Publications by authors named "Marwan G Fakih"

70 Publications

KRAS Inhibition with Sotorasib in Advanced Solid Tumors.

N Engl J Med 2020 09 20;383(13):1207-1217. Epub 2020 Sep 20.

From the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston (D.S.H., F.M.-B.); the Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), the University of California, San Francisco, San Francisco (P.N.M.), and Amgen, Thousand Oaks (H.H., J.N., G.N., J.K., B.E.H., J.C., J.R.L., G.F.) - all in California; Duke University Medical Center, Durham, NC (J.H.S.); Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Melbourne, VIC (J.D.), Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA (T.J.P.), and Scientia Clinical Research, Randwick, NSW (J.C. Kuo) - all in Australia; the Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis (G.A.D.); Dana-Farber Cancer Institute, Harvard Medical School, Boston (G.I.S.); the Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A.S.); Fox Chase Cancer Center, Philadelphia (C.S.D.); the University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh (T.F.B.); Seoul National University College of Medicine (Y.-J.B.), Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), and the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine (T.W.K.) - all in Seoul, South Korea; Roswell Park Cancer Institute, Buffalo (G.K.D.), and Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (P.L., B.T.L.) - all in New York; the University of Michigan, Ann Arbor (J.C. Krauss); the Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan (Y.K.); the Department of Medicine, Division of Oncology, University of Washington, Seattle (A.L.C.); Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille, France (F.B.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis (R.G.).

Background: No therapies for targeting mutations in cancer have been approved. The p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS.

Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.

Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
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http://dx.doi.org/10.1056/NEJMoa1917239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571518PMC
September 2020

SUMOylation of E2F1 Regulates Expression of EZH2.

Cancer Res 2020 10 14;80(19):4212-4223. Epub 2020 Aug 14.

Department of Surgery and Moores Cancer Center, UC San Diego Health, La Jolla, California.

Elevated expression of EZH2, the enzymatic subunit of polycomb repressive complex 2 (PRC2), often occurs in cancer. EZH2 expression results in the silencing of genes that suppress tumor formation and metastasis through trimethylation of histone H3 at lysine 27 (H3K27me3) at their promoters. However, inhibitors of EZH2 enzymatic activity have not shown the expected efficacy against cancer in clinical trials, suggesting a need for other strategies to address EZH2 overexpression. Here, we show that SUMOylation, a posttranslational modification characterized by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins, enhances EZH2 transcription. Either knockdown of the SUMO-activating enzyme SAE2 or pharmacologic inhibition of SUMOylation resulted in decreased levels of EZH2 mRNA and protein as well as reduced H3K27me3 levels. SUMOylation regulated EZH2 expression by enhancing binding of the E2F1 transcriptional activator to the EZH2 promoter. Inhibition of SUMOylation not only resulted in reduced EZH2 mRNA and protein levels but also increased expression of genes silenced by EZH2, such as E-cadherin, which suppresses epithelial-mesenchymal transition and metastasis. In more than 6,500 patient tumor samples across different cancer types, expression of UBA2 and EZH2 was positively correlated. Taken together, our findings suggest that inhibition of SUMOylation may serve as a potential strategy to address EZH2 overexpression and improve current cancer therapeutic approaches. SIGNIFICANCE: These findings provide important biological insights into the mechanism of EZH2 overexpression in cancers and suggest that inhibiting SUMOylation may improve current cancer therapeutic approaches.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1259DOI Listing
October 2020

Management Considerations for the Surgical Treatment of Colorectal Cancer During the Global Covid-19 Pandemic.

Ann Surg 2020 08;272(2):e98-e105

Department of Surgery, City of Hope National Medical Center, Duarte, CA.

Objective: The COVID-19 pandemic requires to conscientiously weigh "timely surgical intervention" for colorectal cancer against efforts to conserve hospital resources and protect patients and health care providers.

Summary Background Data: Professional societies provided ad-hoc guidance at the outset of the COVID-19 pandemic on deferral of surgical and perioperative interventions, but these lack specific parameters to determine the optimal timing of surgery.

Methods: Using the GRADE system, published evidence was analyzed to generate weighted statements for stage, site, acuity of presentation, and hospital setting to specify when surgery should be pursued, the time and duration of oncologically acceptable delays, and when to utilize nonsurgical modalities to bridge the waiting period.

Results: Colorectal cancer surgeries-prioritized as emergency, urgent with imminent emergency or oncologically urgent, or elective-were matched against the phases of the pandemic. Surgery in COVID-19-positive patients must be avoided. Emergent and imminent emergent cases should mostly proceed unless resources are exhausted. Standard practices allow for postponement of elective cases and deferral to nonsurgical modalities of stage II/III rectal and metastatic colorectal cancer. Oncologically urgent cases may be delayed for 6(-12) weeks without jeopardizing oncological outcomes. Outside established principles, administration of nonsurgical modalities is not justified and increases the vulnerability of patients.

Conclusions: The COVID-19 pandemic has stressed already limited health care resources and forced rationing, triage, and prioritization of care in general, specifically of surgical interventions. Established guidelines allow for modifications of optimal timing and type of surgery for colorectal cancer during an unrelated pandemic.
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http://dx.doi.org/10.1097/SLA.0000000000004029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373490PMC
August 2020

The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.

Nature 2019 11 30;575(7781):217-223. Epub 2019 Oct 30.

