tbuckley/cabot-search huggingface dataset:
A phase II study of panitumumab with FOLFOX or FOLFIRI as first-line chemotherapy for KRAS-wild type metastatic colorectal cancer: The PaFF-J study.
Authors: Eiji Shinozaki, Megumi Ishiguro, Eiji Nakatani, Tatsuro Yamaguchi, Masato Nakamura, Yuji Miyamoto, Hitoshi Ojima, Yoshitaka Honma, Masahiro Gotoh, Toshiaki Ishikawa, Keiichi Takahashi, Yasuhiro Shimada, Kazuhiro Yoshida, Nobuyuki Mizunuma, Kei Muro, Yoshito Komatsu, Kensei Yamaguchi, Hiroshi Nakano, Junki Koike, Kenichi Sugihara
Journal: Journal of Clinical Oncology (2017)

722 Background: For the patients with unresectable metastatic colorectal cancer (mCRC), response to the1st line chemotherapy has strong impact on their prognosis. Shrinkage of tumors may result in conversion to surgical resection and, concurrently, improved their survival. We conducted a multicenter phase II trial to investigate the efficacy and safety of panitumumab (Pmab) with chemotherapy as the 1st line treatment in Japanese patients with mCRC. Methods: Patients with no prior chemotherapy for unresectable, KRAS wild type mCRC, 20-80 years, and PS 0-1 were arbitrarily received either FOLFOX + Pmab or FOLFIRI + Pmab. Patients were evaluated every 8 weeks until progression. The primary endpoint was overall response rate (ORR), the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), R0 resection rate, and safety. Results: A total of 162 patients (140 with FOLFOX + Pmab and 22 with FOLFIRI + Pmab) were analyzed. Median follow-up was 28.2 months, median age at enrollment was 64.5 years, and 17.9% of the patients was recurrent disease. Number of target organ was 1 in 35.2%, 2 in 40.7%, and ≥ 3 in 24.1% of the subjects. Median administered cycle was 7, and median treatment duration was 16 weeks. ORR was 51.2% (95%CI: 43.3-59.2), and DCR was 82.1% (95%CI: 75.3-87.7). ≥ 30% tumor shrinkage (PR-in) was observed in 115 patients (71.0%). Median time to PR-in and maximum shrinkage was 10 and 16 weeks, respectively. Surgical resection was done in 66 patients (40.7%), of which R0 was in 43 patients; R0 resection rate was 26.5% (95%CI: 19.9-34.0). Median PFS and OS was 9.2 (95%CI: 7.2-11.4) and 33.8 months (95%CI: 29.4-43.1), respectively. ≥ Grade 3 adverse events with &gt; 5% incidence were neutropenia (31.8%), stomatitis (10.5%), rash acneiform (9.9%), paronychia (9.3%), anorexia (8.6%), and diarrhea (6.2%). Conclusions: In our study, OS was favorable with high R0 resection rate, whereas ORR, DCR, PFS and toxicities were similar to those in previously reported studies. Because the maximum tumor shrinkage was observed around 16 weeks, optimal timing for considering conversion surgery might be 16 weeks from the start of treatment. Clinical trial information: UMIN000004991.
Correlation of polymorphisms of genes involved in platinum/gemcitabine (P/G)-based metabolism with toxicity and clinical response in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: M. Tonato, V. Ludovini, L. Pistola, I. Floriani, M. Meacci, R. Chiari, D. Garavaglia, F. R. Tofanetti, A. Flacco, M. Ferraldeschi, L. Crinò
Journal: Journal of Clinical Oncology (2009)

