STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer.

BACKGROUND: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. METHODS/DESIGN: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. DISCUSSION: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. TRIAL REGISTRATION: STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.

Cancer testiculaire: un modèle pour optimiser le suivi radiologique [Testicular cancer: a model to optimize the radiological follow-up].

Le cancer testiculaire, bien que peu fréquent, revêt une importance particulière en oncologie ; il représente actuellement un modèle pour optimiser un suivi radiologique tout en essayant de diminuer l'apparition de tumeurs radio-induites.En effet, cette pathologie présente un taux très élevé de survie nécessitant, au vu du jeune âge des patients, des bilans radiologiques à long terme, auxquels pourront être liés des effets secondaires, en particulier les tumeurs secondaires.Afin de diminuer cela, les recommandations de prise en charge ont évolué et les protocoles de radiologie s'améliorent afin d'exposer à moins de rayonnements ionisants pour un résultat identique.Il est donc devenu primordial de maintenir un suivi optimal tout en essayant d'en minimiser la toxicité. Despite being rare cancers, testicular seminoma and non-seminoma play an important role in oncology: they represent a model on how to optimize radiological follow-up, aiming at a lowest possible radiation exposure and secondary cancer risk. Males diagnosed with testicular cancer undergo frequently prolonged follow-up with CT-scans with potential toxic side effects, in particular secondary cancers. To reduce the risks linked to ionizing radiation, precise follow-up protocols have been developed. The number of recommended CT-scanners has been significantly reduced over the last 10 years. The CT scanners have evolved technically and new acquisition protocols have the potential to reduce the radiation exposure further.

Rectal enema is an alternative to full mechanical bowel preparation for primary rectal cancer surgery.

AIM: According to the French GRECCAR III randomized trial, full mechanical bowel preparation (MBP) for rectal surgery decreases the rate of postoperative morbidity, in particular postoperative infectious complications, but MBP is not well tolerated by the patient. The aim of the present study was to determine whether a preoperative rectal enema (RE) might be an alternative to MBP. METHODS: An analysis was performed of 96 matched cohort patients undergoing rectal resection with primary anastomosis and protective ileostomy at two different university teaching hospitals, whose rectal cancer management was comparable except for the choice of preoperative bowel preparation (MBP or RE). Prospective databases were retrospectively analysed. RESULTS: Patients were well matched for age, gender, body mass index and Charlson index. The surgical approach and cancer characteristics (level above anal verge, stage and use of neoadjuvant therapy) were comparable between the two groups. Anastomotic leakage occurred in 10% of patients having MBP and in 8% having RE (P = 1.00). Pelvic abscess formation (6% vs 2%, P = 0.63) and wound infection (8% vs 15%, P = 0.55) were also comparable. Extra-abdominal infection (13% vs 13%, P = 1.00) and non-infectious abdominal complications such as ileus and bleeding (27% and 31%, P = 0.83) were not significantly different. Overall morbidity was comparable in the two groups (50% vs 54%, P = 0.83). CONCLUSION: A simple RE before rectal surgery seems not to be associated with more postoperative infectious complications nor a higher overall morbidity than MBP.

Clinical utility of a molecular test in adjuvant treatment decision making in women with endocrine-sensitive early stage breast cancer: a retrospective, single center one year experience