Amgen Research, Amgen Inc, South San Francisco, CA, USA.

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRAS tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.
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http://dx.doi.org/10.1038/s41586-019-1694-1DOI Listing
November 2019

PD-1 Blockade in a Liver Transplant Recipient With Microsatellite Unstable Metastatic Colorectal Cancer and Hepatic Impairment.

J Natl Compr Canc Netw 2019 09;17(9):1026-1030

Department of Hematology and Oncology, University of California, Davis, Sacramento.

Immune checkpoint inhibitors represent a newly established standard of care in patients with refractory metastatic colorectal cancer with mismatch repair deficiency and microsatellite instability. However, the use of immunotherapy is unclear in recipients of liver transplants with or without concurrent liver function abnormalities. Clinical trials investigating immunotherapy have mostly excluded liver transplant recipients and patients with abnormal liver function. This report presents the first case, to our knowledge, of a liver transplant patient with mismatch repair-deficient colon adenocarcinoma with liver metastases and concurrent abnormal liver function who safely responded to immunotherapy. We also review the literature on checkpoint inhibitor use in patients with other metastatic solid tumors after liver transplant and those with baseline liver function abnormalities. An increasing body of evidence supports the safety of checkpoint inhibition in patients with cancer and solid organ transplants, but further prospective studies are warranted. Use of immunotherapy in liver transplant recipients who have metastatic colorectal cancer with microsatellite instability is feasible but should be performed in a multidisciplinary team setting.
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http://dx.doi.org/10.6004/jnccn.2019.7328DOI Listing
September 2019

Trastuzumab Plus Pertuzumab Resistance Does Not Preclude Response to Lapatinib Plus Trastuzumab in HER2-Amplified Colorectal Cancer.

Authors:
Marwan G Fakih

Oncologist 2018 04 12;23(4):474-477. Epub 2018 Jan 12.

Gastrointestinal Cancer Section, City of Hope National Medical Center, Duarte, California, USA

Human epidermal growth factor 2 (HER2) amplification represents a distinct molecular subgroup of colorectal cancers that is associated with anti-epidermal growth factor receptor resistance and sensitivity to dual HER2 targeting. Although clinical trials have reported activity for trastuzumab/pertuzumab and trastuzumab/lapatinib combinations, there are no reports on lapatinib plus trastuzumab activity after resistance to trastuzumab plus pertuzumab. Presented are three cases of HER2 amplified colorectal cancer that developed acquired refractoriness to trastuzumab pertuzumab with subsequent clinical benefit to lapatinib plus trastuzumab, highlighting the potential for HER2 tyrosine kinase inhibition plus trastuzumab in overcoming trastuzumab/pertuzumab resistance.
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http://dx.doi.org/10.1634/theoncologist.2017-0436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896709PMC
April 2018

Effect of increasing radiation dose on pathologic complete response in rectal cancer patients treated with neoadjuvant chemoradiation therapy.

Acta Oncol 2016 Dec 20;55(12):1392-1399. Epub 2016 Oct 20.

a Department of Radiation Oncology , City of Hope National Medical Center , Duarte , CA , USA.

Background: Neoadjuvant chemoradiation therapy (CRT) increases pathological complete response (pCR) rates compared to radiotherapy alone in patients with stage II-III rectal cancer. Limited evidence addresses whether radiotherapy dose escalation further improves pCR rates. Our purpose is to measure the effects of radiotherapy dose and other factors on post-therapy pathologic tumor (ypT) and nodal stage in rectal cancer patients treated with neoadjuvant CRT followed by mesorectal excision.

Material And Methods: A non-randomized comparative effectiveness analysis was performed of rectal cancer patients treated in 2000-2013 from the National Oncology Data Alliance™ (NODA), a pooled database of cancer registries from >150 US hospitals. The NODA contains the same data submitted to state cancer registries and SEER combined with validated radiotherapy and chemotherapy records. Eligible patients were treated with neoadjuvant CRT followed by proctectomy and had complete data on treatment start dates, radiotherapy dose, clinical tumor (cT) and ypT stage, and number of positive nodes at surgery (n = 3298 patients). Multivariable logistic regression was used to assess the predictive value of independent variables on achieving a pCR.

Results: On multivariable regression, radiotherapy dose, cT stage, and time interval between CRT and surgery were significant predictors of achieving a pCR. After adjusting for the effect of other variates, patients treated with higher radiotherapy doses were also more likely to have negative nodes at surgery and be downstaged from cT3-T4 and/or node positive disease to ypT0-T2N0 after neoadjuvant CRT.

Conclusion: Our study suggests that increasing dose significantly improved pCR rates and downstaging in rectal cancer patients treated with neoadjuvant CRT followed by surgery.
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http://dx.doi.org/10.1080/0284186X.2016.1235797DOI Listing
December 2016

Effect of increasing radiation dose on pathologic complete response in rectal cancer patients treated with neoadjuvant chemoradiation therapy.

Acta Oncol 2016 Dec 20;55(12):1392-1399. Epub 2016 Oct 20.

a Department of Radiation Oncology , City of Hope National Medical Center , Duarte , CA , USA.

