tbuckley/cabot-search huggingface dataset:
Preliminary results of a phase I trial of sorafenib combined with cisplatin/etoposide (CE) or carboplatin/pemetrexed (CbP) in solid tumor patients (pts)
Authors: N. S. Dhruva, T. E. Stinchcombe, C. M. Walko, M. A. Socinski, S. Bernard, W. Y. Kim, K. Keller, L. R. Hilbun, E. C. Dees
Journal: Journal of Clinical Oncology (2009)

e13521 Background: Sorafenib had demonstrated single agent activity in non-small cell and small cell lung cancer. Methods: A non-comparative, two arm phase I trial escalating sorafenib in combination with fixed doses of CE or CbP was performed. A 3-patient cohort design was utilized to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Dose level 0 for all pts was a sorafenib dose of 200 mg po BID continuously. Pts on arm A received C (60 mg/m 2 ) on day 1 and E 120 mg/m 2 on days 1,2,3 every 3 weeks with escalating doses of sorafenib. On arm B, pts received treatment with Cb (AUC=6) and P 500 mg/m2 every 3 weeks with escalating doses of sorafenib. However, excessive toxicity was observed on arm B, therefore the trial was amended such that Cb dose was lowered to AUC=5 (arm C). DLT were assessed in the 1st cycle and defined as grade (gr.) 4 anemia or thrombocytopenia, gr. 4 neutropenia lasting &gt; 7 days, gr. ≥ 3 non-hematologic toxicity (except nausea, vomiting, and alopecia) and &gt; 2 week dose delay. Response was assessed every 2 cycles according to RECIST, and best response was recorded. Results: Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 47–73), male/female: 12/8, PS of 0/1: 6/14, and median number of prior therapies 2 (range 1–4). The most common tumor types were NSCLC (n=8), SCLC (n=4) and head/neck (n=2). At dose level 0 arm A (200 mg BID), 2 of 4 patients experienced DLT (gr.4 thrombocytopenia, gr.3 fatigue, febrile neutropenia and gr.4 neutropenia for &gt; 7 days, gr.3 febrile neutropenia, diarrhea, hypokalemia, hyponatremia); 2 pts have been enrolled at dose level -1 (200 mg po QD) without DLT. Two of 3 patients enrolled on arm B at dose level 0 had gr.4 thrombocytopenia. On arm C at dose level 0 (200 mg po BID), 1/6 pts experienced DLT (gr.3 hyponatremia, dehydration, hypoglycemia). Enrollment continued at dose level 1 (400 mg po BID), but 2/5 pts experienced a DLT (both gr. 3 fatigue/anorexia). Responses observed were: PR (n=3) (all arm C), and SD (n=6). Conclusions: The MTD of sorafenib in combination with carboplatin (AUC=5) and pemetrexed 500 mg every 3 weeks is 200 mg po BID. The MTD of sorafenib in combination with cisplatin/etoposide has yet to be determined and is currently accruing at dose level -1. [Table: see text]
Results of a phase I / II and pharmacokinetic study of vinflunine (VFL) in combination with cisplatin (CDDP) for primary treatment of advanced non-small cell lung cancer (NSCLC)
Authors: R. Ramlau, P.-J. Souquet, X. Sun, G. Lopez-Vivanco, K. Afenjar, C. Colin, M. Krzakowski
Journal: Journal of Clinical Oncology (2004)

