tbuckley/cabot-search huggingface dataset:
In-depth analysis of high effectivity in phase II study (irinotecan and doxifluridine, an intermediate form of capecitabine) for metastatic colorectal cancer: MCSGO, Colorectal Cancer Treatment Group
Authors: T. Kato, Y. Miyake, M. Ikenaga, H. Mishima, M. Fukunaga, K. Murata, H. Ota, M. Sekimoto, J. Sakamoto, M. Monden
Journal: Journal of Clinical Oncology (2006)

13570 Background: We have already reported the results of the Phase II multicenter study [a combination of irinotecan (CPT-11) and doxifluridine (5’-DFUR) for MCRC], including the survival period (2006 GI Cancer Symposium Abst #130). In this report, we mention the details of the treatment introduced after this combination and discuss the response observed in each metastatic lesion. Methods: The subjects were 60 CPT-11 naive patients with MCRC. They had a measurable disease that satisfied the RECIST criteria and had gone through not more than one regimen of chemotherapy (median age: 64 years (28–74); male/female: 37/23; ECOG PS 0/1: 52/8; main location of metastatic lesion: liver 31, lung 13, lymph node 15). CPT-11 (150 mg/m 2 , i.v.) was administered on days 1 and 15, 5’-DFUR (800 mg/body, p.p.) was administered day 3 to 15 and day 17 to 28. One cycle of treatment consisted of 5 weeks. No requirements were imposed on the follow-up treatment. Results: According to the results of this regimen, ORR was 40% [23/60, CR;1, PR;23], OS was 20.5 months, and PFS was 5.9 months. The main NCI-CTC grade 3–4 adverse events included neutropenia (28.3%), fatigue (11.6%), nausea (8.3%), vomiting (6.6%), and diarrhea (5.0%).A follow-up therapy regimen was selected and implemented by each investigator. The main regimens adopted for the 49 patients who received this combination as a 1 st line therapy included FOLFOX (n=10), hepatic arterial infusion (HAI) (n=10), and others (n=13). 16 patients received no follow-up therapy. The duration of treatment was 5.0 months in the case of 2 nd line therapy and 3.0 months in the case of 3 rd line therapy. The response rate by metastatic lesion was as follows: liver 35.4% (11/31, PR;11), lung 53.5% (7/13, CR;1, PR;6), and lymph node 46.6% (7/15, PR;7). Conclusions: The combination of CPT-11 and 5’-DFUR is effective in treating lung metastasis and HAI in treating liver metastasis was suggested. No significant financial relationships to disclose.
Preoperative concomitant chemoradiotherapy with capecitabine in locally advanced rectal carcinoma
Authors: B. Larbaoui
Journal: Journal of Clinical Oncology (2009)

e15134 Background: Preoperative concomitant chemoradiotherapy has shown to improve local control and sphincter preservation with decreased acute toxicity compared with postoperative treatment in locally advanced rectal carcinoma. The primary endpoint of this phase II trial was pathologic tumor response. Secondary endpoint was sphincter preservation and toxicity. Methods: Inclusion criteria: rectal adenocarcinoma &lt;12 cms from anal verge, clinical stage T3–4, adequate renal, hematological and liver function. Planned sample for this trial was 40 patients. Treatment schedule: Pelvic radiotherapy (45 Gy : 2 Gy /day ) and chemotherapy: Capecitabine 850 mg/m 2 b.i.d p.o: day 1 to 14 (2weeks of treatment followed by 1 week rest period (cycle repeated every 3 weeks). Surgery with TME was performed after the end of the second cycle of chemotherapy. Adjuvant chemotherapy with 5FULV2 was administered after surgery Results: 15 patients have been recruited between January and October 2007: 12 males/3 females. Median age 40 years (range 22–70). Clinical stage (determined by CT or RMI): T3: 70% and T4: 30%. Tumor location (from anal verge): &lt; 6 cm in 8pts, &gt;6 cm in 7pts. Surgery (performed in 14 patients) consisted of low anterior resection in 7pts and abdominal-perineal resection in 8pts. Tumor down staging was observed in 9pts (60%), including 5pts with complete pathological response (33.3%). Main adverse effects (NCI-CTC): diarrhea G3–4: 15.2%, nausea/vomiting G3–4: 13%, Anemia G3- 4: 8.5%, neutropenia G3–4: 12.5%. Conclusions: Preliminary results show that preoperative concomitant chemoradiotherapy with Capecitabine is an effective regimen with an acceptable safety profile for locally advanced rectal cancer, leading to a high probability of tumor downstaging. No significant financial relationships to disclose.
High proportion of fluoroquinolone mono-resistant mycobacterium tuberculosis (MTB) strains in Pakistan (2010-2012)
Authors: Kauser Jabeen, Faisal Malik, Rumina Hasan
Journal: European Respiratory Journal (2013)

