bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type EGFR (TORG1320).
Authors: Hosokawa Shinobu , Bessho Akihiro , Otani Sakiko , Sasaki Jiichiro , Igawa Satoshi , Nakahara Yoshiro , Fukamatsu Nobuaki , Kasai Takashi , Sugiyama Tomohide , Seki Nobuhiko , Nakamura Yukiko , Tokito Takaaki , Masuda Noriyuki , Watanabe Koshiro ,   Thoracic Oncology Reserch Group
Published: September 2018

e20677

Background: Amrubicin (AMR) is a totally synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We found that the combination of AMR and erlotinib (ERL) had significant synergistic effect on NSCLC cell line with wild-type EGFR in vitro. We conducted a phase I study of AMR and ERL combination therapy in previously treated patients with advanced NSCLC, and have already reported the safety and the effectiveness. Furthermore we observed a high response rate of 33% in EGFR wild-type NSCLC. Methods: We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC, PS 0-1, and aged < 75 years, EGFR wild type. Patients were treated at 3weeks intervals with AMR(35mg/m2, intravenous injection on days 1-3) plus ERL(100mg/day, once daily on days 1-21). The primary endpoint is progression free survival (PFS). Secondary endpoints are response rate (RR), disease control rate (DCR), time to treatment failure (TTF), overall survival (OS), and toxicity. The concentration of trough ERL was measured after first cycle of treatment as additional investigation. Results: From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95%CI 2.1 - 5.1). The RR and the DCR were 24.0% and 64.0%, respectively. We observed grade 3 or 4 hematological toxicities such as leukopenia (68%), neutropenia (72%), anemia (8%) and febrile neutropenia (12%). The grade 3 or 4 non-hematological toxicities were anorexia (12%), oral mucositis (12%) and rash (8%). We had no treatment related death in this study. Conclusions: The PFS of AMR and ERL combination therapy in this study was superior to that of AMR monotherapy in historical setting. This combination therapy might be an option for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information: UMIN 000010582. Clinical trial information: UMIN 000010582.
The relationship between metastatic sites and progression free survival of nivolumab in non-small cell lung cancer patients.
Authors: Tamiya Motohiro , Tamiya Akihiro , Suzuki Hidekazu , Inoue Takako , Taniguchi Yoshihiko , Nakahama Kenji , Shiroyama Takayuki , Isa Shun-ichi , Nishino Kazumi , Okamoto Norio , Kumagai Toru , Hirashima Tomonori , Atagi Shinji , Imamura Fumio
Published: September 2018

e20679

Background: Nivolumab (Nivo) is applicable for all metastatic or unresectable non-small cell lung cancer (NSCLC), however only some patients benefit from it. Therefore, identifying biomarkers predicting efficacy is a crucial topic in the “real world’’ setting. We conducted a retrospective study to analyze the impact of metastatic status on the effect of Nivo in NSCLC patients. Methods: This is a retrospective multicenter study conducted by the three medical centers in Japan. All patients treated with Nivo from January 2016 to July 2016 in these centers were retrospectively reviewed. We collected clinical data including age, sex, smoking history, performance status (PS), and metastatic cites (lymph nodes: lym, liver, brain, bone, pleural effusion, and intrapulmonary metastasis: lung) at the time of starting Nivo treatment. We investigated relationship between metastatic sites and progression free survival (PFS) of Nivo. Patients were followed-up until 30th September 2016. Results: Two hundred and one patients treated with Nivo were enrolled. At the time of administration of Nivo, median age was 68 years old, 137 patients were male, 155 patients had history of smoking status, 152 patients were PS 0 or 1, and 46 patients had squamous cell carcinoma (SQ). For all participants, median PFS was 2.5 months. In univariate analysis, female (hazard ratio (HR): 1.43, 95% confidence interval (CI): 1.02-2.00; p = 0.036), never-smoker (HR: 1.51 , 95% CI: 1.05 – 2.17; p = 0. 0262), PS 2 or more (HR: 1.68, 95% CI: 1.17-2.41; p = 0.0045), metastasis to liver (HR: 2.02, 95% CI: 1.30-3.15; p = 0.0015), brain (HR: 1.42, 95% CI: 0.99-2.03; p = 0.0574), bone (HR: 1.42, 95% CI: 1.01-1.98; p = 0.0642), lung (HR: 1.57, 95% CI: 1.13-2.20; p = 0.0076), and malignant pleural effusion (HR: 1.47, 95% CI: 1.06-2.04; p = 0.0195) had significantly correlated with poor PFS. In multivariate analysis, liver metastasis (HR: 1.59, 95% CI: 0.97-2.61; p = 0.0642) and malignant pleural effusion (HR: 1.47, 95%CI: 1.04–2.07; p = 0.0294) had significantly correlated with poor PFS. Conclusions: Liver metastasis and malignant pleural effusion were independent poor prognostic factors of Nivo treatment in NSCLC patients. (UMIN-ID: UMIN000025908)
The role of positron emission tomography fused with computed tomography (PET/CT) versus CT alone in detecting oligoprogressive disease (OPD) in oncogene-addicted non-small cell lung cancer (NSCLC) receiving tyrosine kinase inhibitor (TKI) therapy.
Authors: Ng Terry L. , Morgan Rustain , Patil Tejas , Barón Anna E. , Camidge D. Ross
Published: September 2018

