Standard versus fractionated high-dose cisplatin plus radiation for locally advanced head and neck cancer: Results of the CisFRad (GORTEC 2015-02) randomized phase II trial.

BACKGROUND: Chemoradiotherapy with high-dose cisplatin (HD-Cis: 100 mg/m2 q3w for three cycles) is the standard of care (SOC) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Cumulative delivered dose of cisplatin is prognostic of survival, even beyond 200 mg/m2 but high toxicity compromises its delivery. AIM: Cisplatin fractionation may allow, by decreasing the peak serum concentration, to decrease toxicity. To date, no direct comparison was done of HD-Cis versus fractionated high dose cisplatin (FHD-Cis). METHODS: This is a multi-institutional randomized phase II trial, stratified on postoperative or definitive chemoradiotherapy, comparing HD-Cis to FHD-Cis (25 mg/m2/d d1-4 q3w for 3 cycles) in patients with LA-HNSCC. The primary endpoint was the cumulative delivered cisplatin dose. RESULTS: Between December 2015 and April 2018, 124 patients were randomized. Median cisplatin cumulative delivered dose was 291 mg/m2 (IQR: 251;298) in the FHD-Cis arm and 274 mg/m2 (IQR: 198;295) in the HD-Cis arm (P = 0.054). The proportion of patients receiving a third cycle of cisplatin was higher, with a lower proportion of grade 3-4 acute AEs in the FHD-Cis arm compared to the HD-Cis arm: 81 % vs. 64 % (P = 0.04) and 10 % vs. 17 % (P = 0.002), respectively. With a median follow-up of 48 months (IQR: 41;55), locoregional failure rate, PFS and OS were similar between the two arms. CONCLUSION: Although the primary endpoint was not met, FHD-Cis allowed more cycles of cisplatin to be delivered with lower toxicity, when compared to SOC. FHD-Cis concurrently with RT is a treatment option which deserves further consideration.

Molecular imaging and related therapeutic options for medullary thyroid carcinoma: state of the art and future opportunities.

Due to its rarity and non-specific clinical presentation, accurate diagnosis, and optimal therapeutic strategy of medullary thyroid carcinoma (MTC) remain challenging. Molecular imaging provides valuable tools for early disease detection, monitoring treatment response, and guiding personalized therapies. By enabling the visualization of molecular and cellular processes, these techniques contribute to a deeper understanding of disease mechanisms and the development of more effective clinical interventions. Different nuclear imaging techniques have been studied for assessing MTC, and among them, PET/CT utilizing multiple radiotracers has emerged as the most effective imaging method in clinical practice. This review aims to provide a comprehensive summary of the current use of advanced molecular imaging modalities, with a particular focus on PET/CT, for the management of patients with MTC. It aims to guide physicians towards a rationale for the use of molecular imaging also including theranostic approaches and novel therapeutical opportunities. Overall, we emphasize the evolving role of nuclear medicine in MTC. The integration of diagnostics and therapeutics by in vivo molecular imaging represents a major opportunity to personalize treatment for individual patients, with targeted radionuclide therapy being one representative example.

Dynamic profiling of immune microenvironment during anti-PD-1 immunotherapy for head and neck squamous cell carcinoma: the IPRICE study.

