bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of RAD001 (everolimus) and depot octreotide (sandostatin LAR) in advanced low grade neuroendocrine carcinoma (LGNET)
Authors: Yao J. C. , Phan A. , Chang D. Z. , Wolff R. A. , Jacobs C. , Mares J. E. , Gupta S. , Meric-Bernstam F. , Rashid A.
Published: March 2020

4503

Background: Effective systemic therapy for advanced LGNET is lacking. Mutations involving the mTOR pathway including TSC2, NF-1, and vHL are associated with development of LGNET. mTOR also mediate signaling downstream of IGF1 and VEGF. RAD001 is a novel oral mTOR inhibitor. Octreotide has been described to inhibit VEGF and IGF1 production in solid tumors. Methods: Patients (pts) received depot octreotide 30 mg q28 days, and RAD001 5 (pts 1–30) or 10 mg (pts 31–60) po daily. Response was evaluated every 12 weeks (wks). Results: 30 carcinoid (C) and 30 islet cell (I) patients (pts) were enrolled between 2/05–7/06. 38 pts (23 C, 15 I) had prior octreotide. By RECIST criteria, there were 10 PR (17%), 45 SD (75%) (15 pts had > 15% reduction), 5 PD (8%). The response rates within C, and I groups were 13% and 20%. The response rates within the 5 mg and 10 mg groups were 13% and 20% respectively. Of 39 pts with PD prior to study entry, there were 7 (18%) PR, 27 (69%) SD (9 pts had > 15% reduction), 5 (13%) PD. PFS rate at 24 wks was 86%. The median PFS duration is 59 wks. The median PFS duration among the C and I groups were 69 and 39 wks. Among the 39 pts with progression at study entry, the median PFS duration was 38 wks. Of 24 pts with elevated chromogranin A at entry, 19 (56%) had > 50% reduction. Treatment was well tolerated. The most common toxicity was mild aphthous ulceration. CTC G3/4 toxicities included: thrombocytopenia (3), neutropenia (3), hypophosphatemia (5), hyperglycemia (4), hypoglycemia (2), hypokalemia (2), fatigue (6), diarrhea (6), aphthous ulcer (5), rash (3), and 1 each of anemia, hypertriglyceridemia, bilirubin, AST/ALT, pain, nausea, nail, dysgeusia, pneumonitis. Conclusions: RAD001 at 5 or 10 mg daily was well tolerated in combination with octreotide. Promising anti-tumor activity has been observed. The RADIANT (RAD001 In Advanced Neuroendocrine Tumors) trials are underway to evaluate RAD001 in larger patient groups.

No significant financial relationships to disclose.
Preoperative chemotherapy (CTX) versus preoperative chemoradiotherapy (CRTX) in locally advanced esophagogastric adenocarcinomas: First results of a randomized phase III trial
Authors: Stahl M. , Walz M. K. , Stuschke M. , Lehmann N. , Seegenschmiedt M. H. , Riera Knorrenschild J. , Langer P. , Bieker M. , Königsrainer A. , Budach W. , Wilke H.
Published: March 2020

4511

Background: Perioperative treatment is common in localized adenocarcinomas of the upper GI-tract. By now, there is no randomized data about the contribution of preoperative radiotherapy additional to chemotherapy. Methods: Based on phase II results of our group we targeted 394 patients to test whether chemoradiation will increase the 3-year survival rate by 10% compared with chemotherapy. Patients with stage T3–4 NX M0 according to EGD, EUS, CT and laparoscopy were included. Patients were randomized to treatment with either (arm A) 2.5 courses of chemotherapy (cisplatin 50mg/m2, d 1,15,29, folinic acid 500 mg/m2 and 5-FU 2g/m2 24h-infusion, weekly times 6, qd 49 or (arm B) 2 courses of the same chemotherapy followed by three weeks of chemoradiotherapy (30 Gy, cisplatin 50 mg/m2 d 2+8 and etoposide 80 mg/m2 d 3–5). Epoetin alpha was recommended to keep the hemoglobin above 12.5 g/dl. Tumor resection was planned 3 to 4 weeks after the end of preoperative therapy for both groups. Results: A total of 126 patients were randomized into the study between 12/00 and 12/05 when the trial was closed due to poor accrual. 120 pts. were eligible (CTX 60, CRTX 60). The toxicitiy of CTX was low. Severe leucocytopenia and thrombocytopenia was 35% and 16%, respectively during CRTX. Until 12/06 ninety pts. underwent surgery and had complete reports. A complete resection was possible in 77% and 85% of operated pts. in arm A and arm B, respectively. The rate of complete histologic response was 2.5% after CTX and it reached 17% after CRTX (p=0.06). Despite increased postoperative mortality after chemoradiotherapy (5 vs. 2 pts.) the median survival time (32.8 mo) and the 3- year survival rate (43%) were improved in this patients group compared with patients of arm A (21.1 mo, 27%)(logrank p=0.14). Conclusions: This randomized study demonstrates that albeit its increased mortality preoperative chemoradiotherapy appears to prolong survival compared with preoperative chemotherapy in locally advanved esophago-gastric adenocarcinomas. Although accrual was below that planned, the observed difference in survival is clinically important and calls for further randomized trials in patients with this disease.