e20683

Background: OPD represents limited extra-central nervous system (eCNS) progression. In oncogene-addicted NSCLC, OPD can be treated with local ablative therapy to prolong TKI control. The impact of PET/CT vs CT to detect OPD at first eCNS progression has not been assessed previously. Methods: Patients with metastatic EGFR-mutant (EGFR-MT), ALK or ROS-1 rearranged (ALK+, ROS-1+) NSCLC with eCNS progression on a relevant TKI (2010-2016) were identified. Scan methodology at first eCNS progression was noted and progression was categorized as OPD using 2 definitions (≤ 2 or ≤ 4 progressing lesions) or non-OPD. Median time-to-progression (MTTP) was calculated from start of TKI to first eCNS progression. Data was analyzed using Chi squared and log rank tests as appropriate using p < 0.05 as significant. Results: Sixty-seven patients (EGFR-MT = 37, ALK+ = 28, ROS-1 = 2) were analyzable. OPD (≤ 2 lesions) occurred in 62.5% (20/32) noted by PET/CT vs. 54.3 % (19/35) by CT (p = 0.496). OPD (≤ 4 lesions) occurred in 84.4 % (27/32) noted by PET/CT vs. 65.7 % (23/35) by CT (p = 0.080). MTTP in PET/CT-detected OPD (≤ 2) (N = 20) was 332.5 days vs. 143 days in CT-detected OPD (N = 19) (p = 0.0092). MTTP in PET/CT-detected non-OPD ( > 2) (N = 12) was 185 days vs. 109 days in CT-detected non-OPD (N = 17) (p = 0.0503). MTTP in PET/CT-detected OPD (≤ 4) (N = 27) was 298 days vs. 143 days in CT-detected OPD (N = 23) (p = 0.0128). MTTP in PET/CT-detected non-OPD ( > 4) (N = 5) was 167 days vs. 104.5 days in CT-detected non-OPD (N = 12) (p = 0.1090). Conclusions: In this non-randomized retrospective study the proportion of OPD (≤ 2 or ≤ 4 progressing lesions) at first eCNS progression did not differ significantly for PET/CT vs. CT. MTTP was significantly longer for PET/CT vs CT detected OPD, but not for non-OPD progression. Potentially longer MTTP in the PET/CT OPD subgroup may reflect preselecting patients with disease difficult to detect by CT (e.g., bone/lymph node) which is more indolent. A prospective randomized study is required to assess the true impact of PET/CT vs CT on detecting OPD in oncogene-addicted NSCLC on TKI therapy.
Cumulative corticosteroid exposure in patients experiencing checkpoint inhibitor toxicity.
Authors: Mir Romaana , Shaw Heather May , Kuhan Hariharan , Bataille Veronique , Vergis Roy , Corner Carie , Nathan Paul D.
Published: September 2018

e21010

Background: Despite significant gains from systemic immunotherapy, prompt recognition and management of immune related adverse events (irAEs) remains key to minimising acute and chronic morbidity, and can sometimes allow treatment to be re-initiated. Active management of irAEs is corticosteroid based, with additional immunosuppressants used for steroid-refractory toxicity. Although the majority of irAEs resolve promptly, prolonged steroid exposure is required to maintain irAE control. Patients are therefore frequently exposed to cumulative high doses of steroids that in turn can be associated with significant long-term morbidity. Methods: Melanoma patients treated at Mount Vernon Cancer Centre (UK) with ipilimumab, pembrolizumab or combination ipilimumab and nivolumab; who were managed for checkpoint inhibitor-induced colitis had their corticosteroid exposure calculated. Data was collected on patient characteristics, onset of colitis and the subsequent use of corticosteroids, immunosuppressant and anti-TNFα agents until complete resolution of symptoms. Results: Of 137 patients, 18 (13.1%) had grade 3-4 colitis. Median time to onset of colitic symptoms was 13 days (IQR 7-20) with 8 (44%) requiring intravenous corticosteroid. Median time from commencement of steroid treatment to grade 1 colitis was 11.5 days (IQR 6.75-25.25), with resolution of symptoms seen at a median of 43 days. Median total corticosteroid exposure was 3000mg oral prednisolone equivalent (range 540-7580mg) with median duration of corticosteroid exposure being 103.5 days (IQR 67-136). 8 patients experienced flare of colitis during corticosteroid dose reduction. In all cases of colitis flare, the anti-TNFα agent infliximab resulted in improvement to grade 1 toxicity within 48 hours. Conclusions: Patients requiring treatment with corticosteroids for checkpoint inhibitor induced colitis are exposed to high doses of corticosteroids for prolonged periods of time, with the potential for significant steroid-associated sequelae. Alternative steroid-sparing regimens to manage checkpoint inhibitor induced autoimmune toxicities are required.
Real world treatment patterns of first-line combination therapies among patients with metastatic melanoma and BRAF mutation.
Authors: Qiu Ying , Li Zhiyi , Tang Jackson , Atanasov Pavel , Mahmood Syed , Grzegorzewski Kris , Chen Lei , Chen Joyce S
Published: September 2018