Introduction:  The prospect of using fluoroquinolones (FQ) as a first line therapy for TB has been challenged due to the concern of increased FQ resistance in countries with high FQ usage for other infections. Increased FQ resistance in multidrug resistant (MDR) MTB strains has already been reported from Pakistan. In this study we have analyzed trend of FQ resistance in non-MDR TB over a three year period (2010-2012).   Methods:   Study was conducted at the Aga Khan University laboratory, a technical partner of Pakistan National TB Program with periodic validation by the WHO Supra-National Reference Laboratory network. The laboratory receives specimens across the country through its peripheral collection units. MTB was isolated using standard methods. Susceptibility testing was performed using agar proportion method with drug concentrations as recommended by Clinical Laboratory Institute Standards (CLSI). FQ susceptibilities were determined using ofloxacin 2ug/ml. MDR was defined as resistance to both isoniazid (0.2 ug/ml) and rifampicin.   Results:   During the study period 8170 MTB strains were isolated. Of these 3321 (40.6%) were MDR and 4849 were non-MDR. In non-MDR MTB strains FQ resistance increased from 214/2059 (10.3%) in 2010 to 184/953 (19.3%) in 2012. The proportion of FQ mono-resistant TB strains in non MDR TB increased from 125/2059 (6%) in 2010 to 108/953 (11.3%) in 2012.   Conclusions:   Increasing trend of FQ resistance in non MDR MTB strains with high proportion of FQ mono-resistant strains in Pakistan is alarming. Our data highlight limited potential of empirical FQ usage for TB treatment in both MDR and non-MDR cases.
Treatment of glioblastoma in Venezuela: Limitations using the current standard of care
Authors: E. I. Arbona-Roche, C. Sucre, R. Vera-Gimón, A. Vera-Gimón, R. Vera-Vera, E. Gutierrez, N. Urdaneta, M. Gutierrez, S. Somaza, I. W. Tremont-Lukats
Journal: Journal of Clinical Oncology (2009)

e13036 Background: The EORTC/NCIC phase III clinical trial using chemoirradiation with temozolomide (TMZ) 75 mg m-2 x 42d, followed by adyuvant TMZ 150–200 mg m-2 daily x 5d q28d x six cycles set a new standard of care for newly diagnosed glioblastoma (GBM). The applicability of this regimen in developing countries can be problematic. Objectives: To review our experience in Venezuela, contrasting overall survival (OS), 6-month progression-free survival (6PFS), and toxicity in our patients with corresponding outcomes from the EORTC/NCIC trial. Methods: We treated 30 patients with this regimen from March 2001 through July 2004. Results: The median age was 51 years; 17 (60%) were men; 27 (90%) had biopsy or partial resection; 27 (90%) took prophylactic anticonvulsants; and 23 (77%) had prophylaxis against P. jiroveci. Most patients (83%) took the full TMZ treatment during radiation, 7% interrupted TMZ during RT, and 10% could not afford the drug. One patient had Stevens-Johnson syndrome and did not complete RT. Twelve (40%) patients had stereotactic radiosurgery for recurrent disease during the adjuvant phase. The 24-month OS was 30%, median OS was 7.5 months, median PFS was 5 months, and 6PFS was 41%. SRS did not have any effect on OS (p = 0.17, logrank). Grade 3–4 hematologic toxicity was seen in two patients (7%). Conclusions: Except for differences in median OS (7.1 mo) and in 6-PFS (12.6 percentage points) all other measures were reasonably close to the EORTC/NCIC trial. Of concern is the high rate of anticonvulsant prophylaxis using enzyme-inducing drugs and the difficult access to TMZ. No significant financial relationships to disclose.
A phase I pharmacokinetic (PK) and pharmacodynamic (PD) trial of weekly 17-allylamino-17 demethoxygeldanamycin (17AAG, NSC-704057) in patients with advanced tumors
Authors: R. K. Ramanathan, D. L. Trump, J. L. Eiseman, C. P. Belani, S. S. Agarwala, E. G. Zuhowski, J. Lan, P. Ivy, S. Tutchko, M. E. Egorin
Journal: Journal of Clinical Oncology (2004)