Background. Molecular tests for breast cancer (BC) risk assessment are reimbursed by health insurances in Switzerland since the beginning of year 2015. The main current role of these tests is to help oncologists to decide about the usefulness of adjuvant chemotherapy in patients with early stage endocrine-sensitive and human epidermal growth factor receptor 2 (HER2)-negative BC. These gene expression signatures aim at predicting the risk of recurrence in this subgroup. One of them (OncotypeDx/OT) also predicts distant metastases rate with or without the addition of cytotoxic chemotherapy to endocrine therapy. The clinical utility of these tests -in addition to existing so-called "clinico-pathological" prognostic and predictive criteria (e.g. stage, grade, biomarkers status)-is still debated. We report a single center one year experience of the use of one molecular test (OT) in clinical decision making. Methods. We extracted from the CHUV Breast Cancer Center data base the total number of BC cases with estrogen-receptor positive (ER+), HER2-negative early breast cancer (node negative (pN0) disease or micrometastases in up to 3 lymph nodes) operated between September 2014 and August 2015. For the cases from this group in which a molecular test had been decided by the tumor board, we collected the clinicopathologic parameters, the initial tumor board decision, and the final adjuvant systemic therapy decision. Results. A molecular test (OT) was done in 12.2% of patients with ER + HER2 negative early BC. The median age was 57.4 years and the median invasive tumor size was 1.7 cm. These patients were classified by ODX testing (Recurrence Score) into low-, intermediate-, and high risk groups, respectively in 27.2%, 63.6% and 9% of cases. Treatment recommendations changed in 18.2%, predominantly from chemotherapyendocrine therapy to endocrine treatment alone. Of 8 patients originally recommended chemotherapy, 25% were recommended endocrine treatment alone after receiving the Recurrence Score result. Conclusions. Though reimbursed by health insurances since January 2015, molecular tests are used moderately in our institution as per the decision of the multidisciplinary tumor board. It's mainly used to obtain a complementary confirmation supporting the decision of no chemotherapy. The OncotypeDx Recurrence Score results were in the intermediate group in 66% of the 9 tested cases but contributed to avoid chemotherapy in 2 patients during the last 12 months.

Stereotactic body radiation therapy with helical tomotherapy for medical inoperable early-stage primary and second-primary non-small cell lung neoplasm : one-year outcome and toxicity analysis

Le cancer du poumon est la première cause de mortalité associée au cancer dans le monde. Le traitement curatif des tumeurs pulmonaires non-à-petites-cellules (NSCLC) diagnostiquées à un stade précoce se base sur une approche chirurgicale. Cependant, étant donné les comorbidités liées à la consommation de tabac, dont la bronchopneumopathie chronique occupe la première place, l'éligibilité chirurgicale pour ce type de cancer se trouve fréquemment limitée. Dans ce contexte, l'emploi de la radiothérapie stéréotaxique (SBRT) est une alternative valable chez les patients atteints d'un NSCLC primaire de stade précoce, et qui sont considérés inopérables à cause de leurs comorbidités. Depuis peu seulemement, le spectre de la SBRT a été élargi aux patients atteints d'un deuxième NSCLC primaire (SPLC), faisant suite à un premier NSCLC, traité avec un but curatif. Ils concernent donc des patients ayant déjà subits une intervention chirurgicale au préalable et qui présentent une réserve fonctionnelle pulmonaire extrêmement réduite. Le succès croissant de la SBRT résulte soit d'une efficacité thérapeutique comparables à la chirurgie, soit de sa toxicité qui semble limitée. À notre connaissance, seulement une étude a reporté des issues cliniques de patients affectés par des NSCLC primaires traités par SBRT. Cette dernière a utilisé la tomothérapie comme système d'irradiation (T-SBRT), sur un faible échantillon de patients (n = 27). Concernant l'irradiation des patients présentant des SPLC, la littérature disponible est pauvre et aucune publication a décrit l'utilisation de la T-SBRT. Ces éléments innovants ont donc motivé la rédaction d'un travail de thèse concernant les premières données cliniques de l'expérience faite au CHUV. Du point de vue des effets secondaires, si la pneumonie actinique précoce et tardive survenant au niveau du champ d'irradiation est désormais une complication iatrogène bien connue de la SBRT, une seule étude s'est intéressée à ce sujet dans le cadre de la T-SBRT. De plus, une entité bénigne et transitoire de pneumonie ( ?) a été reconnue depuis peu : la pneumonie organisée radio-induite (OP). Celle-ci semble se chevaucher comme un autre effet iatrogène à l'extérieur du champ d'irradiation. Originellement, cette dernière avait été rapportée dans les suites de la radiothérapie pour les cancer du sein. Elle a été décrite comme étant initialement limitée au champ d'irradiation et successivement pouvant s'étendre dynamiquement en dehors de celui-ci. Nous avons donc supposé que des infiltrats de OP peuvent être présents chez des patients asymptomatiques, et que ce dynamisme pourrait être identifié déjà au sein du champ d'irradiation. Notre étude a démontré que le traitement par T-SBRT garde des issues cliniques très encourageantes, aussi bien pour les tumeurs primaires que pour les SPLC. Entre autre, ce traitement semble avoir une toxicité limitée, et l'existence vraisemblable de la OP, déjà au sein du champ d'irradiation, peut aider les radiologues à différencier les infiltrats radio-induits d'une une récidive tumorale.