Background: Neoadjuvant chemoradiation therapy (CRT) increases pathological complete response (pCR) rates compared to radiotherapy alone in patients with stage II-III rectal cancer. Limited evidence addresses whether radiotherapy dose escalation further improves pCR rates. Our purpose is to measure the effects of radiotherapy dose and other factors on post-therapy pathologic tumor (ypT) and nodal stage in rectal cancer patients treated with neoadjuvant CRT followed by mesorectal excision.

Material And Methods: A non-randomized comparative effectiveness analysis was performed of rectal cancer patients treated in 2000-2013 from the National Oncology Data Alliance™ (NODA), a pooled database of cancer registries from >150 US hospitals. The NODA contains the same data submitted to state cancer registries and SEER combined with validated radiotherapy and chemotherapy records. Eligible patients were treated with neoadjuvant CRT followed by proctectomy and had complete data on treatment start dates, radiotherapy dose, clinical tumor (cT) and ypT stage, and number of positive nodes at surgery (n = 3298 patients). Multivariable logistic regression was used to assess the predictive value of independent variables on achieving a pCR.

Results: On multivariable regression, radiotherapy dose, cT stage, and time interval between CRT and surgery were significant predictors of achieving a pCR. After adjusting for the effect of other variates, patients treated with higher radiotherapy doses were also more likely to have negative nodes at surgery and be downstaged from cT3-T4 and/or node positive disease to ypT0-T2N0 after neoadjuvant CRT.

Conclusion: Our study suggests that increasing dose significantly improved pCR rates and downstaging in rectal cancer patients treated with neoadjuvant CRT followed by surgery.
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http://dx.doi.org/10.1080/0284186X.2016.1235797DOI Listing
December 2016

Phase Ib Trial of mFOLFOX6 and Everolimus (NSC-733504) in Patients with Metastatic Gastroesophageal Adenocarcinoma.

Oncology 2016 20;90(6):307-12. Epub 2016 Apr 20.

City of Hope National Medical Center, Duarte, Calif., USA.

Objectives: Based upon preclinical data showing synergy with mTOR inhibition and platinum chemotherapy, this study explores the safety and tolerability of combining everolimus with mFOLFOX6 for patients with metastatic gastroesophageal adenocarcinoma.

Methods: Eligible patients with metastatic gastroesophageal adenocarcinoma received standard-dose mFOLFOX6 chemotherapy in combination with escalating doses of everolimus.

Results: Six patients were accrued to the first dose level of 2.5 mg everolimus daily with mFOLFOX6. Overall, the toxicity profile was manageable with expected grade 3 toxicities of mucositis and neutropenia. The dose-limiting toxicity (DLT) included a week delay in therapy greater than 7 days as a result of the first 2 courses of mFOLFOX6. Two patients experienced DLTs at the first dose level due to delays in their treatment caused by prolonged grade 2 neutropenia and fever with fatigue. They were allowed to continue with a dose reduction of their chemotherapy. The median overall survival and progression-free survival were 20.3 and 14.5 months, respectively.

Conclusions: The combination of mFOLFOX6 and everolimus is an active regimen with 83% of the patients experiencing a partial response. p53 mutations were found in the 5 samples analyzed.
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http://dx.doi.org/10.1159/000445297DOI Listing
December 2016

Economic Analysis of Panitumumab Compared With Cetuximab in Patients With Wild-type KRAS Metastatic Colorectal Cancer That Progressed After Standard Chemotherapy.

Clin Ther 2016 Jun 13;38(6):1376-1391. Epub 2016 Apr 13.

City of Hope Comprehensive Cancer Center, Duarte, California.

Purpose: In this analysis, we compared costs and explored the cost-effectiveness of subsequent-line treatment with cetuximab or panitumumab in patients with wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC) after previous chemotherapy treatment failure. Data were used from ASPECCT (A Study of Panitumumab Efficacy and Safety Compared to Cetuximab in Patients With KRAS Wild-Type Metastatic Colorectal Cancer), a Phase III, head-to-head randomized noninferiority study comparing the efficacy and safety of panitumumab and cetuximab in this population.

Methods: A decision-analytic model was developed to perform a cost-minimization analysis and a semi-Markov model was created to evaluate the cost-effectiveness of panitumumab monotherapy versus cetuximab monotherapy in chemotherapy-resistant wild-type KRAS (exon 2) mCRC. The cost-minimization model assumed equivalent efficacy (progression-free survival) based on data from ASPECCT. The cost-effectiveness analysis was conducted with the full information (uncertainty) from ASPECCT. Both analyses were conducted from a US third-party payer perspective and calculated average anti-epidermal growth factor receptor doses from ASPECCT. Costs associated with drug acquisition, treatment administration (every 2 weeks for panitumumab, weekly for cetuximab), and incidence of infusion reactions were estimated in both models. The cost-effectiveness model also included physician visits, disease progression monitoring, best supportive care, and end-of-life costs and utility weights estimated from EuroQol 5-Dimension questionnaire responses from ASPECCT.

Findings: The cost-minimization model results demonstrated lower projected costs for patients who received panitumumab versus cetuximab, with a projected cost savings of $9468 (16.5%) per panitumumab-treated patient. In the cost-effectiveness model, the incremental cost per quality-adjusted life-year gained revealed panitumumab to be less costly, with marginally better outcomes than cetuximab.

Implications: These economic analyses comparing panitumumab and cetuximab in chemorefractory wild-type KRAS (exon 2) mCRC suggest benefits in favor of panitumumab. ClinicalTrials.gov identifier: NCT01001377.
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http://dx.doi.org/10.1016/j.clinthera.2016.03.023DOI Listing
June 2016

Impact of Total Lymph Node Count on Staging and Survival After Neoadjuvant Chemoradiation Therapy for Rectal Cancer.

Ann Surg Oncol 2015 Dec 9;22 Suppl 3:S580-7. Epub 2015 May 9.

Department of Radiation Oncology, City of Hope National Medical Cancer, Duarte, CA, USA.

Purpose: Current guidelines recommend that a minimum of 12 lymph nodes (LNs) be dissected to accurately stage rectal cancer patients. Neoadjuvant chemoradiation therapy (CRT) decreases the number of LNs retrieved at surgery. The purpose of this study was to assess the impact of the number of LNs dissected on overall survival (OS) for localized rectal cancer patients treated with neoadjuvant CRT.

Methods: Treatment data were obtained on all patients treated for rectal cancer (2000-2013) in the National Oncology Data Alliance™, a proprietary database of merged tumor registries. Eligible patients were treated with neoadjuvant CRT followed by surgery and had complete data on number of positive LNs, number of LNs examined, and treatment dates (n = 4565).

Results: Hazard ratios for OS decreased sequentially with increasing number of LNs examined until a maximum benefit was achieved with examination of eight LNs. On multivariate analysis, age, sex, race, marital status, grade, ypT stage, ypN stage, type of surgery, margin status, presence of pathologically confirmed metastasis at surgery, and number of LNs examined were significant predictors of OS.

Conclusions: Examination of eight or more LNs in rectal cancer patients treated with neoadjuvant CRT resulted in accurate staging and assignment into prognostic groups with an ensuing improvement in OS by stage. This study suggests that eight LNs is the threshold for an adequate lymph node dissection after neoadjuvant CRT.
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http://dx.doi.org/10.1245/s10434-015-4585-1DOI Listing
December 2015

Metastatic colorectal cancer: current state and future directions.

Authors:
Marwan G Fakih

J Clin Oncol 2015 Jun 27;33(16):1809-24. Epub 2015 Apr 27.

Marwan G. Fakih, Gastrointestinal Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA.

Substantial improvements have been made in the management of metastatic colorectal cancer over the last two decades. The overall survival of patients diagnosed with unresectable metastatic colorectal cancer has increased from approximately 1 year during the era of fluoropyrimidine monotherapy to more than 30 months with the integration of multiple cytotoxic agents and targeted therapies. More effective therapeutic combinations have increased the rate of curative-intent surgical resections, resulting in median survival in this subgroup that exceed 5 years. Here we review the landscape of systemic therapies for unresectable metastatic colorectal cancer during the current era of targeted therapies, review the effects of RAS and BRAF mutations on clinical decision making, and reflect on future directions for the treatment of metastatic colorectal cancer.
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http://dx.doi.org/10.1200/JCO.2014.59.7633DOI Listing
June 2015

Cost-minimization analysis of panitumumab compared with cetuximab for first-line treatment of patients with wild-type RAS metastatic colorectal cancer.

J Med Econ 2015 20;18(8):619-28. Epub 2015 May 20.

e e West Clinic , Memphis , TN , USA.

Objective: To compare the costs of first-line treatment with panitumumab + FOLFOX in comparison to cetuximab + FOLFIRI among patients with wild-type (WT) RAS metastatic colorectal cancer (mCRC) in the US.

Methods: A cost-minimization model was developed assuming similar treatment efficacy between both regimens. The model estimated the costs associated with drug acquisition, treatment administration frequency (every 2 weeks for panitumumab, weekly for cetuximab), and incidence of infusion reactions. Average anti-EGFR doses were calculated from the ASPECCT clinical trial, and average doses of chemotherapy regimens were based on product labels. Using the medical component of the consumer price index, adverse event costs were inflated to 2014 US dollars, and all other costs were reported in 2014 US dollars. The time horizon for the model was based on average first-line progression-free survival of a WT RAS patient, estimated from parametric survival analyses of PRIME clinical trial data.

Results: Relative to cetuximab + FOLFIRI in the first-line treatment of WT RAS mCRC, the cost-minimization model demonstrated lower projected drug acquisition, administration, and adverse event costs for patients who received panitumumab + FOLFOX. The overall cost per patient for first-line treatment was $179,219 for panitumumab + FOLFOX vs $202,344 for cetuximab + FOLFIRI, resulting in a per-patient saving of $23,125 (11.4%) in favor of panitumumab + FOLFOX.

Conclusions: From a value perspective, the cost-minimization model supports panitumumab + FOLFOX instead of cetuximab + FOLFIRI as the preferred first-line treatment of WT RAS mCRC patients requiring systemic therapy.
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http://dx.doi.org/10.3111/13696998.2015.1035659DOI Listing
December 2016

Multigene assays in metastatic colorectal cancer.

J Natl Compr Canc Netw 2013 Sep;11 Suppl 4:S9-17

From the aCenter for Human Genetics Laboratory, Case Western Reserve University, Cleveland, Ohio; bClinical Molecular Diagnostic Laboratory, Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, California; cFulgent Therapeutics Inc, Temple City, California; and dMedical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California.