e21011

Background: First line (1L) systemic combination (combo) therapies for treatment of metastatic melanoma (MM) include targeted combo therapies such as dabrafenib+trametinib (D+T) or vemurafenib+cobimetinib for patients (pts) with BRAF mutation (BRAF+), or immunotherapy combo ipilimumab+nivolumab (I+N) for pts irrespective of BRAF status. The objective of this study was to describe real world characteristics and treatment patterns among BRAF+ mm pts who were treated with either D+T or I+N as 1L therapy. Methods: This retrospective observational study utilized Flatiron Health’s electronic health record (EHR) data from Jan 2013 to Jul 2016. Pts were aged ≥18 years with a mm diagnosis, and treated with either D+T (N = 86) or I+N (N = 61) as 1L therapy. Prior to therapy initiation, 86/86 of D+T pts were tested BRAF+. 55/61 of I+N pts completed BRAF testing and 19/61 were BRAF+. All analyses focused on BRAF+ pts who were treated with either D+T or I+N as 1L therapy. Baseline characteristics, treatment patterns and data on therapy discontinuation were collected from structured data in patient records and unstructured data in physician notes, and were descriptively assessed. Statistical inferences were not drawn due to sample size limitations. Results: At baseline, 35% of D+T pts vs 32% of I+N pts had brain metastasis, 29% of D+T pts vs 11% of I+N pts had high LDH levels, and 20% of D+T pts vs 42% of I+N pts reported ECOG = 0 status. The median follow-up time was 219 days for the D+T pts vs 150 days for the I+N pts. The 3 and 6 month discontinuation rates were 9% and 24% for the D+T pts vs 21% and 47% for the I+N pts. 13% of D+T pts vs 26% of I+N pts discontinued treatment citing toxicity in physician notes. Among pts with brain metastasis, the 3 and 6 month discontinuation rates were 3% and 20% for D+T pts vs 33% and 50% for I+N pts. Conclusions: Among BRAF+ mm pts who were treated with either D+T or I+N as 1L therapy, D+T pts were more likely to have advanced disease such as brain metastasis and high LDH levels than I+N pts. Compared with 1L D+T pts, 1L I+N pts had higher discontinuation rates due to toxicity, even with a shorter median follow-up time. 1L I+N pts with brain metastasis also had higher discontinuation rates.
Total tumor burden as predictive tool of response and survival of patients with metastatic melanoma treated with nivolumab.
Authors: de Moraes Rafael Vanin , Salgado Boneti Bianca , De Barros E. Silva Milton Jose , Cordeiro De Lima Vladmir Claudio
Published: September 2018

e21022

Background: Nivolumab (NIVO) has shown increased results either in objective response rate (ORR), progression free survival (PFS) and overall survival (OS), which have completely changed the treatment of patients with metastatic melanoma (MM). Tools to guide selection of patients are absent Methods: This is a retrospective, observational, single-center study. The TBT was calculated considering the sum of the largest diameter of all measurable lesions and the smallest diameter of lymph nodes affected Results: 54 patients with histologiacally confirmed mm were included in the protocol (OCT/14-may/16). Patients had a median age of 61 years (22-86 years), 58% were male, and 73% of tumor were located in the skin. 42% had ECOG 1, 72% had M1c, and 36% had LDH over the upper limit of normality (ULN). 34% had the mutation of the BRAF (half of them treated with IBRAF). About 75% had no prior benefit with anti-CTLA4 and 21% of the population had brain metastases. The median follow-up was 11.1 months and the median NIVO doses was 10 cycles. The ORR was 30.2% and the clinical benefit rate was 54.7%. The median PFS was 6.89 months (95% CI 1.12 to 12.6 months) and OS was not reached. TBT being < or > the median impact on OS with HR 4.5 (95% CI 1.22 to 16.9; p = 0.024). Once again, there was a statistically significant difference in terms of PFS and OS when related to pooled TBT ≤ or > 200 mm. The PFSm was 9.4 months (95% CI NR) for TBT ≤ 200 and 2.6 months ( 95% CI 1.9 to 3.2 months) to TBT > 200, with a HR: 2.64 (95% CI 1.03 to 6.74; p = 0.042). OSm regarding TBT ≤ 200 was not reached and was 2.6 months (95% CI 2.0 to 3.2 months) to TBT > 200, with RH:8.9 (95% CI 2.56 to 30.9; p = 0.001). According to the Fisher's exact test analysis, there is a significant association between LDH > ULN and pooled TBT > 200, with p = 0.023. Also, a relation between grouped TBT ( ≤ 200 or > 200) and the type of response seemed to be significant, with p = 0.021. Conclusions: The results of our study are very consistent with current medical literature. In our study, high TBT was associated with less response rates and both less OS and PFS rates.
Gene-signature based prediction of relapse-free survival in melanoma patients with known sentinel lymph node status.
Authors: Gambichler Thilo , Reinhold Uwe , Tsagoudis Konstantinos , Bierhoff Erhard , Dirschka Thomas , Sülberg Heiko , Borowski Matthias , Hinke Axel , Brunner Georg , Stockfleth Eggert
Published: September 2018

e21037

Background: Staging of cutaneous melanoma (CM), as defined by the American Joint Committee on Cancer (AJCC), includes determination of the sentinel lymph node (SLN) status as a major prognostic factor. We have previously identified and validated a gene expression risk score (GRS) in primary CM and adjacent stroma, consisting of 7 protective genes and 1 risk-associated gene, which predicts patient survival, independently of AJCC stage. This external validation study evaluated single and combined performance of GRS and SLN in predicting relapse-free survival (RFS). Methods: The study cohort included 203 formalin-fixed, paraffin-embedded (FFPE) -primary CMs (AJCC stages IA-IIIC, n=31 RFS events). Tissue samples and clinical data were provided by two centers, and gene expression was determined externally using real-time RT-PCR (double-blind study). External prospective data analysis followed a pre-specified protocol. Results: Integration Discrimination Improvement (IDI) analysis demonstrated non-inferiority of GRS vs. SLN status in predicting RFS (IDI estimate=-0.8%, p=0.040). In univariate Cox regression analysis, GRS and SLN status predicted RFS (GRS: p=0.011, HR=2.44 [1.2-4.95]; SLN: p=0.038, HR=2.12 [1.03-4.38]). Multivariate Cox regression demonstrated independent contribution of prognostic information by both parameters (GRS: p=0.015, HR=2.40 [1.18-4.89]; SLN: p=0.046, HR=2.11 [1.02-4.37]. IDI analysis demonstrated that combining GRS and SLN status improved prognostic performance, as compared to SLN status alone (IDI estimate=3.2%, p=0.044). When complementing SLN status with GRS (SLN positive or high GRS), sensitivity of relapse detection increased from 38.7% for SLN alone to 67.7%. Conclusions: GRS is a non-invasive predictor of RFS, complementary to SLN analysis. Combining GRS and SLN status significantly improves accuracy of melanoma prognosis and, therefore, may guide follow-up care as well as treatment decisions regarding new adjuvant therapies, e.g. of SLN positive patients with high GRS. [Table: see text]
Risk factors of fast growing melanomas in a French prospective cohort.
Authors: Gaudy Marqueste Caroline , Troin Laura , Malissen Nausicaa , Loundou Anderson , Monestier Sandrine , Mallet Stéphanie , Hesse Sylvie , Magis Quentin , Richard Marie-Aleth , Grange Florent , Grob Jean-Jacques
Published: September 2018

