bluuebunny/crossref_metadata_2025 huggingface dataset:
Organ preservation with daily concurrent chemoradiotherapy using retrograde superselective intra-arterial infusion for stage III, IV oral cancer: Analysis of therapeutic results in 112 cases.
Authors: Mitsudo Kenji , Koizumi Toshiyuki , Iwai Toshinori , Nakashima Hideyuki , Oguri Senri , Kioi Mitomu , Hirota Makoto , Tohnai Iwai
Published: March 2020

6060

Background: Retrograde superselective intra-arterial chemotherapy for oral cancer has the advantage of delivering a high concentration of the chemotherapeutic agents to the tumor bed, it can be used to provide daily concurrent chemoradiotherapy for patients with advanced oral cancer. The purpose of this study was to evaluate the therapeutic results and rate of organ preservation in 112 patients of stage III or IV (M0) oral cancer treated with retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy. Methods: Between August 2006 and July 2011, 112 patients with stage III or IV oral squamous cell carcinoma underwent intra-arterial chemoradiotherapy. Catheterization from the superficial temporal and occipital arteries was performed. And treatment consisted of superselective intra-arterial chemotherapy (docetaxel, total 60 mg/m2, cisplatin, total 150 mg/m2) and daily concurrent radiotherapy (total 60 Gy) for 6 weeks. Results: The median follow-up for all patients was 46.2 months (range, 10–90 months). The median follow-up for living patients was 49.7 months (range, 36–90 months). After intra-arterial chemoradiotherapy, primary site complete response was achieved in 98 (87.5%) of 112 cases. Thirty patients (26.8%) died. Using the Kaplan-Meier method, 3-year, and 5-year survival rates were 74.6% and 71.3%, respectively, while 3-year, and 5-year local control rates were both 79.3%. Grade 3 or 4 toxicities included mucositis in 92.0%, neutropenia in 30.4%, dermatitis in 28.6%, anemia in 26.8%, and thrombocytopenia in 7.1%. Grade 3 toxicities included dysphagia in 72.3%, nausea/vomiting in 21.4%, fever in 8.0%, and renal failure occurred in 0.9%, no patients died as a result of treatment toxicity. Conclusions: Retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy for Stage III, IV oral cancer provided good overall survival and local control rates, thus preserving organs and contributing to patients’ QOL.
Effect of early detection of recurrent disease by FDG PET/CT on management of patients with squamous cell cancer of the head and neck (HNSCC).
Authors: Kostakoglu Lale , Fardanesh Reza , Genden Eric , Rao Srikar , Doucette John , Som Peter M. , Gupta Vishal , Misiukiewicz Krzysztof , Posner Marshall R.
Published: March 2020

6062

Background: Despite the increasing cure rates a substantial fraction of HNSCC patients (pts) will present with locoregional and/or distant relapse within 3 years of definitive therapy. The prognosis of HNSCC pts after failure of first-line therapy has been poor but recent changes in the biology of HNSCC, advances in surgical techniques and radiotherapy; and new drugs may lead to improved salvage therapy. Notably, the success of these developments are implicitly dependent on early diagnosis disease. Our objective was to compare the efficacy of surveillance FDG-PET/CT to that of high resolution CT (HRCT) and physical exam (PE/E) for detection of early relapse in HNSCC after completion of primary treatment. Methods: A retrospective analysis of FDG-PET/CT, neck HRCT and PE/E was performed in 99 curatively treated HNSCC pts during post-therapy surveillance (PTS) to compare the performance characteristics of the tests in the detection of early recurrence or metachronous cancer. Results: A total of 19/99 (20%) pts had recurrence during a median follow-up of 21mo (range:9-52). Median time to first PET/CT was 3.5mo. The median time to radiological recurrence was 6 mo (range:2.3-32). PET/CT detected more disease recurrences or second primaries and did so earlier than HRCT and PE/E. Sensitivity, specificity, PPVand NPV for detecting locoregional and distant recurrence or metachronous cancer : 100%, 87.3%, 56.5% and 100% for PET/CT vs. 61.5%, 94.9%, 66.7% and 93.8% for HRCT vs. 23.1%, 98.7%, 75% and 88.6% for PE/E. In all 19 pts with a true positive PET/CT there was a significant management change prompting either salvage or definitive surgery or initiation of systemic therapy. Of the 14 recurrent pts treated with curative intent, 11 were alive with no evidence of disease at a median follow up of 31.5 mo. Conclusions: FDG-PET/CT has a high sensitivity in the early detection of relapse or second primary cancer in HNSCC, associated with significant management implications. Given improvements in therapy and changes in HNSSC biology, appropriate modifications in the current recommended algorithms of the NCCN for PTS may be required to engage effective salvage or definitive therapies.
A blood-based epigenetic test for early detection of nasopharyngeal carcinoma (NPC).
Authors: Tan Yew-Oo , Alfanta Eduard M. , Lopa Ramon Antonio B. , Lim Elaine Hsuen , Whang Hwee Yong , Wong Karmen , Jordan Philip , Corfield Emily , Salter Matthew , Field Megan , Akoulitchev Alexandre , Loh Thomas Kwok Seng , Goh Boon C. , Hsieh Wen Son
Published: March 2020

