. The PNI represents a low-cost, easy-to-perform, noninvasive, rapid, and standardized tool for estimating the prognosis of cancer. Many studies have aimed to clarify the prognostic value of PNI for various types of cancer. METHODS: We summarize the studies, particularly the systematic reviews and meta-analyses, that have examined the prognostic value of PNI in common cancers. CONCLUSIONS: The relevant studies indicate that low PNI is an independent prognostic factor for decreasing overall survival in many types of cancers. Disease-free survival and progression-free survival were also associated with PNI in some types of cancer including lung cancer and renal cell carcinoma. Therefore, we suggest that the measurement of PNI is a useful method to identify cancer patients that have a worse prognosis and that the treatment strategy for these patients be adjusted accordingly. We hypothesize that maintaining good nutritional status during treatment may improve outcomes of various cancers.

Radiomics and radiogenomics in head and neck squamous cell carcinoma: Potential contribution to patient management and challenges.

The application of imaging biomarkers in oncology is still in its infancy, but with the expansion of radiomics and radiogenomics a revolution is expected in this field. This may be of special interest in head and neck cancer, since it can promote precision medicine and personalization of treatment by overcoming several intrinsic obstacles in this pathology. Our goal is to provide the medical oncologist with the basis to approach these disciplines and appreciate their main uses in clinical research and clinical practice in the medium term. Aligned with this objective we analyzed the most relevant studies in the field, also highlighting novel opportunities and current challenges.

Prognostic Nutritional Index as an independent prognostic factor in locoregionally advanced squamous cell head and neck cancer.

BACKGROUND: Locally advanced head and neck squamous cell carcinoma (LAHNSCC) is a heterogeneous disease in which better predictive and prognostic factors are needed. Apart from TNM stage, both systemic inflammation and poor nutritional status have a negative impact on survival. METHODS: We retrospectively analysed two independent cohorts of a total of 145 patients with LAHNSCC treated with induction chemotherapy followed by concurrent chemoradiotherapy at two different academic institutions. Full clinical data, including the Prognostic Nutritional Index (PNI), neutrophil to lymphocyte ratio and derived neutrophil to lymphocyte ratio, were analysed in a training cohort of 50 patients. Receiver operating characteristic curve analysis was used to establish optimal cut-off. Univariate and multivariate analyses of prognostic factors for overall survival (OS) were performed. Independent predictors of OS identified in multivariate analysis were confirmed in a validation cohort of 95 patients. RESULTS: In the univariate analysis, low PNI (PNI<45) (p=0.001), large primary tumour (T4) (p=0.044) and advanced lymph node disease (N2b-N3) (p=0.025) were significantly associated with poorer OS in the validation cohort. The independent prognostic factors in the multivariate analysis for OS identified in the training cohort were dRNL (p=0.030) and PNI (p=0.042). In the validation cohort, only the PNI remained as independent prognostic factor (p=0.007). CONCLUSIONS: PNI is a readily available, independent prognostic biomarker for OS in LAHNSCC. Adding PNI to tumour staging could improve individual risk stratification of patients with LAHNSCC in future clinical trials.

Controversies in the multimodality management of locally advanced rectal cancer.

Neoadjuvant radiotherapy previous to radical surgery, both as short-course radiotherapy and as long-course radiotherapy combined with 5-FU-based chemotherapy (LCRCT), is routinely used in the management of locally advanced rectal cancer, with consistent benefits in the reduction in the local relapse risk. Unfortunately, survival benefits have been elusive to demonstrate with this approach, especially in the setting of radical surgery in the form of total mesorectal excision (TME). Concerns about over-treating early-stage patients and about the possible long-term side effects have also cast more doubts in a blanket approach of treating all patients with neoadjuvant radiotherapy, especially with LCRCT. In this review of selected controversial topics in locally advanced rectal cancer, we examine the benefits and drawbacks for the use of both neoadjuvant approaches in the TME era, the role of the intensification of the neoadjuvant regimens with new chemotherapy agents and modifications of the radiotherapy regimen, the usefulness of adjuvant chemotherapy, especially after LCRCT and surgery, and the management of elderly and/or frail patients. Finally, we offer some future perspectives in the management of these patients.

Adjuvant chemoradiation in gastric cancer: long-term outcomes and prognostic factors from a single institution.