No significant financial relationships to disclose.
Randomized phase II trial comparing folfirinox (5FU/leucovorin [LV], irinotecan [I] and oxaliplatin [O]) vs gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA). First results of the ACCORD 11 trial
Authors: Ychou M. , Desseigne F. , Guimbaud R. , Ducreux M. , Bouché O. , Bécouarn Y. , Adenis A. , Montoto-Grillot C. , Luporsi E. , Conroy T.
Published: March 2020

4516

Background: In a phase II trial of Folfirinox (F) in 35 MPA patients (pts), we reported a 26% response rate and median survival of 9.5 months (mo) with quality of life improvement (Conroy, JCO 2005). The aim of this phase II trial was to compare the response rate and safety of F vs G in pts with MPA. Methods: Chemotherapy-naïve pts aged 18–75 years with histologically or cytologically confirmed measurable MPA were randomized to receive G (1,000 mg/m2 IV weekly x 7 for 8 weeks [wks] then weekly x 3 out of 4 wks) or F (O 85mg/m2 d1 + I 180mg/m2 d1 + LV 400mg/m2 d1 followed by 5FU 400mg/m2 bolus d1 and 2,400 mg/m2 46h continuous infusion biweekly). Patients were stratified by centre, performance status (ECOG 0 versus 1), and primary tumor location (head vs other). Primary endpoint was response rate. Results: From 01/05 to 11/06, all planned 88 pts (44 per arm) were enrolled. Median age was 56 yrs [35–76]. Currently, safety data for 81 pts (41F/40G) and efficacy data for 65 pts (31F/34G) are available (17 too early). One pt was ineligible in arm F. Two pts, one in each arm, did not receive protocol therapy. Median number of wks on treatment was 18 (F) and 7 (G). No toxic death occurred. Main grade 3–4 toxicities (arm F vs G) were G3 neutropenia (32%/17.5), G4 neutropenia (19.5%/0), G3–4 thrombocytopenia (12%/0), G3 vomiting (17%/2.5), G3 transaminases (0%/15) and G3–4 fatigue (27%/15).Confirmed partial responses (PR) rates (F/G) were 38.7% (12/31) and 11.7 % (4/34) according to the investigators and median duration of response was 6,3 and 4,6 mo. PR and stable disease (SD) were documented for 21/31 evaluable pts in arm F and expert review confirmed 13 PR (41.9 %) and 6 SD (19.3%). Conclusions: Folfirinox induces a response rate > 30% with manageable toxicity in ECOG 0–1 pts with MPA. According to these interim results, this trial will continue as a phase III study. Updated results will be presented at the meeting. Supported by a PHRC 2004 grant from the French Ministry of Health.

[Table: see text]
Postoperative adjuvant gemcitabine plus oxaliplatin (GemOx) chemotherapy followed by chemoradiation in patients with pancreatic carcinoma: A multicenter phase II study
Authors: Mornex F. , André T. , Louvet C. , Seitz J. , Ychou M. , Lledo G. , Touboul E. , Partensky C. , Balosso J.
Published: March 2020

4520

Background: Gemcitabine (Gem) is an active drug in metastatic pancreatic cancer and a very good radiosensitizer. We evaluated the safety and potential activity of adjuvant GemOx chemotherapy followed by concurrent Gem and irradiation (RT) after curative resection of pancreatic cancer. Methods: Fifty four patients were enrolled from October 2002 to January 2005 in this trial with potentially curative resection of pathologically confirmed adenocarcinoma of the pancreas with negative resection margins (R0). Gem 1000 mg/m2 (100 min) on d1 then Ox 100 mg/m2 (120 min) on d2 were given (q2w for 6 cycles) followed 4 weeks after by Gem 100 mg/m2 (30 min) combined with RT 50 Gy (2Gy fraction) for 5 weeks in patients with no residual toxicity nor recurrence. Results: The treated population (at least 2 induction cycles) included 49 patients (91%). Characteristics at baseline: median age: 59.2 yrs; Karnofsky performance status =80: 96%; stage TX: 10%, T1: 8%, T2: 41%, T3:39%; T4: 2% (TNM classification, 5th edition); lymph node positive: 43%; median time from surgery to inclusion was 43 days. Forty six patients (85%) received the 6 planned induction cycles and 41 patients (76%) completed chemoradiation. The recurrence free 1-year survival rate is 71% (N=49); (95% CI 0.581–0 845). Forty one patients (98% of the irradiated population) received the total 50 Gy radiation dose. The most common Gr 3/4 toxicities during induction chemotherapy (N=51) were: neutropenia 18%, thrombocytopenia 14%; nausea, vomiting, diarrhea:16%, neurotoxicity (Gr 3 only) 4%. Acute Gr 3/4 toxicities during chemoradiation (N=42): neutropenia 19%, thrombocytopenia 7.0%, neurotoxicity (Gr 3 only) 7%. No toxic death occurred on treatment. Conclusions: GemOX in adjuvant followed by Gem + Radiotherapy have a manageable toxicity profile with a promising 71% 1 year RFS. Data of OS will be communicated during the meeting.