6063

Background: NPC is highly curable in early stages but 70% of NPC patients are diagnosed with advanced disease due to lack of effective screening. Genetic and epigenetic alterations involved in the pathogenesis of NPC are known. The higher order chromosomal structures reflecting aberrant transcriptional states of these genes can be measured via techniques such as chromosome conformation capture. Detection of these changes in peripheral blood may provide an accurate test for the early cancer detection. Methods: Blood samples have been collected from 84 patients with histologically confirmed NPC and 100 matched controls. Samples from 45 NPC patients and 68 controls have been analyzed. Fourteen genes known to be dysregulated in NPC were investigated. Potential higher order juxtaposition sites in the candidate genes were predicted using pattern recognition software. PCR primer sets were designed around the chosen sites to screen potential markers. Twenty-two markers showing predictability between NPC and control samples were analysed for optimal reproducibility using alternative primer sets. The optimal sets of markers were then tested amongst the complete set of samples. The dataset was processed by re-sampling using the synthetic minority oversampling technique. The overall sample was split into two groups (66% training set and 34% test set) in the classification. Results: Sixteen markers from 7 candidate genes were found to be optimal in differentiating between NPC and control samples in the first 103 samples. Using the multilayer perceptron (MLP) classification, the following results were obtained: Sensitivity 88.9%, 95% CI (79.2% - 98.6%); Specificity 72.7%, 95% CI (58.9% - 86.5%); PPV 72.7%, 95% CI (58.9% - 86.5%); NPV 88.9%, 95% CI (79.2% - 98.6%). The accuracy of the test was similar in detection of stage I and II NPC versus that of stage III or IV NPC. Conclusions: Using a PCR-based method to detect alterations in the cancer epigenome, the feasibility of developing a blood test of potential utility in early diagnosis of NPC was demonstrated. Analysis of larger numbers of patient samples and optimization of markers are ongoing. The performance characteristics of the test in the total population of 184 samples will be presented.
Genetic profiling of advanced RAI-resistant differentiated thyroid cancer and correlation with axitinib response.
Authors: Schechter Rebecca B. , Nagilla Madhavi , Joseph Loren , Reddy Poluru L. , Khattri Arun , Watson Sydeaka , Locati Laura D. , Licitra Lisa F. , Greco Angela , Pelosi Giuseppe , Carcangiu Maria Luisa , Seiwert Tanguy Y. , Cohen Ezra E.W.
Published: March 2020

6066

Background: The VEGFR inhibitor axitinib has demonstrated compelling antitumor activity in advanced RAI-resistant differentiated thyroid cancer (DTC). Biomarkers predicting which patients may benefit from axitinib are unavailable. We aimed to describe molecular markers in DTC that correlate with clinical outcome to axitinib. Methods: Pretreatment FFPE thyroid cancer blocks from patients treated with axitinib were collected and genomic DNA was isolated. The OncoCarta Mutation Panel was used to test for 238 mutations. Copy number of VEGFR1-3 and PIK3CA was determined using qPCR. Genomic DNA was analyzed for coding regions of VEGFR1-3 with custom primers. Clinical response to axitinib, including best response (BR) (RECIST) and progression free survival (PFS), was ascertained from corresponding patients. Fisher’s exact test and logistic regression models were used to correlate BR with molecular findings. Cox proportional hazards regression was used to correlate PFS with molecular defects. Results: A total of 22 pathology samples (11 primary, 11 metastatic) were identified. In patients with 2 samples (n = 4), results were concordant and only included once for analysis. Of 18 specimens, 4 tumors (22%) harbored BRAF V600E mutations, 2 (11%) had KRAS mutations (G12A, G13D) and 2 (11%) had HRAS mutations (Q61R, Q61K). One sample with mutated KRAS also had a PIK3CA (H1047R) mutation. qPCR showed increased copy numbers of PIK3CA in 6 (33%) tumors, VEGFR1 in 0 (0%) tumors, VEGFR2 in 4 (22%) tumors, and VEGFR3 in 6 (33%) tumors. VEGFR sequencing showed a possibly damaging non-synonymous SNP in VEGFR2 (G539GR) in 2 samples (11%), a possibly damaging SNP in VEGFR3 (E350VE) in 1 sample (6%), and a potentially novel mutation in VEGFR2 (T439IT) in 2 samples (11%). No significant relationship was seen between BR or PFS and the presence of molecular defects. Conclusions: While DTC is genetically heterogenous, primary and metastatic lesions showed identical alterations. Molecular evaluation of DTC specimens did not predict clinical response to axitinib but data were limited by small sample size. We did identify molecular changes in VEGFR that should be further explored. This study was supported by Pfizer, Inc.
Single nucleotide polymorphisms (SNPs) of hypoxia-related and DNA repair genes associated with toxicity and clinical outcome in head and neck squamous cell carcinoma patients treated with cetuximab plus radiotherapy.
Authors: Grau Juan J. , Munoz-Garcia Camen , Feliz Luis R , Caballero Miguel , Sosa Aaron R , Pereira Verónica
Published: March 2020

6072

Background: One of the standard therapy in inoperable head and neck squamous cell carcinoma (HNSCC) patients is cetuximab plus radiotherapy. However, the efficacy of this treatment varies greatly among individuals. In an attempt to identify predictive markers to determine the patients most likely to benefit from this treatment, we examined the potential effect on outcome and skin toxicity according to single SNPs in hypoxia-related genes and DNA repair genes. Methods: Sixty-one patients enrolled between May 2006 and August 2011 and diagnosed with HNSCC were included. Data on epithelitis, mucositis and folliculitis were collected in accordance with WHO criteria. SNPs were analyzed in HIF-1α, HIF-2α, HIF-1β, VHL, FIH-1, XRCC1 and XRCC5 in DNA obtained from paraffin-embedded tumor tissues by allelic discrimination in an ABI PRISM 7500 Sequence detection system. Results were correlated with time to progression (TTP), overall survival (OS) and toxicity. Results: The median of TTPand OSwere better in patients with mucositis severe vs mild (17 vs 7 months, p=0.03, and 26 vs 12 months, p=0.016, respectively) and in those with folliculitis severe vs mild (10 versus 7 months, p=0.01, and 26 vs 10 months, p<0.001, respectively). Patients withHIF-1α CT/TT had better OS than those with HIF-1α CC or wild type (28 versus 13 months, p=0.035). Patients with XRCC5 GG/AA genotypes had longer TTP than patients with XRCC5 AG (11 versus 7 months, p=0.035). Conclusions: Our findings indicate that the presence of severe skin toxicities, as well as SNPs in HIF-1α and XRCC5, are associated with interindividual differences in outcome among HNSCC patients.
Outcomes for stage IVA squamous cell carcinoma of the oral cavity according to staging subtypes.
Authors: Marrone Kristen , Otremba Michael , Groisberg Roman , Deshpande Hari Anant , Crawford Forrest , Acevedo-Gadea Carlos Rodrigo , Gould Rothberg Bonnie , Judson Benjamin , Morgensztern Daniel
Published: March 2020