BACKGROUND: Adjuvant chemoradiotherapy (CRT) improves relapse-free (RFS) and overall survival (OS) in patients with resected gastric cancer. However, difficulties in standardizing an optimal surgical approach and a perceived higher toxicity compared with the perioperative approach have limited its widespread application in Europe. The aim of our study was to assess toxicity and long-term outcomes of adjuvant CRT at our institution. METHODS: A retrospective review (September 2001-January 2012) was completed of patients with resected gastric cancer who received adjuvant CRT (Macdonald regimen). Adverse events and completion rates, RFS and OS were estimated. Univariate and multivariate analyses of prognostic factors for OS were performed. RESULTS: Eighty-seven patients were included. Most had diffuse (52%) and locally advanced tumors (stage III-IV; 66.7%). D2 lymphadenectomy was performed in 80.5%. The most frequent grade 3-4 toxicities were gastrointestinal (28%) and stomatitis (20%), with 78.2% completing treatment. With a median follow-up of 115 months, 58.5% had relapsed, most of them distantly. Median RFS and OS were 9 and 24 months, respectively. Univariate analysis showed that performance status, stage and lymph node burden were significant factors for OS. In the multivariate study, only stage and lymph node burden remained as independent OS predictors. CONCLUSIONS: Our implementation of the Macdonald regimen achieved worse outcomes than those reported in the INT-0116 trial. The rate of distant relapse remains unacceptably high. Higher rate of positive lymph nodes and of diffuse tumors could explain some differences. The use of perioperative chemotherapy, especially in patients with a poorer prognosis, might improve these results.

Heart failure as first sign of development of cardiac metastases in a patient with diagnosis of papillary thyroid carcinoma on treatment with tyrosine-kinase inhibitors: differential diagnoses and clinical management.

BACKGROUND: Cardiac metastases from papillary thyroid carcinoma are very uncommon. Their incidence is rising due to improvements in survival and diagnosis; nevertheless, our patient is the fourth case reported up to date. There are no clinical trials available in this scenario. Therefore, treatment choice is made based on clinical experience and case reports; notably, the largest case report series was prior to the approval for using tyrosine-kinase inhibitors in thyroid cancer. PATIENT: A 73-year-old lady had dedifferentiated papillary thyroid cancer with ongoing sorafenib. After 9 months on this treatment, she presented with dyspnea and heart failure. Differential diagnosis included infection, progression of disease and cardiotoxicity. After a comprehensive assessment (echocardiography, computed tomography, PET, magnetic resonance), we found progression of lung disease, and the appearance of heart metastases. RESULTS: After recovering from the basal status, she started on second-line treatment with sunitinib, which was well-tolerated. She achieved stable disease with a decrease in tumor marker levels. CONCLUSIONS: We should include cardiac metastases in the differential diagnosis of heart failure in cancer patients. Magnetic resonance imaging is the gold standard for assessment. Sorafenib is the mainstay of the first-line therapy in metastatic thyroid cancer, achieving long-term disease control with good tolerance. Sunitinib could be a safe second-line treatment option (not cardiotoxicity related) with promising results. Therefore, our report presents a sequence of treatment with tyrosine-kinase inhibitors in metastatic thyroid carcinoma with an encouraging outcome, which deserves further investigation.

Pleuropulmonary angiosarcoma involving the liver, the jejunum and the spine, developed from chronic tuberculosis pyothorax: Multidisciplinary approach and review of literature.

Pleuropulmonary angiosarcomas are very rare, with less than fifty cases reported in the literature. In most cases, the etiology is unknown but the presence of a chronic tuberculous pyothorax has been reported in several Asian case reports as a possible risk factor. We report the case of a Caucasian 68-year old man who presented with a pleuropulmonary angiosarcoma that arose from a chronic tuberculous pyothorax and which involved the ribs and the vertebrae, the psoas muscle, and the jejunum. The patient received adapted anti-tuberculosis treatment, embolization of the mass in the small bowel, palliative external beam radiotherapy on the spine and systemic chemotherapy with liposomal non-pegylated doxorubicin and ifosfamide. With this multidisciplinary approach the patient's symptoms were well controlled and he achieved a complete metabolic response after six cycles of chemotherapy. Unfortunately, the patient died after eight months from the beginning of chemotherapy due to an acute lung injury secondary to extensive bilateral interstitial infiltrates. Opportunistic pathogens or drug-induced lung toxicity were the most probable causes. Treatment with liposomal non-pegylated doxorubicin and ifosfamide could be a reasonable option in pleuropulmonary angiosarcoma but it should be validated in clinical trials. Chronic pyothorax seems to be a predisposing factor for the development of pleural angiosarcoma but further investigations are required to assess a causal association.