e21042

Background: Rate of growth (ROG) of the primary tumor is a known prognostic factor in melanoma (MM). Fast growing melanomas (FGMM) could account for an important part of the thick tumors which still exist despite earlier and earlier detection. Methods: All patients referred for a primary mm to two French Dermatology Department from the period 2012-2016 were prospectively enrolled in an observational case control study. ROG was calculated as the ratio of Breslow thickness to time to mm development according to patient, following a well-established process. FGMM were defined as those with a ROG > 0.5 mm/month and MMs with a ROG ≤05mm/month were used as controls. Differences in epidemiological, clinical and pathological features were evaluated with univariate and multivariate analysis. Results: 464 patients were enrolled. 149 mm (32.1%) were FGMM. Factors associated with FGMM in univariate analysis were age > 70 years (p = 0.006), tumor location (p = 0.032), histological subtype (p = 0.021), median thickness (p < 0.001), ulceration (p < 0.001), high mitotic rate ( > 1/mm2 )(p = 0.002), sentinel node involvement (p = 0.008), hair color at the age of 20 (p = 0.011), lower NSAIDS consumption (p = 0.012) and lower number of sunburns (p = 0.002). Age > 70 years (OR 1.88 95%CI 1.19-2.98, p = 0.007), ulceration (OR 3.70 95%CI 2.05-6.61) p < 0.001), sentinel node involvement (OR 1.93 95%CI 1.01-3.69 p = 0.046), regression (OR 0.37 95%CI 0.15-0.94) p = 0.037) and NSAIDS exposure (OR 0.29 95%CI 0.11-0.78, p = 0.014) remained associated with FGMM in multivariate analysis. OS and PFS were significantly lower in the FGMM group (HR 1.98 (95%CI 1.11-3.54, p = 0.02) and HR 1.79 (95%CI 1.17-2.73, p = 0.007), respectively). Conclusions: Fast growth characterizes a subset of primary mm which are intrinsically more aggressive and have different risk factors than other MM, namely more frequent in the elderly and with no association with skin type, nevus count or sun exposure. Association with ulceration could reflect a specific immune context. Negative association with NSAIDS exposure warrants more investigation, since it may have therapeutic implications.
Genomic profiling of melanomas of unknown primary.
Authors: Wells Keith Ryan , Hintzsche Jennifer , Amato Carol M , Robinson William
Published: September 2018

e21048

Background: Approximately 2-10% of metastatic melanoma patients present without an identifiable primary melanocytic lesion. These melanomas of unknown primary (MUP) are clinically classified into stage III or stage IV based upon extent of spread of metastatic disease. Previous studies, evaluating MUP using a limited sequencing of BRAF, NRAS, and KIT, have shown a similar frequency of mutations as cutaneous samples. Methods: We identified and performed retrospective chart review on 43 patients treated at the University of Colorado who presented with a melanoma of unknown primary. We excluded patient who presented with a preceding pigmented lesion treated with excision or cryotherapy without a histological diagnosis. After informed consent, DNA was extracted from the tumor samples of these 43 patients. Whole exome sequencing (WES) was performed with exome capture on an Illumina HiSeq sequencer. Results: Our cohort showed a male predominance at 58.1%. The median age at diagnosis was 50.6 years. In our cohort, 93% were Caucasian, while 4.7% were Hispanic and 2.3% were of unknown ethnic origin. 9.3% of patient had a family history of melanoma. Sun exposure was documented in 39.5% of patients and its presence was associated with an increased survival (Median OS of 3.7 vs 1.3 years, p = 0.026). Patients with stage III melanoma had an increased survival (Median OS of 6.8 vs 1.3 years, p = 0.013). Genomic analysis showed mutational pattern similar to cutaneous melanoma with 50% harboring a BRAF mutation, 12% with an NRAS mutation, and 19% carrying an NF1 variant. We found mutational signatures for each tumor and classified each against a larger cohort of cutaneous, mucosal and acral melanomas. Conclusions: We present the genomic data of a large cohort of MUP. The mutational profile of MUP is consistent with other cutaneous melanomas.
Photoacoustic detection of circulating melanoma cells as a predictor of metastasis in stage III patients.
Authors: Viator John Andrew , Sanders Martin , Tarhini Ahmad A. , Sander Cindy , Edgar Robert Hugh , Goldschmidt Benjamin ,   Viator
Published: September 2018