Specific genomic colorectal cancer alterations are increasingly linked to prognosis and/or response to specific anticancer agents. The identification of KRAS mutations as markers of resistance to epidermal growth factor receptor (EGFR) inhibitors has paved the way to the interrogation of numerous other markers of resistance to anti-EGFR therapy, such as NRAS, BRAF, and PI3KCA mutations. Other genomic and protein expression alterations have recently been identified as potential targets of treatment or as markers of chemotherapy or targeted-therapy resistance, including ERCC1 expression, c-Met expression, PTEN expression, HER2 amplification, HER3 expression, and rare KRAS mutations. As the number of distinct validated intratumor genomic assays increases, numerous molecular assays will need to be compiled into one multigene panel assay. Several companies and academic centers are now offering multigene assays to patients with metastatic colorectal cancer and other solid tumors. This article discusses the technology behind multigene assays, its limitations, its current advantages, and its potential in the clinical care of metastatic colorectal cancer.
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http://dx.doi.org/10.6004/jnccn.2013.0221DOI Listing
September 2013

Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines.

J Natl Compr Canc Netw 2013 May;11(5):531-46

University of Texas MD Anderson Cancer Center, USA.

The NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer provide evidence- and consensus-based recommendations for a multidisciplinary approach for the management of patients with gastric cancer. For patients with resectable locoregional cancer, the guidelines recommend gastrectomy with a D1+ or a modified D2 lymph node dissection (performed by experienced surgeons in high-volume centers). Postoperative chemoradiation is the preferred option after complete gastric resection for patients with T3-T4 tumors and node-positive T1-T2 tumors. Postoperative chemotherapy is included as an option after a modified D2 lymph node dissection for this group of patients. Trastuzumab with chemotherapy is recommended as first-line therapy for patients with HER2-positive advanced or metastatic cancer, confirmed by immunohistochemistry and, if needed, by fluorescence in situ hybridization for IHC 2+.
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http://dx.doi.org/10.6004/jnccn.2013.0070DOI Listing
May 2013

Localized colon cancer, version 3.2013: featured updates to the NCCN Guidelines.

J Natl Compr Canc Netw 2013 May;11(5):519-28

Robert H. Lurie Comprehensive Cancer Center of Northwestern University, USA.

The NCCN Clinical Practice Guidelines in Oncology for Colon Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Colon Cancer Panel meets annually to review comments from reviewers within their institutions and to reevaluate and update their recommendations. In addition, the panel has interim conferences as new data necessitate. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel's discussions regarding the treatment of localized disease for the 2013 update of the guidelines.
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http://dx.doi.org/10.6004/jnccn.2013.0069DOI Listing
May 2013

Serum vitamin D metabolites in colorectal cancer patients receiving cholecalciferol supplementation: correlation with polymorphisms in the vitamin D genes.

Horm Cancer 2013 Aug 28;4(4):242-50. Epub 2013 Feb 28.

Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Cholecalciferol (D(3)) supplementation results in variable increases in serum 25(OH)D(3) levels, however, the influence of genetic polymorphisms on these variable responses is unclear. We measured serum 25(OH)D(3), 24,25(OH)(2)D(3), 1,25(OH)2D(3) and VDBP levels in 50 colorectal cancer (CRC) patients before and during 2,000 IU daily oral D(3) supplementation for six months and in 263 archived CRC serum samples. Serum PTH levels and PBMC 24-OHase activity were also measured during D(3) supplementation. TagSNPs in CYP2R1, CYP27A1, CYP27B1, CYP24A1, VDR, and GC genes were genotyped in all patients, and the association between these SNPs and serum vitamin D(3) metabolites levels before and after D(3) supplementation was analyzed. The mean baseline serum 25(OH)D(3) level was less than 32 ng/mL in 65 % of the 313 CRC patients. In the 50 patients receiving D(3) supplementation, serum levels of 25(OH)D(3) increased (p = 0.008), PTH decreased (p = 0.036) and 24,25(OH)(2)D(3), 1,25(OH)(2)D(3), VDBP levels and PBMC 24-OHase activity were unchanged. GC SNP rs222016 was associated with high 25(OH)D(3) and 1,25(OH)(2)D(3) levels at baseline while rs4588 and rs2282679 were associated with lower 25(OH)D(3) and 1,25(OH)(2)D(3) levels both before and after D(3) supplementation. CYP2R1 rs12794714 and rs10500804 SNPs were significantly associated with low 25(OH)D(3) levels after supplementation but not with baseline 25(OH)D(3). Our results show that D(3) supplementation increased 25(OH)D(3) levels in all patients. GC rs4588 and rs2283679 SNPs were associated with increased risk of vitamin D(3) insufficiency and suboptimal increase in 25(OH)D(3) levels after D(3) supplementation. Individuals with these genotypes may require higher D(3) supplementation doses to achieve vitamin D(3) sufficiency.
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http://dx.doi.org/10.1007/s12672-013-0139-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689467PMC
August 2013

Metastatic colon cancer, version 3.2013: featured updates to the NCCN Guidelines.