No significant financial relationships to disclose.
A patterns-of-care study of post-progression treatment (Rx) among patients (pts) with advanced pancreas cancer (APC) after gemcitabine therapy on Cancer and Leukemia Group B (CALGB) study #80303
Authors: Schrag D. , Archer L. , Wang X. , Romanus D. , Mulcahy M. , Goldberg R. , Kindler H.
Published: March 2020

4524

Background: Gemcitabine is the mainstay of Rx for pts with APC. Practice guidelines encourage participation in trials after disease progression. We evaluated Rx after APC progression for pts in CALGB 80303 a randomized trial of gemcitabine + bevacizumab (GB) or placebo (GP). Methods: Of the 552 pts who began GP or GB Rx, 457 had comprehensive medical record review. Of these 355 progressed on protocol Rx. We evaluated post-progression Rx for these 355 pts - the record review (RecR) group. We also phoned a subgroup of 126 pts to inquire about Rx delivered at sites other than the accruing center - the record review & interview group (RecR + I) to determine whether any Rx had been administered and the specific agents used. Results: ChemoRx after progression on gemcitabine was distinctly uncommon. Based on RecR 239/355=67.3% and on RecR + I, 70/126=55.6% of pts received no chemoRx after progression on the study Rx. These proportions did not vary based on Rx assignment. Worse ECOG performance status at baseline and older age were associated with lower likelihood of post progression Rx. Notably, 99/355=27.9% of pts died within 4 weeks of progression. Conclusions: After progression on a clinical trial of gemcitabine Rx, <half of pts receive 2nd line Rx and remarkably few (<2%) receive further experimental Rx. Given the lack of well established Rx options, there appear to be lost opportunities for participation in early phase clinical trials. Coordinated strategies for second line Rx options might increase the evidence base for this challenging malignancy. Patterns of Post-Progression ChemoRx after Progression on Gemcitabine ± Bevacizumab in APC.

[Table: see text] [Table: see text]
ATTAX: Randomised phase II study evaluating weekly docetaxel-based chemotherapy combinations in advanced esophago- gastric cancer, final results of an AGITG trial
Authors: Tebbutt N. , Sourjina T. , Strickland A. , Van Hazel G. , Ganju V. , Gibbs D. , Gebski V. , Munro S. , Cummins M.
Published: March 2020

4528

Background: Docetaxel (T), cisplatin (C) and 5FU(F) are active agents in esophago-gastric cancer. A recent phase III study evaluating 3-weekly TCF demonstrated a survival advantage over standard therapy, but TCF was associated with high rates of hematological toxicity (30% incidence of febrile neutropenia/neutropenic infection) as well as non-hematological side effects (Van Cutsem et al, J. Clin Oncol. 24 4991–4997 2006). Weekly docetaxel is associated with a lower incidence of hematological toxicity. This randomized phase II study aimed to test weekly docetaxel based combination chemotherapy regimens with the aim of maintaining the activity of such regimens but reducing toxicity. Methods: Eligibility included; histologically confirmed, metastatic esophageal or gastric (OG) carcinoma, measurable disease, PS0–2, adequate organ function, no prior treatment, informed consent. Patients (Pts) were randomized to receive weekly (w) T 30mg/m2 d1,8 C 60 mg/m2 d1 F 200 mg/m2/d continuously q 3w or wT 30 mg/m2 d1,d8 and capecitabine (X)1,600 mg/m2/d d1–14 q3w. The primary endpoint is confirmed response rate (RR), with each arm analyzed independently. Simon’s 2-stage design was used, with 5/21 responses required in the first stage to allow continuation to 50 pts per arm. Results: Response rates in each arm satisfied the first stage, and complete accrual of 106 pts was completed in May 2006. Demographics, toxicity and response rates are shown in the table . With a median follow-up of 14.6 months, progression free and overall survival times are 5.9 m and 12.8 m, and 4.2m and 10.1 m for wTCF and wTX, respectively. Conclusions: wTCF and wTX have encouraging activity and a far more favorable toxicity profile than TCF administered 3-weekly. Weekly docetaxel-based combination regimens should be evaluated further in this disease.

