bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with delayed time to adjuvant chemotherapy (AC) in stage III colon cancer: British Columbia Cancer Agency (BCCA) cohort experience.
Authors: Chan Angela , Woods Ryan , Gill Sharlene
Published: February 2017

574

Background: The current standard for resected stage 3 colon cancer after surgical resection is adjuvant 5FU-based chemotherapy. In trials, AC is mandated within 8 weeks after surgery, but outside the trial setting, up to 19% of patients do not receive treatment within 8 weeks. A recent meta-analysis confirms that AC started more than 8 weeks after surgery results in significantly decreased overall survival. Our objective was to ascertain logistical and patient factors associated with delayed AC delivery (defined as >56 days from surgery) in referred patients with resected stage 3 colon cancer.

Methods: A population-based cohort of patients diagnosed with stage 3 colon cancer between January 2008 to December 2009 referred to the BCCA and treated with at least one cycle of AC were identified. Patient characteristics, and time intervals between surgery, referral, medical oncology consultation (MOC) and AC were assessed. Differences in patient characteristics and time intervals between patients were assessed using the Chi-square and Wilcoxon Rank-sum tests.

Results: Median time from surgery to AC was 58 days with 54% of patients receiving AC beyond 56 days. Temporal differences were identified in all intervals between the between the timely and delayed groups (see table 1). Referral was most commonly initiated after hospital discharge. The only patient factors associated with delayed initiation included poorer ECOG status and being treated at the most urban centre within BCCA. Age, gender, comorbidity index, T stage and tumour location were not different between the groups.

Conclusions: 54% of patients with stage 3 colon cancer had a delayed AC initiation. Process related delays at each step of the referral process need to be addressed including timely referral, MOC triage and addressing chemotherapy waitlists.

[Table: see text]
Do cancer-specific variables improve risk-adjusted hospital quality comparisons?
Authors: Merkow Ryan P. , Kmiecik Thomas E. , Bentrem David J , Cohen Mark E , Hall Bruce L , Chow Warren B. , Ko Clifford Y. , Bilimoria Karl Y.
Published: February 2017

585

Background: For patients undergoing surgery for cancer, it has been suggested that risk-adjustment with cancer-specific variables is needed when evaluating short-term outcomes. Our objectives were to assess the influence of cancer-related variables on postoperative complications and hospital quality comparisons.

Methods: Patients from ACS NSQIP and NCDB who underwent colorectal resection for cancer were linked (2006-2008) to create a dataset containing robust information on comorbidities, complications, and oncologic variables. Three hierarchical models were developed predicting the NSQIP outcome 30-day mortality or any serious morbidity using variables from (1) NSQIP only, (2) NCDB only, and (3) a combined model using NSQIP and NCDB. Models were compared with fit statistics and hospital outlier agreement.

Results: From 146 NSQIP hospitals, 11401 patients underwent a colorectal resection for cancer, of which, 1954 (17%) experienced a mortality or serious morbidity event. The first five variables selected in the NCDB-only model were Charlson comorbidity score, neoadjuvant therapy use, T stage, primary payer, and M stage (c-statistic, 0.64; AIC, 9886). The first five variables selected in the NSQIP-only model were ASA class, preop sepsis, albumin, surgical procedure, and COPD (c-statistic, 0.66; AIC, 9787). In the combined model, neoadjuvant therapy use was the only cancer-specific variable selected in the top five. The remaining variables were ASA class, preop sepsis, albumin, and wound class (c-statistic, 0.67; AIC, 9455). At the hospital-level, the NCDB-only model identified three high outliers (worse than expected) and one low outlier (better than expected). Both the NSQIP-only and combined models identified the same four high and two low outlying hospitals (kappa: 1.0), which agreed marginally with the NCDB-only model (kappa: 0.59).

Conclusions: Addition of cancer-specific variables to NSQIP models slightly improved model fit; however, hospital outcome comparisons were identical. For patients with colorectal cancer undergoing resection, cancer-related factors have limited predictive ability for short-term outcomes and did not influence hospital quality comparisons.
Evaluation of the necessity of primary tumor resection for synchronous metastatic colorectal cancer.
Authors: Miyamoto Yuji , Sakamoto Yasuo , Ida Satoshi , Watanabe Masayuki , Baba Hideo
Published: February 2017

592

Background: Recent advances in chemotherapy have improved survival in patients with metastatic colorectal cancer. Resection of primary tumor for patients with metastatic colorectal cancer remains controversial. Primary tumor with obstruction or bleeding may be recommended to resection pior to chemotherapy. In contrast, it should be considered potential complications associated with resection of primary tumor and disadvantage of the delay in chemotherapy. Here, we evaluate the needs of primary tumor resection for colorectal cancer patients with synchronous metastases.

Methods: A retrospective analysis of patients with synchronous metastatic colorectal cancer treated at Kumamoto University Hospital between April, 2005 and December, 2009 was performed. We compared the survival of resected patients and non-resected patients.

Results: 104 patients were identified. Sixty-four and 40 patients were included in the resected group and the non-resected group respectively. The mean follow-up time was 16.1 months. Median age was 61.9 and 64.3 years respectively. The non-resected group was more likely to have right-sided tumors (resected: 28%, non-resected: 43%). The number of patient with metastatic disease limited to the liver was similar in both group(resected: 48%, non-resected: 50%). In the resected group, 12 patients (18%) developed postoperative complications. In the nonresected group, 5 patients (12.5%) required creation of a diverting colostomy during the course of their treatment due to obstruction, and 2 patients (5%) required emergency surgical treatment for intestinal perforation due to the primary tumor. No significant difference in survival was observed between the groups, (logrank P=0.33). Median survival period was not significantly different (resected: 27.3 months, non-resected: 21.5 months, P=0.43).