e21053

Background: Circulating tumor cells have been correlated with disease state and distant metastatic spread in cancer patients. We postulated that enumerating circulating melanoma cells (CMCs) may predict the onset of distant metastasis in Stage III patients. We detected CMCs using our photoacoustic flow cytometer, in which we irradiated enriched blood samples with nanosecond pulsed laser light. While there is no effect on non-optically active leukocytes, absorption of laser light by pigmented melanoma cells resulted in robust ultrasonic waves that indicated CMCs in the sample. Methods: We tested 32 archived samples from 9 Stage III melanoma patients using our photoacoustic flow cytometer. Each patient had between 2 and 6 serial blood samples. We used a pulsed Nd:YAG laser to irradiate mononuclear cells in suspension and under flow. The number of CMCs detected after testing was recorded, indicating the time sequence of circulating tumor cell activity. Results: The numbers of CTCs for each sample is shown in the table below. The ultimate disease state, whether the patient became metastatic or not, was blinded to the investigators who performed the photoacoustic tests. One sample for patient 3 indicated 63 CMCs, though this test was known to be contaminated and had an unknown number of false detections. Conclusions: We found that patients who had a series of more than 4 CMCs were more likely to become metastatic than those patients who tested for 4 CMCs for fewer, indicating that a sequence of CMC detections in serial blood draws provides a potentially strong predictor of metastasis in Stage III melanoma patients warranting further investigation at this and lower stages of melanoma. We are developing a more rigorous model based on time series analysis of CMCs for prediction of metastasis. [Table: see text]
Assessment of treatment response to immunotherapy in melanoma patients with pathogenic mutations of NRAS, BRAF, CDKN2A and P53.
Authors: DeLeon Thomas , Kipp Benjamin , Langlais Blake , Flotte Thomas , Winters Jennifer , Kosiorek Heidi E. , Joseph Richard Wayne , Markovic Svetomir , Dronca Roxana Stefania , Block Matthew Stephen , McWilliams Robert R. , Kottschade Lisa A. , Borad Mitesh J. , Rumilla Kandelaria M. , Voss Jesse S , Bryce Alan H.
Published: September 2018

e21057

Background: BRAF, NRAS, CDKN2A and P53 mutations are commonly observed pathogenic mutations in cutaneous melanoma. The influence of mutations such as BRAF, NRAS, CDKN2A and P53 on treatment response in the PD1 inhibitor era has not been well defined. Methods: This study included patients with melanoma with a cutaneous or unknown primary. All patients had genomic profiling with the Mayo Clinic 50-gene solid tumor mutation panel. Treatment response to first line immunotherapy with PD1, CTLA-4, or combination PD1/CTLA-4 inhibitors were assessed by response rate and time-to-progression (TTP) rate at 12 months. Each patient outcome was stratified by non-mutually exclusive gene mutation status into BRAF, NRAS, P53, CDKN2A, or quadruple negative (N4) groups. Results: Genomic profiling was performed on 208 patients, of whom 102 received first line immunotherapy. Most patients received a PD1 inhibitor (n = 62), followed by CTLA-4 inhibitor (n = 34), and combination therapy (n = 6). A trend towards improved outcomes was observed in CDKN2A and BRAF mutated patients with worse outcomes noted in P53, N4, and NRAS patients. The percent without progression at 12 months were BRAF 52.2%, CDKN2A 58.2%, NRAS 30.5%, P53 37.7%, and N4 26.7% (see table below). Response rates were BRAF 46.4%, CDKN2A 38.5%, NRAS 22.2%, P53 40.0%, and N4 33.3%. Conclusions: There is a trend towards improved outcomes with immunotherapy in BRAF and CDKN2A mutated patients while P53, NRAS and N4 patients have inferior outcomes. [Table: see text]
Burden of Merkel cell carcinoma: A targeted literature review.
Authors: Narayanan Siva , Gala Smeet
Published: September 2018

e21073

Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer characterized by high incidence of local recurrences, regional nodal metastases, distant metastases, and high mortality rates. It has no approved drug therapies and limited treatment options, especially to manage the metastatic disease. Our objective was to conduct a comprehensive review of MCC disease burden. Methods: We conducted a targeted literature review of studies published from 2010 to 2016 to assess epidemiology, patient burden, and unmet needs associated with MCC. An article was retrieved for full review if the abstract met each of the following criteria: reported incidence, natural morbidity or mortality of MCC; derived from a peer-reviewed journal; and reported in English-language published since January 2010. Results: The incidence of MCC (per 100,000 persons per year) is reported highest in Australia (0.82-1.60), followed by the US (0.6), Netherlands (0.35), Sweden (0.18-0.33), Finland (0.24-0.25), Spain (0.28), Denmark (0.22), South East Scotland (0.133), France (0.13). Inadequate data available from countries like Canada, UK, Germany and most part of Asia-Pacific. Typically, stage I-II MCC is observed in approximately 60% - 75% patients, stage III in 10% - 30% patients, and stage IV (metastatic) in 2% - 16% patients. The 5-year and 10-year survival is 0% - 68%, and 21% - 65% respectively, based on factors such as disease stage and gender. Although less than 20% patients progress to advanced metastatic stage IV MCC, they experience the highest unmet need due to lack of effective therapeutic options. Data on economic burden and humanistic burden (e.g., impact on patient quality of life) is not available. Conclusions: Epidemiological review indicates an increasing incidence of MCC; however, available estimates are at least 5 years old. Epidemiological data as well as data on clinical, economic and humanistic burden of MCC is lacking from several parts of the world. Further research is warranted to adequately quantify the burden-of-illness of MCC and assess comparative effectiveness of evolving treatment options to better inform patients, prescribers and payer organizations concerning optimal cost-effective modalities of disease management.
End-of-life chemotherapy and adherence to ASCO’s Top Five List recommendations: A single-center retrospective review.
Authors: Tancredi Richard , Stefani Sara , Gervaso Lorenzo , Fregoni Vittorio , Poojary Priti , Cefalì Marco , Piacentini Giulia , Riccardi Alberto
Published: September 2018