7110 Background: VFL (Javlor) is a new semi-synthetic vinca alkaloid which has shown synergistic effects in vitro againts A549 human NSCLC line when combined with CDDP. Platinum-based doublets are the standard treatment in advanced NSCLC. Methods: The phase I part of this trial was designed to determine the recommended dose (RD) and to study the possible pharmacokinetic (PK) interaction of the combination VFL and CDDP. The RD was established at of VFL 320 mg/m2 plus CDDP 80 mg/m2 on day 1 every 3 weeks; no PK interaction was observed. We describe the results of the phase II part of the study, which was designed to to determine the response rate (WHO) and safety (NCI-CTC) of the combination. Results: At the RD 53 patients (41 males, 12 females), median age 57, initial stages IIB 2 pts, IIIB 15 pts and IV 36 pts were treated. Karnofsky performance status was: 100 % 11 pts, 90 % 32 pts, 80 % 10 pts. The median number of cycles administered was 6 [1–8] and the median dose intensities of both drugs are > 97 %. Disease control was achieved in 77 % of the 49 evaluable pts: there were 16 confirmed responses (after external radiological review) (33 %) (95 % CI [20–48]) and 22 stabilizations. In terms of tolerance, among 237 cycles analyzed grades 3/4 neutropenia and anemia were reported in 43 % and 7 % of cycles respectively; 5 patients experienced febrile neutropenia and there were 2 neutropenic infections. Grades 3/4 non-hematological toxicities observed were: fatigue 3.8 % cycles (15.1 % pts), abdominal pain 3 % cycles (9.4 % pts), nausea 1.7 % cycles (3.8 % pts), vomiting 1.2 % cycles (3.8 % pts) constipation: 1.3 % cycles (5.7 % pts), diarrhea and dehydration 0.4 % cycles (1.4 % pts). No peripheral neuropathy grades 3/4 has been observed.Conclusions: Very good results were achieved in terms of dose intensities and toxicity profile. In first line treatment of advanced NSCLC patient, the combination of VFL 320 mg/m2 plus CDDP 80 mg/m2 both given once every 3 weeks is an highly active combination in terms of response rate. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Institut de Recherche Pierre Fabre (IRPF), France
Multicenter phase II trial of S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable colorectal cancer
Authors: S. Shin, Y. Park, T. Kim, D. Oh, B. Shim, K. Lee, M. Lee, Y. Kim, Y. Kim, J. Ahn
Journal: Journal of Clinical Oncology (2008)

15057 Background: This study was conducted to evaluate the efficacy and safety of S-1 monotherapy as first-line treatment in elderly patients with metastatic or recurrent colorectal cancer (CRC). Methods: Patients with CRC who were either age 65–69 years with ECOG 2 or 70–85 years of age with ECOG 0–2 were eligible. S-1 was administered in 35mg/m2 twice daily for 2 weeks followed by 1 week rest period (one cycle). Results: Thirty-three patients with the median age of 73 years (range, 66 - 84 years) entered the current study and six (18.2%) patients had ECOG performance status 2. S-1 produced an objective response rate of 21.2% (seven partial responses) and stable disease in 14 patients (42.4%). The median times to progression was 4.0 months (95% CI, 2.9 to 6.1 months) but the median overall survival was not reached until now. S-1 demonstrated a favorable safety profile, with no treatment-related grade 4 adverse events and deaths. Grade 3 anemia, neutropenia and thrombocytopenia were observed in 6.1%, 3.0% and 3.0% of patients, respectively. The most frequent adverse events were diarrhea (grade 3, 12.1%) and grade 3 hand-foot syndrome was observed in only one patient (3.0%). Conclusions: S-1 monotherapy appears to be an effective and safe option in elderly patients who had metastatic or recurrent CRC. In addition, promising results indicate further trials with combination of S-1 with oxaliplatin or irinotecan required, which may prove to be more effective. No significant financial relationships to disclose.
Long-term follow-up of patients with minimal sentinel node tumor burden (&lt; 0.1mm) according to Rotterdam criteria: A study of the EORTC Melanoma Group
Authors: A. C. van Akkooi, P. Rutkowski, I. M. van der Ploeg, C. A. Voit, H. J. Hoekstra, O. E. Nieweg, G. Schäfer-Hesterberg, Z. I. Nowecki, J. H. de Wilt, A. M. Eggermont
Journal: Journal of Clinical Oncology (2009)