Conclusions: We concluded that it was not necessary to resect the primary lesion in patients with synchronous metastatic colorectal cancer when obstruction or bleeding was not found in primary lesions.
Influence of bevacizumab on early postoperative complications after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis of colorectal origin.
Authors: Eveno Clarisse , Glehen Olivier , Goéré Diane , Lukaszewicz Anne-Claire , Passot Guillaume , Elias Dominique , Pocard Marc
Published: February 2017

601

Background: Increasingly patients with IV stage colorectal cancer received systemic chemotherapy combined with targeted therapy among which bevacizumab. In neoadjuvant situation, a delay of at least 6 weeks between discontinuation of bevacizumab and surgery is recommended, not to increase the risk of complications (delayed healing, bleeding) related to bevacizumab. The goal of this study was to analyze the potential impact of bevacizumab on early morbidity after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal carcinomatosis of colorectal origin.

Methods: From 2004 to 2010, in three hospitals, 183 patients treated with complete cytoreduction followed by HIPEC for colorectal carcinomatosis, received preoperative treatment. It was either systemic chemotherapy alone (Chemo group, n = 100) or by chemotherapy combined with bevacizumab (Beva group, n = 83).

Results: Both patient groups were comparable in the extent of carcinomatosis, assessed on peritoneal cancer index means (10.4 vs 10, p> 0.05), number of resected organs (4.3 vs 3.8, p> 0.05), operative time (420 vs. 380 minutes, p> 0.05) and volume of blood loss (470 vs 510ml, p> 0.05). The median time from discontinuation of bevacizumab and HIPEC was 7 weeks (6-10), always greater than 6 weeks. Nine patients postoperatively died, 4 (4%) in the chemo group and 5 (6%) in the beva group (ns). Grade 3 to 5 complication rate was higher in the beva group (25 vs 12%, p <0.05). Whatever the hospital, complications that may be related to bevacizumab occurred more frequently in patients in the beva group: with more digestive fistulas (18 vs 8%, p <0.05), deep abscesses (13 vs 3 %, p <0.01) and delayed healing (11 vs 2%, p <0.02).

Conclusions: Administration of bevacizumab before surgery with complete cytoreduction followed by HIPEC for carcinomatosis colorectal is associated with increased morbidity, probably due to multiple organ resections performed during the surgery. The oncologic benefit of bevacizumab before HIPEC remains to be evaluated.
Impact of mismatch repair (MMR) testing on colorectal cancer (CRC) oncology clinical practice.
Authors: Hewish Madeleine , Stamp Gordon , Puckey Loretto , Shanley Susan , Costello Clare , Webb Janine , Hulkki Wilson Sanna , Gonzalez de Castro David , Barbachano Yolanda , Saffery Claire , Swanton Charles , Lord Christopher J. , Reis-Filho Jorge S. , Ashworth Alan , Chau Ian , Cunningham David
Published: February 2017

603

Background: MMR deficiency (dMMR) has been reported in 15% of CRC, but with a lower frequency in advanced disease. Most cases are due to sporadic MLH1 promoter hypermethylation (often with BRAF mutations), with a minority reflecting germline mutations in MLH1, MSH2, PMS2, or MSH6 (Lynch Syndrome [LS]). The Revised Bethesda Guidelines (RBG) are one means of selecting individuals at risk of LS for further assessment, but will miss a proportion of cases.

Methods: We screened all consenting patients for eligibility for CRC trials recruiting specific genetic aberrations, which included MMR assessment.

Results: Of 314 patients, immunohistochemistry (IHC) for MMR protein expression is complete on 171. Staining was reduced/absent in 19.3% of tests, and heterogeneous in 12.1%. The dMMR rate was 6.4%. 2 dMMR patients* were identified as at risk of LS, and referred to genetics by their treating clinician before IHC results were known. However 4 other cases† were not referred, and an underlying predisposition would have been missed without this unbiased approach. 4 patients developed metastatic disease, with none experiencing a partial response to chemotherapy thus far. (Table.)

Conclusions: This data is representative of a practice with a high proportion of metastatic disease. It suggests that within oncology, an unbiased screening approach for LS is preferable. Whilst the RBG detect the majority of cases, they may be underutilised as other management issues take precedence in oncology clinics. A cost-effective alternative may be the introduction of a nurse-led programme to identify cases at risk, as is being introduced at our centre. A spectrum of clinical behavior exists amongst metastatic dMMR CRC, and larger numbers will reveal if this affects therapeutic response.

[Table: see text]
IXOA regimen, irinotecan (I), capecitabine (X), oxaliplatin (O), and bevacizumab (A), as first-line therapy for advanced unresectable colorectal cancer (aCRC): Preliminary results.
Authors: Maroun Jean Alfred , Jonker Derek J. , Cripps M. Christine , Goel Rakesh , Asmis Timothy R. , Goodwin Rachel Anne , Yarom Nirit , Marginean Horia
Published: February 2017

604

Background: IXO showed acceptable toxicities and promising efficacy in a phase I/II study as 1st-line therapy for aCRC patients (pts). Combination with A might enhance the efficacy of IXO treatment.

Methods: The objectives of the study were to evaluate the recommended dose (RD) of IXO regimen when used in combination with A (IXO+A), and to document safety and efficacy of the combination. Starting dose was: I 160mg/m2 IV d1, X 950mg/m2 bid PO d2-15, O 100mg/m2 IV d1, A 7.5 mg/kg iv d1, q3w. IXO regimen dose adjustments were planned in case of therapy-attributed severe toxicities.