BACKGROUND: Immune checkpoint inhibitors of programmed cell death protein 1 (PD-1) represent a significant breakthrough in treating head and neck squamous cell carcinoma (HNSCC), with long-lasting responses and prolonged survival observed in first- and second-line therapy. However, this is observed in < 20% of patients and high primary/secondary resistance may occur. The primary objective of the identification of predictive factors for the response to anti-PD-1 immunotherapy in head and neck squamous cell carcinoma (IPRICE) study is to identify predictive factors of response to anti-PD-1 immunotherapy. METHODS: The IPRICE study is a single-center, prospective, non-randomized, open-label, and interventional clinical trial. Liquid and tumor biopsies will be performed in 54 patients with recurrent/metastatic (R/M) HNSCC undergoing anti-PD-1 immunotherapy alone to compare the evolution of gene expression and immunological profile between responders and non-responders. We will use a multidisciplinary approach including spatial transcriptomics, single seq-RNA analysis, clinical data, and medical images. Genes, pathways, and transcription factors potentially involved in the immune response will also be analyzed, including genes involved in the interferon-gamma (IFN-γ) pathway, immunogenic cell death and mitophagy, hypoxia, circulating miRNA-mediated immunomodulation, cytokines, and immune repertoire within the tumor microenvironment (TME). With a follow-up period of 3-years, these data will help generate effective biomarkers to define optimal therapeutic strategy and new immunomodulatory agents based on a better understanding of primary/secondary resistance mechanisms. Tumor biopsy will be performed initially before the start of immunotherapy at the first tumor assessment and is only proposed at tumor progression. Clinical data will be collected using a dedicated Case Report Form (CRF). DISCUSSION: Identifying predictive factors of the response to anti-PD-1 immunotherapy and optimizing long-term immune response require a thorough understanding of the intrinsic and acquired resistance to immunotherapy. To achieve this, dynamic profiling of TME during anti-PD-1 immunotherapy based on analysis of tumor biopsy samples is critical. This will be accomplished through the anatomical localization of HNSCC, which will allow for the analysis of multiple biopsies during treatment and the emergence of breakthrough technologies including single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. TRIAL REGISTRATION: Clinicaltrial.gov. Registered April 14, 2022, https://www. CLINICALTRIALS: gov/study/NCT05328024 .

A novel ΔNp63-dependent immune mechanism improves prognosis of HPV-related head and neck cancer.

Background: Deconvoluting the heterogenous prognosis of Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) is crucial for enhancing patient care, given its rapidly increasing incidence in western countries and the adverse side effects of OSCC treatments. Methods: Transcriptomic data from HPV-positive OSCC samples were analyzed using unsupervised hierarchical clustering, and clinical relevance was evaluated using Kaplan-Meier analysis. HPV-positive OSCC cell line models were used in functional analyses and phenotypic assays to assess cell migration and invasion, response to cisplatin, and phagocytosis by macrophages in vitro. Results: We found, by transcriptomic analysis of HPV-positive OSCC samples, a ΔNp63 dependent molecular signature that is associated with patient prognosis. ΔNp63 was found to act as a tumor suppressor in HPV-positive OSCC at multiple levels. It inhibits cell migration and invasion, and favors response to chemotherapy. RNA-Seq analysis uncovered an unexpected regulation of genes, such as DKK3, which are involved in immune response-signalling pathways. In agreement with these observations, we found that ΔNp63 expression levels correlate with an enhanced anti-tumor immune environment in OSCC, and ΔNp63 promotes cancer cell phagocytosis by macrophages through a DKK3/NF-κB-dependent pathway. Conclusion: Our findings are the first comprehensive identification of molecular mechanisms involved in the heterogeneous prognosis of HPV-positive OSCC, paving the way for much-needed biomarkers and targeted treatment.

Tumor-Suppressive and Immunomodulating Activity of miR-30a-3p and miR-30e-3p in HNSCC Cells and Tumoroids.

Head and neck squamous cell carcinomas (HNSCCs) are heterogeneous tumors, well known for their frequent relapsing nature. To counter recurrence, biomarkers for early diagnosis, prognosis, or treatment response prediction are urgently needed. miRNAs can profoundly impact normal physiology and enhance oncogenesis. Among all of the miRNAs, the miR-30 family is frequently downregulated in HNSCC. Here, we determined how levels of the 3p passenger strands of miR-30a and miR-30e affect tumor behavior and clarified their functional role in LA-HNSCC. In a retrospective study, levels of miR-30a-3p and miR-30e-3p were determined in 110 patients and correlated to overall survival, locoregional relapse, and distant metastasis. miR-30a/e-3p were expressed in HNSCC cell lines and HNSCC patient-derived tumoroids (PDTs) to investigate their effect on tumor cells and their microenvironment. Both miRNAs were found to have a prognosis value since low miR-30a/e-3p expression correlates to adverse prognosis and reduces overall survival. Low expression of miR-30a/e-3p is associated with a shorter time until locoregional relapse and a shorter time until metastasis, respectively. miR-30a/e-3p expression downregulates both TGF-ßR1 and BMPR2 and attenuates the survival and motility of HNSCC. Results were confirmed in PDTs. Finally, secretomes of miR-30a/e-3p-transfected HNSCC activate M1-type macrophages, which exert stronger phagocytic activities toward tumor cells. miR-30a/e-3p expression can discriminate subgroups of LA-HNSCC patients with different prognosis, making them good candidates as prognostic biomarkers. Furthermore, by targeting members of the TGF-ß family and generating an immune-permissive microenvironment, they may emerge as an alternative to anti-TGF-ß drugs to use in combination with immune checkpoint inhibitors.

Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction.

(1) Background: Epiregulin (EREG) is a ligand of EGFR and ErB4 involved in the development and the progression of various cancers including head and neck squamous cell carcinoma (HNSCC). Its overexpression in HNSCC is correlated with short overall survival and progression-free survival but predictive of tumors responding to anti-EGFR therapies. Besides tumor cells, macrophages and cancer-associated fibroblasts shed EREG in the tumor microenvironment to support tumor progression and to promote therapy resistance. Although EREG seems to be an interesting therapeutic target, no study has been conducted so far on the consequences of EREG invalidation regarding the behavior and response of HNSCC to anti-EGFR therapies and, more specifically, to cetuximab (CTX); (2) Methods: EREG was silenced in various HNSCC cell lines. The resulting phenotype (growth, clonogenic survival, apoptosis, metabolism, ferroptosis) was assessed in the absence or presence of CTX. The data were confirmed in patient-derived tumoroids; (3) Results: Here, we show that EREG invalidation sensitizes cells to CTX. This is illustrated by the reduction in cell survival, the alteration of cell metabolism associated with mitochondrial dysfunction and the initiation of ferroptosis characterized by lipid peroxidation, iron accumulation and the loss of GPX4. Combining ferroptosis inducers (RSL3 and metformin) with CTX drastically reduces the survival of HNSCC cells but also HNSCC patient-derived tumoroids; (4) Conclusions: The loss of EREG might be considered in clinical settings as a predictive biomarker for patients that might undergo ferroptosis in response to CTX and that might benefit the most from the combination of ferroptosis inducers and CTX.

Impact of the app-based and nurse-led supportive care program AKO@dom on dose intensity of oral-targeted therapies in patients with metastatic renal cell cancer: a multicentric observational retrospective study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) remain a cornerstone of metastatic kidney cancer (mRCC). Adverse events (AEs) may lead to dose downregulation, and optimal management of AEs is needed to maintain an efficient dose intensity (DI). The aim of our study was to evaluate the impact of an app-based and nurse-led supportive-care program on DI in mRCC patients. METHOD: This multicenter (n = 3), retrospective study evaluated all consecutive mRCC patients who participated in the AKO@dom program, which consisted of an app-based and nurse-led weekly patient evaluation at home during the first 3 months of TKI intake. Treatment patterns and modifications were described, and the mean DI (mDI) was calculated at the end of AKO@dom. RESULTS: Eighty-nine patients were included: 12 had sunitinib, 18 pazopanib, 12 axitinib, and 47 cabozantinib. Median age was 69 years (60-76). TKIs were mainly initiated at standard doses except for cabozantinib (53% started at 40 mg/day); 71% had prior systemic treatment. Nine patients discontinued permanent treatment during the program. Thirty-two patients required ≥ 1 dose interruption, and 29% experienced ≥ 1 grade 3 AE of any type. The mDI (in mg/day) at 3 months was 34.4 ± 17.7 for sunitinib, 672.8 ± 144 for pazopanib, 8.6 ± 2.6 for axitinib, and 40 (36-48) for cabozantinib. Fifty-five patients [68.75% (95% CI: 57-78%)] had a mDI ≥ than reported in the literature. Overall survival at 12 months was 64.2% (CI 95%: 55-75%). CONCLUSION: The AKO@dom program allowed 68.75% of patients to maintain a high dose intensity after 3 months of TKI treatment. The impact on survival outcomes needs to be evaluated in randomized clinical trials.