6076

Background: Patients with locoregionally advanced squamous cell carcinoma of the oral cavity (SCCOC), defined as stages III to IVB without T4b, are treated similarly and combined for enrollment into most clinical trials. There are several combinations of tumor (T) and lymph node (N) categories for stage IVA. We evaluated the differences in outcomes according to subtypes of patients with stage IVA SCCOC. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients with stage IVA SCCOC diagnosed between 1988 and 2007. Patients were subdivided according to tumor (T) and lymph node (N) status. Overall survival (OS) was estimated by the Kaplan-Meier method and compared by using log-rank test. Cox proportional hazard regression models were used for multivariate analyses. Results: Among the 3,904 patients meeting inclusion criteria, most patients underwent surgery, either alone (24%) or with radiation (59%). There was a significant difference in outcomes according to AJCC subsets (T4aN0, T4aN1, T1N2, T2N2, T3N2 and T4N2), with 5-year OS ranging from 15.8% in T4aN2 to 41.3% in T4aN0 (HR 2.3; 95% CI 2.03-2.62, p < 0.001). Since the 5-year OS was similar for patients with T1N2-T2N2 and T3N2-T4aN2, these groups were further subdivided according to the T (T1-2 or T3-4a) and N2 subsets. The 5-year OS was significantly different according to the subgroups, ranging from 11.8% in T3-4aN2c to 37.5% in T1-2N2a (Table). The stage subgroups remained independent predictors for survival after adjusting for age, gender, race and treatment. Conclusions: Stage IVA SCCOC is a heterogeneous disease with significant differences in outcomes according to its subsets. If these findings are confirmed in additional studies, further subdivision of stage IVA may be warranted. [Table: see text]
Carboplatin (C), cetuximab (Cet), and everolimus (E) in recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Results of a phase Ib study.
Authors: Saba Nabil F. , Kono Scott A , Mendel Jennifer Robin , Hurwitz Selwyn J , Owonikoko Taofeek Kunle , Lewis Colleen Margaret , Harvey Donald , Rogerio Jaqueline Willemann , Chen Zhengjia , Wadsworth Trad , El-Deiry Mark , Chen Amy Y. , Higgins Kristin , Ramalingam Suresh S , Beitler Jonathan Jay , Shin Dong M , Khuri Fadlo Raja
Published: March 2020

6083

Background: Platinum-based therapy in combination with Cet is the standard first line systemic therapy in RMSCCHN. Preclinical studies suggest that mTOR inhibitors may restore sensitivity to EGFR inhibitors in resistant cell lines, and that in combination with Cet may augment anti-tumor activity. We conducted a phase Ib trial of C, Cet and E for untreated RMSCCHN. Methods: Patients received C at AUC=2 on a 3 weeks on 1 off schedule with Cet weekly at a fixed dose and E at escalating dose levels of 2.5, 5.0, 7.5 and 10 mg daily using a 3+3 design. After 4 cycles of therapy patients without disease progression continued on maintenance Cet and E until disease progression or intolerable toxicity. Patients had previously untreated RMSCCHN not amenable to surgery or radiotherapy, age ≥ 18 years and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2. Results: After IRB approval, the study enrolled 18 patients with RMSCCHN between February 8, 2011 and Jan 25 2013. One patient was a screen failure. Four had an anaphylactic reaction to Cet and were excluded from the analysis. A total of 13 patients received E (M/F: 92%); median age 65 (44-75yrs). Two of six patients treated at dose level 1 (E-2.5 mg/day) experienced dose limiting toxicity (DLT) with grade 3 hyponatremia and nausea. Additional 7 patients were treated with de-escalated dose of E (2.5 mg QOD). No DLTs were observed at this dose level. Salient clinically relevant Grade >2 toxicities included: leukopenia (23%), neutropenia (15%) hyponatremia (18%), hyperglycemia, nausea, rash, hypokalemia, urinary infection, bacteremia, (each 8%). Dose reductions of C were necessary for a total of 18/61 delivered cycles of therapy. A response rate (RR) of 62.5% with all responders having partial responses (PR) was observed. The PFS was 7.8 months. Conclusions: The MTD of E in combination with Cet and C is estimated at 2.5 mg QOD. Though this is less than the commonly utilized dose of E, the regimen was associated with encouraging response rate and PFS Clinical trial information: NCT01283334.
Are three drugs better than two and does docetaxel trump paclitaxel in induction therapy for locally advanced oral cavity cancers?
Authors: Noronha Vanita , Patil Vijay , Joshi Amit , Juvekar S , Bhosale Bharatsinha Baburao , Poladia Bhavesh , Rath Sushmita , Chaturvedi Pankaj , Chaukar D. , Pai P. S. , Dcruz A. K. , Prabhash Kumar
Published: March 2020