[Table: see text]

[Table: see text]
A randomized trial of chemoradiotherapy versus surgery alone in patients with resectable esophageal cancer
Authors: Carstens H. , Albertsson M. , Friesland S. , Adell G. , Frykholm G. , Wagenius G. , Myrvold H. E. , Farago I. , Stockeld D.
Published: March 2020

4530

Background: The aim of this study was to compare survival in a randomized phase III trial of chemoradiotherapy (CHRT) versus surgery alone for localized resectable oesophageal cancer. Methods: Between 2000 and 2004, 91 patients with oesophageal cancer were enrolled in a Scandinavian multicenter study. Patients with resectable oesophageal squamous cell carcinoma (50%) or adenocarcinoma (50%) were randomized to chemoradiotherapy (CHRT) or surgery alone. Chemotherapy (CHT) was given in 3 cycles with cisplatin 100 mg/m2, day 1 and 5-fluorouracil 750 mg/m2/24 hours, infusion day 1–5, every three weeks. After one induction chemotherapy course, radiotherapy including the primary tumour and defined locoregional lymph nodes, was given concomitant with the following CHT cycles, to a total dose of 64 Gy, in 32 fractions. Surgery was performed according to Ivor Lewis and lymph nodes resected with standard two-field technique. Results: At a median follow-up of 51.8 month’s 65 deaths are noted. In the chemoradiation group 50% of the patients accomplished therapy according to protocol, 40% were treated with modifications of the protocol and radical resection was performed 76% of the patients. Median survival was 12.8 months for chemoradiation and 15.8 months for the surgery group. There was no significant difference in 1-year survival 56% and 55% for CHRT and surgery, respectively. By two years, survival curves diverge and 2-years survival was 37% (CI 95%: 23–51%) for the CHRT group and 25% (CI 95%: 12–39%) for the surgery group. At four years, survival was 29% for CHRT versus 23% for surgery (CI 95% CHRT: 16–43%, CI 95% Surgery: 10–36%). Both treatments were well tolerated and no treatment related deaths were recorded in any of the treatment arms. Most deaths were due to tumor disease (66%) in both groups. Conclusions: No statistically significant differences between the treatment arms were seen and survival results are equal to earlier reported. Both treatment arms were well tolerated.

No significant financial relationships to disclose.
A multicenter phase II study of gemcitabine and S-1 combination therapy (GS therapy) in patients with metastatic pancreatic cancer
Authors: Ueno H. , Okusaka T. , Furuse J. , Yamao K. , Funakoshi A. , Boku N. , Ohkawa S. , Makimoto A. , Sato T.
Published: March 2020

4550

Background: As shown in our previous phase I study (Oncology 2005, 69:421–427), gemcitabine and S-1 combination therapy (GS therapy) appears to be feasible and effective against advanced pancreatic cancer. The present multicenter phase II study was conducted to confirm the efficacy and toxicity of GS therapy for metastatic pancreatic cancer. Methods: Patients with histologically or cytologically proven pancreatic adenocarcinoma with at least one measurable metastatic lesion were eligible for the study. Other eligibility criteria included: no previous treatment for pancreatic cancer except surgery, age =20 and =74 years, ECOG performance status of 0 or 1, and adequate organ function. Gemcitabine was given intravenously at a dose of 1,000 mg/m2 over 30 min on days 1 and 8, and S-1 was given orally at a dose of 40 mg/m2 twice daily from day 1 to day 14, repeated every 3 weeks. The objective response rate was assessed according to RECIST. Results: A total of 55 patients from 10 institutions were enrolled between October 2004 and July 2005. The efficacy and toxicity were analyzed in 54 patients who received at least one course of GS therapy. The median number of treatment courses was 7 (range, 1–24+). Although no complete response was seen, a partial response was achieved in 24 patients, resulting in an overall response rate of 44% (95% CI, 30.9–58.6%). Twenty-six patients (48%) had stable disease. The median progression-free survival was 5.9 months (95% CI, 4.1–6.9 months) and the median overall survival was 10.1 months (95% CI, 8.5–10.8 months) with a 1-year survival rate of 33%. The major grade 3–4 toxicities were neutropenia (80%), leucopenia (59%), thrombocytopenia (22%), anorexia (17%), rash (7%), nausea (6%) and fatigue (6%). Hematological toxicity was mostly transient and there was only one episode of infection with grade 3–4 neutropenia. No treatment-related deaths occurred during the study. Conclusions: GS therapy produced a high response rate and good survival associated with an acceptable toxicity profile in patients with metastatic pancreatic cancer. A randomized phase III trial to confirm the efficacy of GS therapy is planned.

No significant financial relationships to disclose.
Phase II trial of bevacizumab, gemcitabine, oxaliplatin in patients with metastatic pancreatic adenocarcinoma
Authors: Kim G. P. , Oberg A. L. , Foster N. R. , Jaslowski A. , Flynn P. J. , Campbell D. , Hedrick E. , Gray L. , Grothey A. , Alberts S.
Published: March 2020

4553

Background: The combinations of gemcitabine and oxaliplatin (GemOx) and bevacizumab and gemcitabine have activity in pancreatic cancer. Based on these observations, the NCCTG initiated a multicenter phase II study to evaluate the combination of an active cytotoxic doublet and a targeted agent to determine whether improvement in 6-month survival in previously untreated patients with metastatic pancreas cancer could be achieved. Methods: Treatment consists of gemcitabine 1000 mg/m2 IV over 100 minutes and bevacizumab 10 mg/kg IV given on day 1, 15; oxaliplatin 100 mg/m2 IV is given on day 2, 16, repeated every 28 days. Eligibility includes: no prior chemotherapy, ECOG PS 0–2, bili< 2x UNL, AST< 5x UNL. Pts with stable full dose anticoagulation are eligible. Bevacizumab specific exclusions include no recent stroke, heart attack, embolus, tumor invasion or significant proteinuria. CT scans are obtained every 2 cycles. Treatment continues until disease progression, severe adverse events (AEs), or patient refusal. Results: Eighty-two patients were enrolled from 7/05 to 2/06. Median age was 63 (range: 32 - 86). 24 of 82 (29%) evaluable pts had a maximum grade ≥ 4 AE (at least possibly related to treatment). Grade 4 events included (% of pts): neutropenia (7%), thrombosis (6%), thrombocytopenia (5%), pneumonitis (2%), ischemia-cerebral (1%), abdominal infection (1%), small intestine perforation (1%), and small bowel leak (1%). Three patients died from grade 5 events (1-gastric perforation, 1-cerebral ischemia, 1-multi-organ failure). 80 patients were evaluable for outcome assessment (excludes 2 ineligible cases). Median follow-up was 10.3 months (range: 6.3 - 14.7) in the 19 patients still alive. 6-month survival was 65.0% (95% CI: 53.5% - 75.3%). Median survival was 8.1 months (95% CI: 6.5 - 9.3) and median TTP was 5.7 months (95% CI: 4.4 - 6.4). The confirmed response rate was 11.3% (95% CI: 5.3 - 20.3%) with 1 complete and 8 partial responses. Conclusions: In this multi-centered, cooperative group study, promising efficacy with this three-drug combination was observed especially in regards to six- month and median survival. The observed adverse events are comparable to historical controls although caution should be exercised in light of the three grade 5 events.

[Table: see text]
Akt-mediated YB-1 phosphorylation induces resistance for chemotherapy of gastric cancer
Authors: Oki E. , Kakeji Y. , Tokunaga E. , Yoshida R. , Egashira A. , Sadanaga N. , Morita M. , Taguchi K. , Kuwano M. , Maehara Y.
Published: March 2020

4554

Background: Y-box-binding protein 1 (YB-1), a member of the DNA-binding protein family which contains a cold-shock domain, has pleiotropic functions in response to stimuli of the AKT/PI3K signal pathway. We have previously described a pathway that involves PTEN/AKT/PI3K, thereby mediating chemoresistance in gastric cancer patients. We studied the Akt-mediated YB-1 phosphorylation and resistance to anti-cancer drugs for the treatment of gastric cancer. Methods: Primary gastric carcinoma tissue and the corresponding normal mucosa were both obtained from 81 gastric cancer patients who underwent surgery in the Department of Surgery II at Kyushu University Hospital from the years 1996 to 2000. YB-1 nuclear expression was investigated by immunostaining while AKT activation was investigated by immunostaining with a phosphorylation-specific antibody. The chemotherapeutic sensibilities of these patients were investigated using an MTT assay. LOH of PTEN was studied using a DNA sequencer with D10S796 and D10S1173 microsatellite markers in the same samples. Results: We found the activated AKT to be associated with an increased resistance to multiple chemotherapeutic agents, including those currently used on gastric cancer patients (5-fluorouracil, adriamycin, mitomycin C, and cis-platinum). The YB-1 nuclear expression was recognized in some patients and they closely correlated with a high expression of phosphorylated AKT. A high level of AKT phosphorylation (activated AKT) correlated closely with the LOH of PTEN (p < 0.0008), and the prognosis of patients who had LOH of PTEN was significantly poor in comparison to the other patients. Conclusions: The results of this study indicate that AKT activation and LOH of PTEN mediated the YB-1 activation, thus suggesting that they play an important role in conferring broad-spectrum chemoresistance in gastric cancer patients. These findings thus support the carrying out of new clinical trials for investigations of combination chemotherapy using conventional drugs with a new generation of signal transduction inhibitors.

No significant financial relationships to disclose.
Combination chemotherapies in advanced gastric cancer: An updated systematic review and meta-analysis
Authors: Wagner A. D. , Grothe W. , Haerting J. , Kleber G. , Grothey A. , Fleig W. E.
Published: March 2020

4555

Background: Combination chemotherapy is widely accepted for patients with advanced gastric cancer, but uncertainty remains regarding the choice of the regimen. Methods: Our objectives were to assess the effect of: 1) 5-FU/cisplatin combinations with versus without anthracyclines; 2) 5-FU/anthracycline combinations with versus without cisplatin; 3) Irinotecan versus non-irinotecan containing combination chemotherapies; 4) Docetaxel versus non-docetaxel containing combinations; on overall survival and toxicity. Search strategy: We searched: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, proceedings from DDW, ECCO, ESMO, ASCO until october 2006. Selection criteria: Randomised controlled trials on different combination chemotherapies as above in advanced gastric cancer. Results: 13 trials including in total 2,184 patients (pts) are included in this meta-analysis. Comparison 1) including 501 pts (HR 0.77; 95% CI 0.62–0.95); and 2) including 1,147 pts (HR 0.83; 95%CI 0.76–0.91) both demonstrate a significant survival benefit for three-drug regimens including 5-FU, anthracyclines and cisplatin. Among these, the rate of treatment-related deaths was higher when 5-FU was administered as bolus compared to infusional 5-FU (exact Mantel-Haenszel OR 2.33, p=0.285). Comparison 3) including 536 pts results in a HR of 0.88; 95% CI 0.73- 1.06. The rate of treatment related deaths was 0.7% versus 2.6% in the irinotecan versus non-irinotecan-containing arms (exact Mantel-Haenszel OR 0.275, p=0.166). Comparison 4) 4 relevant trials were identified. A meta-analysis will be performed as soon as the final results of at least 3 trials are available. Conclusions: Three-drug regimens containing 5-FU, anthracyclines and cisplatin achieve superior survival results compared to cisplatin/5-FU or antracycline/5-FU combinations. Among these, ECF (epirubicin, cisplatin and 5-FU) is tolerated best. Combinations including irinotecan demonstrate a non-significant trend towards better survival in this meta-analysis, but have never been compared against three-drug regimens containing 5-FU/cisplatin and an anthracycline. Supported by: KKS Halle, grant number [BMBF/FKZ 01GH01GH0105].

No significant financial relationships to disclose.
The effects of pasireotide (SOM230) on health-related quality of life in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR
Authors: Kvols L. , Glusman J. E. , Hahn E. A. , Wang E. , Öberg K. , Anthony L. , O’Dorisio T. M. , de Herder W. , Darby C. H. , Wiedenmann, G. B.
Published: March 2020

4558

Background: Pasireotide is a novel multi-ligand somatostatin analogue with high affinity binding for four of the five somatostatin receptor subtypes (sst1,2,3 and sst5). This Phase II clinical trial showed that pasireotide is effective in controlling the symptoms of diarrhea and flushing in 27% of patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR. The impact of pasireotide therapy on health-related quality of life (HRQL) was also evaluated. Methods: Patients in this open-label, multicenter study initially received pasireotide 300 μg sc bid which was escalated to a maximum dose of 1,200 μg sc bid until clinical response was achieved. Data are reported for the Functional Assessment of Chronic Illness Therapy-Diarrhea (FACIT-D) instrument. FACIT-D comprises the Functional Assessment of Cancer Therapy-General (FACT-G) score, which measures physical, social, emotional and functional well-being, plus a symptom-specific sub-scale which measures HRQL specific to diarrhea. FACIT-D baseline assessment was obtained on day 1 immediately before dosing, and then monthly thereafter. FACIT-D sub-scale and total scores at baseline and after 1, 2, and 3 months of pasireotide treatment are described by categories of clinical response. Results: 45 patients (mean age 61 years; range 40–83) received treatment, and 44 were eligible for the efficacy and HRQL analyses. Functional well-being scores, symptom-specific scores and total FACIT-D scores of non-responders tended to be lower at baseline and during treatment than those of responders. The three sub-scale and summary FACIT-D scores exhibited relatively stable mean HRQL scores and similar patterns of variability in clinical responders and non- responders through the third month of pasireotide treatment. Conclusions: HRQL was stable during treatment with pasireotide in patients with advanced metastatic disease refractory or resistant to octreotide LAR. Additional work in HRQL study design and evaluation of HRQL endpoints in patients with carcinoid disease is indicated, and will further improve our understanding of quality of life in patients with this disease.

[Table: see text]
A randomized clinical study of chemoradiotherapy versus radiotherapy in locoregional advanced unresectable esophageal cancer
Authors: Zupanc D. , Roth A. , Kolaric K. , Tometic Z.
Published: March 2020

4565

Background: To compare the treatment results chemoradiotherapy that include split-course radiotherapy versus continuous radiotherapy for patients with locoregional advanced unresectable esophageal cancer. Methods: The randomized clinical study included 120 patients, of them 107 eligible. The eligible patients with locoregional advanced unresectable esophageal cancer were randomized in two groups. The first group of 55 patients was treated with chemotherapy in combination with split-course radiotherapy and second group of 52 patients received radiation therapy alone.The chemoradiotherapy group was treated with 5-fluorouracil (1,000 mg/m2 i.v. for six hours) and cisplatin (20 mg/m2 i.v.) for four consecutive days at the beginning of each part of therapy plus split-course irradiation (2x20 Gy, 200 cGy daily) separated by a rest of 2 weeks. The patients in radiotherapy group received totally up to 60 Gy, 200 cGy daily. Chemotherapy for clinical recurrence and salvage therapy. Results: The 2-,5-,10- years overall survival rate were 32.2 %, 24.5% and 7.3% in the chemoradiotherapy group and 22.2%,14.5% and 1.9% in the radiotherapy group.Median survival was 15 months in the chemoradiotherapy group and 11.5 months in the radiotherapy group. There was the statistically significant difference (p<0.05) between the groups due to overall survival. The hematological toxicity, nausea and alopecia were more common in the chemoradiotherapy group, but esophagitis and pain in the irradiated region were more common in the radiotherapy group. Conclusions: Chemoradiotherapy with cisplatin, 5-fluorouracil and split-course radiotherapy showed superior results to radiotherapy alone and did not produce any severe side effects in patients with locoregional advanced unresectable esophageal cancer.

No significant financial relationships to disclose.
Triple induction chemotherapy and chemoradiotherapy in locally advanced esophageal cancer: Final results of a multicenter phase II trial
Authors: Eisterer W. M. , De Vries A. , Spechtenhauser B. , Kendler D. , Königsrainer A. , Nehoda H. , Lukas P. , Wöll E. , Öfner D.
Published: March 2020

4568

Background: Surgery is the standard treatment for patients with resectable esophageal carcinoma, but 5-year survival rates rarely exceed 20%. Neoadjuvant chemoradiotherapy (CRT) may lead to downstaging of the tumor and thus improve the possibility of complete oncologic resection. Docetaxel (Dx) showed considerable activity in combination with hyperfractionated radiotherapy and only moderate toxicity. We evaluated a triple neoadjuvant regime including Dx in patients with locally advanced esophageal adenocarcinoma (AC) or squamos cell carcinoma (SCC). Methods: 24 patients (pts) with AC (n=8) or SCC (n=16) medically fit, no prior therapy, ECOG-performance status = 2 were included. Pts received 2 cycles of cisplatin (Cis) 15mg/ms2 d1–5, 5-fluorouracil (5-FU) 750mg/m2 continuous infusion (CI) d1–5, and Dx 75mg/m2 d1 repeated every 29 days followed by radiotherapy (RT) 39.6 Gy total dose (daily fraction 1.8Gy) concomitant to Dx 15mg/m2 on days 1, 8, 15, 22 and 5-FU 300mg/m2 CI on the days of RT followed by resection or definitive RT up to 59.6 Gy in case of inoperability. Results: See table . Grade 3/4 toxicity (n/%): neutropenia 10/43%, diarrhea 4/18%, alopecia 2/9%; deep vein thrombosis 1/5%, blurred vision 1/5%, fever 1/5%, pulmonary embolus 1/5%, arterial hypertension 1/5%. 1 pt died 39 days post resection due to fatal anastomical bleeding. 6/16 operated pts (37%) showed morbidity (anastomical stenosis/insufficiency, fistula, nervus recurrens palsy). 4/22 pts (18%) died 7- 25 months after therapy due to metastatic disease. At a median follow-up of 12 months 18 pts (82%) are alive, median survival has not been reached yet. Conclusions: Triple induction CT and CRT with Dx, Cis, and 5-FU is safe, feasible, and effective with CPR in 31%, downstaging in 81% and R0-resection in 100% of pts. Main toxicities are neutropenia (43%) and postoperative morbidity (37%). A follow-up phase II trial of triple induction therapy in combination with an EGFR-directed antibody is planned.

[Table: see text]

No significant financial relationships to disclose.
Cervical squamous cell carcinoma of the esophagus-a unique series of limited resection and free jejunal graft interposition after neoadjuvant RCTx in 94 patients
Authors: Ott K. , Lordick F. , Feith M. , Bartels H. , Fink U. , Stein H. J. , Molls M. , Biemer E. , Siewert J.
Published: March 2020

4572

Background: The treatment of cervical squamous cell carcinoma (SCC) is discussed controversial. A limited resection of the cervical esophagus and reconstruction with a free jejenunal graft interposition using a microsurgical technique has been evaluated in our department. Methods: From 1986–2006 94 patients with the initial staging uT2–4, N any cM0 (75 male, 19 female; age 56+9.6, range: 19–74 years) with cervical SCC of the esophagus were treated with limited esophageal resection and reconstructed with a free jejunal autograft in combination after neoadjuvant RCTx within phase II studies. The median follow up is 23 months (0.1–120). Results: Laryngectomie had to be performed in 13 patients (14%). Recurrent nerve palsy on one side was found in 15/77 (19.5%) and on both sides in 13/77 (17%). Complications occurred in 70 (75%) of the patients, 47% of the patients had more than one complication. Reoperations were necessary in 29 patients (31%). The 30-day mortality was 2/94 (2.1%). Median survival is 29.9 months (1-, 3 and 5-year survival rates: 81%, 43%, 41%). 27/94 (29%) patients showed complete tumor regression (ypT0) after RCTx. Prognostic factors are complete tumor regression (p=0.007), ypT-(p=0.006), the R-category (p=0.018), but not the ypN-category (p=0.06). Neither the occurrence of complications (p=0.57) nor reoperation (p=.89) are associated with survival. The complete resection rate was 76 % (71/94). Median survival is 34.3 months, median recurrence free survival is 21.4 months for the R0 resected patients. 30/71 (42%) had a recurrence (locoregional in 27% (19/71), distant metastases in 10% (7/71) and a combination of both in 6% (4/71). Conclusions: Limited resection of the esophagus and reconstruction by a free jejunal graft after neoadjuvant RCTx is highly sophisticated and complex. Despite a high complication and reoperation rate the results are excellent with a low mortality and a good prognosis. This approach seems to be appropriate for cervical SCC in oncological centers with an infrastructure providing interdisciplinary management. Comparable data for cervical SCC of the esophagus without the inclusion of hypopharyx carcinoma do not exist in literature so far.