9005 Background: Many studies have identified Sentinel Node (SN) tumor burden as a prognostic factor for additional non- SN (NSN) positivity and / or disease-free (DFS) and melanoma specific survival (MSS). It remains unclear if pts with minimal SN tumor burden can safely be managed without Completion Lymph Node Dissection (CLND). Pts with minimal SN tumor burden might be at risk for late recurrences (&gt; 5 years). Methods: Slides of 595 SN positive patients were reviewed for this pan-European study collaboration in 5 major centers. Slides were reviewed for the microanatomic location and SN tumor burden according to the Rotterdam Criteria (&lt; 0.1mm, 0.1 - 1.0mm and &gt; 1.0 mm) for the maximum diameter of the largest metastasis. MSS, DFS and distant metastasis-free survival (DMFS) rates were calculated, as was NSN positivity. Results: In 595 SN positive pts, the mean and median Breslow thickness was 4.73 and 3.5 mm. Ulceration was present in 51% of melanomas. 67 pts had metastases &lt; 0.1 mm (11%), 226 pts (38%) had 0.1 - 1.0 mm metastases and 302 pts had metastases &gt; 1.0 mm (51%). Mean and median follow-up was 48 and 40 months for all patients (range 1 - 172). Patients with metastases &lt; 0.1 mm had mean and median follow-up of 61 and 57 months, 46% (31pts) had follow up &gt; 5 years and 25% (17 pts) had follow-up longer than 80 months (range 3 - 132). 5-year MSS rates were 94% for metastases &lt; 0.1 mm, 70% for 0.1 - 1.0 mm and 57% for &gt; 1.0 mm (p&lt;0.001). 5-year DMFS rate was 91% for metastases &lt; 0.1 mm. NSN positivity occurred in 5% of &lt; 0.1mm, 17% of 0.1 - 1.0 and 29% of metastases &gt; 1.0 mm (p&lt;0.001). Conclusions: This large multicenter experience (n=595) has demonstrated that long-term follow-up of melanoma patients with minimal SN tumor burden (&lt; 0.1 mm) indicates very low relapse rates and excellent MSS, seemingly identical to SN negative patients. With prolonged follow-up, an increase in the occurrence of relapses of any kind between 5 and 10 years follow up has not been identified, and excellent 10-year survival rates are expected. No significant financial relationships to disclose.
Late sequelae of localized neuroblastoma presenting with epidural compression. A study of the Italian and French Neuroblastoma Groups
Authors: P. Angelini, B. De Bernardi, D. Plantaz, C. Perrin, G. Pastore
Journal: Journal of Clinical Oncology (2008)

10053 Background: Symptomatic epidural spinal cord compression (EC) occurs in 5–10% of neuroblastoma (NB) patients at presentation. Survival is excellent, but sequelae of EC can be severe. Severity of motor impairment at presentation correlates with probability of neurological recovery, and chemotherapy (CT) and neurosurgery (NS) have been shown to be equally effective in relieving EC. However, so far only few studies focused on late sequelae of EC, mainly scoliosis. Methods: We retrospectively reviewed a cohort of children with localized NB, presenting with EC and surviving more than 2 years from time of diagnosis, to report late sequelae and correlate them with clinical features and tumour’s characteristics at diagnosis, and treatment. Chi-squared test, Odd-ratios and 95% confidence intervals were applied for statistical analysis. P<0.05 was considered statistically significant. Results: 102 eligible children were identified in the Italian and French NB Registries, and for 98 adequate information was available. Symptoms of EC at diagnosis included motor deficit in 94 cases and sphyncteric deficits in 33. Initial treatment consisted of CT in 66 cases, NS in 29 and radiotherapy in 3. Overall treatment consisted of CT alone in 44 cases, NS and CT in 38, radiotherapy and CT ± NS in 16. After a median follow-up of 7.3 years, 57children (58.2%) had one or more sequelae. Motor deficit at follow-up correlated only with severity of motor deficit at diagnosis. Spine deformities, mostly scoliosis, correlated with severity of motor deficit at diagnosis and at follow-up, length of follow-up and treatment including NS or radiotherapy. Sphyncteric dysfunctions correlated with severity of motor deficit at follow-up and presence of either dysfunction at diagnosis. Conclusions: More than half of children with localized NB and symptomatic EC enrolled into this study had one or more sequelae. The severity of motor deficit at diagnosis was the major factor accounting for the development and severity of late sequelae. Neurosurgery and radiotherapy increase the risk of spine deformities, which can develop after more than 10 years from diagnosis. No significant financial relationships to disclose.
Cardiac abnormalities may help identify women at risk of recurrent pre-eclampsia
Authors: Jacqui Wise
Journal: BMJ (2016)