e21509

Background: End-of-life palliative chemotherapy does not improve quality of life nor does it prolong survival of terminal cancer patients. On the contrary, it is related not only to increased health costs, but also to severe therapy related side effects and to patient and caregiver distress. The first point of the ASCO’s Top Five List, released in 2012, tried to address the issue of chemotherapy overuse near the end of life. We tried to determine the aggressiveness of end of life care at our Institute by evaluating the number of patients who received end-of-life chemotherapy. We also aimed to verify whether the recent ASCO recommendations were followed or not. Methods: Electronic medical records were examined to identify patients who received at least one cycle of palliative chemotherapy and who died either in the Oncology or in the Palliative Care unit of the ICS Maugeri hospital between January 2014 and December 2015. Results: 181 patients were included in the study. 22% (40 patients) of these received chemotherapy in the last 4 weeks, and 6% (10 patients) in the last 2 weeks of life. 45% (18) of patients who were actively treated in the last month of life began a new chemotherapeutic regimen within the same period of time. Recently diagnosed patients were more likely to be treated aggressively in their last weeks of life (chi-square test, p value = 0.007). 12% of patients (7 patients) who started a new chemotherapeutic regimen within 90 days of death had already received 3 or more previous regimens. Futhermore, 16% of them (19 patients) had an ECOG PS of 3 or 4 at the beginning of the last regimen. The median survival since the beginning of the last chemotherapeutic regimen was 63 days for patients with a PS of 1 or 2 and 32 days for patients with a PS of 3 or 4 (Logrank test, p = 0.005). Conclusions: Almost 1 patient out of 4 receives end-of-life chemotherapy at our institute. About 30% of our patients began a new chemotherapeutic regimen even though they were in compromised clinical conditions or did not respond to 3 or more previous regimens. Our data highlight a relevant abuse of active anticancer treatments; efforts should be done to reduce these figures and to focus on supportive care near the end of life.
A rules-based algorithm to identify patients who would benefit from re-addressing advanced care planning.
Authors: Bestvina Christine M. , Daly Robert Michael , Wroblewski Kristen , Huber Michael , Malec Monica , Chow Selina Lai-ming , Hantel Andrew , Beach Brittany , Polite Blase N.
Published: September 2018

e21510

Background: Advance care planning (ACP) should be initiated early and readdressed often for cancer patients. We hypothesize that a rules-based algorithm based on occurrence of high-risk events can predict decreased overall survival, and can be used to target patients who would benefit from readdressing ACP. Methods: We performed a retrospective analysis of 221 patients receiving palliative chemotherapy with a diagnosis of leukemia, cholangiocarcinoma, esophageal, gastric, pancreatic, lung or urothelial cancer at the University of Chicago Medicine. Patients were included if they had an index outpatient oncology visit from April 1, 2015 through June 30, 2015. Starting at the date of index visit, we examined a three-month window for a “high-risk event,” defined as: 1. change in chemotherapy 2. emergency department visit 3. hospitalization. Patients were followed from index visit until date of death or last clinical encounter as of January 31, 2017. Each “high-risk event” was treated as a time-varying covariate in a Cox proportional hazards regression model to calculate a hazard ratio of death compared to those without an event. Results: Sixty-six percent of patients (146/221) experienced at least one high-risk event over the 3 month time frame. A change in chemotherapy regimen, an ED visit, and a hospitalization occurred in 53% (118/221), 10% (22/221) and 26% (57/221) of patients respectively. The hazard ratio of death for patients with at least one high-risk event when compared to those without was 1.86 (95% CI: 1.26-2.74, p = 0.002), when adjusted for age, gender, and race. Inpatient admission had the highest hazard of death among the high-risk events (HR 2.52: 95% CI: 1.69-3.76, p < 0.001). Conclusions: The rules-based algorithm identified patients with a greater risk of death. Implementation of this algorithm in the electronic medical record can identify patients with increased urgency to readdress goals of care.
Hospitalizations in elderly glioblastoma patients.
Authors: Moroney Claire Elizabeth , Perry James R. , Tsang Derek S , Bilodeau Denise , Mueller Christina , Soliman Hany , Myrehaug Sten , Sahgal Arjun , Tseng Chia-Lin , Tsao May
Published: September 2018

e21529

Background: Elderly glioblastoma (GB) patients are at risk of hospitalizations due to the morbidity of the disease and possible treatment toxicity. Methods: In this observational cohort study, 255 newly diagnosed GB patients age 65 years and older were included. Survival, emergency room visits and admissions to an acute care hospital were determined. Mean and median total health care costs were calculated. Risk factors for Emergency room visits and acute care hospital admissions were determined. Results: Median overall survival was 6 months. The majority of patients (68%) had at least one visit to the emergency department and 77% had at least one admission to acute care. The mean and median length of hospital stay per patient was 20.5 days and 14 days respectively. Forty-three percent of patients spent 0-4% of their survival as an inpatient. Only 3% spent 70% or more of their survival as an acute care inpatient. There was a mean of 79.7 days and a median of 43 days from the last emergency department visit to death. The mean and median total costs (hospital, ambulatory, physician billing, other health care costs) per patient were $162 479.78 (CAN) and $125 511.00 (CAN), respectively. Treatment with radiation or treatment with radio-chemotherapy was associated with a relative risk (RR) of 2.31 (95% CI 1.44, 3.7; p = 0.0005) and 2.19 (95% CI 1.28, 3.74; p = 0.0 04), respectively for emergency department visits as compared to patients who were managed with comfort measures only. Patients with a baseline ECOG 0 had a RR of 1.71 (95% CI 1.06, 2.77; p = 0.0289) and patients with baseline ECOG 1 had a RR of 1.49 (0.98, 2.26; p = 0.0623) for hospital admission as compared to patients with ECOG 4. Conclusions: A large proportion of elderly GB patients (particularly those with good baseline performance status who underwent active treatment) presented to the emergency department and had at least one admission to acute care.
Longitudinal trajectory of frailty and related factors in 376 breast cancer patients aged 50+ compared to controls.
Authors: Magnuson Allison , Mohile Supriya Gupta , Lei Lianlian , Gilmore Nikesha , Esparaz Benjamin , Giguere Jeffrey K. , Misleh Jamal Ghazi , Janelsins Michelle Christine
Published: September 2018