6085

Background: A variety of regimens have been used for induction chemotherapy in locally advanced head & neck cancers. Cisplatin & 5 FU drug combination is inferior to the combination of taxane & these 2 drugs. However, often in clinical practice at our center giving TPF is difficult in view of logistics & tolerance issues. In such scenarios we prefer to use 2 drug combination of platinum & taxane. However no study has addressed whether when the 2 drug combination includes taxane, is it still inferior to the 3 drug combination and which the taxane of choice is. Methods: This is a retrospective analysis of prospectively collected data of patients undergoing induction chemotherapy in oral cavity cancers from 2010-2012. We chose for analysis those patients who had a baseline scan and a follow-up scan done within 2 weeks of completion of the second cycle of induction chemotherapy. Response was scored in accordance with RECIST 1.1. Data was analyzed using SPSS, version 16. Chi- square analysis was done to compare response rates between regimens. Results: Two hundred & forty five patients were indentified. The median age was 45 years (24-70 years), 208 (84.9%) were male patients & in 154 patients (62.9%) had primary in buccal mucosa. The regimen received were TPF 22 (9%), TP (Docetaxel + cisplatin) 97 (39.6%), PP (paclitaxel+cisplatin) 89 (36.3%), TC (Docetaxel+ carboplatin) 16 (6.5%) & PC (paclitaxel + carboplatin) 21 (8.6%).The overall response rates (RR) were CR, PR,SD & PD in 4 (1.6%), 56 (22.9%), 145 (59.2%) & 40 (16.3%). On comparison, 3 drug regimen (TPF) had 50% RR as against 22% RR with 2 drug regimen (p=0.004). On comparison for taxane, docetaxel containing regimens had 30.3% RR as against 17.2% RR with paclitaxel containing regimens (p=0.018). There was no statistically significant difference in RR between patients receiving carboplatin or cisplatin. Conclusions: TPF had better RR than a 2 drug taxane-containing regimen and docetaxel leads to a better RR than paclitaxel for induction chemotherapy in locally advanced oral cavity cancers.
A comparative study of the response and toxicities in locally advanced head and neck cancer patients treated with paclitaxel, cisplatinum, 5-FU versus docetaxel, cisplatinum, 5-FU as neoadjuvant chemotherapy followed by concurrent chemoradiation.
Authors: Samanta Diptirani , Senapati Surendra nath , Mohanty Kirti Ranjan , Das Saroj
Published: March 2020

6089

Background: To evaluate the response and toxicity of docetaxel, cisplatinum, 5-FU vs paclitaxel, cisplatinum, 5-FU as neoadjuvant chemotherapy (NACT) followed by concurrent chemoradiation (CTRT) with weekly cisplatinum in locally advanced head and neck cancer. Methods: 40 locally advanced head and neck cancer patients who satisfied the eligibility criteria were randomized.21 patients received three cycles of NACT i.e paclitaxel (175 mg/m2) on d1, cisplatinum (30 mg/m2) and 5-FU (600 mg/m2) d2-d4 (TCF) and 19 patients received three cycles of NACT docetaxel (75 mg/m2) on d1, cisplatinum (30 mg/m2) and 5-FU (600 mg/m2) d2-d4 at three week intervals, followed by concurrent weekly cisplatinum 30 mg/m2 along with conventional external beam radiation of total tumor dose dose 66 Gy. Response was assessed after NACT and again after six weeks, three months and six months of completion of chemoradiation. Toxicities were assessed after each cycles of NACT and also weekly during CTRT and thereafter. Results: Two weeks after completion of NACT complete response (CR) in TCF was 4.76%, partial response (PR) 80.9% and no response 9.5%. However in DCF, CR was 15.78 % PR was 73.68%. 10.52% patientd died due to toxicity. With a median follow up of seven months, in TCF CR was 57.14%, PR 33.33% and no response was 4.76%, whereas in DCF CR was 78.94%, PR 10.52% and death 10.5%. On evaluation of toxicities during NACT, patients in DCF had more significant neutropenia and in TCF more incidence of neuropathy. During CTRT, in TCF grade II and III mucositis was 54%, grade II neutropenia 5.6%, and grade II anemia 5.3%. In DCF mucositis grade II and III was 49.0%, neutropenia grade II 18.7% and anemia grade II was 7.4%. Late toxicities included were comparable in both arms. Conclusions: With a median follow up of 7 months, the CR in DCF was 78.94%, superior than TCF i.e 57.14%. Neutropenia was significant in DCF and neuropathy was high in TCF. In CTRT mucositis was the commonest toxicity observed in both TCF and DCF which was not statistically significant.
Comparison of patient performance between PEG/no PEG placement in head and neck cancer patients during chemoradiotherapy treatment.
Authors: Metcalfe-Klaw Robin , Husaini Hasan , Lazarus Cathy L , Harrison Louis Benjamin , Culliney Bruce , Li Zujun , Urken Mark L , Jacobson Adam , Buchbinder Daniel , Persky Mark , Tran Theresa , Pitman Michael , Concert Catherine , Palacios Daisy Maria , Bennett Bridget , Kumar Mahesh , Hu Kenneth
Published: March 2020