Weekly Paclitaxel, Carboplatin, and Cetuximab as First-Line Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma for Patients Ineligible to Cisplatin-Based Chemotherapy: A Retrospective Monocentric Study in 60 Patients.

OBJECTIVE: For most patients suffering from recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), chemotherapy is the main option after considering surgery and reirradiation. Cetuximab combined with a platinum-fluorouracil regimen (EXTREME) has been the standard of care for over a decade. Nevertheless, a significant number of patients remain unfit for this regimen because of age, severe comorbidities, or poor performance status. The aim of this study is to investigate an alternative regimen with sufficient efficacy and safety. METHODS: We reviewed retrospectively the medical charts of all patients treated with paclitaxel, carboplatin, and cetuximab (PCC) at our institution. Eligibility criteria were as follows: first-line R/M-HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx not suitable for local therapy, cisplatin, and/or 5-FU ineligibility, ECOG-PS: 0-2. PCC consisted of paclitaxel 80 mg/m2, carboplatin AUC 2, and cetuximab at an initial dose of 400 mg/m2 then 250 mg/m2, for 16 weekly administrations followed by cetuximab maintenance for patients for whom a disease control was obtained. The primary endpoint was overall survival (OS), and secondary endpoints were overall response rate (ORR), progression free survival (PFS), and safety. RESULTS: We identified 60 consecutive patients treated with PCC between 2010 and 2016 at our institution. Thirty-one patients (52%) were ECOG-PS 2. Fifty-five patients (92%) were cisplatin ineligible. ORR was 43.3% (95% CI, 30.8-55.8), and disease control rate was 65% (95% CI, 52.9-77.1). With a median follow-up of 35.7 months (IQR 28.6-48.8), median PFS was 5.8 months (95% CI, 4.5-7.2), and median OS was 11.7 months (95% CI, 7.5-14.8). For ECOG-PS 0-1 patients, median OS was 14.8 months (95% CI, 12.2-21.7) while it was only 7.5 months (95%CI: 5.5-12.7) for ECOG-PS 2 patients (p < 0.04). Grades III-IV toxicities occurred in 30 patients (50%). Most toxicities were hematologic. Six patients (10%) had febrile neutropenia. Nonhematologic toxicities were reported such as cutaneous toxicities, neuropathy, infusion-related reactions, or electrolyte disorders. CONCLUSION: The weekly PCC regimen seems to be an interesting option in cisplatin-unfit patients. This study shows favorable PFS and OS when compared with what is achieved with the EXTREME regimen and a high controlled disease rate with predictable and manageable toxicities even in the more fragile population.

Cav1/EREG/YAP Axis in the Treatment Resistance of Cav1-Expressing Head and Neck Squamous Cell Carcinoma.

The EGFR-targeting antibody cetuximab (CTX) combined with radiotherapy is the only targeted therapy that has been proven effective for the treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Recurrence arises in 50% of patients with HNSCC in the years following treatment. In clinicopathological practice, it is difficult to assign patients to classes of risk because no reliable biomarkers are available to predict the outcome of HPV-unrelated HNSCC. In the present study, we investigated the role of Caveolin-1 (Cav1) in the sensitivity of HNSCC cell lines to CTX-radiotherapy that might predict HNSCC relapse. Ctrl- and Cav-1-overexpressing HNSCC cell lines were exposed to solvent, CTX, or irradiation, or exposed to CTX before irradiation. Growth, clonogenicity, cell cycle progression, apoptosis, metabolism and signaling pathways were analyzed. Cav1 expression was analyzed in 173 tumor samples and correlated to locoregional recurrence and overall survival. We showed that Cav1-overexpressing cells demonstrate better survival capacities and remain proliferative and motile when exposed to CTX-radiotherapy. Resistance is mediated by the Cav1/EREG/YAP axis. Patients whose tumors overexpressed Cav1 experienced regional recurrence a few years after adjuvant radiotherapy ± chemotherapy. Together, our observations suggest that a high expression of Cav1 might be predictive of locoregional relapse of LA-HNSCC.