Spleen Volume Variation in Patients with Locally Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemo-Radiotherapy.

There is renewed interest in the immune regulatory role of the spleen in oncology. To date, very few studies have examined macroscopic variations of splenic volume in the setting of cancer, prior to or during therapy, especially in humans. Changes in splenic volume may be associated with changes in splenic function. The purpose of this study was to investigate variations in spleen volume in NSCLC patients during chemo-radiotherapy. Sixty patients with stage I-IIIB NSCLC underwent radiotherapy (60Gy/30 fractions) for six weeks with concomitant carboplatin/paclitaxel (Ca/P; n = 32) or cisplatin/etoposide (Ci/E; n = 28). A baseline PET/CT scan was performed within 2 weeks prior to treatment and during Weeks 2 and 4 of chemo-radiotherapy. Spleen volume was measured by contouring all CT slices. Significant macroscopic changes in splenic volume occurred early after the commencement of treatment. A significant decrease in spleen volume was observed for 66% of Ca/P and 79% of Ci/E patients between baseline and Week 2. Spleen volume was decreased by 14.2% for Ca/P (p<0.001) and 19.3% for Ci/E (p<0.001) patients. By Week 4, spleen volume was still significantly decreased for Ca/P patients compared to baseline, while for Ci/E patients, spleen volume returned to above baseline levels. This is the first report demonstrating macroscopic changes in the spleen in NSCLC patients undergoing radical chemo-radiotherapy that can be visualized by non-invasive imaging.

Prospective evaluation of circulating VEGF in patients with advanced non-small cell lung cancer treated with bevacizumab, pemetrexed and cisplatin in the trial SAKK19/09.

Aim: Bevacizumab is a monoclonal antibody directed against the vascular endothelial growth factor (VEGF). The previous phase II trial ABIGAIL (Reck, 2010) suggested circulating VEGF as a prognostic, but not predictive, biomarker for patients (pts) with non-small cell lung cancer (NSCLC) treated with bevacizumab. We prospectively measured VEGF in the multicenter phase II trial SAKK19/09 (NCT01116219). Methods: SAKK19/09 enrolled 77 evaluable patients (pts) with previously untreated, advanced nonsquamous NSCLC and EGFR wild type. Pts received 4 cycles of cisplatin 75mg/m2 (or carboplatin AUC5), pemetrexed 500mg/m2 and bevacizumab 7.5mg/kg, followed by maintenance therapy with pemetrexed and bevacizumab until progression by RECIST1.1. Follow-up CT scans were performed every 6 weeks until week 54 and every 12 weeks thereafter. Baseline EDTA blood samples were sent by same-day courier to the central laboratory for centrifugation, aliquoting, and freezing. Upon completion of enrollment, aliquots were thawed, and VEGF quantification was performed centrally using Luminex® Performance Assay Human Base Kit A (R&D Systems, Abingdon, UK). The mean value was used to stratify pts into two groups (low versus high VEGF). Best response rate assessed by RECIST1.1 (CR + PR versus SD + PD). Results: Clinical results of the SAKK19/09 trial were reported previously (Gautschi, 2013). Baseline plasma VEGF was detectable in 71 of 77 (92%) evaluable patients treated with chemotherapy and bevacizumab. The mean value was 74.9 pg/ml, the median 47.5 pg/ml, and the range 3.55 to 310 pg/ml. Using the mean as a predefined cutoff value, 50 patients had low VEGF levels and 21 patients had high VEGF levels. High VEGF was significantly associated with shorter PFS (4.1 vs 8.3 months, HR = 2.56; 95%CI: 1.43- 4.57; p = 0.0015) and OS (8.7 vs 17.5 months, HR = 2.67; 95% CI: 1.37-5.20; p = 0.0041), but not with best response rate ( p = 0.2256). Conclusions: Consistent with the ABIGAIL trial, circulating VEGF was prognostic, but not predictive for response, in the current trial. Further work is ongoing to identify potentially predictive biomarkers for bevacizumab, using comprehensive proteomic analyses. Disclosure: S.I. Rothschild: I received honoraria for the participation in advisory boards from Eli Lilly and Roche and for presentations at scientific symposiums sponsored by Roche; O. Gautschi: Honoraria for advisory boards of Eli Lilly and Roche; R. Cathomas: Advisory board member: Eli Lilly. All other authors have declared no conflicts of interest.