6091

Background: Many head and neck cancer patients suffer from side effects of chemoradiotherapy that can result in reduced oral intake, and weight loss. To prevent this malnutrition they often undergo preventative percutaneous endoscopic gastrostomy (PEG) placement. We aim to determine whether PEG placement is necessary for successful patient performace during treatment. Methods: We compared 2 groups: patients that underwent PEG (Gp-1=P) (n=20), and those that did not undergo PEG (GP-2=NP) (n=47). All patients were treated with chemoradiotherapy. All were assessed at baseline (BL), and wk 5 of tx. WHO variables including weight loss, mucositis, dysphagia, and odynophagia ratings, along with patient-rated modified “distress thermometers”, were analyzed. Results: Patients with no PEGs had higher weights at BL (NP=193 vs P= 171, p=0.073) and at wk 5 (NP=179 vs P= 160, p=0.056). Weight loss in these groups were 8.09 % - P (p=0.000), 8.25% - NP (p=0.000) respectively from BL - wk 5. The median distress level of each group was 0-P and 1-NP at BL (p=0.302) and 6-P and 3-NP at wk 5 (p=0.086). 27 patients had a distress level of > = 4 at wk 5. Of these 27, 12 were PEG’d and 15 were not (p=0.008). 86 % of patients in the PEG group had distress >=4 and 44 % in the NP group had distress levels >=4. Patients that underwent PEG had slightly higher odds (NS) of associating their distress to nausea, fatigue and/or eating than patients that were not PEG’d. The wk 5 WHO toxicity scale assessment showed 15 PEG’d patients had Grade 1 (n=5), Grade 2 (n=9) & Grade 3 (n=1) dysphagia and 28 NP patients had Grade 1 (n=23) & Grade 2 (n=5) dysphagia (CHI square =11.66, p=0.009). Conclusions: Patients that underwent PEG placement before or during treatment performed worse in every assessment (weight loss, distress thermometer & toxicity scale) as compared to the no PEG group. Patients who have a normal or above average BMI are candidates to be monitored for PEG placement. However, both groups examined were able to complete treatment without significant treatment breaks. Close multidisciplinary monitoring and more intensive supportive care are needed when determining need for PEG placement during treatment.
Sequential TKI treatments for iodine-refractory differentiated thyroid carcinomas.
Authors: de la Fouchardiere Christelle , Massicotte Marie-Helene , Borget Isabelle , Brassard Maryse , Claude-Desroches Mederic , Giraudet Anne Laure , Docao Christine , Bonichon Francoise , Chougnet Cecile , Leboulleux Sophie , Baudin Eric , Schlumberger Martin
Published: March 2020

6092

Background: Tyrosine kinase inhibitors (TKI) are currently used to treat patients with advanced iodine-refractory differentiated thyroid cancers (DTC) but none has been approved by the FDA or the EMA until now. Sometimes, patients are treated with off-label TKI when a clinical trial is not available or in second- and third-line therapy. Methods: We hereby report the efficacy of “off-label” sorafenib and sunitinib treatments as first-, second- and third-line therapy in metastatic DTC patients from the French TUTHYREF (TUmeurs THYroïdiennes REFractaires) network. Primary endpoints were progression free survival (PFS) and tumor response according to sequential TKI treatment. Secondary endpoint was organ-specific metastatic site analysis. Results: 45 patients with advanced iodine-refractory DTC treated with off-label TKI were included in this study (26 men, mean age: 62 years). 22 had papillary, 10 had follicular and 13 had poorly DTC. 24/45 patients were treated with two and 3/45 with three lines of TKIs. Sorafenib was the most frequently used (57%) followed by sunitinib (21.5%) and vandetanib (21.5%). Partial response (PR) rate was of 29% in the 21 patients who received first-line sorafenib therapy whereas PR was observed in 57% of the 7 first-line sunitinib patients. There was no PR with second- (n=24) and third-line (n=3) treatments. However, median progression free survival (PFS) was similar in second- as compared to first-line sorafenib or sunitinib treatment (6.7 vs. 7.6 months, HR 0.85 (95CI 0.45-1.61) p=0.6). Liver metastases were the most responsive to treatment (n=7; mean of -30%), followed by lung (n=57; mean of -19%) and lymph node (n=43; mean of -13%) metastases. Bone (n=14) and pleural (n=9) lesions were the most refractory to treatment (mean of -1% and -5%, respectively). Conclusions: Due to the small number of patients, we could not recommend a specific treatment sequence (sorafenib then sunitinib) over another (sunitinib then sorafenib). But TKI therapy appears to be beneficial in refractory DTC patients even in second- and third-line therapy, with similar PFS and stable disease as best response. Bone and pleural metastases were the most refractory and liver lesions the most responsive to treatment.
Completion of adjuvant trastuzumab for older patients with early-stage breast cancer (BC).
Authors: Freedman Rachel A. , Luis Ines Maria Vaz Duarte , Lin Nancy , Lii Joyce , Winer Eric P. , Keating Nancy Lynn
Published: March 2020

616

Background: Few data are available about factors associated with completion of adjuvant trastuzumab in older women with BC. We examined rates and predictors of adjuvant trastuzumab completion for older women with early-stage BC. Methods: We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to identify 1,319 patients ≥66 years with early-stage BC diagnosed between 1999-2007 who received trastuzumab. Completion of trastuzumab was defined as >270 days of therapy. We examined patient, clinical and geographic characteristics associated with trastuzumab completion using multivariable logistic regression. We also assessed rates of hospital admissions for cardiac events during treatment. Results: Most of the 1,319 women were aged ≤76 (70%) and had a comorbidity score=0 (88%); 37% and 23% received anthracyline-taxane-based and taxane-based therapy, respectively, and 16% received trastuzumab without chemotherapy. Overall, 982 women (74.5%) completed trastuzumab. Factors associated with completion are shown below. During treatment, 56 patients (4.2%) had 65 hospital admissions for cardiac events (3.0% in those who completed trastuzumab versus 8.0% in those who did not, p<.001). Conclusions: One-quarter of older patients who initiated adjuvant trastuzumab did not complete therapy. Older women, Hispanic women, those with more comorbidity, and those receiving anthracycline-taxane-based chemotherapy all had lower odds of completion. Rates of hosptializations for cardiac events were higher in those who did not complete therapy. [Table: see text]
Effect of afatinib alone and in combination with trastuzumab in HER2-positive breast cancer cell lines.
Authors: Canonici Alexandra , Pedersen Kasper , Browne Brigid , McDermott Martina , Walsh Naomi , Crown John , O'Donovan Norma
Published: March 2020

632

Background: Trastuzumab and lapatinib have been shown to significantly improve the prognosis for HER2 positive breast cancer patients. However, resistance is a significant clinical problem. The aim of this study is to assess the activity of afatinib, an irreversible pan-HER tyrosine kinase inhibitor, in HER2 overexpressing breast cancer cell lines, including trastuzumab and/or lapatinib resistant cells. Methods: Using proliferation assays, the effect of afatinib was assessed alone and in combination with trastuzumab in HER2 positive cell lines. The effect of afatinib on HER2, Erk and Akt was determined by immunoblotting. Results: The eight HER2 positive breast cancer cell lines tested, including trastuzumab and/or lapatinib resistant cells, responded to afatinib with IC50values ranging from 5 to 80 nM. The combination of afatinib and trastuzumab was additive in four trastuzumab sensitive cell lines and one model of acquired trastuzumab resistant HER2 positive breast cancer. In the remaining three trastuzumab and/or lapatinib resistant cell lines, combined treatment with trastuzumab and afatinib showed no enhancement compared to afatinib alone. Finally, afatinib decreased the phosphorylation of HER2 and Erk in all cell lines tested. Conclusions: Our results suggest that afatinib has activity in HER2 positive breast cancer, including trastuzumab and/or lapatinib resistant breast cancer. We also demonstrate that afatinib in combination with trastuzumab may be more effective than either agent alone in trastuzumab sensitive breast cancer. [Table: see text]
Second-line treatment of HER2+ metastatic breast cancer (MBC): Trastuzumab (T) beyond progression or lapatinib (L)? A retrospective database study.
Authors: Yerushalmi Rinat , Feldhamer Ilan , Greenberg-Dotan Sari , Bitterman Haim , Hammerman Ariel
Published: March 2020

639

Background: L and T “beyond progression” (TBP) for MBC pts who progressed on 1st line therapy with T, are both reimbursed in Israel since 1/2010. The relative efficacy of L vs. T when combined with chemotherapy in 2nd line therapy for HER2+ MBC is unknown. In this retrospective database study we compared outcomes of 2ndline L or TBP, in the daily practice ("real life") in Israel. Methods: Using the computerized databases of Clalit Health Services' (CHS), Israel's largest health care provider, we identified all MBC pts that received 2nd line anti HER2 therapy, with either L or TBP after a 1stline protocol containing T, between 1/1/2010 and 31/12/2011. Pts characteristics and treatments were retrieved. The primary end point was overall survival (OS) defined as the time interval between date of initiation of 2nd line anti HER2 therapy and death or last day of follow-up. Secondary endpoint was progression free survival (PFS), defined as duration of 2nd line therapy. Results: The study population included 83 pts (28 L and 55 TBP). Mean age (59.9 vs. 61.4) and average Charlson co-morbidity index score (6.54 vs. 6.13) were similar between the cohorts. The groups differed in rates of prior adjuvant T (32.1% vs. 10.9%, p=0.017). The interim cutoff date for analysis was 31/12/2012 (allowing at least 12 months of follow-up). Median OS was 10.0 months for L pts (95% CI: 7.41–12.59) and was not reached for TBP, with a total of 31 deaths: 19 [67.9%] in the L group and 22 [40.0%] in the TBP group. A Cox regression showed an adjusted hazard ratio (HR) of 1.44 (95% CI 0.74-2.81), not significant (p=0.28).Prior adjuvant therapy with T was found to be a significant cofounder; HR=3.16 (95% CI 1.52-6.56). Median PFS was 6.0 months (95% CI: 4.31–7.69) for L and 7.0 months (95% CI: 4.30-9.70) for TBP, with a Cox regression adjusted HR of 0.87 (95% CI: 0.50-1.52), not statistically significant (p=0.87). Conclusions: In this retrospective database analysis, our interim results suggest no statistically significant difference in OS and PFS between L and TBP, as 2nd line therapy for HER2+ MBC, however the data showed a strong trend toward a survival benefit with TBP. A longer follow-up is required.
Impact of single and dual neoadjuvant HER2-directed therapy on clinical outcomes among patients with HER2-positive breast cancer (BC).
Authors: Reynolds Kerry Lynn , Bhatia Ashmeet , Cheng XingXing , Smith Barbara Lynn , Specht Michelle Connolly , Moy Beverly , Bardia Aditya
Published: March 2020

647

Background: While the addition of trastuzumab to neoadjuvant chemotherapy (CTX) is well established for HER2+ BC, the use of dual agent HER2 blockade in the preoperative setting is not considered standard of care. We conducted a comprehensive systematic review and meta-analysis to evaluate the impact of neoadjuvant dual and single agent HER2 blockade on breast conserving surgery (BCS), pathological complete response (pCR) for estrogen receptor (ER)+ and ER- tumors, and impact of pCR on disease-free survival (DFS) and overall survival (OS) for HER2+ BC. Methods: Based on QUORUM guidelines, MEDLINE and Cochrane Controlled Clinical Trials Register databases were queried to identify eligible trials. Inclusion criteria were prospective, neoadjuvant trials that had at least one arm with HER2 directed therapy, and reported pCR. Pooled relative risk ratios (RRs) and 95% confidence intervals (CIs) were estimated for endpoints using the random effects model. Results: We identified 34 trials (N = 4064). High pCR rates (> 40%) were seen with anthracycline-based CTX and trastuzumab, as well as taxane based CTX alone with dual HER2 blockade. The addition of trastuzumab to CTX did not improve BCS rate (RR 1.40, CI: 0.89-2.22, p=.15), but significantly increased rates of pCR (RR 1.91, CI: 1.38-2.64, p=.0001). Similarly, dual HER2 blockade compared to trastuzumab alone did not improve BCS rate (RR 1.03, CI: 0.77-1.38, p=.84), but significantly increased rates of pCR overall (RR 1.38, CI: 1.24-1.53, p<0.00001), in both ER+ (RR 1.72, CI: 1.14-2.61, p=.01) and ER- subsets (RR 1.91, CI: 1.38-2.64, p=.0001). Higher pCR was associated with improved DFS (RR 2.29, CI: 1.27-4.12, p=.006) and OS (RR 4.61, CI: 1.46-14.56, p=.009). Conclusions: Neither the addition of trastuzumab to CTX, nor the dual-HER2 blockade compared to trastuzumab, improves rates of BCS, but both significantly improve rates of pCR, which is associated with improved DFS and OS. A subgroup of HER2+ BC patients can achieve pCR with dual HER2 blockade without dependence on anthracycline-based therapy. Predictive biomarkers are needed to improve patient selection and personalize the optimal regimen for HER2+ BC.
Participation in cancer pharmacogenomic studies in 8,456 patients registered to Cancer and Leukemia Group B (Alliance) clinical trials.
Authors: Dressler Lynn G. , Deal Allison Mary , Watson Dorothy , Hollis Donna , Owzar Kouros , Donohue Kathleen , Friedman Paula N. , Ratain Mark J. , McLeod Howard L. ,   Cancer and Leukemia Group B (Alliance)
Published: March 2020

6501

Background: Clinically annotated specimens from cancer clinical trial participants offer an opportunity for discovery and validation of pharmacogenomic findings. This observational study assessed patient (pt) and institutional factors that may contribute to participation in pharmacogenomic components of prospective cancer clinical trials. No trial in the study used pharmacogenomic results to guide therapy, but germline DNA was collected from consenting pts for future study of potential heritable variations associated with clinical outcome. Methods: Pt demographic data (age, sex, diagnosis, self-reported race) and institutional characteristics (CALGB/CTSU site, diversity, accrual rate) were evaluated for 8546 pts enrolled in 7 CALGB phase III trials with a pharmacogenomic component. Participation was defined as pt consent specific to this component documented in the CALGB database. Results: Most pts (81%) enrolled on the clinical trials consented to participate in the pharmacogenomic component. In a multivariable analysis, site (CALGB vs CTSU), self-reported race (non-white vs white) and institutional diversity (% minority cancer pts on national trials) were significantly associated with participation. Pts from CALGB sites were more likely to participate than pts at CTSU sites (OR 2.09, CI 1.60-2.73, p<0.0001). Non-white pts were less likely to participate than white pts (OR 0.48, CI 0.41-0.56, p<0.0001). A significant interaction between site and race was observed (OR 0.41, CI 0.37-0.47, p<0.0001). As institutional diversity increased, likelihood of participation in the pharmacogenomic component decreased for both white (p=0.0001) and non-white pts (p=0.054). Conclusions: Pharmacogenomic studies are achievable in the context of multicenter cancer clinical trials, but optimization of pt and institution participation is needed. Institutional factorsappear to be more important than pt demographics. To promote equitable pt benefit, prospective studies should be conducted to understand barriers and incentives to participation in pharmacogenomic research at the patient, clinician and institutional levels.
A population-based analysis of outcomes in cancer patients who do not satisfy clinical trial eligibility criteria (CTEC).
Authors: Cheung Winson Y. , Kennecke Hagen F. , Lim Howard John , Renouf Daniel John , Gill Sharlene , Goktepe Ozge , Speers Caroline
Published: March 2020

6502

Background: Trials have stringent inclusion and exclusion criteria to maintain internal validity. However, study findings are often applied to patients in routine practice who do not meet CTEC. Our aim was to characterize the outcomes and magnitude of treatment benefit in these patients. Methods: Patients diagnosed with stage III colon cancer from 2006 and 2008, referred to 1 of 5 regional cancer centers in British Columbia, and assessed for adjuvant chemotherapy (AC) within 12 weeks of surgery were analyzed. Patients were considered trial-eligible (TE) if aged 18 to 79 years, ECOG 0/1, CEA <10, did not receive prior chemotherapy or radiation, and had adequate blood counts and normal cardiac, liver and kidney function. All other patients were deemed trial-ineligible (TI). Results: A total of 820 patients were identified: median age was 69 years (range 60-76), 423 (52%) were men, 365 (45%) were ECOG 0/1 and 592 (72%) received AC. Among patients treated with AC, 370 (63%) were TE and 222 (37%) were TI. Compared to TI patients, those who were TE were younger (63 vs 70 years, p<0.01) and more likely to receive combination regimens rather than single agent AC (56 vs 33%, p<0.01). Outcomes were significantly different among patients who were TE, TI, and those who did not receive AC (Table). In multivariate analyses that adjusted for known prognostic factors such as age, ECOG and T and N stages, both TI patients and those not treated with AC had worse outcomes than TE patients (HR for colon cancer death 1.32, 95%CI 0.86-2.02 and 2.77, 95%CI 1.92-3.99, respectively, p trend <0.01; HR for all cause death 1.24, 95%CI 0.85-1.80 and 2.95, 95%CI 2.17-4.00, respectively, p trend <0.01). Conclusions: In this population-based cohort, colon cancer patients who did not fit CTEC were frequently treated with AC. Outcomes in this TI group were inferior to those in the TE group, but they were better than the subset that did not receive AC. Broadening CTEC to include a segment of the TI population should be considered as there appears to be benefit in selected individuals. [Table: see text]
Financial distress, communication, and cancer treatment decision making: Does cost matter?
Authors: Zafar Yousuf , Abernethy Amy Pickar , Tulsky James A , Ubel Peter A , Schrag Deborah , Rushing Christel , Chino Fumiko , Nicolla Jonathan , Altomare Ivy , Samsa Greg , Peppercorn Jeffrey M.
Published: March 2020