e21532

Background: Frailty, a clinical syndrome of vulnerability, is associated with adverse outcomes; however, the trajectory of frailty in cancer patients is not well understood. This longitudinal analysis evaluates frailty, and related factors, over the course of chemotherapy in breast cancer patients (BCa pts) aged 50+. Methods: BCa pts aged 50+ scheduled to receive adjuvant/neoadjuvant chemotherapy (n = 376) and age matched controls without cancer (n = 234) were recruited from the University of Rochester NCI Community Oncology Research Program as part of an observational study. Frailty was assessed by a modified Fried frailty score (range 0-4) using self-reported weakness, exhaustion, physical activity, and walk speed. Cognition was assessed objectively (Controlled Oral Word Association [COWA]) and subjectively (FACT-Cog). Frailty and cognition were measured pre- and post-chemotherapy (similar time lapse for controls). Linear regression models evaluated associations between cognition and frailty, controlling for age, race, marital status, education, performance status and baseline frailty score. Results: Average age was 59 (50-64: 77%; 65-79: 23%). At baseline, the cancer group had more people aged 65+ (24% vs 20%, p = 0.002), a higher mean frailty score (1.2 vs 0.73, p < 0.001), and lower mean FACT-Cog score (158.5 vs 167.4, p < 0.001) compared to controls. In unadjusted analysis, BCa pts had greater increase in frailty and cognitive problems than controls over time (mean change frailty score: cancer 0.87 vs control 0.05; mean change FACT-Cog: cancer 12.78 vs control 1.58; mean change COWA: cancer -0.41 vs control 0.43; p < 0.001 for all). In adjusted analysis, cancer (p < 0.001) and lower baseline FACT-Cog score (p = 0.01) were associated with an increase in frailty score over time. In a separate model, a decline in subjective and objective cognition was associated with increased frailty score (COWA p = 0.03, FACT-Cog p = 0.07). Conclusions: Frailty is prevalent in BCa pts prior to chemotherapy and increases during treatment. Lower baseline cognition and decline in cognition were associated with increased frailty. Frailty and cognition are important survivorship factors for BCa pts aged 50+.
Predicting cumulative incidence of chemotherapy toxicity in older patients with cancer: Korean Cancer Study Group prospective cohort study (KCSG) PC 13-09.
Authors: Kim Jee Hyun , Kim Jin Won , Kim Se Hyun , Lee Yun-Gyoo , Hwang In Gyu , Song Hong-Suk , Koh Su-Jin , Ko Yoon Ho , Shin SeongHoon , Woo In Sook , Hong Soojung , Kim Tae Yong , Kim Sun Young , Nam Byung-Ho , Kim Hyun Jung , Kim Hyo Jung , Lee Myung Ah , Kwon Jung Hye , Hong Yong Sang , Ryoo Hun-Mo ,   Korean Cancer Study Group Geriatric Oncology Working Party
Published: September 2018

e21539

Background: Older adults have increased risk of developing chemotherapy toxicity. Currently available prediction tools do not provide information on cumulative risk and none are from Asia. Methods: Patients with histologically confirmed solid cancer aged ≥70 years were prospectively enrolled from 17 centers and underwent geriatric assessment before starting their 1st line chemotherapy. Chemotherapy toxicity prediction model was built for adverse events (AEs) ≥G3, among geriatric assessment, laboratory and clinical variables. Model discrimination values were evaluated using c-statistics compared with actual cumulative incidence of AE ≥G3 in each cycle. Results: 301 patients were enrolled with a median age of 75 years (range 70-93). Primary site included colorectal (28.9%), lung (24.6%), hepato-biliary-pancreatic (22.3%), stomach (10.6%) and others (13.6%). Median chemotherapy cycle was 4 (2-7 cycles). During first line chemotherapy, 53.8% of patients experienced AEs ≥G3. Six variables significantly associated with occurrence of AEs ≥ G3 were serum protein < 6.7 g/dL, no dose reduction at first cycle, suffering from psychological stress or acute disease in the past 3 months, water consumption of less than 3 cups per day, not being able to obey command of 'Grab a piece of paper in your hand', and self-perception of ‘not in good health’. Model with all six variables was selected with the highest mean value of c statistics (0.646) and prediction tool indicated score ranging from 0 to 8 points. Patients were classified to 4 risk groups; 61 (21.0%), 143 (49.3%), 66 (22.8%), and 20 (6.9%) in low (0, 1 point), medium-low (2, 3), medium-high (4, 5), and high risk group (6, 7, 8). Predicted cumulative incidence of AEs ≥G3 was discriminated according to risk groups; low risk group: 13%, 19%, 27%, 30%, 30% in cycle 1, cycle 2, cycle 3, cycle 4, cycle 5, medium-low risk: 17%, 37%, 48%, 56%, 60%, medium-high risk: 26%, 44%, 50%, 68%, 75%, and high risk: 45%, 62%, 87%, 94%, 94%. Conclusions: Novel prediction tool could identify those at high risk of developing AEs ≥G3 after chemotherapy, which provided information on cumulative incidence in each cycle.
Efficacy of PD-1 and PD-L1 inhibitors in older adults: A meta-analysis.
Authors: Elias Rawad , Giobbie-Hurder Anita , Rahma Osama E.
Published: September 2018