3031 Background: 17AAG is a benzoquinone antibiotic known to down regulate oncoproteins, by binding to heat shock protein 90 (HSP90). The study objective was to establish the dose limiting toxicity (DLT), recommended phase 2 dose (RP2D) and to characterize the PK and PD. Methods: Escalating doses of 17AAG were given IV over 1 or 2 hrs on a weekly x 3 schedule every 4 weeks to cohorts of 3–6 patients (pts) each. Plasma PKs of 17AAG and its major metabolite, 17AG, were measured on day 1 by HPLC. Expression of HSP70 and HSP90 were measured by Western blot in patient peripheral blood mononuclear cells obtained at 4, 8 and 24 h after the 17AAG infusion. Actin was measured for comparison. Results: 45 pts were enrolled to 11 dose levels from 10 mg/m2 to 395 mg/m2. Patient characteristics: Male 25 pts; age 24–83, median 64 yrs; ECOG performance status 0,1 and 2 are 12, 30 and 3 pts respectively. Common tumor types were colorectal (14pts), lung (8pts), head & neck (7pts) and genito urinary (7pts). The maximal tolerated dose was 395 mg/m2 with DLT's in 2 pts (grade 3 pancreatitis and grade 3 fatigue). The most common toxicity was reversible elevation of liver enzymes. No tumor response was observed. The AUC of 17AAG increased with dose, with a linear relationship between end of infusion 17AAG plasma concentration and AUC. Clearance ranged between 8.7–76.6 l/hr/m2 (median, 20.6 l/h/m2) and did not change with increasing doses. Peak plasma concentration and AUC of 17AG increased with increasing dose, but the relationship between 17AAG dose and 17AG peak plasma concentrations or 17AG AUC was more variable than that between 17AAG dose and 17AAG peak concentrations or 17AAG AUC. Both 17AAG and 17AG were >90% protein bound. There were no consistent changes in any of the evaluated PD markers. Conclusions: 17AAG is well tolerated, the RP2D is 295 mg/m2 given weekly x3, repeated every 4 weeks as a 1 hour infusion. Based on these results and other studies, it is now undergoing clinical evaluation in combination with taxanes, cisplatin and imatinib. (Grant support: 1UO1-CA099168–01, NIH/NCCR/GCRC #5M01 RR 00056 to Univ Pittsburgh) No significant financial relationships to disclose.
Phase II study of adjuvant imatinib mesylate (IM) in patients after resection of primary gastrointestinal stromal tumor (GIST): Efficacy and safety at one year.
Authors: Suayib Yalcin, Suleyman Buyukberber, Ugur Yilmaz, Po-Huang Lee, Vichien Srimuninnimit, Pin-Wen Lin, Mostafa M. Elserafy, Moustafa Manieh, Patrapim Sunpaweravong, Yuriy Istomin, Virote Sriuranpong, Tsann-Long Hwang
Journal: Journal of Clinical Oncology (2012)

e20514 Background: The mainstay treatment of primary GIST is surgery, but GIST often recurs even after complete resection. This study assessed the safety and efficacy of adjuvant IM in patients (pts) with resected GIST at intermediate/high risk of tumor recurrence. Methods: This open-label, single arm, prospective Ph II study (NCT01172548) was conducted in Asia Pacific/Africa/Russia/Middle East/Europe in eligible pts: aged ≥18 years (yrs), having had complete gross resection of primary GIST within 70 days of enrollment, with CD117 +ve, WHO PS ≤1, and no other adjuvant therapy. The planned sample size was 150 pts. Pts were to receive IM (400 mg/day, po) for 2 yrs post surgery. Dose modifications were allowed for toxicity. The primary endpoint was recurrence-free survival (RFS) rate at 2 yrs (based on CT/MRI and survival) in ITT pts (all pts who received ≥1 dose of study drug); null hypothesis based on historic data controls treated with surgery alone: RFS rate at 2 yrs of 0.7 (1 yr rate 0.98) (NCT00041197). A protocol-planned analysis at 1 yr in all enrolled pts (mITT) included safety, RFS, and overall survival. The study was approved by IRB/IEC/REB; all pts provided written informed consent. Results: Pt accrual was complete with 127 pts in the mITT population. Most pts (n=94, 74%) were &lt;65 yrs (median 56 [19–81] yrs); female (53%). Most common primary tumor sites: stomach (n=68, 54%), small intestine (n=48, 38%), colon/rectum (n=7, 6%). Main discontinuations (n=24, 18%): disease progression (n=8, 6%); withdrawal of consent (n=7, 5%); adverse events (AEs) and lost to follow-up (each n=3, 2%). Mean RFS rate at 1 yr was 0.95 (95% CI 0.907–0.993). Most AEs were mild or moderate (Table); no deaths occurred by 1 yr. Conclusions: Adjuvant IM 400 mg/day was efficacious and had a promising safety profile at 1 yr in pts after complete resection of primary GIST. [Table: see text]
A phase II study of imatinib for advanced melanoma patients with KIT aberrations.
Authors: J. Guo, L. Si, Y. Kong, X. w. Xu, K. T. Flaherty, C. L. Corless, Y. Y. Zhu, L. Li, H. F. Li
Journal: Journal of Clinical Oncology (2010)