J Natl Compr Canc Netw 2013 Feb;11(2):141-52; quiz 152

Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Colon Cancer Panel meets annually to review comments from reviewers within their institutions and to reevaluate and update their recommendations. In addition, the panel has interim conferences as new data necessitate. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel's discussions surrounding metastatic colorectal cancer for the 2013 update of the guidelines. Importantly, changes were made to the continuum of care for patients with advanced or metastatic disease, including new drugs and an additional line of therapy.
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http://dx.doi.org/10.6004/jnccn.2013.0022DOI Listing
February 2013

A phase II study of high-dose cetuximab plus irinotecan in colorectal cancer patients with KRAS wild-type tumors who progressed after standard dose of cetuximab plus irinotecan.

Oncology 2013 17;84(4):210-3. Epub 2013 Jan 17.

Roswell Park Cancer Institute, Buffalo, NY, USA.

Objectives: We conducted a phase II clinical trial of high-dose cetuximab plus irinotecan in KRAS wild-type patients who progressed on standard-dose cetuximab plus irinotecan.

Methods: Patients who progressed within 4 weeks from receiving a minimum of 6 weeks of standard-dose cetuximab plus irinotecan were included in this study. Cetuximab was administered at 500 mg/m(2)/week and irinotecan was administered at the same dose/schedule on which each individual patient had previously progressed. The study was closed early after having met its primary end point.

Results: Twenty patients were treated. The regimen was found to be efficacious, with 9 patients achieving disease control lasting more than 12 weeks. The median progression-free survival and overall survival were 2.8 and 6.6 months, respectively. The toxicity profile was favorable, with the exception of grade 3-4 hypomagnesemia which was noted in 25% of patients.

Conclusions: High-dose cetuximab plus irinotecan rechallenge can re-elicit clinical benefits in patients who have previously failed cetuximab plus irinotecan treatment. The clinical benefits are modest and may be related to cetuximab rechallenge rather than cetuximab dose escalation.
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http://dx.doi.org/10.1159/000346328DOI Listing
May 2013

Rectal cancer.

J Natl Compr Canc Netw 2012 Dec;10(12):1528-64

Robert H. Lurie Comprehensive Cancer Center of Northwestern University, USA.

These NCCN Clinical Practice Guidelines in Oncology provide recommendations for the management of rectal cancer, beginning with the clinical presentation of the patient to the primary care physician or gastroenterologist through diagnosis, pathologic staging, neoadjuvant treatment, surgical management, adjuvant treatment, surveillance, management of recurrent and metastatic disease, and survivorship. This discussion focuses on localized disease. The NCCN Rectal Cancer Panel believes that a multidisciplinary approach, including representation from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology, is necessary for treating patients with rectal cancer.
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http://dx.doi.org/10.6004/jnccn.2012.0158DOI Listing
December 2012

Anal Carcinoma, Version 2.2012: featured updates to the NCCN guidelines.

J Natl Compr Canc Netw 2012 Apr;10(4):449-54

Robert H. Lurie Comprehensive Cancer Center of Northwestern University, USA.

The workup and management of squamous cell anal carcinoma, which represents the most common histologic form of the disease, are addressed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Anal Carcinoma. These NCCN Guidelines Insights provide a summary of major discussion points of the 2012 NCCN Anal Carcinoma Panel meeting. In summary, the panel made 4 significant changes to the 2012 NCCN Guidelines for Anal Carcinoma: 1) local radiation therapy was added as an option for the treatment of patients with metastatic disease; 2) multifield technique is now preferred over anteroposterior-posteroanterior (AP-PA) technique for radiation delivery and the AP-PA technique is no longer recommended as the standard of care; 3) PET/CT should now be considered for radiation therapy planning; and 4) a section on risk reduction was added to the discussion section. In addition, the panel discussed the use of PET/CT for the workup of anal canal cancer and decided to maintain the recommendation that it can be considered in this setting. They also discussed the use of PET/CT for the workup of anal margin cancer and for the assessment of treatment response. They reaffirmed their recommendation that PET/CT is not appropriate in these settings.
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http://dx.doi.org/10.6004/jnccn.2012.0046DOI Listing
April 2012

Phase II study of irinotecan and cetuximab given every 2 weeks as second-line therapy for advanced colorectal cancer.

Clin Colorectal Cancer 2012 Mar 2;11(1):53-9. Epub 2011 Aug 2.

University of Pittsburgh Cancer Institute, PA 15232, USA.

Background: Irinotecan and weekly cetuximab (I+C) is a standard second-line regimen for metastatic colorectal cancer (mCRC). This study investigated the safety and efficacy of every 2 weeks I+C in patients with mCRC.

Patients And Methods: Patients with mCRC refractory to first-line fluoropyrimidine/oxaliplatin regimens and not previously treated with I+C were eligible. Response rate (RR) was the primary endpoint. Cetuximab 500 mg/m(2) and irinotecan 180 mg/m(2) were administered intravenously (I.V.) on day 1 every 2 weeks.

Results: Patient characteristics (n = 31): male (n = 17), median age 62; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1 (n = 30), and PS = 2 (n = 1). Median number of cycles = 3 (range, 1-22). I+C doses were modified in 18 and 12 patients, respectively. Grade 3/4 adverse events: acneiform rash (n = 6); neutropenia (n = 6); and diarrhea (n = 5); there was one grade 5 respiratory failure, possibly related to therapy. Two patients had a partial response, 11 had stable disease, and 18 had progressive disease resulting in an overall RR of 6% and disease control rate of 41.9%. Median overall survival (OS) was 9.3 months (95% CI, 5.1-15), and time to progression (TTP) was 2.4 months (95% CI, 1.3-4.6). K-ras and BRAF mutations were detected in 39% and 9%, respectively, of the patients tested. There was a trend toward longer TTP among patients with wild-type K-ras and BRAF (2.6 vs. 1.7 months; P = 0.16), and OS was significantly longer in those patients (14.1 vs. 5.5 months; P = 0.04).