e21544

Background: Immune checkpoint inhibitors (ICIs) have a promising activity in variety of malignancies however little is known regarding their efficacy and toxicity profile in older adults (≥65 yo). Accordingly, we performed a meta-analysis of published trials using anti-PD-1 or PD-L1 to define the activity of these agents in this subset of patients. Methods: We conducted a search using PubMed and Web of Science databases for randomized controlled trials (RCTs) of PD-1 and PD-L1 inhibitors including nivolumab (N), pembrolizumab (P), and atezolizumab (A). We then identified the studies that reported a subgroup analysis of overall survival (OS) based on an age cutoff. Results: We identified a total of 17 RCTs that compared N, P and A to chemotherapy or targeted therapy. Out of those trials only 9 reported hazard ratio (HR) based on age and were included in this meta-analysis. These trials treated a total of 5033 patients including 2315 patient ≥65 yo (46%). The overall estimated, random-effects hazard ratio (HR) for death was 0.69 with 95% CI of 0.63 -0.74 (p < 0.0001) in the general population favoring ICIs. Based on the selected trials, there was evidence of a 31% reduction in the hazard of death with PD1/PDL1 inhibitors compared with chemo/targeted therapy. This OS benefit persisted when the analysis was done based on disease type (NSCLC or others) or the drug target (PD-1 or PD-L1). Analysis based on age cutoff of 65 yo showed that the efficacy of PD-1 and PD-L1 inhibitors did not vary for older or younger patients. The overall estimated random-effects HR was 0.64 with 95% CI of 0.54 -0.76 in patients ≥65 yo vs. 0.68 with 95% CI of 0.61-0.75 in patients < 65 yo. Data regarding toxicity based on age was available only for 3 trials. The rate of grade 3-4 toxicities was comparable between the 2 groups (45-50% in patients ≥ 65 compared to 37.1-50% in patients < 65). Conclusions: PD-1 and PD-L1 inhibitors efficacy using N, P or A is comparable in older and younger adults when using an age cutoff of 65 years. Future ICIs trials should report efficacy and toxicity based on age.
Supportive care needs among Mexican young women with breast cancer.
Authors: Galvez C. Lizette , Villarreal-Garza Cynthia , Mohar Alejandro
Published: September 2018

e21552

Background: Despite high rates of breast cancer (BC) in young Mexican women, information about their particular needs and concerns is largely unknown. Understanding the patients individual needs in a population with unique socio-cultural features is essential to guide supportive care and improve their quality of life. We aim to describe the unmet needs of Mexican young women with breast cancer (YWBC). Methods: A cross-sectional study including women with stage I-III BC aged 40 years or younger at diagnosis was conducted at the National Cancer Institute in Mexico City. YWBC were invited to complete the Supportive Care Needs Survey, Short Form-34 (SCNS-SF34), a comprehensive tool that measures the perceived unmet needs of cancer patients. The survey was previously adapted and validated in our population for its use. Results: 81 consecutive patients with median age at diagnosis of 35.09 (SD 3.9) years were included. 45.7% were married and 29.2% completed secondary school. 92.6% had stage II-III BC. 70.4% were undergoing active treatment and 29.6% were either on hormonal therapy or surveillance. From a total standardized score of 100, the health systems and information domain had the highest mean score (39.3), followed by the psychological domain (36.3). The sexuality domain had the lowest mean score (27). The highest ranked items of unmet needs (by mean crude score) were: to be informed about cancer is under control or diminishing (2.9), to be informed about things you can do to help yourself get well (2.8), lack of energy and fatigue (2.7), and fear about the cancer spreading (2.7). Perceived needs among patients undergoing active treatment were greater compared to those in follow-up (z = -2.390 p = 0.017), predominantly in the sexuality domain (z = -2.084 p = 0.037). Conclusions: Mexican YWBC have specific needs that are currently not systematically addressed. The predominant unmet need regarding health systems and information should be a priority. Further research to understand the needs and concerns of this unique and understudied patient population will aid tailor clinical interventions and supportive care.
A prognostic index to stratify survival benefit in patients of solid tumor metastases treated with stereotactic body radiotherapy.
Authors: Lu Yi , Tang Chad
Published: September 2018

e21578

Background: To investigate the clinical factors related to the prognosis of solid tumor metastases treated with SBRT and to create a scoring system that stratifies survival benefit. Methods: The clinical factors and follow-up data of 404 patients with metastases from solid primary (127 liver metastases, 205 lung metastases and 72 adrenal gland metastases), treated with SBRT from 2005 to 2016, were analyzed retrospectively. The prognostic index (PI) of patients was calculated based on the results of multivariate cox regression model from liver metastases cohort and pretreatment variables included were race, gender, age, KPS, primary tumor and histology, number of metastases, status of disease outside, previous treatment at SBRT site, and interval time from diagnosis to metastases. This model then was used in lung and adrenal gland metastases cohorts. Results: Median follow-upwas 24 months for liver metastases cohort. The median survival time of liver metastases was 21.8 months. Three variables were selected from liver cohort-database training as independent prognostic index for survival benefit: age (HR =1.81, p =0.03), KPS (HR =0.72, p =0.03), number of organs with active disease outside (HR =1.68, p<0.01). Patients were classified into three hazard groups with significant difference. The median survival of group 1(poor) was 8.1 months, group 2 (intermediate) reached 25 months, and group 3 (excellent) reached 39.1 months (p< 0.001). This prognostic index model was also been approved effectively in lung and adrenal gland metastases cohorts, which identified patient subgroups into poor and excellent prognosis. Conclusions: The prognostic index model allows solid tumor metastases patient to stratify survival benefit based on the three predictive factors. Table 1 Survival score and groupings [Table: see text]