Results: 23 pts enrolled and evaluable for toxicity, 16M/7F, median age 65 years (range 28-77), PS 0/1/2 in 7/16/0, sites of disease (colon 18/rectum 5) received 288 cycles, median 8 (range 1-40). Gr.4 neutropenia and thromboembolic toxicity in the first 6 pts induced a 15% I and 20% X dose reduction, followed by another 10% I dose reduction in the following 6 pts due to diarrhea and febrile neutropenia. The adjusted regimen with reduced I 25% and X 20% from initial IXO, was considered safe for cohort expansion. Overall Gr.3+ toxicity included: 35% neutropenia, 4% febrile neutropenia, 13% leucopenia, 4% thrombopenia, 7% thromboembolic events, 44% diarrhea, 22% nausea and vomiting, 22% fatigue, 17% dehydration. Two treatment-related deaths (MI and pancolitis) were observed. Among 18 evaluable pts (2 NE, 3 too early for evaluation) response was 12 PR (up to 37 months), 5 SD and one DP. At a median follow-up of 16.5 months, 7 pts have progressed after median 15 months (range 2.5-32.1). Median PFS and OS were not reached.

Conclusions: The IXO+A combination required I and X dose adjustment as compared with the initial IXO regimen, with diarrhea, neutropenia and thromboembolic events being the main toxicities. Recruitment continues in an expanded cohort at the newly identified phase II RD: I 125mg/m2, X 750mg/m2, O 100mg/m2, A 7.5 mg/kg. IXO+A shows promising efficacy and acceptable toxicity. Supported by Roche Canada.
Number of lymph nodes recovered as an independent prognostic factor in predicting outcome in patients with pathologically node-negative rectal cancer following preoperative chemo/radiotherapy.
Authors: Rodda Sree Lakshmi , Dhadda Amandeep Singh , Dickinson Peter D. , Zaitoun Abed M , Bessell Eric M
Published: February 2017

606

Background: To determine the importance of number of lymph nodes recovered on outcome in pathological node negative rectal cancer patients who had received chemo/radiotherapy prior to surgery.

Methods: We retrospectively analysed data from 262 patients with locally advanced rectal cancer who received pre-operative chemo/radiotherapy at Castle Hill Hospital, Cottingham and Nottingham University Hospital between 2001 and 2008. Patients were treated with CT planned radiotherapy to a dose of 45-50 Gy in 25 fractions with concurrent fluoropyrimidine chemotherapy. Surgery was normally performed at an interval of 6-8 weeks. There were 152 patients who were found to be pathologically node negative for further analysis. Median follow-up was 51.5 months Patients were grouped into < 10 nodes recovered or > 10 nodes recovered. Disease free survival (DFS) and overall survival (OS) was assessed using Log rank test. Multivariate analysis was performed using Cox-regression analysis.

Results: Of the 152 patients analysed, 67.1 % (n=102 ) had fewer than 10 nodes recovered and 32.8% (n=50) had greater than 10 nodes recovered. The median number of nodes recovered was 7 (range 0-39). There was a improvement in 5 year DFS and OS in group who had more than 10 nodes recovered compared to group with less than 10 nodes recovered ( DFS at 5yrs :86.5% vs. 61.5%, p=0.01, OS at 5 yrs : 77.8% vs. 67.4% , P =0.059). On multivariate analysis pathological T-stage , circumferential resection margin (CRM) status and number of lymph nodes recovered were found to be independent predictors of disease free survival (p=0.002).

Conclusions: The number of lymph nodes retrieved following surgery for locally advanced rectal cancer patients following chemo/radiotherapy is an independent prognostic factor in pathologically node negative patients. This may need to be considered when making subsequent adjuvant chemotherapy decisions.
Accuracy of computed tomography in staging colon cancer patients.
Authors: Oxner Christopher Ryan , Nelson Rebecca A. , Lee Wendy , Duldulao Marjun Philip , Wiatrek Rebecca Lynn , Chen Steven , Pigazzi Alessio , Kim Joseph , Garcia-Aguilar Julio
Published: February 2017

614

Background: Though adjuvant chemotherapy is well-established for treating patients with AJCC Stage III colon cancer, there is growing interest in giving chemotherapy neoadjuvantly for these patients. Since clinical staging to determine eligibility requires accurate preoperative imaging, our objective was to determine whether computed tomography (CT) scans can be used to detect nodal disease in colon cancer patients.

Methods: We identified patients with AJCC stage I-III colon cancer who underwent curative resection between 2006 and 2010 at our institution. Patient CT scans were obtained and final radiologic reports were recorded in a database. CT images underwent secondary prospective review by a blinded independent surgeon with the intent to identify mesenteric lymphadenopathy (N+). Clinical staging from the original radiologic report and secondary surgeon review of the CT images were then compared with pathologic staging.

Results: Imaging and pathology were available for 67 colon cancer patients. Original radiologic review reported N+ disease in 10 of 67 patients (15%), but final pathology revealed 31 of 67 (46%) patients to be N+. Therefore, radiological review correctly predicted Stage III disease in 10 of 31 (32%) patients. On final pathology, 36 of 67 (54%) patients had no nodal disease (N0). Radiologic reports noted absence of lymphadenopathy in 29 of 67 (43%) patients, thus accurately predicting N0 disease in 29 of 36 (80%) patients. Of 67 studies, 14 (21%) had no mention of lymphadenopathy and were considered N0. Of these 14, 6 were N+ on final pathology. Surgeon review accurately identified N+ disease in 4 of these 6 patients. On surgeon review, sensitivity increased from 32% to 68% while specificity dropped from 80% to 61%, corresponding to a decrease in false negatives from 68% to 32% and an increase in false positives from 20% to 39%.

Conclusions: Current clinical staging of colon cancer by CT has low accuracy. However, actively seeking nodal disease improves sensitivity but with minor loss of specificity. Improved radiologic criteria and technology may further increase accuracy in clinical staging of Stage III colon cancer patients who will receive neoadjuvant treatment.
Comparison of prognostic factors and survival outcome between gastrointestinal tract and cutaneous invasive malignant melanoma.
Authors: Lin Chi , Brown Christopher K , Enke Charles Arthur , Loberiza Fausto R.
Published: February 2017

618

Background: Gastrointestinal melanoma (GIM) is a rare disease. The objective of this study is to compare the overall survival (OS), cancer specific survival (CSS) and prognostic factors of GIM to those of skin melanoma (SKM) using the Surveillance, Epidemiology, and End Results (SEER) registry.

Methods: Patients diagnosed with invasive GIM (406) and SKM (173,622) between 1973 and 2008 were identified from the SEER database. Factors analyzed included age (18-40/41-60/61-100), gender, race (White/nonwhite), marital status, stage (localized/regional/distant), year of diagnosis (1973-87/1988-97/1998-2008), and type of treatment (radiotherapy (RT)/surgery). OS and CSS were evaluated using the Kaplan-Meier method. Cox proportional hazards regression analysis examined what factors were prognostic of survival.

Results: The median age was 69 and 57 for patients with GIM and SKM, respectively. The GIM group was older with more advanced-stage cancer than the SKM group. Surgery was performed on 85% and 95%, while RT was received by 18% and 2% of GIM and SKM patients, respectively. The GIM group had a median OS and CSS of 15 and 16 months, respectively, while the SKM group had a median OS of 283 months and did not reach a median CSS. Cox analysis showed that SKM had significantly lower risk of total and cancer-specific mortality compared to GIM (Hazard Ratio (HR) 0.40, p<0.0001) and (HR 0.34, p<0.0001). Factors associated with improved OS and CSS in SKM included: age ≤60, female gender, non-white race, early stage, being married, more recent diagnosis, undergoing surgery and not receiving RT. Factors associated with improved OS and CSS in GIM included: age ≤60, early stage, non-white race and undergoing surgery. Subgroup analysis on patients who underwent surgery showed that lymph node status was the only prognostic factor for GIM, while all of the previously identified prognostic factors except for race were associated with OS and CSS for SKM.

Conclusions: Outcomes of patients with GIM are inferior to those with SKM. The melanomas in these two sites also have different prognostic factors. Future studies should explore the reasons behind these differences to improve treatment outcomes.
Physical function and quality of life in frail and/or elderly metastatic colorectal cancer patients treated with bevacizumab and capecitabine: An exploratory analysis.
Authors: Ward Peter Richard , Liem Andre K. D. , Wang He-jing , Patel Ravi , Hu Eddie Hong-Lung , Tchekmedyian Nerses Simon , Wainberg Zev A. , Hecht J. Randolph , Naeim Arash
Published: February 2017

627

Background: Optimal treatment strategies in frail and/or elderly patients with metastatic colorectal cancer have not been well defined. Although the safety and efficacy of bevacizumab and capecitabine in this population has been reported, the impact on functional measures and quality of life has not been well described. In a prospective, phase II study of elderly metastatic colorectal patients with ECOG performance status (PS) 1 or 2 treated with first-line bevacizumab and capecitabine, we collected data on geriatric functional status and quality of life. The primary aim of this analysis was to explore the differences in geriatric health measures between patients with ECOG status 1 and 2.

Methods: Functional status was measured by patient-reported limitations in ADLs and IADLs and ECOG PS was assessed. A “Get up and Go” test, hearing test, and 3-item recall exam was also performed. Quality of life (QoL) was assessed by means of the FACT-C questionnaire and patient-rated health status was measured by the EQ-5D questionnaire. The prognostic impact of baseline characteristics on survival was studied using univariate Cox-regression analysis.

Results: The majority (62%) of the 45 participants treated were ECOG 2. This group had more limitations in IADLs, lower baseline QoL, and a lower patient-rated health score. For all participants, QoL significantly improved from baseline to the start of cycle 2 (FACT-C: 99.9 vs. 105.4, p=0.01) and did not deteriorate when baseline scores were compared to when participants went off study. (FACT-C: 99.9 vs. 98.6, p=0.59). In the Cox-regression analysis, the participant’s ability to perform the “Get up and Go” test was the only baseline characteristic that was prognostic for improved survival (HR = 0.31, p = 0.01).

Conclusions: Our analysis shows that in this study of frail and/or elderly patients with metastatic colorectal cancer treated with bevacizumab and capecitabine, there is a significant amount of heterogeneity between the ECOG 1 and 2 groups in both functional measures and quality of life. We also showed that the “Get up and Go” test may be a useful prognostic indicator for survival in this population.
Evaluating the agreement between the empirical volumes of tumor lesions and the estimated volumes of tumor lesions based on the longest diameter.
Authors: Laubender Ruediger P. , Schlichting Michael , Sartorius Ute , Modest Dominik Paul , Mansmann Ulrich Robert , Heinemann Volker , Graser Anno
Published: February 2017

635

Background: Tumor lesions are commonly evaluated by RECIST or WHO criteria, which involves reducing the development of a three-dimensional tumor to a two-dimensional process. However, volume measurements might reflect the clinical impact of the disease process more precisely. Therefore, we investigated if the volume of a tumor lesion can be reconstructed from RECIST- or WHO-based measurements.

Methods: 20 colorectal cancer patients underwent routine staging MDCT examinations as part of the multicenter phase II CIOX trial comparing cetuximab + XELOX versus cetuximab + XELIRI. Two hepatic target lesions per patient were defined at baseline and measured using 1) semi-automated volumetry (Siemens Syngo Via Oncology, Siemens Healthcare) with manual correction and 2) semi-automated measurement of the longest diameter (LD) according to RECIST 1.1 and the corresponding longest orthogonal diameter (LOD). Patient lesions were followed over time using the same measurement strategies. An algorithm was developed for reconstructing the volume of a lesion based on the LD and the corresponding LOD. Agreement of the volume data generated by both methods was analyzed by a Bland-Altman plot. The limits of agreements were calculated using a variance components model considering repeated tumor assessments based on the log-transformed sum over the volume of a patient’s lesions.

Results: 151 lesions from the 20 patients were measured at 73 tumor assessments. Volume was slightly overestimated by the algorithm compared to the volumetric measurements (p = 0.07). The Bland-Altman plot showed good agreement (mean difference −0.05, limits of agreement [−0.40, 0.30]). As expected, three out of the 73 measurements fell outside the limits of agreement.

Conclusions: The proposed algorithm for the WHO-based reconstruction of the tumor volume provides a good approximation to the true sum of the volumes of the lesions. In future studies, volumetric tumor information can be included even if not all centers have full volumetric software available. This enables further research on the impact of changes in tumor volume on disease prognosis and/or prediction of treatment efficacy.
A novel approach to manage skin toxicity caused by therapeutic agents targeting epidermal growth factor receptor.
Authors: Berardi Rossana , Campanati Anna , Onofri Azzurra , Pierantoni Chiara , Conte Irene , Giuliodori Katia , Molinelli E , Marcucci Fabiana , Offidani Annamaria , Cascinu Stefano
Published: February 2017

636

Background: Inhibition of EGFR represents an important field in cancer therapy.Skin rash is a common adverse reaction in patients receiving EGFR inhibitors. Nicotinamide has been shown to be an effective treatment for skin inflammation in various conditions, since nicotinamide inhibits IL-8 production through the NF-kB and MAPK pathways in an in vitro keratinocytes/P. acnes model of inflammation. Furthermore green tea polyphenols could be useful in attenuation of solar UVB light-induced oxidative stress-mediated and MAPK-caused skin disorders in humans.In this study we evaluated the effect of nicotinamide and green tea polyphenols on skin toxicity EGFRI related.

Methods: Patients with skin toxicity induced by EGFRI were enrolled. They underwent a skin biopsy and skin samples for microbiological analyses at first presentation of skin toxicity (T0). Skin toxicity was assessed with NCI-CTACE,EGFR index and Dermatology Life Quality Index (DLQI) test. Therapy protocol consisted in topical application of moisturizing cream containing green tea polyphenols plus oral administration of nicotinamide 200 mg/die for 12 weeks. Topical application of 1% clindamycin gel and/or systemic administration of minocicline were provided in case of superbacterial infection. All treated patients were monitored for at least 12 weeks (T12), across three time points (T0,T6,T12).

Results: 24 colorectal cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab) and developing skin toxicity were treated by a multidisciplinary team including oncologists, dermatologists, a pathologist and a nurse. All the patients experienced a significant reduction of skin toxicity according to the NCI-CTACE and EGFR index (p<0.05). Papulo-pustular eruption and itching significantly improved after 6 weeks of treatment and erythema decreased after 12 weeks. A significative improvement of the global score and of DLQI was evident. No toxicity related to the treatment of skin toxicity was observed.

Conclusions: Treatment with nicotinamide and green tea polyphenols represent a novel effective approach to manage skin toxicity caused by EGFRI.
Effect of lymphadenectomy on survival in patients with esophageal cancer.
Authors: Almhanna Khaldoun , Weber Jill M. , Shridhar Ravi , Hoffe Sarah E. , Karl Richard C. , Meredith Kenneth
Published: February 2017

65

Background: The number of resected lymph nodes is associated with overall and disease-free survival in some gastrointestinal malignancies. The impact of nodal harvest during esophagectomy remains to be determined. We examined the influence of lymphadenectomy on overall survival in patients with esophageal cancer.

Methods: Utilizing a prospectively maintained comprehensive esophageal cancer database we identified patients who underwent esophagectomy with between 1994 and 2011. The association between disease free survival (DFS), overall survival (OS) and nodal harvest was evaluated using multivariable Cox regression models. The number of harvested nodes was examined as a categorical variable based on strata(S): 1) ≤8, 2) 9-12, 3) 13-20, and 4) >20.

Results: We identified 635 patients, 541 males and 94 females with a median age of 65 years (28-86) and median follow-up of 22 months (0-168). Adenocarcinoma 559 (88 %) was the predominant histology where as squamous cell carcinoma represented 76 (12%) of the cases. The 5-year OS and DFS rate for S1-S4 was (43%, 42%, 55%, and 36%, p=0.1836) and (44%, 37%, 46%, and 36%, p=0.5166) respectively. There were 209 patients with metastatic disease in 1 or more lymph nodes. The 5-year OS and DFS for S1-S4 was (17%, 31%, 21%, and 27%, p=0.4372) and (17%, 23%, 16%, and 25%, p=0.2726). There were 418 node negative patients. The 5-year OS and DFS rates by S1-S4 was (54%, 51%, 79%, and 26%, p=0.0538) and (55%, 48%, 64%, and 27%, p=0.3703). Multivariate analysis revealed that patients within S3 exhibited a survival benefit adjusted odds ratio (AOR) 0.57 (CI 0.360-0.916, p=0.020). However patients within S1 were more likely to die, AOR 1.74 (CI 1.09-2.78, p=0.020). No survival benefit was demonstrated for patients within (S4) AOR 1.11 (CI 0.60-2.09, p=0.731). There were 171 (27.5%) recurrences with a median time to recurrence of 12.2 (1-101) months. There were no differences in recurrences between strata p=0.129.

Conclusions: We demonstrated that patients with ≤8 lymph nodes resected were more likely to die of their disease compared to those with 13-20 nodes resected. Additionally, extended lymphadenectomy (>20 nodes) does not increase the likelihood of proper staging and does not improve patient outcome.
Use of anti-EGFR agents among elderly patients with metastatic colorectal cancer (mCRC).
Authors: D'Silva Ashley James , Dotan Efrat , Kloth Dwight D. , Beck Andrew , Cohen Steven J. , Denlinger Crystal Shereen
Published: February 2017

657

Background: Limited data are available regarding the tolerance of older mCRC patients to anti-EGFR therapy. To evaluate the treatment patterns and tolerability of cetuximab/panitumumab in this patient population, we conducted a retrospective review of elderly patients treated with these agents at Fox Chase Cancer Center between 2004-2010.

Methods: Patients ≥ age 65 with mCRC treated with cetuximab/panitumumab were included in the analysis. Patient demographics, disease characteristics, treatment drugs and duration, KRAS status and overall survival were recorded. Toxicity evaluation included review of common hematologic and non-hematologic toxicities seen with these agents.

Results: 118 patients were included; 100 received cetuximab and 18 received panitumumab therapy. The majority of patients were male (59.3%) with colon cancer (82.2%) and stage IV disease at presentation (50.8%). The median age at treatment initiation was 73 yrs (range: 65-90). Median overall survival was 510 days, and the median time on treatment 73 days. Most patients were treated prior to the incorporation of routine KRAS testing thus, KRAS status was available for 35 patients (29.7%) with 14.2% KRAS mutant tumors. 66% of cetuximab and 45% of panitumumab treatments were given in combination with another agent. The overall incidence of any grade 3/4 non-hematologic toxicity was 36% (34% for single agent; 37.8% for combination therapy). Common grade 3/4 non-heme toxicities were: hypomagnesemia-16.9%, diarrhea-10.2%, and rash-9.3%. Diarrhea and hypomagnesemia were more common among patients receiving combination therapy. The overall incidence of any grade 3/4 hematologic toxicity was 15.2% (6.8% for single agent ; 20.3% for combination therapy). Anemia was the most common heme toxicity in both single and combination therapy. Advanced age at treatment initiation was associated with higher incidence of single agent therapy (p=0.0005, ANOVA statistics).

Conclusions: Our data demonstrate that elderly patients with mCRC tolerate anti-EGFR therapy, with toxicity rates similar to those reported in large clinical trials with younger patient populations. Older mCRC patients can safely receive anti-EGFR treatment as part of their therapy.
Phase II study of capecitabine in substitution of 5-FU in the chemoradiotherapy regimen for patients with squamous cell carcinoma of the anal canal.
Authors: Ribeiro Suilane Coelho , Venchiarutti Camila , Riechelmann Rachel , Gil Erlon , Nahas Caio , Coudry Renata , Freitas Daniela , Saragiotto Daniel F. , Arruda Fernando , Azambuja Rodrigo , Hoff Paulo
Published: February 2017

659

Background: Squamous cell carcinoma (SCC) of the anal canal is an uncommon malignancy accounting for 1-5% of intestinal tumors; however, its incidence has been increasing. The standard treatment of anal canal SCC stage II-III consists of infusional 5-fluorouracil associated with mitomycin and radiotherapy. This scheme was proposed by Nigro in 1974, and since then no other effective treatment was developed.

Methods: Patients with SCC of anal cancer T2-4N0M0 or T (any) N1-3M0, with good performance status, normal blood and renal function were treated with capecitabine 825 mg/m2 12/12hs during radiotherapy associated with a single dose of mitomycin 15 mg/m2 on Day 1. Primary objective is determine local control rate in 6 months with capecitabine, mitomycin and radiotherapy in patients with SCC of the anal canal. After the end of the treatment patients were reassessed for clinical and radiological response. Sample size was calculated using Fleming's single stage. Considering 85% of expected events (rate of local control in 6 months), standard deviation and a 5% error, sample size calculated was 51 patients.

Results: 13 patients have been included, 9 patients have finished, 3 patients are still in treatment and 1 patient was excluded because of poor compliance with oral medications. Regarding the staging, 5 patients (38,4%) with stage II, 4 patients ( 30,8%) with stage IIIA and 4 patients (30,8%) with stage IIIB. Among patients who finished the treatment and were reevaluated 1 patient ( 16,7%) presented partial clinical response, 6 patients (83,3%) had clinical complete response. Three patients are waiting for clinical and radiologic reassessement. The main toxicities observed were grade I diarrhea ( 30,7%), grade II (38,5%) and III (30,7%) radiodermitis, nausea ( 38,5%), grade I-II plaquetopenia( 30,7%). Grade I hand–foot syndrome was observed in 1 patient and hemorrhagic cystitis related to radiotherapy was observed in 1 patient. No serious adverse event was observed. Colostomy was required in 1 patient before the beginning of the treatment.

Conclusions: The study is ongoing but capecitabine and mytomicin with radiotherapy seem to be a safe treatment for SCC of the anal cancer.
Propensity score–based comparison of outcomes with 3D conformal radiotherapy (3D-CRT) versus intensity-modulated radiation therapy (IMRT) in treatment of esophageal cancer.
Authors: Lin Steven H. , Myles Bevan H , Wang Lu , Thall Peter F. , Vaporciyan Ara A. , Mehran Reza J. , Swisher Stephen , Lee Jeffrey H , Bhutani Manoop S. , Maru Dipen , Ajani Jaffer A. , Cox James D. , Komaki Ritsuko , Liao Zhongxing X.
Published: February 2017

66

Background: Although 3D-CRT is the current standard for treatment of esophageal cancers, IMRT improves dose conformality and reduces radiation exposure to normal tissue. There is no assessment of long term clinical outcomes comparing these two modalities.

Methods: Between 1998-2008, 676 patients (3D-CRT=413, IMRT=263) with stage Ib-IVa (AJCC 2002 edition) esophageal cancers were treated with chemoradiation with or without surgery. To correct for potential bias inherent in observational studies, we employed inverse probability of treatment weighted (IPW) methods based on propensity scores. IPW survival plots and IPW log rank tests were used to adjust for potential bias in treatment selection. Treatment probabilities (propensity scores) were estimated using logistic regression.

Results: IMRT patients were less likely to receive induction chemotherapy (35.7% vs 46.7%, p<0.01) and had poorer performance status (KPS≤80: 66.5% vs 50.0%, p<0.01). A fitted multivariate IPW-adjusted Cox model showed that overall survival was significantly associated with age (HR 1.10 for 10 years older, p=0.02), KPS (≤70 vs 90-100, HR 1.5, p=0.0002), having surgery (HR 0.56, p<0.0001), lower vs upper esophagus (HR 1.4, p=0.009), stage (3-4a vs 1-2, HR 2.6, p<0.01), and radiation modality (IMRT vs 3D-CRT, HR 0.68, p<0.0001). 3D-CRT patients had a greater risk of dying at 5 years compared to IMRT (72.6% vs 52.9%, p<0.0001) without a difference in cancer-specific mortality (Gray’s test p=0.86), time to local recurrence (p=0.27) or distant metastasis (p=0.13). Cumulative incidence of documented cardiac deaths trended higher in the 3D-CRT group (p=0.16), but most deaths were due to unknown causes (5 year estimate: 13.4% in 3D-CRT vs 4.2% in IMRT, Gray’s test p<0.0001). Analyses using propensity score as a covariate gave very similar results.

Conclusions: There was a substantially higher risk of non-cancer related deaths in 3D-CRT versus IMRT. While the true cause of death cannot be determined for many 3D-CRT patients, our results suggest that improvements in radiation technology may improve treatment-related mortality in management of esophageal cancer.
5-flourouracil (5FU) shortage: Clinical implications and costs in a single month.
Authors: Gupta Shweta , Jain Prantesh , Gupta Saurabh , Yim Barbara , Mullane Michael Russell
Published: February 2017

663

Background: Capecitabine (XELODA) is an orally active fluoropyrimidine that is absorbed intact through the gastrointestinal tract and converted in to 5FU. Standard chemotherapy for advanced colon cancers includes infusional 5FU with leucovorin in combination of oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). With the national shortage of 5FU we had to switch our FOLFOX and FOLFIRI regimens to XELOX or XELIRI. Although in trials the xeloda regimens were non-inferior, the PFS (progression free survival) and OS (overall survival), survival curves tailed behind the infusional 5FU regimens.

Methods: At our institution over one month period from August 18th 2011 to September 18th 2011, all patients who were switched from 5FU to xeloda due to national shortage were identified. All charts were retrospectively reviewed identifying patients with colon cancer. Patients with other cancer histologies, were excluded. The charts were reviewed for number of cycles, clinical toxicity, admission to hospital.

Results: A total of 90 patients were switched form 5FU to xeloda. 51 had colon cancer. Out of which, 6 (11.7%) patients had the drug discontinued due to toxicity and 4 out of the 6 required hospitalization due to adverse effects of xeloda, mainly diarrhea and vomiting. 80% of these had left sided colon cancer and 50% each received oxaliplatin and irinotecan respectively. The total number of hospitalization days was 20. The average wholesale price (AWP) of one cycle of xeloda for body surface area range from 1.5m2 to 2m2 ranges from 2605.68$ to 3474.24$ for every 3 week cycle. In comparison the corresponding AWP for 2 cycles of 5FU over a month is 51.81$ to 69.08$. This would become a net higher price of 2553.87$ to 3405.16$ for BSA of 1.5 to 2m2 per month for the switch to xeloda. There were 51 patients who received xeloda at least one cycle which costed about 151,954.50$ if we average the body surface area. Additionally there were 20 admission days costing about 50,000$, making the net costs of switching to xeloda more than 200,000$ in a single month.

Conclusions: Although xeloda is non-inferior to 5FU and can be a substitute, left sided colon cancers tend to do have more adverse effects. Additionally Xeloda is associated with higher administration costs.
Use of calcium and magnesium to prevent oxaliplatin-related neurotoxicity.
Authors: Brady Bernadette , Cogan Grainne , Grogan William , Hennessy Bryan
Published: February 2017

672

Background: Sensory neurotoxicity is a dose limiting side effect of oxaliplatin. The postulated cause is interference with ionic channels. Calcium and magnesium pre and post oxaliplatin infusion have been suggested to prevent this as they act as chelators.