Immunotherapy Breakthroughs in the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) in the recurrent or metastatic (R/M) setting is a devastating disease with a poor prognosis. Until recently, the reference first line treatment was the EXTREME protocol, which yields a 10.1 months median survival, and almost no effective treatment are available in second line. Immune checkpoint inhibitors (ICIs) have changed the prognosis of several metastatic solid tumors. Given their inflammatory profile and high mutational burden, HNSCC is a good candidate for ICIs treatments. First, a strong pembrolizumab efficacy signal was shown in the Keynote-012 Phase Ib study. Then, the phase III Checkmate-141 study validated the efficacy of nivolumab in platinum-resistant patients. Finally, the first line conquest is acquired since the final results of the keynote-048 phase III study that demonstrated the superiority of pembrolizumab versus EXTREME in CPS ≥ 1 patients, and with the addition of platinum and 5FU in all patients. However, the first line treatment landscape is not frozen. Two studies (Checkmate-651 and Kestrel) are investigating the efficacy of the combination of antibodies raised against CTLA-4 and PD-(L)1. Results are impatiently awaited. Further progress needs the use of new immunotherapeutic agents such as monalizumab or ICOS agonist rather in combination with an anti-PD(L)1. New associations of ICIs and chemotherapeutic or targeted therapeutic agents are also actively investigated. Finally, ICIs has to be studied in the locally advanced setting where there is a chance of cure. Several trials are testing the potential synergistic combination of ICIs with radiotherapy and platinum or cetuximab, or ICIs used in a neoadjuvant setting.

Bone metastases from a 1p/19q codeleted and IDH1-mutant anaplastic oligodendroglioma: a case report.

BACKGROUND: Oligodendroglioma is a rare type of primary brain tumor which, like other malignant gliomas, metastasizes very rarely even when in high-grade form. CASE REPORT: A 36-year-old white man diagnosed 29 months previously as having 1p/19q codeleted anaplastic oligodendroglioma presented bilateral cruralgia and lower limb motor deficits. A computed tomography scan showed multiple osteoblastic bone lesions. The presence of oligodendroglial cells was revealed by bone marrow biopsy and confirmed by immunohistochemical analyses. A positon emission tomography-computed tomography scan confirmed the exclusive involvement of bones. CONCLUSION: This case joins less than 20 other reported cases of oligodendroglioma bone marrow metastasis, and is one of only a handful of cases of diffuse bone metastases beyond the axial skeleton. To the best of our knowledge, the early relapse of 1p/19q codeleted anaplastic oligodendroglioma with this distribution of metastases has never been described in the literature.

Factors improving the outcome of patients re-irradiated with intensity-modulated radiotherapy (IMRT) for relapse or new head and neck cancer developed in irradiated areas.

BACKGROUND: Patients with secondary/recurrent squamous cell head and neck cancer have poor prognoses. Re-irradiation is a treatment option. However, best technique to re-irradiate is not known. This study aims to evaluate the outcome of patients treated with curative-intent intensity-modulated radiotherapy (IMRT) re-irradiation (re-RT) for head and neck (H&N) cancers. METHODS: Fifty patients with recurrent H&N cancers underwent fractionated IMRT re-RT. The median time between the two courses of radiotherapy was 22 months. The median dose of re-RT was 66 Gy. RESULTS: The median follow-up of surviving patients was 13.6 months. The median overall survival (OS) was 15.7 months, and the 1- and 2-year OS rates were 62.4% and 33.9%, respectively. On multivariate analysis, performance status (PS) 0-1 (HR, 0.518; 95% CI: 0.292-0.917; P=0.024) and 3D-RT use during the first irradiation course technique (HR, 0.415; 95% CI: 0.183-0.938; P=0.035) were favorable, independent of significant prognostic factors of OS. The median loco-regional progression-free survival (LRPFS) was 8.3 months, and, the 1- and 2-year LRPFS rates were 46.6% and 35.9%, respectively. On multivariate analysis, a surgical resection before re-RT (HR, 0.107; 95% CI: 0.027-0.428; P=0.002), a higher age (HR, 0.894; 95% CI: 0.833-0.960; P=0.002), a PS 0-1 (HR, 0.316; 95% CI: 0.140-0.715; P=0.006), and a long re-RT interval (HR, 0.970; 95% CI: 0.945-0.996; P=0.024) were favorable independent significant prognostic factors of LRPFS. The median progression-free survival (PFS) was 7.0 months and, the 1- and 2-year PFS rates were 45.0% and 30.4%, respectively. On multivariate analysis, a surgical resection before re-RT (HR, 0.129; 95% CI: 0.036-0.466; P=0.002), a PS 0-1 (HR, 0.399; 95% CI: 0.208-0.764; P=0.006) and, a long re-RT interval (HR, 0.958; 95% CI: 0.927-0.989; P=0.009) were favorable, independent significant prognostic factors. The early and late toxicities rates were 28% and 34%, respectively. CONCLUSIONS: Re-RT for H&N cancers can be curative, and the complications can be manageable but patients need to be strictly selected. Surgery before re-RT could improve the patient outcome. Dose and irradiation schedules should be prospectively evaluated.

Any place left for induction chemotherapy for locally advanced head and neck squamous cell carcinoma?

The issue of induction chemotherapy (ICT) interest in locoregionally advanced squamous cell cancer of the head and neck is a real epic that has been carried out over four phase III studies: PARADIGM, DECIDE, NCT01086826 and lastly the conclusive GORTEC 2007-02. With no significant benefit in overall survival of ICT, followed by concurrent chemoradiation over the standard chemoradiotherapy alone, in three of these studies, and a significant number of treatment-related deaths with the standard regimen docetaxel, cisplatin, and fluorouracil, ICT is no longer a hot topic. However, this strategy might still be useful in the aim of limiting the metastatic extension affecting up to 30% of patients: ICT is systematically associated with a reduced metastatic relapse even though the survival effect is never statistically significant when compared directly with concomitant radiochemotherapy. This review summarizes the major studies with their limits and discusses how the ICT could improve the patients' prognosis in the future.

Interest to consider re-challenging by cetuximab and platinum containing regimen in recurrent Head and Neck Cancer.

BACKGROUND: The EXTREME protocol is the standard of care for recurrent or metastatic head and neck squamous-cell carcinoma (R/M HNSCC) in first line. Beyond the first-line except immunotherapy, poor efficacy was reported by second-line chemotherapy. Re-challenge strategies based on a repetition of the first line with platinum and cetuximab regimens might have been an option to consider. METHODS: We performed a retrospective study in order to assess the efficacy of the cetuximab plus platinum doublet-based chemotherapy regimen in patients with R/M HNSCC progressing after at least 3 months of cetuximab maintenance (EXTREME protocol). We complete a retrospective review of all medical records from R/M HNSCC patients treated after 16 weeks with the EXTREME regimen and treated with a re-challenge strategy between January 2010 and December 2014 in our institution (Centre Paul Strauss, Strasbourg, France). RESULTS: 33 patients were identified. The re-challenged strategy provided an ORR in 33.3% of cases and a DCR of 69.6% of cases. The median OS and PFS observed from the second line were 11.2 months and 6.5 months for the subset re-challenged by EXTREME or PCC regimens respectively. The response rate between patients with a platin free interval within 3 and 6 months and greater than 6 months were equal. Drugs dose intensity were better with the PCC protocol than the EXTREME regimen used as a rechallenge. CONCLUSIONS: This study suggest re-challenging strategy by these regimens could be considered beyond the first line as an option when the platin free interval is greater than 3 months.

Cetuximab-Carboplatin-5-Fluorouracil Regimen in Elderly Patients with Recurrent or Metastatic Head and Neck Squamous-Cell Carcinoma: A French Retrospective Survey.