PI3K and AKT: Unfaithful Partners in Cancer.

The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway regulates multiple cellular processes. An overactivation of the pathway is frequently present in human malignancies and plays a key role in cancer progression. Hence, its inhibition has become a promising approach in cancer therapy. However, the development of resistances, such as the abrogation of negative feedback mechanisms or the activation of other proliferative signaling pathways, has considerably limited the anticancer efficacy of PI3K/AKT inhibitors. In addition, emerging evidence points out that although AKT is acknowledged as the major downstream effector of PI3K, both PI3K and AKT can operate independently of each other in cancer, revealing another level of complexity in this pathway. Here, we highlight the complex relationship between PI3K and AKT in cancer and further discuss the consequences of this relationship for cancer therapy.

A cast of shadow on adjuvant radiotherapy for prostate cancer: A critical review based on a methodological perspective.

OBJECTIVE: To perform a critical review focusing on the applicability in clinical daily practice of data from three randomized controlled trials (RCTs): SWOG 8794, EORTC 22911, and ARO/AUO 96-02. METHODS AND MATERIALS: An analytical framework, based on the identified population, interventions, comparators, and outcomes (PICO) was used to refine the search of the evidence from the three large randomized trials regarding the use of radiation therapy after prostatectomy as adjuvant therapy (ART). RESULTS: With regard to the inclusion criteria: (1) POPULATION: in the time since they were designed, in two among three trial (SWOG 8794 and EORTC 22911) patients had a detectable PSA at the time of randomization, thus representing de facto a substantial proportion of patients who eventually received salvage RT (SRT) at non-normalised PSA levels rather than ART. (2) INTERVENTIONS: although all the trials showed the benefit of postoperative ART compared to a wait-and-see approach, the dose herein employed would be now considered inadequate; (3) COMPARATORS: the comparison arm in all the 3 RCTs was an uncontrolled observation arm, where patients who subsequently developed biochemical failure were treated in various ways, with up to half of them receiving SRT at PSA well above 1ng/mL, a level that would be now deemed inappropriate; (4) OUTCOMES: only in one trial (SWOG 8794) ART was found to significantly improve overall survival compared to observation, with a ten-year overall survival rate of 74% vs. 66%, although this might be partly the result of imbalanced risk factors due to competing event risk stratification. CONCLUSIONS: ART has a high level of evidence due to three RCTs with at least 10-year follow-up recording a benefit in biochemical PFS, but its penetrance in present daily clinics should be reconsidered. While the benefit of ART or SRT is eagerly expected from ongoing randomized trials, a dynamic risk-stratified approach should drive the decisions making process.

"Hit the primary": A paradigm shift in the treatment of metastatic prostate cancer?

Patients with metastatic prostate cancer (PC) represent a heterogeneous group with survival rates varying between 13 and 75 months. The current standard treatment in this setting is hormonal therapy, with or without docetaxel-based chemotherapy. In the era of individualized medicine, however, maximizing treatment options, especially in long-term surviving patients with limited disease burden, is of capital importance. Emerging data, mainly from retrospective surgical series, show survival benefits in men diagnosed with metastatic PC following definitive therapy for the prostate. Whether the irradiation of primary tumor in a metastatic disease might improve the therapeutic ratio in association with systemic treatments remains investigational. In this scenario, modern radiation therapy (RT) can play a significant role owing to its intrinsic capability to act as a more general immune response modifier, as well as to the potentially better toxicity profile compared to surgery. Preclinical data, clinical experience, and challenges in local treatment in de novo metastatic PC are reviewed and discussed.

Gender differences in cancer patients with acute venous thromboembolism.