Conclusions: The RR and TTP were lower than expected and may reflect the reduced dose intensity due to toxicities. While the OS was consistent with previous publications, the efficacy of this combination was not demonstrated.
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http://dx.doi.org/10.1016/j.clcc.2011.05.003DOI Listing
March 2012

Making sense of anti-EGFR plus oxaliplatin-based therapy in the first-line treatment of metastatic colorectal cancer.

Authors:
Marwan G Fakih

Future Oncol 2011 Feb;7(2):223-6

University at Buffalo & Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.

EGF receptor (EGFR) targeting in patients with wild-type KRAS metastatic colorectal cancer has been associated with clinical activity in first-, second- and third-line therapies. Panitumumab, a human monoclonal antibody that targets EGFRs, had previously been associated with tumor regressions and improved progression-free survival in patients with chemotherapy-resistant metastatic colorectal cancer. Douillard et al. have reported on the results of the Phase III Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) Phase III of fluoroucil, leucovorin and oxaliplatin, with and without panitumumab, in patients with metastatic colorectal cancer. This article focuses on the PRIME study and its implications on clinical practice. In addition, the results of the PRIME study in the context of another EGFR-targeting agent, cetuximab, when combined with oxaliplatin-based first-line treatment of metastatic colorectal cancer, is discussed.
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http://dx.doi.org/10.2217/fon.10.181DOI Listing
February 2011

5-FU-induced hyperammonemic encephalopathy in a case of metastatic rectal adenocarcinoid successfully rechallenged with the fluoropyrimidine analog, capecitabine.

Anticancer Res 2011 Jan;31(1):335-8

Roswell Park Cancer Institute, Buffalo, NY 14203, USA.

Neurological complications of both fluorouracil (5-FU) and its oral prodrug, capecitabine, have been described in the literature. This study reported the case of a 70-year-old female with metastatic adenocarcinoid of the rectum who developed hyperammonemic encephalopathy, following infusional 5-FU therapy, manifesting itself as intractable nausea, vomiting, confusion and disorientation. Interestingly, when the patient was rechallenged with the fluoropyrimidine analog, capecitabine, neither hyperammonemia nor symptom recurrence was observed. 5-FU is an integral component of effective anti-neoplastic treatment for metastatic colorectal cancer, but is often discontinued when neurotoxicity develops. This case highlighted the use of capecitabine as an alternative for patients who have demonstrated evidence of 5-FU-induced hyperammonemic encephalopathy. Re-challenging the patient with capecitabine, at a low daily dose intensity, accounted for the overall tolerability of the treatment, as demonstrated by normal ammonia levels and the lack of neurological symptoms.
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January 2011

Management of stage II/III rectal cancer.

J Gastrointest Oncol 2010 Dec;1(2):112-9

Department of Radiology, Tripler Army Medical Center, Honolulu, HI.

Pelvic and distant recurrences in rectal cancer can be associated with substantial morbidity, and patients with stage II and III disease are at increased risk for both local and distant failure when compared to patients with earlier stage disease. Refinement of surgical techniques have helped to reduce the risk of recurrence, and adjuvant therapies such as radiation to the tumor and regional lymph nodes and 5-fluorouracil-based systemic therapies have helped to further provide local control and may have an impact on overall survival. Numerous studies have been completed internationally in an effort to determine the optimal treatment regimen for this patient population. The importance of pre-therapy staging is of key importance as sequencing of therapy appears to significantly impact outcome. In the United States, patients with stage II/III rectal cancer are recommended to undergo preoperative concurrent pelvic radiation and chemotherapy followed by surgery several weeks later in order to maximize treatment response, which is then followed by approximately 4 months of adjuvant 5-fluorouracil-based systemic therapy. In Europe, there is substantial evidence supporting the use of neoadjuvant radiation therapy, however the role of concurrent chemotherapy remains a question of debate. Regardless of definitive management strategy, close follow-up in the post-treatment setting is important for early tumor detection and for managing treatment-related side-effects.
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http://dx.doi.org/10.3978/j.issn.2078-6891.2010.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397578PMC
December 2010

Stop and go FOLFOX plus bevacizumab chemotherapy in the first-line treatment of metastatic colorectal cancer.

Oncology 2010 12;79(1-2):67-71. Epub 2010 Nov 12.

Department of Internal Medicine, University at Buffalo, Buffalo, NY 14263, USA.

Background: Infusional 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) plus bevacizumab chemotherapy is commonly implemented in the first-line treatment of metastatic colorectal cancer. A stop and go oxaliplatin strategy has been recommended to reduce oxaliplatin-associated neuropathy. Despite the acceptance of this strategy by community and academic practices, efficacy data with this approach are limited.

Methods: We analyzed the efficacy of a stop and go FOLFOX regimen combined with bevacizumab in a single institute between January 2007 and December 2009. Oxaliplatin was withdrawn electively after 8 cycles of treatment and patients were maintained on 5-fluorouracil/leucovorin and bevacizumab until progression. When feasible, patients were rechallenged with oxaliplatin upon progression.