Doctors may be able to identify which women are at high risk of recurrent pre-eclampsia by using echocardiography to look for certain cardiovascular abnormalities between pregnancies, say researchers in the journal Hypertension .1

Previous research has shown that women who have had pre-eclampsia are seven times as likely as women who had normal pregnancies to develop pregnancy related high blood pressure in later pregnancies and to …
Acute toxicity to the skin and mucosa of radiotherapy alone versus radiotherapy in combination with cetuximab or chemotherapy in patients with head and neck cancer
Authors: H. I. Garcia-Huttenlocher, C. Timke, A. D. Jensen, P. E. Huber, J. Debus, M. W. Muenter
Journal: Journal of Clinical Oncology (2009)

e17007 Background: To evaluate acute toxicity of the skin and mucosa in patients with head and neck cancer who received Radiotherapy alone (RT) or in combination with cetuximab (IRT) or chemotherapy (CRT). Methods: We retrospectively analyzed 204 patients with head and neck cancer, treated between 2006 and 2008. RT was combined with cetuximab (n = 57), or with platinum-based chemotherapy (n = 99), 48 patients received RT alone. We included 149 male and 55 female patients with a median age of 62 years (range 22–92). Median radiation dose was 66 Gy (range 26.4–71.6Gy). 126 patients received intensity modulated radiotherapy (IMRT), 78 patients had conventional RT. Toxicity was assessed according to CTCAE Version 3.0. Results: Median follow-up was 9 months (range 1–34). Acute grade 3 toxicity of the skin was observed in 26% of IRT, 0% of RT, and 7% of CRT patients. Typical appearance of grade 3 skin toxicity in IRT was a massive confluent epitheliolysis of the RT field. Grade 3 mucositis appeared in 21% of IRT-, 12.5% of RT-, and 16% of CRT-patients. Rates of skin toxicity grade 3 were 8% in patients with IMRT and 15% in patients with conventional RT. Grade 3 mucositis was seen in 22% of the IMRT-patients and 8% of the patients with conventional RT. Cetuximab did not lead to a higher rate of RT interruptions as compared to RT and CRT. Early intervention and supportive care in case of high grade toxicity was performed for all patients. 8 weeks after RT all patients showed recovery from toxicity. Conclusions: Higher toxicity to the skin and to the mucosa occurred in the IRT group, and seems to be a specific side effect in the treatment of head and neck cancer patients with concomitant cetuximab and RT. But severity of toxicity may also be influenced by other factors such as RT technique. IRT patients need close observation and early intervention in case of therapy induced toxicity in order to prevent RT interruption, which might limit the advantage of cetuximab. Longer follow-up is needed to evaluate outcome and late toxicity of the different treatment groups. [Table: see text]
Analysis of BRAF mutation status in high-risk malignant melanoma patients having received HD IFNa therapy in adjuvant setting.
Authors: Zuzana Hlavata, Tomas Salek, Iveta Andrezalova, Jozef Dolinsky, Veronika Svabova, Stefan Porsok, Jitka Berkovcova, Iveta Waczulikova
Journal: Journal of Clinical Oncology (2012)