BACKGROUND: The outcome of cancer patients with acute venous thromboembolism (VTE) may differ according to gender. METHODS: We used the RIETE database to compare the rate of VTE (pulmonary embolism [PE] or deep vein thrombosis [DVT]) recurrences), major bleeding and mortality during the course of anticoagulation, according to gender. RESULTS: As of August 2014, 11,055 patients with active cancer were enrolled in RIETE, of whom 5,104 (46%) were women. During the course of anticoagulation (mean: 142 days), 505 patients developed recurrent VTE, 429 bled and 2730 died. Compared with men, women had a significantly lower rate of fatal bleeding (risk ratio [RR]: 0.69; 95% CI: 0.47-0.99) and death (RR: 0.90; 95% CI: 0.83-0.97), and a non-significantly lower rate of PE recurrences (RR 0.83; 95% CI: 0.65-1.06) and major bleeding (RR: 0.89; 95% CI: 0.74-1.08). CONCLUSIONS: During the course of anticoagulation, cancer women with VTE had a better outcome than men.

Identification of Low-Risk Patients with Acute Symptomatic Pulmonary Embolism for Outpatient Therapy.

RATIONALE: Patients with acute symptomatic pulmonary embolism (PE) deemed to be at low risk for early complications might be candidates for partial or complete outpatient treatment. OBJECTIVES: To develop and validate a clinical prediction rule that accurately identifies patients with PE and low risk of short-term complications and to compare its prognostic ability with two previously validated models (i.e., the Pulmonary Embolism Severity Index [PESI] and the Simplified PESI [sPESI]) METHODS: Multivariable logistic regression of a large international cohort of patients with PE prospectively enrolled in the RIETE (Registro Informatizado de la Enfermedad TromboEmbólica) registry. MEASUREMENTS AND MAIN RESULTS: All-cause mortality, recurrent PE, and major bleeding up to 10 days after PE diagnosis were determined. Of 18,707 eligible patients with acute symptomatic PE, 46 (0.25%) developed recurrent PE, 203 (1.09%) bled, and 471 (2.51%) died. Predictors included in the final model were chronic heart failure, recent immobilization, recent major bleeding, cancer, hypotension, tachycardia, hypoxemia, renal insufficiency, and abnormal platelet count. The area under receiver-operating characteristic curve was 0.77 (95% confidence interval [CI], 0.75-0.78) for the RIETE score, 0.72 (95% CI, 0.70-0.73) for PESI (P < 0.05), and 0.71 (95% CI, 0.69-0.73) for sPESI (P < 0.05). Our RIETE score outperformed the prognostic value of PESI in terms of net reclassification improvement (P < 0.001), integrated discrimination improvement (P < 0.001), and sPESI (net reclassification improvement, P < 0.001; integrated discrimination improvement, P < 0.001). CONCLUSIONS: We built a new score, based on widely available variables, that can be used to identify patients with PE at low risk of short-term complications, assisting in triage and potentially shortening duration of hospital stay.

Long-Term Anticoagulant Therapy of Patients with Venous Thromboembolism. What Are the Practices?

Current guidelines of antithrombotic therapy suggest early initiation of vitamin K antagonists (VKA) in non-cancer patients with venous thromboembolism (VTE), and long-term therapy with low-molecular weight heparin (LMWH) for those with cancer. We used data from RIETE (international registry of patients with VTE) to report the use of long-term anticoagulant therapy over time and to identify predictors of anticoagulant choice (regarding international guidelines) in patients with- and without cancer. Among 35,280 patients without cancer, 82% received long-term VKA (but 17% started after the first week). Among 4,378 patients with cancer, 66% received long term LMWH as monotherapy. In patients without cancer, recent bleeding (odds ratio [OR] 2.70, 95% CI 2.26-3.23), age >70 years (OR 1.15, 95% CI 1.06-1.24), immobility (OR 2.06, 95% CI 1.93-2.19), renal insufficiency (OR 2.42, 95% CI 2.15-2.71) and anemia (OR 1.75, 95% CI 1.65-1.87) predicted poor adherence to guidelines. In those with cancer, anemia (OR 1.83, 95% CI 1.64-2.06), immobility (OR 1.51, 95% CI 1.30-1.76) and metastases (OR 3.22, 95% CI 2.87-3.61) predicted long-term LMWH therapy. In conclusion, we report practices of VTE therapy in real life and found that a significant proportion of patients did not receive the recommended treatment. The perceived increased risk for bleeding has an impact on anticoagulant treatment decision.