6506

Background: Financial distress (FD) increases the burden of living with cancer. Even insured patients may experience considerable FD, but little is known about whether patients want to include cost discussions in treatment decision-making. Methods: This is an ongoing cross-sectional study of insured adults with solid tumors on anticancer therapy for ≥1 month. Consecutive patients were surveyed, in person, at a referral center and 3 rural oncology clinics. Participants were asked about FD (via a validated measure), out-of-pocket (OOP) costs, discussion of costs with their doctor, and decision-making. Medical records were reviewed for disease and treatment data. Logistic regression assessed the relationship between FD and cost communication. Results: 119 participants (85% response) had a median age of 60 years (range 27-86). 54% were men, 29% non-white, and 96% completed high school. 81% had incurable cancer. 58% had private insurance. Median income was $50,000/yr. Median OOP costs were $480/mo. The mean FD score (6.7, SD 2.5) corresponded to moderate FD. 19% reported high/overwhelming FD. Overall, 48% (n=57) expressed any desire to discuss costs with their doctor, but only 21% (n=25) had actually done so. Of the 19% with highest FD, 36% (n=8) had discussed costs with a doctor, and 68% (n=15) expressed any desire to discuss costs. The most common reasons for not discussing costs with doctors were: “no problems with costs” (n=47); “want best care regardless of cost” (n=36); and “doctors shouldn’t have to worry about costs” (n=19). Of those who discussed costs with their doctor, 48% (n=12) felt the discussion helped decrease costs. 54% (n=64) wanted their doctors to account for costs in cancer treatment decision-making; 20% (n=24) always wanted costs considered in decision-making. High FD was the only variable associated with greater willingness to discuss costs (adjusted OR 2.81; 95%CI 1.05-7.50; p=0.04). Conclusions: FD was prevalent among insured cancer patients. A large proportion wanted costs discussed with doctors and included in treatment decision-making. Discussing finances may lower costs, but the discussion rarely occurs. Communication and decision-making present a potential focus for intervening on FD.
Beyond Jeopardy!: Harnessing IBM's Watson to improve oncology decision making.
Authors: Bach Peter , Zauderer Marjorie Glass , Gucalp Ayca , Epstein Andrew S. , Norton Larry , Seidman Andrew David , Caroline Aryeh , Grigorenko Alexander , Bartashnik Aleksandra , Wagner Isaac , Keesing Jeffrey , Kohn Martin , Hsiao Franny , Megerian Mark , Stevens Rick J , Malin Jennifer , Whitney John , Kris Mark G.
Published: March 2020

6508

Background: Electronic decision support is increasingly prevalent in clinical practice. Traditional tools map guidelines into an interactive platform. An alternative method builds on experience-based learning. Methods: Memorial Sloan-Kettering (MSK), IBM and WellPoint teamed to develop IBM Watson – a cognitive computing system leveraging natural language processing (NLP), machine learning (ML) and massive parallel processing – to help inform clinical decision making. We made a prototype for lung cancers using manufactured and anonymized patient cases. We configured this tool to read medical language and extract specific attributes from each case to identify appropriate treatment options benchmarked against MSK expertise, anonymized patient cases and published evidence. Treatment options reflect consensus guidelines and MSK best practices where guidelines are not granular enough to match treatments to unique patients. Analysis and building accuracy is ongoing and iterative. Results: 420 manufactured and 525 anonymized patient cases trained the initial models. Early results show accuracy improvement in NLP and ML in identifying treatment options (Table). All treatment plans were guideline adherent. A proportion of cases showed the need to incorporate tailored treatment plans reflecting MSK’s practice beyond guidelines – e.g. 11% of cases required addressing a site of critical metastasis before initiating guideline supported treatment. Conclusions: IBM Watson is extracting information from free text medical records that supports building ML models to assist in selecting treatments for persons with lung cancers. This tool can select treatment options from consensus guidelines, and, through ML, it will identify personalized treatment plans. Training is ongoing to improve individualized decision making and optimize the web-based tool that connects with IBM Watson. [Table: see text]
Impact of Medicaid reimbursement and eligibility policies on receipt of cancer screening.
Authors: Halpern Michael T. , Romaire Melissa A. , Haber Susan G. , Tangka Florence K. , Sabatino Susan A. , Howard David H.
Published: March 2020

6514

Background: State Medicaid programs cover receipt of cancer screening services. However, coverage of cancer screening tests does not guarantee access to these services. Medicaid beneficiaries are less likely to be screened for cancer and more likely to present with advanced stage cancers. State-specific variations in Medicaid program eligibility requirements and reimbursements for medical services may affect cancer screening rates among Medicaid enrollees. This study examined how eligibility and reimbursement policies affected receipt of breast, cervical, colorectal, and prostate cancer screening. Methods: We examined 2007 Medicaid data for individuals age 21-64 enrolled in fee-for-service Medicaid for at least 4 months from 46 states and the District of Columbia. We examined the association of state-specific Medicaid cancer screening test and office visit reimbursements, income and financial asset eligibility requirements, physician copayments, and frequency of Medicaid eligibility renewal on receipt of cancer screening. Analyses used multivariate logistic regressions with generalized estimating equations to control for correlation between beneficiaries within a state. Results: Increased Medicaid screening test reimbursements were significantly associated with small increases in receipt of colonoscopy, mammograms, and PSA tests. Increased reimbursements for office visits were associated with increased receipt of colonoscopy, FOBT, Pap tests, and mammograms. Greater asset thresholds for Medicaid eligibility increased the likelihood of all screening tests except FOBT. Beneficiaries in states requiring more frequent (<12 month) renewal of Medicaid eligibility were more likely to receive FOBT, PSA, or mammograms, but less likely to receive Pap tests. Conclusions: Increasing Medicaid reimbursement rates and asset policies was generally associated with increases in cancer screening. As proposed Medicaid eligibility expansions will almost certainly increase the number of enrollees in this program, it is crucial to provide adequate reimbursements and develop eligibility policies to promote cancer screening and thereby increase early cancer detection among this underserved population.