8527 Background: KIT is an important oncogene in acral and mucosal melanomas, which account for 70% of melanomas in Asian patients (Pts). We conducted a phase II study (NCT00881049) to test the KIT inhibitor imatinib in metastatic melanoma pts with KIT aberrations. Methods: Pts with metastatic or unresectable melanoma whose tumor had KIT aberrations (KIT mutation [mut] and/or KIT gene DNA amplification [amp]) and who had measurable disease were enrolled. Pts received imatinib 400 mg/d continually until disease progression or intolerable toxicity. The dosage of Imatinib was escalated to 600 mg or 800 mg per day if progression was observed. Response was assessed monthly using RECIST criteria. The endpoints were progression-free survival (PFS), overall response rate (ORR) and toxicity. Results: Of 390 cases screened, 67 (17.4%) had a KIT mut or amp: 26/137 (18.9%) acral, 21/110 (19.1%) mucosal, 9/26 (34.6%) CSD, 6/75 (8%) NCSD, 5/42 (11.9%) unknown primary. 41 (10.5%) had a mut only; 23 (5.9%) had an amp only; 3 (0.8%) had both. Thus far, 28 patients have been treated with 26 pts currently evaluable: 5 stage M1a/3 M1b/20 M1c; median prior therapies: 2. Six patients (21%) achieved PR (5 mut, 1 amp, 4∼10+m); nine patients (35%) received SD (≥ 3 m, 3.5∼9+m). Pts who failed on 400mg also failed on escalation to 600mg and could not tolerate 800mg due to toxicities. Samples of new or progressive lesions were obtained from 5 PR pts after they failed on imatinib 400mg, and were analyzed in KIT, BRAF and PDGFRA. In one pt (emerging metastasis in liver) new mutations were found in BRAF (V600E) and PDGFRA (W559stop) which were wild-type before treatment, and loss of the KIT mutation present at baseline. Common toxicities at 400 mg were rash, vomiting, edema and myelosuppresion. Conclusions: Imatinib (400mg/d) provides a beneficial therapeutic effect for a significant proportion of Chinese metastatic melanoma pts with KIT aberrations. Acquired genetic mutations after treatment may account for emergence of resistance in some pts. Supported by the National Natural Science Foundation of China (30973483), 985-2-085-113 and Novartis Oncology in China. No significant financial relationships to disclose.
Recombinant human granulocyte-macrophage colony-stimulating factor reduces hematologic toxicity and widens clinical applicability of high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin's lymphoma.
Authors: A M Gianni, M Bregni, S Siena, A Orazi, A C Stern, L Gandola, G Bonadonna
Journal: Journal of Clinical Oncology (1990)

High-dose administration of anticancer agents is attractive both on theoretic and clinical grounds. Yet, high-dose regimens are usually used as salvage treatments, mainly as a consequence of their considerable hematologic toxicity. One pertinent example is represented by cyclophosphamide, an alkylating agent with a wide spectrum of marked antitumor activity. When used at doses up to 7 g/m2 (190 to 200 mg/kg) this drug does not cause myeloablation, but induces a severe, albeit transient, myelosuppression, which requires platelet transfusions in approximately 50% of treated patients, and is frequently complicated by infectious episodes, occasionally lethal. To accelerate hematopoietic recovery, we continuously infused for 14 consecutive days 5.5 micrograms/kg/d of the glycosylated human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) into 15 patients with breast cancer and non-Hodgkin's lymphoma treated with 7 g/m2 cyclophosphamide. This schedule was chosen having obtained the fastest hematopoietic recovery among four different options during an initial schedule-finding phase on 12 overall patients. Twenty-one comparable subjects with solid tumors served as controls. We report here that this relatively low, well-tolerated dose of rhGM-CSF reduces from 20 to 14 (median) and from 24 to 14, the number of days required to recover circulating granulocyte counts over 1,000 and 2,500/microL, respectively. The stimulatory effect was associated with a remarkable clinical benefit. In fact, treated patients experienced less infectious complications (7% v 24%) were eligible to receive chemotherapy earlier (median, by day +14 v day +20 for controls), and fewer required prophylactic platelet transfusions (13% v 43%). Our results show that even very high doses of cyclophosphamide can be administered with improved hematologic toxicity, tolerable morbidity, and reduced supportive care requirements. The increase in the therapeutic index made possible by rhGM-CSF infusion prompts the use of high-dose cyclophosphamide, and possibly of other agents with similar myelotoxic activity, early in the clinical course of chemotherapy-sensitive tumors.
Potential clinical and economic impact of switching U.S. women to exemestane following 2–3 years of therapy with tamoxifen for early breast cancer
Authors: D. Thompson, D. C. Taylor, E. L. Montoya, S. E. Jones, M. C. Weinstein
Journal: Journal of Clinical Oncology (2006)