Methods: We performed a review of all patients who were treated with oxaliplatin over a 2 year period. 25 patients received oxaliplatin with calcium gluconate 1g and magnesium sulphate 1g (Ca/Mg group) and 33 did not (no Ca/Mg group). 49 (84%) patients received oxaliplatin as part of the FOLFOX regimen. Other regimens included XELOX, EOX and FLOX. Peripheral neuropathy was defined and graded by the Common Terminology Criteria for Adverse Events v3.0 and was assessed by a clinical nurse specialist (CG).

Results: 55 (95%) patients had peripheral neuropathy. There was no significant difference in overall neuropathy and the grade of neuropathy between the Ca/Mg group and no Ca/Mg group. 4 patients required discontinuation of oxaliplatin. One patient (Ca/Mg group) required dose reduction. Patients requiring medical treatment were treated with pregabalin.

Conclusions: Oxaliplatin-induced neuropathy is a drug limiting adverse effect. We found that the addition of calcium gluconate and magnesium sulphate did not reduce the incidence or severity of peripheral neuropathy experienced in our cohort. It has been suggested (Park S.B. et al. The Oncologist. 2011;16:708-716) that oxaliplatin induced peripheral neuropathy may not be reversible. This emphasises the importance of managing this difficult symptom appropriately.

[Table: see text]
Effect of moisturizers on prevention of hand-foot syndrome associated with capecitabine plus oxaliplatin.
Authors: Kawakami Kazuyoshi , Suenaga Mitsukuni , Yokokawa Takashi , Sugita Kazuo , Mae Yutaro , Nakamoto Eri , Imada Hiroshi , Mizunuma Nobuyuki , Yamaguchi Toshiharu , Hama Toshihiro
Published: February 2017

681

Background: Capecitabine plus oxaliplatin (XELOX) has been established as first-line treatment for patients with metastatic colorectal cancer. Hand-foot syndrome (HFS) is the most common toxicity associated with capecitabine, and the mechanism of which remains to be clarified. Appropriate management of HFS for continuing treatment is needed to ensure improved survival. In this study, we evaluated the efficacy of our candidate moisturizers for HFS, considering its compliance in each patient at a single institute.

Methods: Patients who received XELOX for metastatic colorectal cancer at the Japanese Foundation for Cancer Research, Cancer Institute Hospital, between Apr 1 2010 and Apr 30 2011 were included in this study. Pharmacists conducted the skin care for HFS using moisturizers: heparinoid ointment, a mixture of vitamin A oil and white petrolatums (1:1). All HFS events were graded according to NCI–CTC, version 4.0. The relationship between accumulated dose of capecitabine and incidence of HFS events stratified by frequency of daily moisturizers application was analyzed by using the Kaplan-Meier method. P value of <0.05 was considered significant.

Results: Moisturizers were applied two or more times a day in 45 patients (Good compliance group) and once a daily in 28 patients (Poor compliance group). In terms of incidence of grade ≥1 HFS, no significant differences were observed between good compliance group and poor compliance group (p = 0.764). Incidence of grade ≥2 HFS was observed slightly higher in the poor compliance group than in the good compliance group, though the differences were not statistically significant (p = 0.286).

Conclusions: The onset of capecitabine-associated HFS is independent of frequency of using moisturizers. However, more frequent application of moisturizers appeared to have a possibility to prevent severe HFS. Assessment for compliance with the moisturizers is important as well as patient-compliance-instruction by pharmacist.
Sentinel lymph node mapping for T1 esophageal cancer.
Authors: Takeuchi Hiroya , Kawakubo Hirofumi , Saikawa Yoshiro , Nakahara Tadaki , Omori Tai , Mukai Makio , Kitagawa Yuko
Published: February 2017

7

Background: Extended radical esophagectomy with three-field lymph node dissection has been recognized as the standard procedure for thoracic esophageal cancer in Japan, even for clinically T1N0 cases. However, to eliminate the uniform application of the highly invasive surgery, we hypothesized that sentinel lymph node (SLN) mapping would play a key role to obtain individual information and allows modification of the surgical procedure for early esophageal cancer.

Methods: We have established radio-guided method to detect SLNs in patient with early esophageal cancer using endoscopic injection of technetium-99m tin colloid. Preoperative lymphoscintigraphy and intra-operative use of hand held gamma probe were reliable to locate the radioactive SLNs. Intra-operative gamma probing was also feasible in thoracoscopic or laparoscopic surgery using a special gamma detector which is introducible from trocar ports.

Results: SLN mapping has been performed for 70 patients with clinically N0 and early (pT1) esophageal cancer in our institute since 1999. Detection rate of hot node using our procedure was 94% (66/70). The mean number of sentinel nodes per case was 4.6. Twenty-one of 23 cases (91%) with lymph node metastasis showed positive SLNs. Accuracy of metastatic status based on SLN was 97% (64/66). SLNs widely spread from cervical to abdominal areas. In more than 80% of the cases, at least one SLN was located in the 2nd or 3rd compartment of regional lymph nodes. However, 56 (85%) of 66 patients had no lymph node metastasis or metastasis (+) only in SLNs.

Conclusions: Our results suggest that SLN concept for clinically N0 and T1 esophageal cancer could be validated. Theoretically more than 80% of patients with pT1b esophageal cancer may be controlled by local treatments such as surgery and chemoradiotherapy targeting primary tumors plus their SLNs. Individualized selective and modified lymphadenectomy targeted on SLN basins for clinically N0 early esophageal cancer should become feasible and clinically useful as less invasive surgical procedures.