8093 Background: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in NSCLC. Genetic variations in drugs metabolism may affect the clinical response, toxicity and prognosis of NSCLC pts treated with P/G-based therapy. Methods: We evaluated 8 single nucleotide polymorphisms (SNPs) of 6 genes (P53 Arg72Pro (G/C); XRCC3 Thr241Met (C/T); XPD Lys751Gln (A/C); ERCC1 Asn118Asn (C/T); CDA Lys27Gln (A/C), Ala70Thr (G/A), Thr145Thr (C/T) and RRM1 C524T) involved in P/G-based metabolism in a homogeneous population of pts with advanced NSCLC treated with this regime. Genomic DNA was extracted from whole blood samples using the QIAamp DNA estraction kit on Biorobot EZ1 (Qiagen). Polymorphisms were detected with TaqMan-probe based assays using the 7300 Real-Time PCR System (Applied Biosystems, Foster City, CA). Association between SNPs and response, toxicity, progression free survival and overall survival was estimated using logistic regression model, the Kaplan-Meier method, the long-rank test and the Cox proportional hazard model. Results: We performed a retrospective analysis in 192 chemotherapy-naive pts (median age 63 years), including M/F:74/26%; stage IIIb/IV:24/76%; Adeno/Squa/other Ca:42/27/31%; ECOG PS:0–1/2–3:94/6%. Overall response rate was 32.3%, stable disease 25% and disease progression 42.7%. The CDA Thr145Thr T/T genotype significantly correlated with poorer response (partial response in 23.1% of pts versus 42.3% and 34.6% in C/T and C/C genotypes, respectively; p=0.03). The ERCC1 T/T genotype was significantly associated with haematological toxicity (G1–4) (p=0.05) compared to ERCC1 C/C allele. The CDA Thr145Thr C/T genotype was significantly associated with non-haematological toxicity (G3–4) (p=0.02) compared to CDA Thr145Thr C/C allele. The median overall survival (OS) time and progression free survival (PFS) were 12.7 and 4.7 months, respectively. None of the analyzed polymorphisms was related to PFS or OS. Conclusions: These data suggest that genetic polymorphisms in the ERCC1 and CDA genes may modulate the toxicity and response to P/G-based therapy in pts with advanced NSCLC. No significant financial relationships to disclose.
Chemotherapy in the oldest old: The feasibility of cytotoxic therapy in the 80+ population.
Authors: Shelly Sud, Pamela Lai, Katelyn Balchin, Mark Clemons, Paul Wheatley-Price
Journal: Journal of Clinical Oncology (2012)

6083 Background: The incidence of most common malignancies increases with age. As life expectancy improves globally, more elderly cancer patients will be candidates for systemic therapy. There is little data investigating chemotherapy (CT) in those over 80 – the “oldest old”. Our hypothesis is that CT in the 80+ population may be associated with significant toxicities and is therefore not feasible for many patients. Methods: A retrospective chart review was undertaken to report outcomes of patients ≥80 years old who initiated CT for solid tumors at the Ottawa Hospital Cancer Center between Nov. 2005 and Jan. 2010. Baseline data on patient demographics, cancer type and CT were collected. Primary endpoints included: rates of CT dose reduction, omission, delay and discontinuation due to toxicity, hospitalization and blood transfusion rates. Results: CT was initiated on 212 occasions (32% lung, 31% GU, 24% GI, 13% other cancer). Median age was 83 (range 80-92) and 60% of patients were male. Where data were available, 60% had a good performance score (ECOG 0-1) and 63% were current or ex-smokers. 82% had Charlson risk index scores of ≥5, 37% had ≥6 baseline medications, 18% lived alone independently. At baseline, 11% were anemic, 12% had leukocytosis, and 45% had impaired renal function (eGFR&lt;60). Most patients had stage 4 disease (76%), were treated with palliative intent (75%) and were receiving first line CT (77%). Initial dose was adjusted in 34% of cases. Therapy was discontinued due to toxicity in 30% of cases, and 53% of patients required dose reduction, omission or delay. In 38% of cases, patients were hospitalized during their course of therapy or within 30 days thereof. Blood transfusions were required in 24%. Factors associated with risk of hospitalization included baseline number of medications ≥6 (OR 1.96, 95% CI 1.1-3.5) and baseline anemia (OR 2.55, 95% CI 1.07-6.05). Initial dose reduction at cycle 1 did not significantly affect rates of hospitalization, transfusion or CT discontinuation. Conclusions: CT in the 80+ population is associated with a significant risk of hospitalization, transfusion and discontinuation due to toxicity, even when doses are adjusted from the outset. We plan to prospectively validate these findings.
Feasibility of cotargeting cell cycle and androgen signaling in metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Phillip Lee Palmbos, Scott A. Tomlins, Neeraj Agarwal, Przemyslaw Twardowski, Alicia Katherine Morgans, William Kevin Kelly, Vivek Arora, Emmanuel S. Antonarakis, Javed Siddiqui, Stephanie Daignault, Karen E. Knudsen, Felix Yi-Chung Feng, Maha Hussain
Journal: Journal of Clinical Oncology (2017)