BACKGROUND: The cetuximab plus platinum-based chemotherapy regimen is a standard of care in the treatment of recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The feasibility in the elderly population is currently unknown. METHODS: We performed a retrospective study in order to assess the efficacy and safety of the cetuximab plus platinum-based chemotherapy regimen in patients >65 years with recurrent or metastatic HNSCC. We performed a retrospective review of all medical records from recurrent or metastatic HNSCC patients >65 years treated with the cetuximab plus platinum-based chemotherapy regimen between September 2008 and December 2013 in our institution (Centre Paul Strauss, Strasbourg, France). RESULTS: A total of 59 patients were identified. Carboplatin in combination with 5-fluorouracil (FU) was the only cetuximab-associated chemotherapy regimen used for treating elderly patients. The median progression-free survival was 4 months (95% confidence interval [CI]: 2.9-4.7), and the median overall survival was 9.1 months (95% CI: 6.5-13.1). Grade 3 or 4 toxicity adverse events occurred in 52% (n = 31) of the patients (mostly hematologic toxicities and infections). CONCLUSIONS: This retrospective study suggests that the cetuximab plus carboplatin-5FU chemotherapy is an effective treatment option for elderly patients with recurrent or metastatic HNSCC.

Prognostic factors in second-line targeted therapy for metastatic clear-cell renal cell carcinoma after progression on an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor.

BACKGROUND: About 40% of metastatic clear-cell renal cell carcinoma (m-ccRCC) patients receive a second-line targeted therapy after failure of anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGFR-TKI). Efficacy of second-line therapy is usually limited and prognostic and predictive factors at the start of second-line therapy are lacking. To identify the subgroup of patients that will benefit from such treatment remains a challenge. METHODS: We performed a multi-institutional, retrospective study of patients who received a second-line therapy after progression on an anti-VEGFR-TKI. Univariate and multivariate analyses were performed in order to identify prognostic factors for progressive disease (PD) as best response, progression-free survival (PFS) and overall survival (OS) on second-line therapy. RESULTS: For the whole cohort of 108 patients, mOS from the start of second-line therapy was 8.9 months while mPFS on second-line therapy was 2.8 months. A total of 49/105 (47%) patients had PD, 50/105 (48%) stable disease (SD) and 6/105 (6%) a partial response (PR). On multivariate analysis, the following markers were associated with improved outcome on second-line therapy: a PFS on first-line therapy ≥12 months (HR for PFS: 1.961; p = 0.008) (HR for OS: 1.724; p = 0.037) and Fuhrman grade 1-2 tumors (HR for OS: 2.198; p = 0.007). Markers associated with poorer outcome on second-line therapy were: elevated serum lactate dehydrogenase (LDH) levels (HR for PFS: 0.511; p = 0.04) (HR for OS: 0.392; p = 0.017), low albumin (HR for OS: 0.392; p = 0.01) and elevated corrected calcium levels (HR for OS: 0.416; p = 0.01). The impact on OS of the Memorial Sloan Kettering Cancer Centre (MSKCC) and International Renal Cell Carcinoma Database Consortium (IMDC) prognostic scores as calculated at start of second-line therapy was validated in our patient series. CONCLUSIONS: Duration of first-line PFS, Fuhrman grade, serum LDH levels, albumin levels, corrected calcium levels and the MSKCC and IMDC scores calculated at start of second-line therapy are prognostic factors for m-ccRCC patients treated with second-line targeted therapy.

First report of trastuzumab treatment after postoperative Takotsubo cardiomyopathy.

BACKGROUND: Trastuzumab is a humanized monoclonal antibody used for the treatment of HER2-positive breast cancer. Cardiotoxicity is a well-known adverse event of trastuzumab use but little has been documented regarding its use in patients with a history of cardiac disease. CASE REPORT: We describe a case in which trastuzumab treatment was administered to a 40-year-old female patient with early breast cancer after acute heart failure secondary to postoperative Takotsubo cardiomyopathy. After one year of follow-up with close monitoring by echocardiography, there have been no heart-related symptoms. Additional surgery was performed because of positive resection margins at first surgery, without complications, despite the risk of recurrence of Takotsubo cardiomyopathy. CONCLUSION: Trastuzumab can be safely administered after acute heart failure secondary to postoperative Takotsubo cardiomyopathy.