Results: Sixty-seven patients were treated and analyzed for outcome. The response rate of this group was 58%. The median progression-free and overall survival was 10.6 and 26.7 months, respectively. The median duration of disease control in the 18-patient subgroup that was rechallenged with oxaliplatin was 21.2 months.

Conclusions: Elective withdrawal of oxaliplatin after 8 cycles in the setting of FOLFOX and bevacizumab does not appear to compromise the activity of this regimen. A stop and go approach of FOLFOX plus bevacizumab is effective and may reduce treatment costs and toxicity in comparison with a continuous FOLFOX treatment strategy.
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http://dx.doi.org/10.1159/000319549DOI Listing
January 2011

Randomized, phase II study of the insulin-like growth factor-1 receptor inhibitor IMC-A12, with or without cetuximab, in patients with cetuximab- or panitumumab-refractory metastatic colorectal cancer.

J Clin Oncol 2010 Sep 16;28(27):4240-6. Epub 2010 Aug 16.

Department of Medicine, Division of Solid Tumors, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Howard 1004, New York, NY 10065, USA.

Purpose: To evaluate the safety and efficacy of IMC-A12, a human monoclonal antibody (mAb) that blocks insulin-like growth factor receptor-1 (IGF-1R), as monotherapy or in combination with cetuximab in patients with metastatic refractory anti-epidermal growth factor receptor (EGFR) mAb colorectal cancer.

Methods: A randomized, phase II study was performed in which patients in arm A received IMC-A12 10 mg/kg intravenously (IV) every 2 weeks, while patients in arm B received this same dose of IMC-A12 plus cetuximab 500 mg/m(2) IV every 2 weeks. Subsequently, arm C (same combination treatment as arm B) was added to include patients who had disease control on a prior anti-EGFR mAb and wild-type KRAS tumors. Archived pretreatment tumor tissue was obtained when possible for KRAS, PIK3CA, and BRAF genotyping, and immunohistochemistry was obtained for pAKT as well as IGF-1R.

Results: Overall, 64 patients were treated (median age, 61 years; range, 40 to 84 years): 23 patients in arm A, 21 in arm B, and 20 in arm C. No antitumor activity was seen in the 23 patients treated with IMC-A12 monotherapy. Of the 21 patients randomly assigned to IMC-A12 plus cetuximab, one patient (with KRAS wild type) achieved a partial response, with disease control lasting 6.5 months. Arm C (all patients with KRAS wild type), however, showed no additional antitumor activity. Serious adverse events thought possibly related to IMC-A12 included a grade 2 infusion-related reaction (2%; one of 64 patients), thrombocytopenia (2%; one of 64 patients), grade 3 hyperglycemia (2%; one of 64 patients), and grade 1 pyrexia (2%, one of 64 patients).

Conclusion: IMC-A12 alone or in combination with cetuximab was insufficient to warrant additional study in patients with colorectal cancer refractory to EGFR inhibitors.
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http://dx.doi.org/10.1200/JCO.2010.30.4154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296668PMC
September 2010

A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors.

Clin Cancer Res 2010 Jul 12;16(14):3786-94. Epub 2010 May 12.

Department of Medicine, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York 14263, USA.

Purpose: We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks.

Experimental Design: Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m(2) i.v. over 2 hours followed by FU 400 mg/m(2) i.v. bolus and 2,400 mg/m(2) over 46 hours (sLV5FU2).

Results: Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU.

Conclusions: The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-0547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931804PMC
July 2010

Serological immune responses to influenza vaccine in patients with colorectal cancer.

Cancer Chemother Pharmacol 2011 Jan 5;67(1):111-5. Epub 2010 Mar 5.

Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton, Buffalo, NY 14221, USA.

Background: The immune responses to influenza vaccination in patients with colorectal cancer on surveillance or active chemotherapy have not been previously reported. We conducted a prospective influenza vaccination study to determine the serological immune response rate in patients with colorectal cancer.

Methods: During the 2006-2007 influenza season, patients with colorectal cancer treated at Roswell Park Cancer Institute were offered vaccination with the trivalent influenza vaccine (Fluzone, 2006-2007). Blood samples for hemagglutination inhibition (HI) assay titers were collected before and 3 months after vaccination. Response to vaccination was determined using an endpoint of ≥ 1:40 HI titer ratio or a fourfold HI increase at 3 months from vaccination. A response in HI to at least one of the 3 strains was considered an immune response.

Results: Eighty-five patients with colorectal cancer participated in the study. The immune response in the overall population was 70.6%. No differences in response were noted between the 58 patients on active chemotherapy and the 27 patients on surveillance [Odds Ratio (OR) = 0.78; P = 0.8]. The odds of response did not vary by chemotherapy regimen or by chemotherapy-vaccination timing. HI response in all 3 titers concurrently were low in both the chemotherapy (12.1%) and surveillance groups (11.1%) (OR = 1.10; P = 1).

Conclusions: Patients with colorectal cancer mount an immune response to influenza vaccination irrespective of their chemotherapy regimen or timing. However, concurrent responses to all three strains in the individual patient with colorectal cancer are uncommon. The investigation of a booster vaccine in this population is warranted.
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http://dx.doi.org/10.1007/s00280-010-1292-2DOI Listing
January 2011