151 Background: Most patients (pts) with mHSPC treated with androgen deprivation therapy (ADT) will progress to castration resistance. Androgens drive PC cell proliferation via upregulation of cyclin D which complexes with the cyclin-dependent protein kinases 4/6 (CDK4/6) resulting in phosphorylation of retinoblastoma (Rb) tumor suppressor protein and G1/S progression. Alterations in this pathway contribute to progression to castration-resistance (CR). In preclinical PC models, palbociclib, a novel specific CDK4/ 6 inhibitor, blocked proliferation and promoted G1 arrest in an Rb and Cyclin D dependent manner. Rb is lost in &lt;10% of localized PC, but &gt;30% of CR disease. Rb loss in mHSPC is estimated to be 10-20%. Based on this preclinical data, we designed a randomized phase II clinical trial (NCT02059213) to test the hypothesis that palbociclib + ADT in newly metastatic Rb-positive PC pts will significantly increase ADT efficacy. Methods: mHSPC pts with Rb intact tumors based on metastatic biopsy are stratified by disease extent and randomized (1:2) to ADT or ADT+ palbociclib. Primary endpoint is confirmed prostate specific antigen (PSA) response (≤ 4 ng/mL) after 28 weeks of therapy. With 20 patients randomized to ADT and 40 to ADT + palbociclib there will be a 64.2% power to detect a 20% difference in proportions with a one-sided type I error of 0.10 using the mid p-value method of the Fisher’s exact test. Secondary endpoints: safety and tolerability, rate of undetectable PSA (≤ 0.2ng/mL), biochemical and clinical PFS, overall PSA and radiographic RR, therapeutic biomarkers (circulating DNA and tumor cells, tumor protein and transcriptome) and to establish a repository of mHSPC samples. Results: Since July 2014, 68 patients have been registered and underwent tumor metastatic disease biopsy (36 soft tissue, 32 bone). 60/68 (88%) had adequate tissue for Rb assessment. 58/60 (97%) tumors were Rb positive (IHC). To date, 58/60 patients have been randomized to ADT (19 patients) or ADT + palbociclib (39 patients). Conclusions: Biopsy driven studies are feasible in the mHSPC population. Rb expression was present in 58/60 (97%) patients. This study is ongoing. Support: Movember-PCF Challenge Award, Pfizer. Clinical trial information: NCT02059213.
Serum levels of the cancer-testis antigen POTEE and its clinical significance in non-small cell lung cancer.
Authors: Qi Wang, Xuefei Li, Shengxiang Ren, Ningning Cheng, Weijing Cai, Chao Zhao, Mingchuan Zhao, Jiayu Li, Caicun Zhou
Journal: Journal of Clinical Oncology (2015)

e22213 The first two authors contributed equally to this article. Background: POTEE (POTE ankyrin domain family, member E) is a newly identified cancer-testis antigen that has been found to be expressed in a wide variety of human cancers including cancers of the colon, prostate, lung, breast, ovary, and pancreas. Methods: 104 NSCLC patients, 66 non cancer patients and 80 healthy volunteers were enrolled in this study from May 2013 to February 2014. Serum POTEE levels were measured using enzyme-linked immunosorbent assay (ELISA). Numerical variables were recorded as means ± standard deviation (SD) and analyzed by independent t tests. Categorical variables were calculated as rates and were analyzed using a χ2 test or Fisher’s exact test. Survival curves were estimated and compared using the Kaplan-Meier method and log-rank tests. Results: Serum POTEE levels were significantly higher in NSCLC patients than in non cancer patients and healthy controls (mean ± SD [pg/ml], 324.38± 13.84 vs. 156.93 ± 17.38 and 139.09 ± 15.80, P< 0.001) and were significantly correlated with TNM stage. Survival analysis revealed that patients with low serum POTEE had longer progression-free survival (PFS) than those with high serum POTEE (P= 0.021). Cox multivariate analysis indicated that POTEE was an independent prognostic factor of progression-free survival (P = 0.009, hazard ratio, 2.440). Conclusions: Serum POTEE level in NSCLC patients is associated with TNM stage and is a potential prognostic factor.
Quantification of tumor stroma as a biomarker in pancreatic adenocarcinoma.
Authors: Robert J. Torphy, Keith E. Volmar, Rashid Naim, Sonia Rosanne Cader, Julia S. Johansen, Michael A. Hollingsworth, Eric Andrew Collisson, Jen Jen Yeh
Journal: Journal of Clinical Oncology (2015)

4021 Background: Desmoplastic tumor stroma (TS) characterizes the primary tumor in pancreatic ductal adenocarcinoma, but its role in tumor progression and metastasis is less clear. The objective of this study was to evaluate the presence and prognostic significance of TS at primary and metastatic sites. Methods: Tissue sections of primary tumors from 57 patients who underwent curative resections and 46 primary and metastatic tumors from 15 patients with metastatic pancreatic cancer were digitally annotated for tumor epithelium and TS, reviewed by a pathologist, and quantified using Spectrum WebScope. Tumor stroma density (TSD) was quantified as TS per total tumor area. Resected patients received no adjuvant chemotherapy. Association of TSD with overall survival (OS) and recurrence-free survival (RFS) was performed using the multivariate Cox proportional hazards model from the “survival” R statistical package (3.1.1); where significance was determined with log-rank test p-value less than 0.05. Results: Median TSD in primary tumors was 0.57. TSD was no different in the primary tumors of patients who had localized compared to metastatic disease. TSD was decreased in solid organ (0.12) and lymph node metastases (0.22) (ANOVA, p = 0.0001). Furthermore in patients who underwent curative resections, high TSD was associated with longer OS (HR = 0.237; p = 0.009), with a median OS of 11 months in the low TSD ( < 0.57) group and 21.5 months in the high TSD ( ≥ 0.57) group. TSD was also associated with RFS (HR = 0.286, p = 0.022), with a median RFS of 9 months in the low TSD group and 19 months in the high TSD group. The association of TSD with OS and RFS was adjusted for tumor grade, T, N and overall stage, ASA score, and smoking status. Conclusions: We demonstrate that stromal content is a measurable biomarker in this disease with meaningful clinical associations.Our results nominate that TSD should be used as an objective, quantitative assessment of TS in correlative and therapeutic trials of pancreatic cancer. TS appears to be associated with restraining tumor growth with decreasing TSD in patients with more aggressive disease. Also, the low TSD at metastatic sites should be considered in the context of stroma modulating therapies.
Modes of action of low-dose cabazitaxel in combination with the antiangiogenic and antitumoral pigment epithelium-derived factor in prostate cancer.
Authors: Thomas Nelius, Courtney Jarvis, Stephanie Filleur
Journal: Journal of Clinical Oncology (2017)

275 Background: Despite the approval of several new agents, taxanes remain the main alternative treatment for castration-refractory metastatic prostate cancer (mCRPC). In a previous work, we have demonstrated that cabazitaxel is more efficient in a low-dose setting than docetaxel in inhibiting the proliferation and inducing apoptosis of CRPC cells in vitro, and delaying tumor growth in vivo. In the present study, we have investigated the efficacy of low-dose cabazitaxel when combined with the anti-angiogenic and anti-tumoral Pigment Epithelium-Derived Factor (PEDF). Methods: CRPC CL1 cells (LNCaP-derivative) that express PEDF or control plasmid were used. Tumor cells were injected s.c. into C.B.17-SCID mice. After two weeks, mice were randomized into groups: 1) Placebo; 2) Docetaxel: 5mg/kg i.p. d4; and 3) Cabazitazel 5-1-0.5-0.1mg/kg i.p. d4, d1-7, d2, and daily. To investigate the molecular mechanisms involved in the anti-tumor effect of the combined treatment, tumor cell migration was measured using the inverted Boyden chamber assay. Tumor cell phagocytosis was also assessed in CL1-RAW264.7 macrophages co-cultures. Results: We showed that while 0.5 and 0.1 mg/kg cabazitaxel did not improve PEDF efficacy on tumor growth, 1mg/kg was extremely toxic, killing 1/2 animals within the first week of treatment. In contrast, we demonstrated that PEDF combined with 5mg/kg cabazitaxel lead to stabilization of the disease. PEDF/cabazitaxel was also found to be drastically more efficient than PEDF/docetaxel in delaying the disease. In vitro, PEDF/cabazitaxel inhibited tumor cell migration at a superior level compared to PEDF/docetaxel. Finally, PEDF/cabazitaxel induced more phagocytosis of the tumor cells by macrophages than PEDF/docetaxel suggesting that the combination may target macrophages within the tumor microenvironment. Conclusions: Our data demonstrated that PEDF with low-dose cabazitaxel could be used as a novel therapeutic combination to treat CRPC. Our results also emphasize on the importance in closely evaluating the cytotoxicity of the combination tested and investigating the role of the tumor microenvironment in the anti-tumor effect.
Concurrent weekly taxane (T) and radiation therapy (RT) in the adjuvant treatment of breast cancer (BrCa)
Authors: S. P. Rajurkar, T. Singh, M. Arora, S. Saha, H. Gayar, N. Talwar, J. Nettleton
Journal: Journal of Clinical Oncology (2004)

858 Background: High-risk BrCa pts receive adriamycin(A) + cyclophosphamide(C) followed by a T given every 3 wks × 4 followed by radiation therapy (RT). RT is started after completion of all chemotherapy, a delay of 3 months. A delay of RT has been shown in studies to increase the risk of recurrence. T is suggested to act as radiosensitisers. In the case of wkly T administration, the cellular cytokinetic considerations imply that frequent exposure to cytotoxic agents with brief intervals between exposures affords less opportunity for the emergence and regrowth of drug-resistant cell clones. The purpose of this study was to analyze the skin and pulmonary toxicity of concurrent weekly T and RT in BrCa pts. Methods: Between 1998 and 2002, 51 pts with BrCa (Stage II=40,Stage III=10,Stage IV=1) underwent lumpectomy plus axillary LN dissection or MRM. Then they received A + C every 3 wks × 4 followed by either Paclitaxel (P)(80 mg/m2/wk) or Docetaxel (D)(30 mg/m2/wk) every wk with concurrent RT 5 days/wk for 6 wks followed by a T alone every wk for 6 wks. The dose of RT was: Breast/Chest wall: 5040 cGy + Supraclavicular area: 4500 cGy + boost of 1000 cGY to the lumpectomy site/MRM scar. Skin and pulmonary toxicity was graded wkly according to the RTOG criteria. Median follow-up=3.5 years. Results: Significant grade 2 and grade 3 skin toxicity was observed. RT was interrupted for an average of 10(3–24) days in 11(22%) pts because of the skin toxicity. Toxicity was equal in P and D groups. No local recurrences have occurred. Systemic recurrence was seen in 2 pts who had biologically aggressive disease. No pulmonary toxicity was observed. Conclusions: Although there have been no local recurrences, an interruption in RT of 10 days in 22% patients is concerning. Long-term follow-up of these pts is warranted. At this point, we cannot recommend concurrent weekly Taxane and Radiation therapy in the adjuvant treatment of breast cancer pts. No significant financial relationships to disclose.
Benefit of adjuvant chemotherapy after curative resection of lung metastasis from colorectal cancer.
Authors: Chang Gon Kim, Su Jin Heo, Hyung Soon Park, Minkyu Jung, Chang Young Lee, Jin Gu Lee, Dae Joon Kim, Seung Hoon Beom, Sang Joon Shin, Joong Bae Ahn
Journal: Journal of Clinical Oncology (2015)

e14593 Background: The role of metastasectomy for treatment of lung metastasis from colorectal cancer (CRC) is widely accepted. However, the clinical use of adjuvant chemotherapy after lung metastasectomy is uncertain. The aim of this study is to evaluate the benefit of adjuvant chemotherapy after lung metastasectomy in colorectal cancer. Methods: From October 2002 to July 2013, 221 patients with lung metastasis from colorectal cancer were enrolled. Patients with previous liver metastasis were included, but extra-pulmonary metastasis. At the time of first detection of lung metastasis were excluded. Time to event endpoint was analyzed by Kaplan-Meier survival curves for disease free survival (DFS) and overall survival (OS) and we also performed univariate and multivariate cox proportional hazards model to determine the influence of prognostic factors on DFS and OS. Results: Among 221 patients, 176 patients received chemotherapy including 5FU, oxaliplatin and irinotecan based regimen and the remaining 45 patients had no chemotherapy. Median follow up time was 34.7 months from the time of surgery (range 0.4 to 166.9 months). Patients with adjuvant chemotherapy showed longer DFS (median, 32.7 vs. 11.2 months, P= 0.0757) compared to surgery alone. On multivariate analysis liver metastasis (OR, 1.89; 95% CI, 1.19-3.03), pre-operative CEA ≥ 5 (OR, 2.00; 95% CI, 1.33-3.01), DFI < 24 months (OR, 2.20; 95% CI, 1.42-3.41) and surgery alone (OR, 1.55; 95% CI, 1.00-2.38) were significant risk factor for recurrence. Subgroup analysis of 192 patients with metachronous lung metastasis showed significant benefit from adjuvant chemotherapy compare to surgery alone (median, 37.6 vs 11.7 months, P= 0.0368). For OS, patients with adjuvant chemotherapy showed no superior survival outcome compared with surgery alone (median, 89.6 vs. 86.8 months, P= 0.8326) Conclusions: Adjuvant chemotherapy significantly increases DFS in patients after resection of lung metastasis from colorectal cancer. This is the first report to demonstrate significant improved survival for adjuvant chemotherapy in patients with lung metastasis from CRC.