e19020 Background: Mutation in BRAF gene is considered to be a predictor of response to vemurafenib. However, it still remains to be demonstrated wheter BRAF mutational status is a prognostic factor in high risk melanomas. Methods: Between May 2003 till July 2011, there were 100 patients with a wide local excision of high risk malignant melanoma removed, who received HD IFNa adjuvant treatment. We retrospectively analyzed the data of 57 patients, who had determined BRAF V600 mutation status by real-time PCR assay (Cobas 4800 BRAF V600 Mutation Test). 48 patients were identified as a high-risk melanoma initialy, 9 after locoregional recurrence. Results: We have analysed samples from primary tumors (N35), lymph nodes (N16) and mets (N6). BRAF V600 mutation was found in 35 cases (61.4%). The median age was 52 yrs (range 19-66 yrs) in the whole group, in the subgroup of BRAF MT/WT it was 52.5/51 yrs (nonsignificant). The female/male ratio was 22/35, with no sex dependent differences for the BRAF MT or WT. The most frequent tumor stage T4N0M0 (29.8%) was the most common indication to the IFN treatment. The recurrence (distant mets) of melanoma was observed in 33 patients (57.8%); BRAF MT/WT 21 vs 12, HR 0.74, (95%CI 0.37-1.48) p =0.25. We observed 24 deaths (42.1%); BRAF MT/WT 16 vs 8, HR 0.72 (95%CI 0.32-1.62) p =0.46. We found a statistically significant higher risk of death associated with lower age in the whole group (p =0.006; OR =0,92). Logistic regression in the subgroup of BRAF MT patients revealed that the positivity of lymph nodes was associated with 5.6-times higher probability of death (OR =0.89, p =0.094). Additionally, a higher age was significantly associated with better overall survival (OS) p=0.012. On the other hand, in the subgroup of BRAF WT patients neither the age nor the positivity of lymph nodes influenced OS. Conclusions: We confirmed that BRAF mutation occurs in approximately 60% high-risk malignant melanomas. There were no statistically significant differences in DFS or OS between BRAF MT/WT form. However, our analysis corroborates the notion that BRAF MT patients have higher risk of death or recurrence, which we consider to be clinically relevant.
Hypoxia-inducible factor (HIF) 1α and 2α levels in cell lines and human tumor predicts response to sunitinib in renal cell carcinoma (RCC)
Authors: P. H. Patel, R. S. Chadalavada, N. M. Ishill, S. Patil, V. E. Reuter, R. J. Motzer, R. S. Chaganti
Journal: Journal of Clinical Oncology (2008)

5008 Background: Up to 40% of metastatic RCC patients (pts) achieve an objective [complete (CR) or partial (PR)] clinical response to sunitinib treatment (NEJM 2007:356:115–24). HIF1α and HIF2α actions underlie progression of RCC; and their relationship to clinical response warrants study. Methods: Metastatic clear cell RCC pts with archived frozen tumors, resected prior to sunitinib were eligible. HIF1α and HIF2α levels were determined from patient RCC lysates following immunoblot analysis, and scored as either: none, low, or high, based on staining intensity, relative to controls. Best clinical response to sunitinib was assessed by RECIST. In addition, pathways inhibited by sunitinib were studied on 10 unique RCC cell lines. Results: HIFα levels in tumors were strongly associated with sunitinib sensitivity. Pts with tumors containing high level of HIF1α (p=0.003) or high level of HIF2α (p=0.001) were more likely to achieve a favorable objective clinical response (CR or PR) to sunitinib, relative to tumors containing low or absent HIFα levels. For example, 76% (13 of 17) tumors with high HIF2α vs. 13% (2 of 15) tumors with no detectable HIF2α showed objective responses. Immunohistochemistry staining from paraffin-embedded RCC showed HIF1α is present in the nucleus of cancer cells, and not within the adjacent stromal cells. In RCC cells lines, sunitinib results in cell death exclusively in 5 of 10 lines showing high baseline HIF1α and 2α. In these 5 cell lines, sunitinib decreases levels of HIF1α and HIF2α by inhibiting translation of these proteins. Conclusions: HIF1α and 2α levels predict sensitivity to sunitinib therapy. In vitro, sunitinib functions to suppress levels of HIF1α and 2α, leading to cell death. These discoveries may provide the opportunity to optimize treatment, either by patient selection or directed therapy trials. Prospective studies are underway to validate these findings. Clinical response to sunitinib relative to level of HIF1α and HIF2α Pretreatment Tumor HIF levels # patients CR or PR (n=21) # patients Stable or Progression (n=28) p-value Hif 1α none 2 9 0.003 low 6 15 high 13 4 Hif 2α none 2 13 0.001 low 6 11 high 13 4 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer, Inc .
Androgen deprivation therapy (ADT) for node postive prostate cancer
Authors: Y. Wong, S. Freedland, G. Hudes, N. Mitra, C. Montagnet, K. Armstrong
Journal: Journal of Clinical Oncology (2007)