6109 Background: Switching postmenopausal women with early breast cancer to exemestane after 2–3 years of tamoxifen therapy has been reported to increase disease-free survival. However, the potential impact of this management strategy on the U.S. health-care system is unknown. The objective of this study was to estimate the 10-year clinical and economic consequences that would accrue if all eligible U.S. patients in 2006 were switched from tamoxifen to exemestane. Methods: A Markov model with a 10-year time horizon was used to predict patients’ transitions across various health states based on treatment strategy (continuing tamoxifen versus switching to exemestane), breast cancer status (no recurrence, local or distant recurrence, contralateral breast cancer), and other related health events (osteoporosis, endometrial cancer, death). Disease- and treatment-related events were estimated using data from the Intergroup Exemestane Study (IES); survival and medical-care costs by type of recurrence were estimated using SEER-Medicare data and published literature. The switch-eligible cohort was defined to be consistent with IES selection criteria and its size in 2006 estimated based on SEER-Medicare and market research data. Costs incurred in future years were discounted at 3% annually. Results: We estimate that 71,800 U.S. women would be eligible to switch from tamoxifen to exemestane in 2006. Doing so would be expected to prevent 3,000 cases of recurrence (21,100 vs 24,100) and 2,000 breast cancer deaths (12,800 vs 14,800) over 10 years. The net budgetary impact over 10 years is projected to be $320M ($992M vs $672M), reflecting a $336M increase in costs of adjuvant hormonal therapy ($500M vs $164M), a $32.1M increase in costs of monitoring and treatment of adverse events ($73.7M vs. $41.6M), and a $47.4M reduction in recurrence-related treatment costs ($419M vs $466M). Conclusion: Switching all eligible U.S. breast cancer patients from tamoxifen to exemestane in 2006 would increase medical-care costs by $4,460 per patient but reduce breast cancer recurrences by 12% and breast cancer deaths by 14% over 10 years. [Table: see text]
A phase II trial of DTIC with thalidomide (thal) in metastatic melanoma (MM)
Authors: M. Fink, A. C. Pavlick, A. Bailes, K. Farrell, M. Volm, R. Oratz, F. Muggia
Journal: Journal of Clinical Oncology (2004)

7543 Background: Single agent DTIC has a response rate of 10–20% in metastatic melanoma. In an attempt to improve disease response, thalidomide was added to standard dose DTIC in patients with MM. Methods: Eligibility: Stage IV MM, ECOG performance status 0–1, no prior chemotherapy, no brain mets and adequate hematologic and organ function. Patients received DTIC 1000 mg/m2 IV every 3 weeks with thal 200 mg daily at night (hs). Thal doses were escalated in 100 mg increments every 3 weeks as tolerated. Responses were assessed after 3 cycles. Results: 15 patients were accrued between 6/00 and 7/03 (IV1a-2, IV1b-7, IV1c-6). 6 patients had prior adjuvant vaccine or immunotherapy and 9 had no prior adjuvant therapy. LDH was elevated in 8/15. Ages ranged from 30–77. M:F=8:7. Thal doses ranged from 200–400 mg/d. The median tolerated dose of thal was 200 mg/d. Patients received 1–18 cycles of therapy (median = 5). Responses were as follows: complete-0, partial-1( in subcutaneuos tissue), stable-4, progression-5 with 5 patients not evaluable for response. 2 early withdrawl due to toxicity and 3 deaths due to rapidly progressive disease. Grade III/IV toxicity attributed to DTIC was neutropenia and thrombocytopenia. Grade III/IV toxicity due to thal was severe constipation, peripheral neuropathy, fatigue, peripheral edema and rash. Conclusions: Thal added to DTIC does not appear to improve response rates in MM and is poorly tolerated in escalating doses greater than 200 mg/d. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene