bluuebunny/crossref_metadata_2025 huggingface dataset:
Low preoperative platelets to predict postoperative liver dysfunction in patients with metastatic colorectal cancer undergoing liver resection.
Authors: Starlinger Patrick , Herberger Beata , Tamandl Dietmar , Stremitzer Stefan , Brostjan Christine , Gruenberger Birgit , Gruenberger Thomas
Published: February 2017

634

Background: Despite improving median survival of metastatic colorectal cancer (mCRC) patients, chemotherapy (CTx) compromises liver function. Therefore, selection of patients who are of high risk to develop liver dysfunction (LD) after surgery is important. As platelets are of major importance in liver regeneration, we investigated the impact of preoperative platelet counts on the incidence of postoperative LD and its correlation to postoperative morbidity and mortality.

Methods: Patients treated with liver resection for mCRC between January 2000 and December 2010 were eligible. LD was defined as bilirubin > 5 mg/dL or prothrombin time <50% within the first postoperative week. The association of preoperative platelets < 150 x 103/ml with LD, 90 days mortality and surgical complications was analyzed.

Results: 518 patients with metastatic CRC cancer underwent liver resection, of whom 68% had received neoadjuvant CTx. 21% of all patients developed LD. Postoperative complications occurred in 13.5%. 10 patients died within 90 days after liver resection (1.9%). The incidence of LD and complications was significantly higher in patients with preoperative platelets < 150 x 103/ml (P=0.010, P=0.047). 90 days mortality was nearly 3 times higher in patients with reduced preoperative platelets (9.8% vs. 3.7%). Neoadjuvant CTx was associated with an increased rate of platelets < 150 x 103/ml (with CTx 25%, without CTx 17%; P=0.051), LD (with CTx 23%, without CTx 15%; P=0.029) and postoperative mortality (with CTx 5.3%, without CTx 2.5%).

Conclusions: Patients with platelets < 150 x 103/ml have an increased incidence of postoperative LD, major complications and 90 days mortality. Using this simple routine parameter, it might be possible to select patients that could be better served with alternative treatments such as radiofrequency ablation. Furthermore, reduced platelet counts and the incidence of LD were more frequent in patients after neoadjuvant CTx resulting in an increased 90 days mortality. This suggests that patients after extensive CTx accompanied by low platelets are of high risk to suffer from postoperative complications and surgical treatment should be reconsidered.
Patient versus clinician symptom reporting during chemoradiation for rectal cancer.
Authors: Flores Libertad T. , Bennett Antonia V , Law Ethel B , Hajj Carla , Griffith Mindy P , Goodman Karyn A.
Published: February 2017

646

Background: Pelvic radiotherapy with concurrent 5-fluorouracil based chemotherapy (chemoradiation) is a component of standard therapy for patients with T3/T4 or node-positive rectal cancer. Chemoradiation can be associated with significant acute gastrointestinal toxicity. This study sought to retrospectively compare patient and clinician reports of acute symptoms experienced by rectal cancer patients receiving chemoradiation.

Methods: The charts of 199 rectal cancer patients who received chemoradiation from 11/06 to 2/11 were reviewed. Clinicians assessed toxicity weekly using Common Terminology for Clinical Adverse Event (CTCAE) version 3.0. Patient-reported outcomes (PROs) were collected weekly, in clinic, beginning 9/09 using the 7-item Bowel Problems Scale. 197 patients had at least one clinician assessment or PRO and were eligible for this study. Patient and clinician assessments were compared among a subgroup of 65 patients (paired group) who had at least one patient and clinician assessment on the same date using descriptive statistics. Agreement between patient and clinician assessments was evaluated by Cohen’s kappa coefficient.

Results: Characteristics were well-balanced between all rectal patients and the paired group, with the exception of the use of intensity modulated radiotherapy (IMRT). IMRT has been used increasingly over time, and IMRT was therefore used in a larger proportion of the paired group versus all patients (77% vs. 51%, respectively). Diarrhea and proctitis were reported more often by patients than clinicians throughout treatment. Uncorrected agreement for diarrhea and proctitis was 82% and 72%, respectively. Corrected for chance, Cohen’s kappa was .64 for diarrhea, indicating moderate agreement, and .22 for proctitis, indicating only slight agreement.

Conclusions: Our findings suggest a discrepancy between clinician and patient symptom reports. Further study is warranted to discern potential benefits of including PROs in prospective studies, and to find whether PROs can help clinicians set patient expectations, and/or enhance communication for optimal symptom management.
Effect of chemoradiotherapy (CRT) for rectal cancer on the lymph nodes (LNs): Exploration of the number of retrieved LNs, number of metastatic LNs, and the size of LNs.
Authors: Okada Kazutake , Sadahiro Sotaro , Suzuki Toshiyuki , Tanaka Akira , Okamura Hiroko , Kamijo Akemi
Published: February 2017

651

Background: For accurate staging of colon cancer, 12 or more LNs are recommended to be explored. Although the total number of LNs in rectal cancer was reported to be decreased after CRT, the number of LNs to be explored is not yet clear. We investigated the number of retrieved LNs, number of metastatic LNs, and the LN sizes within the radiation field in comparison with those outside the radiation field, to clarify the influence of CRT.

Methods: The subjects were 211 patients with cStage II/III rectal adenocarcinoma who underwent radical surgery between 1991 and 2010. Of these, 111 patients underwent surgery alone (S group) and 100 patients also received preoperative CRT (40 or 45Gy) with concurrent oral UFT or S-1 (RT-group). The numbers of LNs were reviewed by pathological chart, and HE-stained specimens were examined with a digitizer to evaluate the LN sizes (short-axis, long-axis and area).

Results: A total of 2049 LNs were retrieved, of which 230 were metastatic LNs. The average number of retrieved LNs was significantly higher in the S group (16±11) than that in the RT group (9±7) (P < 0.0001). The number of LNs inside the radiation field was significantly higher in the S group (6±6) than that in the RT group (4±4) (P = 0.001), whereas outside the radiation field, there was no significant difference between the two groups (5±4 in the S group vs. 5±4 in the RT group). The short-axis of the retrieved LNs was significantly larger in the S group (within the radiation field: 3.5±2.1 mm in the S group vs. 3.0±1.9 mm in the RT group, P < 0.0001; outside the radiation field: 4.3±2.6 in the S group vs. 3.8±2.4 in the RT group, P = 0.05).

Conclusions: Preoperative CRT significantly decreased the total number of LNs compared to the surgery alone, attributable to the decrease in the number of LNs inside the radiation field. CRT reduced the size of the LNs and the degree of reduction was larger in the nodes within the radiation field than in those outside. And it was suggested that CRT also had an effect on the LNs outside the radiation field.
The prognostic signficance of pretreatment leukocytosis in patients with anal cancer treated with radical chemoradiotherapy or radiotherapy.
Authors: Banerjee Robyn , Roxin George , Eliasziw Misha , Joseph Kurian , Buie Donald , Doll Corinne
Published: February 2017

656

Background: There are emerging data showing prognostic significance of pre-treatment leukocytosis (elevated white blood cell count) in cervical cancer patients. However the prognostic impact of leukocytosis in anal cancer patients has not been previously reported. The purpose of this study was to determine the association of pre-treatment leukocytosis on outcome in patients with anal cancer treated with radical chemoradiotherapy (CRT) or radiotherapy (RT).

Methods: 126 patients with anal cancer, treated with radical CRT (91.3%) or RT (8.7%) from 2 major Canadian cancer centers (University of Calgary, n=65 and University of Alberta, n=61), between 2000 and 2008 were evaluated. Demographic, clinical, hematologic and treatment factors were retrieved from retrospective review of the patients’ records. The association of clinical factors and hematologic status with overall survival (OS) and disease-free survival (DFS) was analyzed using Cox proportional hazards regression models.

Results: Median follow-up was 24 months. Median tumor size was 4 cm. Mean age was 59 years and M:F was 29:97. Pre-treatment leukocytosis (WBC count greater than 10^9/L) was identified in 16% (20/126) of patients. After adjusting for gender, tumor size and stage in a multivariate analysis, leukocytosis remained significantly associated with worse 2-year OS [HR 2.9 (95% CI 1.1-7.9), p=0.036] and worse DFS [HR 2.2 (95% CI1.1-4.8), p=.045]. The patient group with both pre-treatment hemoglobin (Hgb) less than 125 g/L (lowest quartile) and leukocytosis had very poor outcomes, 2-year OS 61% versus 89% for patients without these factors; more than doubling the hazard for DFS [HR2.7 (95% CI 1.1-6.8), p=0.033] and for OS [4.5 (95% CI 1.5-13.2), p=.006].

Conclusions: Pre-treatment leukocytosis is associated with worse OS and DFS in patients with anal cancer treated with radical CRT or RT. Patients with both low Hgb and leukocytosis had very poor outcomes. These hematologic parameters represent potential biomarkers for prognosis and treatment response, and warrant further investigation to uncover the underlying biologic mechanisms and therapeutic strategies in this patient group.
Phase II intermittent (or stop and go) l-OHP administration of first-line bevacizumab (BV) plus mFOLFOX6 or CapeOX therapies in Japanese patients with mCRC: The interim report of T-CORE0901.
Authors: Gamoh Makio , Kato Shunsuke , Niitani Tomohito , Murakawa Yasuko , Sakayori Masato , Isobe Hideki , Shimodaira Hideki , Akiyama Shoko , Yoshida Kozue , Yoshioka Takashi , Ishioka Chikashi ,   Tohoku Clinical Oncology Research and Education Society
Published: February 2017

664

Background: Cumulative sensory neurotoxicity of l-OHP used in standard 1st-line FOLFOX / CapeOX +/− BV therapies in mCRC results in impairment of patient's quality of life (QoL) and discontinuation of the treatment. CONcePT trial revealed that intermittent l-OHP use in BV plus FOLFOX7 is safe, keeping efficacy comparing with BV plus FOLFOX7 in which l-OHP is administered until time to treatment failure. But it is unknown that intermittent l-OHP administration is also safe and effective in Japanese pts with mCRC

Methods: This trial aims to enroll 65 of Japanese pts with mCRC. Either BV+FOLFOX or BV+CapeOX is selected by decision of physician in charge. In BV+FOLFOX arm, pts receive 6 cycles of BV plus mFOLFOX6 (5 mg/kg of BV, 85 mg/m2 of l-OHP, 200 mg/m2 of I-LV, 400 mg/m2 of 5-FU by rapid IV infusion on day1, and 2,400 mg/m2 of 5-FU 46 hr by continuous IV infusion as a 2 weeks course) and 6 cycles of BV plus sLV5FU2. In BV+CapeOX arm, pts recieve 4 cycles of BV plus CapeOX (7.5 mg/kg of BV, 120 mg/m2 of l-OHP and capecitabine 1,000mg/m2 twice daily, day1 to 14 as a 3weeks course) and 4 cycles of BV+capecitabine. The primary endpoint is progression free survival (PFS) and secondary endpoints are tumor response (RR), overall survival (OS), time to treatment failure (TTF) and frequency of neurotoxicity.

Results: According the protocol, interim analysis about efficacy and safety was performed at the time the 13th pts was received the treatment for 7 months. Median progression free survival is 290+ days (95% CI 119 - 558 days) and PFS of 9 cases were more than 7 months, which is threshold value. No serious adverse effects were observed in 13 cases. The efficacy and safety evaluation committee recommended continuing the study and the current accrual is 47 cases.

Conclusions: This is the interim report of T-CORE0901 trial and the study remains open to accrual with projected enrollment completion in 2012.
Predictive factors of early and late local toxicities in anal cancer treated by radiotherapy in combination with or without chemotherapy.
Authors: Doyen Jerome , Benezery Karen , Ortholan Cecile , Gérard Jean-Pierre , Hannoun-Levi Jean-Michel , Follana Philippe , Francois Eric
Published: February 2017

667

Background: Treatment of anal cancer is based on combined radiotherapy and chemotherapy (CT). Some patients present early (<2 months) and late (>2 months) toxicities of grade 3 or greater which can strongly impair quality of life. We aimed to identify predictive factors of toxicities in 106 patients treated in a single center between January 2000 and February 2010.

Methods: Retrospective analysis of our databases reported severe local toxicities (grade 3 or higher) during treatment of proven localized epidermoid carcinoma of the anal cancer. The following factors were screened as potential predictive factors: gender, age, irradiation dose, HIV status, type of boost (external vs brachytherapy), circumferential extension, type of chemotherapy, invasion of anal margin, clinical T and N stage, and clinical stage.

Results: With a median follow-up of 54.1 months (46.8-61.4) early severe local toxicities occurred in 42 patients (pts) (39.6%) whereas late severe toxicities happened in 21 pts (19.8%). Both early and late toxicities were dominated by proctitis (diarrhea and/or rectal bleeding) (7 pts, 6.6% and 6 pts, 5.6% respectively) and recto-anal epithelial toxicities (27 pts, 25.4% and 17 pts, 16% respectively). Two patients got colostomia because of treatment toxicities (1,8%). Predictive factors of increased early toxicities were as follows: clinical stage III/IV (p=0.04), no brachytherapy boost (p=0.008) and type of CT (no CT, 5.9%, CT, 48.8% p=0.001). Brachytherapy boost and presence of CT retained their independency in multivariate analysis (respectively, p=0.001 and p=0.05). Only HIV positivity (p=0.02) was identified as a predictive factor of late toxicities. HIV positivity (p=0.02), invasion of anal margin (p=0.01) and circumferential extension > 33% (p=0.007) correlated with epithelial ulcer. Invasion of anal margin (p<0.001) and circumferential extension (p=0.02) were identified as independent factors in multivariate analysis.

Conclusions: In this cohort absence of brachytherapy boost and CT correlated with more severe early local toxicities whereas HIV positivity was the only predictor of local late toxicities.
Feasibility of dignity therapy in patients with stage IV colorectal cancer receiving chemotherapy.
Authors: Vergo Maxwell Thomas , Nimeiri Halla Sayed , Mulcahy Mary Frances , Von Roenn Jamie H. , Benson Al Bowen , Emanuel Linda
Published: February 2017

671

Background: Dignity Therapy (DT) is a structured psychotherapeutic interview which allows people to create a permanent document to validate their existence and leave a legacy. It focuses on life review, meaningful relationships, and words of comfort to loved ones. In terminal patients no longer receiving chemotherapy, this intervention improved the majority of patients’ sense of dignity, purpose, and meaning, and also reduced depression and self reported suffering (Chochinov, J Clin Oncol, 2005). This study evaluates the feasibility of DT in patients receiving active chemotherapy.

Methods: Outpatients ≥ 18 years of age with metastatic colorectal cancer recently starting second line chemotherapy were recruited. DT was administered, the interview transcribed, and the transcription edited into a proof version. This version was read to the patient and given to them after it was finalized. Main outcome was feasibility as measured by enrollment rate, discontinuation rate, and satisfaction after completing therapy. Other secondary measures included assessments for terminal illness acknowledgement (TIA), symptoms, peacefulness, quality of life, and finally preferences in a hypothetical end-of-life scenario.

Results: Overall, there has been a 91% enrollment rate (10 out of 11 approached), 0% discontinuation, and a 100% rate of being satisfied or very satisfied (7 patients). 3 patients were removed due to non-compliance, sedation, or lost data. Of those who completed therapy, > 70% felt it was helpful or very helpful and strongly or very strongly felt it increased their sense of dignity, purpose, and meaning as well as the potential to help their family in the future. Symptoms remained stable over time. Exploratory endpoints included a 33% increase in TIA (p=0.23), no increase in peacefulness (p=0.44), less aggressive goals of care (p=0.28), and decreased distress.

Conclusions: DT is a highly satisfying and meaningful intervention for advanced colorectal cancer patients receiving chemotherapy. Given its feasibility, an ongoing randomized wait-list control study should help answer if DT effects TIA, end-of-life goals of care, or distress levels in this population. Funding: ACS-IRG 93-037-15.
Predicting acute small-bowel toxicity in patients with rectal cancer treated with neoadjuvant chemoradiation: A comparison of peritoneal space versus small-bowel loop contouring techniques.
Authors: Banerjee Robyn , Chakraborty Santam , Nygren Ian , Sinha Richie
Published: February 2017

673

Background: In lieu of contouring individual small bowel loops, the peritoneal space (PS) has been suggested as a possible surrogate volume for predicting small bowel toxicity. A dose-volume relationship for the PS has not been firmly established. The aim of this study was to determine whether contours of the PS better predict significant acute small bowel toxicity in neoadjuvant rectal cancer patients when compared with contours of individual small bowel loops.

Methods: A standardized contouring method was developed for the PS and retrospectively applied to the radiation treatment plans of sixty-seven patients treated with neoadjuvant chemoradiotherapy for rectal cancer. All patients had locally advanced disease, no evidence of metastases, and received concurrent radiation and infusional 5-Fluorourocil chemotherapy. Dose-volume histogram (DVH) data was extracted and analyzed against patient toxicity. Receiver operating characteristic analysis and logistic regression was carried out for both contouring methods.

Results: Grade ≥ 3 small bowel toxicity occurred in 16% (11/67) of patients. Volumes of the contoured small bowel loops correlated with grade ≥ 3 toxicity at each 5 Gray (Gy) dose level from 5 to 45 Gy, with the greatest area under the curve (AUC) measuring .964 (p=.000) associated with the volume receiving at least 25 Gy (V25). Volumes of the contoured PS predicted toxicity from 5 to 40 Gy, with the greatest AUC also at the V25 and measuring .896 (p=.000). Logistic regression analysis demonstrated a less than 15% risk of acute grade ≥ 3 toxicity was associated with a V25 of 215 cc for the small bowel and 710 cc for the PS.

Conclusions: DVH analysis of peritoneal space volumes predicts grade ≥ 3 small bowel toxicity in neoadjuvant rectal cancer patients, suggesting the peritoneal space is a reasonable surrogate for contouring individual small bowel loops. However, contouring individual small bowel loops is a more sensitive method for predicting toxicity at each dose increment. For both contouring methods, the greatest sensitivity for predicting toxicity was associated with the volume receiving at least 25 Gy (V25).
Assessment of safety of bevacizumab (bev) use for metastatic colorectal cancer (mCRC) in elderly patients treated at the Centre Hospitalier de l’Université de Montréal (CHUM): A retrospective study.
Authors: Otte Francois-Xavier Bicharh , Aubin Francine , Tehfe Mustapha Ali , Letourneau Richard , Lougnarath Rasmy , Richard Carole S. , Soulieres Denis , Charpentier Danielle , Biron Guy , Ayoub Jean-Pierre M.
Published: February 2017

677

Background: A 2004 randomized study showed a meaningful improvement in survival with bev added to chemotherapy (CT) for patients with mCRC. This combination is now widely used and generally well tolerated although adverse events (AEs) are described associated with the use of bev, some of which may be increased in incidence in an elderly population. In this study, we assessed these AEs in a population of elderly patients treated with bev in a major center in Montréal.

Methods: Patients with mCRC who received bev at our institution outside a clinical trial were retrieved from the pharmacy registry. Medical records were sought from patients who qualified for the inclusion criteria: ≥ 65 years, bev therapy at 5mg/kg every two weeks, combination with CT, period 2007-2011. A retrospective analysis of specific AEs was done and grade according to NCI-CTC (version 4.0) was assessed: febrile neutropenia, hypertension, proteinuria, diarrhea, venous thromboembolic event (VTE), arterial thromboembolic event (ATE), bleeding and gastrointestinal perforation.

Results: 47 patients received a total of 486 cycles of bev. Out of these cycles, 210 were given with FOLFOX, 199 with FOLFIRI and 77 with other combinations. Median age of the patients was 69 years. 3 episodes of febrile neutropenia were noted. Grade 3 or 4 arterial hypertension occurred in 4 patients of which 2 had to definitively stop bev. Grade 3 proteinuria was reported with definitive cessation of bev in 2 patients. Grade 3 or 4 diarrhea was observed in 2 cases. We reported 1 cerebral ATE leading to discontinuation of bev and grade 2 VTE in two patients. One grade 5 gastrointestinal perforation was reported. No major bleeding was noted.

Conclusions: The number of adverse events observed in this population of elderly patients is comparable to other studies. Thus, age should not be an exclusion criteria for treatment with bev and CT.
A phase I/II study of capecitabine (Cape), oxaliplatin (Ox), panitumumab (Pmab), and external beam radiation therapy (RT) for patients with esophagogastric carcinoma (EC).
Authors: Czito Brian G. , Willett Christopher , Palta Manisha , McCall Shannon , Gee Nathan , Hurwitz Herbert , Coleman R Edward , Zafar Yousuf , Kennedy-Newton Paula , Uronis Hope
Published: February 2017

68

Background: EC is commonly managed with concurrent chemoradiotherapy, with or without surgical resection. The optimal combination and dose of agents is the subject of continued investigation. This study examines chemotherapeutic agents with known efficacy in EC in combination with the EGFR inhibitor panitumumab.

Methods: Eligible pts received RT (1.8 Gy qd to 50.4 Gy) combined with concurrent chemotherapy. Dose-level (DL) 1 was cape (625 mg/m2/bid RT days), ox (40 mg/m2 weekly X 6 weeks), and pmab (3.6 mg/kg, weeks 1, 3 and 5). Chemotherapy doses were escalated barring dose limiting toxicity (DLT). The primary endpoint was defining the maximally tolerated dose with this combination. Secondary endpoints included toxicity and radiographic/pathologic response rates.

Results: Twenty-nine pts were enrolled. Twenty-five had adenocarcinoma, 24 (83%) were cN+ and 9 (31%) had M1a/b disease. DLT was not encountered in DL 1. Two of 6 patients at DL 2 (cape 825 mg/m2/bid RT days, ox 50 mg/m2 weekly, pmab 4.8 mg/kg, weeks 1, 3 and 5) developed DLT (one hospitalization due to dehydration; one with drug reaction requiring hospitalization). Twenty additional pts were enrolled at DL1. Primary toxicities were EGFR-rash, esophagitis, nausea/vomiting and fatigue. On repeat endoscopy, 16 (55%) had CR, 10 (35%) PR and 2 (7%) SD. Using PERCIST criteria, 12 (41%), 11 (38%), 2 (7%) and 3 (10%) had CR, PR, SD and PD response on restaging PET, respectively. Twenty pts underwent esophagectomy, revealing Gr 0 response (no residual disease) in 9 (45%), Gr 1 (single/microscopic cells) in 3 (15%), Gr 2 (fibrosis > gross disease) in 4 (20%) and Gr 3 (gross residual > fibrosis or no evident response) in 4 (20%). Seven pts (35%) experienced anastomotic leak (2 requiring reoperation and 3 stent placement).

Conclusions: Concurrent chemoradiotherapy utilizing capecitabine, oxaliplatin, panitumumab is reasonably well-tolerated and associated with high rates of radiographic, endoscopic and pathologic response. Postoperative anastomotic leak rates were higher than expected. Further study of this regimen in the operative and nonoperative settings is warranted.
Patterns of care according to treatment intent for metastatic colorectal cancer (mCRC): A two-year review of routine practice.
Authors: Field Kathryn Maree , Desai Jayesh , Tie Jeanne , Kosmider Suzanne , Bae Susie , McKendrick Joseph James , Harold Michael , Gibbs Peter
Published: February 2017

682

Background: Cure is potentially achievable in select patients (pts) with mCRC with limited metastatic disease to liver and/or lung. To date the peri-operative strategies undertaken by oncologists in routine practice for such pts have not been well documented.

Methods: A clinical database recording information on all pts diagnosed with mCRC since July 2009 from 5 hospitals was analysed. Management strategies where a curative-intent resection had occurred; was planned; or was a potential option were compared with those managed with palliative intent.

Results: Status at the time of first review regarding systemic chemotherapy (CT) was documented for 280 pts. 11 (4%) had already undergone curative-intent resection; 31 (11%) had a resection planned; 27 (10%) were considered potentially resectable if their response to treatment was good; and 207 (74%) were treated with palliative intent. No pts already resected or planned for resection were >ECOG 1, compared with 11% (3/27) potentially resectable and 17% (36/207) palliative pts. CT was delivered in 9 (82%) already-resected, 26 (84%) planned for resection, 26 (96%) potentially-resectable and 159 (77%) palliative-intent pts. Combination CT was the dominant strategy, although 7 of 11 (66%) already-resected pts received single agent treatment. No already-resected pts received bevacizumab with CT, compared with 27% (n=14) of planned or potentially-curative pts and 55% (n=88) of those treated with palliative intent. At the time of analysis 13 pts (42%) with a planned resection and 8 (30%) considered potentially curative have had surgery, while 3 (1.4%) where treatment was initially considered palliative have had curative-intent surgery.

Conclusions: Treatment strategies for pts with mCRC differ significantly based on the treatment intent, and may be affected by surgical preference and referral pattern. Bevacizumab was less likely to be used for already-resected pts and the use of single agent therapy in this group was also not uncommon. Many pts initially considered resectable do not ultimately undergo resection, whereas occasional ‘palliative’ pts may become resectable, confirming the importance of continued consideration of this option.
Pathologic complete response to standard preoperative chemoradiation in patients with locally advanced rectal cancer.
Authors: Naseem Madiha , Murray Joshua , Simmons Christine E. , Baxter Nancy , Burnstein Marcus J. , Brezden-Masley Christine
Published: February 2017

686

Background: Pathologic complete response (pCR) is associated with lower rates of recurrences and longer disease-free survival rates in locally advanced rectal cancer (LARC) patients. The purpose of this study was to evaluate clinical outcomes of neoadjuvant chemoradiation and pCR among these patients.

Methods: A retrospective chart review was performed for all patients treated for LARC between August 2005 and May 2011 at St. Michael's Hospital, Toronto. Patients were stratified into pCR and no-pCR groups and compared with respect to tumor size, nodal status, and treatment characteristics. Descriptive statistics were calculated for all variables of interest. Chi-square and t-tests were conducted to test for associations between categorical and continuous variables respectively. Disease free survival was calculated as the time between diagnosis and recurrence date, censored at last follow up.

Results: A total of 92 patient charts were reviewed; 21 patients had metastatic carcinoma and were excluded from analysis. 63.4% (45/71) were male, with a mean age of 61.2 years and median follow up of 15 months. 12.7% (9/71) of patients achieved a pCR, while the remaining 87.35% (62/71) were no-pCR. All pCR patients received and completed standard pre-operative chemotherapy-radiotherapy. 73.4% (52/71) of the patients had complications from chemoradiotherapy. Furthermore, there was a significant association between having a significant response to treatment and achieving a pCR; where 78% (7/9) of pCR patients had a significant response to treatment. Overall, 4/71 patients had a local recurrence, 22.2% (2/9) pCR and 3.2% (2/62) no-pCR. Those with no-pCR had a recurrence at 1 and 2.2 years post diagnosis, while those with pCR had a recurrence at 3.7 years.

Conclusions: This study suggests that patients undergoing standard pre-operative chemoradiotherapy are likely to have a significant response and achieve a pCR. Based on this study, although a pCR does not prevent the risk of recurrence, it delays the onset of local recurrence. Longer follow-up is required to determine if these results are robust and to develop future studies to improve efficacy of treatment delivery in LARC patients.
Surgical treatment of colorectal liver metastasis after neoadjuvant chemotherapy.
Authors: Zegarac Milan , Nikolic Srdjan , Djurisic Igor , Buta Marko
Published: February 2017

688

Background: Liver is typical place for metastasis for patients with colorectal carcinoma. During the period of disease, 50% of patients with colorectal carcinoma will get liver metastases, 20% of the will have synchronous and 30% metachronous. Surgical resection is modality of choice in treatment for liver metastases in colorectal carcinoma. Applying neoadjuvant chemotherapy in patients with colorectal cancer liver metastases, which are primarily nonresectable or potentially resectable, it is possible to transform in resectable state. The goal of treatment is R0 liver resection and putting the patient in the NED stage of disease.

Methods: All patients received protocol for potentially resectable metastase- FOLFOX-bevacizumab. The assessment was conducted on the basis of angioCT and NMR. With all patients liver resection procedures and RFA were applied.

Results: During the period from June 2007 to December 2009 in 40 patients with nonresectable or potentially resectable metastases the neoadjuvant HT FOLFOX-bevacizumab was applied on average for three months. The patients were operated 6 weeks after the last application of bevacizumab, because of the possibility of intraoperative bleeding. The number of metastases ranged from 1 to 6. With 17 patients lobar resection was performed, and with 10 patients segmental resection was performed. With another 11 patients metastasectomy was performed, while RFA was performed with 2 patients. 3 years survival is 57.5%.

Conclusions: By applying neoadjuvant HT and bevacizumab with patients suffering from colorectal cancer liver metastases as the only existing metastases, it is possible to significantly reduce metastases, and thereby resection as well. With this approach time without disease and survival are increased.
A phase I evaluation of vandetanib plus paclitaxel, carboplatin, 5-fluorouracil, and XRT induction therapy followed by surgery for previously untreated locally advanced cancer of the esophagus and GE junction.
Authors: Astsaturov Igor A. , Meyer Joshua E. , Cheng Jonathan D. , Olszanski Anthony J. , Dushkin Holly , Berger Adam C. , Davey Monica , Cohen Steven J. , Burtness Barbara , Scott Walter Joseph
Published: February 2017

74

Background: Vandetanib (Vb) is an oral inhibitor that selectively targets VEGFR2, VEGFR3, RET and EGFR. Preclinical models indicate synergy with radiation and chemotherapy. We report the final results from an open-label phase I study of pre-operative Vb with carboplatin, paclitaxel, 5FU and radiation in pts with operable esophageal and GE junction (GEJ) carcinomas.

Methods: Pts with operable PET/CT and EUS-staged carcinoma of the esophagus and GEJ received once daily Vb with concomitant RT (1.8 Gy/d, total 45 Gy) plus carboplatin AUC5 (d1 and 29), paclitaxel (50 mg/m2, d1,8,15,22,29), and 5-FU (CI 225 mg/m2, M-F, 5 wks). The primary objective was the safety, tolerability and the maximum tolerated dose of Vb in this combination. Planned dose escalations of Vb: 100, 200 and 300 mg daily with a “3+3” design.

Results: Nine male pts (median age 58 (35-77), stage II, T2-3N0 (2 pts), III, T2-3N+ (7 pts)) were accrued between 03/2009 and 08/2010 at Fox Chase Cancer Center: 2/9 pts had esophageal squamous carcinoma (SCC) and 7/9 pts had adenocarcinoma including GEJ (2 pts). All patients completed the planned induction chemoradiation and underwent esophagectomy with curative intent. Of 3 initial pts at Vb 100 mg, one with SCC died on day 99 from GI hemorrhage which was considered treatment-related. Three more pts received Vb 100 mg and 3 pts received Vb 200 mg daily. Dose limiting toxicities (DLT) occurred in 2/3 pts receiving Vb 200 mg (esophago-gastric anastomotic leak, and diarrhea requiring Vb dose reduction). Grade 3 non-hematological toxicities included diarrhea (2), anorexia (1), abdominal pain (1), hyponatremia (1), AST/ALT (1), depression (1). Dose escalation to 300 mg Vb was not attempted. 5/9 pts had a pathologic complete response (no tumor seen, 56%), 5/9 remain disease free with median followup of 23 months (13-31). 3 pts had distant recurrences at 322, 334 and 561 days.

Conclusions: Targeting VEGFR/RET/EGFR with Vb at 100 mg daily in combination with induction chemoradiotherapy for operable esophageal and GEJ cancer is well tolerated and with promising clinical activity warranting further phase II evaluation.
Survival differences between preoperative and postoperative radiation in esophageal cancer treated with combined modality therapy: A SEER analysis.
Authors: Wojcieszynski Andrzej Pawel , Milby Abigail Berman , Plastaras John Peter , Metz James M. , Apisarnthanarax Smith
Published: February 2017

78

Background: The effect of radiation therapy (RT) sequencing with surgery on clinical outcomes for locally advanced esophageal cancer patients is unclear. We hypothesized that RT given prior to surgery has superior survival outcomes compared to RT delivered after surgery.

Methods: Patients with the following inclusion criteria were identified within 17 Surveillance, Epidemiology, and End Results (SEER) registries from 1988-2006: adenocarcinoma or squamous cell carcinoma of the esophagus, esophagectomy, and RT. Data on demographics, tumor characteristics, and survival outcomes were extracted and compared between patients receiving preoperative and those receiving postoperative RT. Cox regression univariate and multivariate analyses were performed to identify parameters that were associated with cause-specific (CSS) and overall survival (OS).

Results: A total of 2,579 patients met the defined criteria. Of these patients, 1,689 received preop RT and 890 received postop RT. Patients receiving preop RT compared to postop RT had improved 5-yr CSS (41% vs. 31%, p<0.0001) and OS (33% vs. 23%, p<0.0001). On univariate analysis, RT sequence, histology, T stage, nodal status, number lymph nodes examined, age, gender, marital status, race, and county income were significant independent predictors of OS. On multivariate analysis ( table ), preop RT continued to remain statistically significant for OS (HR 0.88; p = 0.034).

Conclusions: Preoperative RT is associated with superior overall and cause-specific survival compared to postoperative RT and should be the preferred approach in combination with surgery for locally advanced esophageal cancer.

[Table: see text]
Three, two, or one drug chemotherapy for frail or elderly patients with advanced gastroesophageal cancer (321GO): A feasibility study.
Authors: Hall Peter S. , Lord Simon , Collinson Michelle , Marshall Helen , Jones Marc , Olivier Catherine , Howard Helen , Seligman Jenny , Swinson Daniel , Roy Rajarshi , Dent Jo , Cheeseman Sue , Last Kim William , Seymour Matthew T.
Published: February 2017

97

Background: The median age of death from gastroesophageal (GO) cancer is 77 years. Palliative chemotherapy can improve survival and quality of life. Current standard combination regimens have been developed in trials involving patients of median age under 65 years with predominantly good performance status (PS). In light of audit and survey evidence of widespread use of arbitrarily modified chemotherapy schedules in frail and elderly patients, better evidence is needed to guide treatment. Based on our experience with the MRC FOCUS trial in colorectal cancer, 321GO aimed to test the feasibility of a randomised trial comparing chemotherapy in frail and elderly patients with advanced GO cancer.

Methods: Patients with advanced GO cancer considered unfit for full-dose 3-drug chemotherapy, were randomly allocated (1:1:1) to 3, 2 or 1 drug chemotherapy at 80% dose of standard regimens with EOX: epirubicin 40mg/m2 d1, oxaliplatin 104mg/m2 d1, capecitabine 500mg/m2 bd x21d, OX: oxaliplatin 104mg/m2 d1, capecitabine 500mg/m2 bd x21d or X: capecitabine 1000mg/m2 bd d1-14, then 7 day rest. The primary endpoint for feasibility required 45 patients to be recruited over 18 months. Secondary endpoints included tolerability, treatment benefit and compliance with detailed health and quality of life (QoL) assessment.

Results: 55 patients were recruited over an average of 18 months for each of the six recruiting centres; 17 to EOX, 19 to OX and 18 to X. The median age was 75. 37 (66%) patients were of WHO PS 0 or 1 and 18 (33%) were of PS 2. After 6-weeks, 12 (71%), 9 (47%) and 9 (50%) patients in the EOX, OX and X arms had experienced a treatment delay, dose reduction, grade 3 toxicity or stopped treatment. Treatment benefit (no radiological progression or clinical deterioration) at 12 weeks was seen in 8 (47%), 11 (58%) and 3 (16%) patients for EOX, OX and X respectively. Compliance with baseline health and QoL assessment was 98% at baseline and 69% at 12 weeks.

Conclusions: A phase III trial randomising frail or elderly patients with advanced GO cancer to alternative chemotherapy regimens is feasible. EOX was associated with greater toxicity compared with OX; X offered no improvement in tolerability over OX.
Long-term cardiopulmonary mortality after radiation for locally advanced esophageal cancer.
Authors: Milby Abigail Berman , Wojcieszynski Andrzej Pawel , Apisarnthanarax Smith , Metz James M. , Plastaras John Peter
Published: February 2017

99

Background: Radiation (RT) is considered an integral component of trimodality therapy for locally-advanced esophageal carcinoma to improve locoregional control and potentially survival. However, the long-term risk of cardiopulmonary mortality (CPM) is not well-understood in this population.

Methods: Patients age 20-85 with esophageal carcinoma with T3, T4 or node positive (N+) disease who underwent esophagectomy were identified within 17 Surveillance, Epidemiology, and End Results registries from 1988-2006. Patients with metastatic disease or <6 mo follow up were excluded. CPM was calculated for patients receiving vs not receiving RT and compared by the Kaplan-Meier method. The log-rank test was used for univariate associations and Cox proportional hazards model was used for multivariate analysis (MVA).

Results: A total of 4,079 patients met the defined selection criteria of whom 2,408 were treated with RT, and 1,671 were not. Median age was 62.2 yrs (22-84) and follow-up was 22 mos (6-248). There was no significant difference in CPM in patients who received RT versus those who did not (p=0.8). At 10 yr, the majority of deaths were from esophageal cancer (73 with vs 78% without RT) compared to CPM (13.7 with vs 11.6% without RT). On univariate analysis ( table ), age <60, diagnosis era, and histology were significant independent predictors of CPM. On MVA, age <60 (HR 0.36) and diagnosis era (0.63 for 1994-2000 and 0.55 for 2000-2006) remained statistically significant for CPM.

Conclusions: RT for esophageal cancer is not associated with an increased long-term risk of CPM in the overall population. Older age and earlier diagnosis era predict for CPM. Although survival in esophageal cancer is dominated by cancer deaths, advances in RT are still needed to prevent excess treatment-related mortality.

[Table: see text]
Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediate-stage hepatocellular carcinoma (HCC): Phase II, randomized, double-blind SPACE trial.
Authors: Lencioni Riccardo , Llovet Josep M. , Han Guohong , Tak Won-Young , Yang Jiamei , Leberre Marie-Aude , Niu Woody , Nicholson Kate , Meinhardt Gerold , Bruix Jordi
Published: February 2017

LBA154^

Background: The global SPACE trial was conducted to evaluate the efficacy and safety of S in combination with TACE with DEBDOX in patients (pts) with intermediate-stage HCC (BCLC B).

Methods: Pts were eligible if they had asymptomatic, unresectable, multinodular tumors without vascular invasion (VI) or extrahepatic spread (EHS); Child-Pugh A liver functional status; and ECOG PS 0. Pts were randomized to receive S 400 mg bid or matching P continuously (1 cycle = 4 wks) until progression. All pts received TACE with DEBDOX (150 mg doxorubicin; Biocompatibles UK Ltd) 3-7d after first dose of study drug, and then on d1 (±4d) of months 3, 7, and 13, and q6 months thereafter. The primary endpoint was time to radiologic progression (TTP) by independent review (predefined alpha = 0.15). Secondary endpoints were overall survival (OS), time to VI/EHS, time to untreatable progression (TTUP), and safety.

Results: Of 452 pts screened, 307 were randomized to S (n=154) or P (n=153). The HR for TTP was 0.797 (95% CI, 0.588, 1.080; p=0.072). Median TTP (50th percentile) was 169d/166d in the S and P groups, respectively; TTP at the 25th and 75th percentiles (preplanned) was 112/88d and 285/224d in the S and P groups, respectively. There were no unexpected safety findings. Median treatment duration in the S and P groups was 4.8 and 6.3 months, respectively, and median daily dose of study drug was 566 mg and 791 mg, respectively.

Conclusions: The study met its primary endpoint of improving TTP when S was added to a regimen of TACE with DEBDOX, compared with TACE with DEBDOX alone. The combination was well tolerated; no new safety findings that would preclude use of the combination were observed. The encouraging efficacy signal requires confirmation with data from ongoing phase III trials evaluating the combination of S plus TACE.

[Table: see text]
Prognostic factors for survival in the phase III TROPIC trial.
Authors: Sartor A. Oliver , Oudard Stéphane , Ozguroglu Mustafa , Hansen Steinbjorn , Machiels Jean-Pascal H. , Kocak Ivo , Gravis Gwenaelle , Bodrogi Istvan , MacKenzie Mary J. , Orlandi Francisco Jorquera , Shen Liji , De Bono Johann Sebastian
Published: February 2017

102

Background: In TROPIC ( NCT00417079 ) 755 men were randomized (378 cabazitaxel/prednisone [CbzP]; 377 mitoxantrone/prednisone [MP]). Treatment arms were well balanced; ECOG PS 0–1 (93% CbzP vs 91% MP), measurable disease (53% vs 54%), baseline pain (46% vs 45%) and ≤ 6 months from last dose of docetaxel (D) to randomization (62% vs 72%). CbzP significantly improved overall survival (OS) in mCRPC pts who progressed on or after D treatment compared with MP (HR 0.70; CI 0.59–0.83; P < 0.0001). We investigated overall prognosis and performed a multivariate analysis of factors implicated in OS from this robust dataset.

Methods: A univariate analysis of a variety of factors followed by a multivariate analysis of all factors was conducted. Interactions with treatment arms were explored. Cox proportional hazard models were used to examine the effect of treatment and prognostic factors on OS.

Results: In addition to the significant effect of treatment received, the univariate analysis identified ECOG PS and measurable disease at baseline, time from last dose of D to randomization, time of progression after last D treatment and pain scores at baseline as significant prognostic factors for OS. Interactions of each of these factors with the treatment were not statistically distinct, suggesting that CbzP survival benefit was consistent among the subgroups defined by these factors. After adjustments for all prognostic factors, multivariate analysis identified ECOG PS 2, measurable disease, time of last dose of D to randomization (≤ 6 months vs > 6 months) and presence of baseline pain as statistically significant prognostic factors. Following adjustments, the treatment effect on survival (CbzP vs MP) remained statistically significant (Table).

Conclusions: ECOG PS, measurable disease at baseline, time from last D dose to randomization, baseline pain and CbzP treatment predicted OS in patients in the TROPIC study in a multivariate analysis.

[Table: see text]
A multicenter, randomized phase II study of rilotumumab (R) (AMG 102) or placebo (Pbo) plus mitoxantrone (M) and prednisone (P) in patients (pts) with previously treated castrate-resistant prostate cancer (CRPC).
Authors: Ryan Charles J. , Rosenthal Mark , Ng Siobhan , Alumkal Joshi J. , Picus Joel , Gravis Gwenaelle , Fizazi Karim , Forget Frederic , Machiels Jean-Pascal H. , Zhu Min , Jiang Joe , Dubey Sarita , Loh Elwyn , Gerritsen Winald R.
Published: February 2017

115

Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor (HGF) that prevents HGF binding to the c-Met receptor. We conducted a 3-arm, double-blind, randomized phase 2 study to examine the safety and estimate the efficacy of adding R to MP in CRPC pts.

Methods: Eligible pts (≥ 18 years) had progressive CRPC, prior taxane-based chemotherapy, and ECOG PS ≤ 1. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), PSA response, pharmacokinetics (PK), and safety. Pts were randomized 1:1:1 to R (15 mg/kg IV Q3W) + MP (12 mg/m2 IV Q3W, 5 mg BID orally) [Arm A]; R (7.5 mg/kg IV Q3W) + MP [Arm B]; or Pbo + MP [Arm C] for up to 12 cycles.

Results: 142 pts (Arms A/B/C: 45/48/49 pts) were enrolled between March 10, 2009 and December 2, 2009. Median age: 67/67/69 yrs; ECOG PS 1: 69/71/61%; progression during prior taxane therapy: 51/54/47%. Most common reason for discontinuation was disease progression (60/58/69%). Efficacy is shown in the table. R + MP showed no statistically significant difference in OS. Adverse events (AE) with ≥ 5% difference in Arms A + B vs C included peripheral edema, 24/8%; nausea, 44/35%; mucosal inflammation, 8/0%; rash, 8/0%; arthralgia, 16/8%; neutropenia, 16/8%. Grade 5 AE: cardiac arrest, pulmonary embolism, septic shock (1 each in Arm B). R showed linear PK with mean (SD) steady state Cmin of 251 (100) and 127 (35) μg/mL and Cmax of 609 (126) and 297 (75) μg/mL in Arms A and B. R did not affect PK of M.

Conclusions: R + MP was well tolerated with no unexpected toxicities. R + MP showed no significant improvements in OS, PFS, and PSA response.

[Table: see text]