5061 Background: The role of ADT for men with node positive prostate cancer following radical prostatectomy (RP) is unclear. One randomized trial has shown a survival advantage for men treated with immediate adjuvant (adj) ADT compared treatment at onset of clinical metastases. However, benefit of immediate therapy is less clear in the PSA era when ADT can initiated at the time of biochemical relapse. Methods: We used linked Surveillance, Epidemiology and End Results-Medicare Data to identify a cohort of men who underwent RP between 1991–1999 and were found to have positive regional lymph nodes. We searched Medicare claims to identify men with claims for ADT (hormonal therapy or orchiectomy) within 3 years of diagnosis. We excluded men who received ADT prior to RP. We classified men as receiving adj ADT if they received treatment within 120 days of RP and compared them to men who had not received adj ADT. We used propensity scores to balance potential confounders of receiving adj ADT (age, tumor characteristics, extent of nodal disease, demographics). We used Cox proportional hazard methods to estimate the impact of adj ADT on overall survival (OS) adjusting for propensity score. We conducted a sensitivity analysis using 90, 150, 180 and 365 days as the time limit for adj ADT. Results: 719 men were identified, of whom 190 received adjuvant ADT within 120 days of RP. There was no statistically significant difference in overall survival between the men who did or did not receive adj ADT (HR 0.96 95% CI 0.70–1.32) The results were similar for men who received ADT within 90 and 150 days. However, when the definition of adj ADT was moved to 180 days (HR 1.08 (0.80–1.47)) and 365 days (HR 1.24 (0.92–1.65)) the men receiving adj ADT had a slightly higher risk of death, suggesting some in the adj ADT groups using these later definitions may have received therapy as salvage therapy for progressive disease. Conclusions: This observational study suggests that in the PSA era when men can be started on ADT at the time of biochemical recurrence, overall survival may not be significantly compromised by deferring immediate ADT in men with positive lymph nodes following RP. Further clinical research is needed to better understand which patients are likely to benefit from immediate ADT, and which men can be spared the long term toxicities. [Table: see text]
Drug company sponsorship of education: the response to the FDA draft concept paper
Authors: E. J. Lazar
Journal: JAMA (1992)

<h3>In Reply.</h3> —We agree with Drs Clarfield, Friedman, and Bergman that hypertension is an important risk factor in the elderly; in fact, some of our previous work is on this topic.<sup>1</sup>However, the present study focused on middle-aged men because the goal was to examine findings in the Multiple Risk Factor Intervention Trial (MRFIT), which found an association between diuretic therapy (especially hydrochlorothiazide) and an increased rate of sudden death in hypertensive men 35 to 57 years of age with electrocardiographic abnormalities.<sup>2</sup>In our study, we extended the age range to 35 to 70 years. It is of interest that the Systolic Hypertension in the Elderly Program study cited by Clarfield and colleagues restricted enrollment to individuals 60 years and above. There may be research questions [ill] most appropriate for particular age groups. In general, we agree with the thrust of Dr Papademetriou's work, which indicates that hydrochlorothiazide