No significant financial relationships to disclose.
Surrogate endpoints for overall survival (OS) in advanced pancreatic cancer (APC): Analysis of randomized clinical trials (RCTs) exploring gemcitabine (G)-based combinations
Authors: Milella M. , Bria E. , Carlini P. , Cuppone F. , Gelibter A. , Nisticò C. , Ruggeri E. M. , Terzoli E. , Cognetti F. , Giannarelli D.
Published: March 2020

4575

Background: G-based combinations often result in an improved overall response rate (ORR) in APC; this improvement in ORR, however, seldom translates into a significant OS advantage. We therefore evaluated the appropriateness of ORR and progression-free survival (PFS) as surrogate endpoints for OS in RCTs comparing single-agent G and G-based combinations as first-line treatment for APC. Methods: Phase III trials reporting ORR or PFS and OS data were considered eligible. Potential correlations were explored according to a linear regression model considering both the actual outcome (ORR or PFS and OS) for each single arm and the calculated relative risk (RR) for each outcome in paired comparisons. Correlation was estimated according to Pearson’s (r) and R2 coefficients (parametric) and Spearman’s (Rho) coefficient (non-parametric). A model to calculate the target sample size to correctly identify 0.4, 0.7, and 1.5 mos benefits in OS was derived as well. Results: Nineteen (6,288 pts) and 17 (4,882 pts) RCTs were identified for the ORR/OS and PFS/OS correlation, respectively. When considering ORR rates and medians, ORR did not significantly correlate with OS (r=0.23, R2=0.06, p=0.14; Rho=0.16, p=0.33), while PFS showed a strong linear correlation (r=0.75, R2=0.56, p<0.0001; Rho=0.90, p<0.0001). Similarly, when considering RRs, ORR did not significantly correlate with OS (r=-0.17, R2=0.03, p=0.46; Rho=-0.18, p=0.44), while PFS showed a strong linear correlation (r=0.91, R2=0.82, p<0.0001; Rho=0.59, p=0.01). Based on these data, we derived a sample size model (beta-coefficient=0.75) to calculate how many patients would be necessary to demonstrate a significant OS advantage of 0.4, 0.7 and 1.5 mos, respectively, using PFS as a surrogate endpoint; according to this model, 0.5, 1, and 2 months improvements in PFS would be necessary to translate into the target OS advantages, requiring 2,370, 678 and 222 pts, respectively. Conclusions: In APC, ORR does not seem to correlate with OS. Conversely, PFS could be a reliable surrogate endpoint for survival in this setting, although the detection of relatively small differences in PFS would require a remarkably large sample size.

No significant financial relationships to disclose.
Volumetric 3D CT analysis - an early predictor of response to therapy
Authors: Schwartz L. H. , Curran S. , Trocola R. , Randazzo J. , Ilson D. , Kelsen D. , Shah M.
Published: March 2020

4576

Background: Evidence suggests that changes in unidimensional measurements (using RECIST criteria) may not accurately reflect actual changes in tumor size, and do not correlate well with other biomarkers of response, tumor progression, or patient outcome. We evaluated changes in tumor volume of target lesions with volumetric CT, and compared them with response assessments derived from RECIST criteria. Methods: We evaluated target lesions, including lymph node, liver, peritoneal and lung metastases in 25 patients with metastatic gastric cancer or gastroespohageal junction adenocarcinoma treated on a phase II clinical trial with irinotecan, cisplatin and bevacizumab. All patients underwent thin-section multidetector CT at baseline and 6-week follow-up for 10 cycles. Target lesions were measured unidimensionally and volumetrically, using validated automated and semiautomated segmentation algorithms. For initial analysis, correlation was made with the RECIST response using a cut-off value of 65% volume change. A ratio of change in RECIST measure to volume measure was calculated at time of maximal clinical response for each patient, as well as for responders versus non-responders. Results: 18 of 25 (72%) patients showed a clinical response. Of these 18 responders, 5, 6, 4, and 3 were identified as responders using RECIST criteria after cycles 1, 2, 3, and 4, respectively. Using a cut-off of 65% volume change, 14 of these responders were indentified after cycle 1, and 4 were identified after cycle 2. Using a cut-off value of 65%, volume measurements identified responders a mean of 50.3 days earlier than did RECIST criteria. There was a statistically significant (p<0.01) change in ratio of volume measurement change to RECIST measurement change for responding versus stable patients. Conclusions: Volumetric change in tumor size appears to predict clinical response earlier than do RECIST criteria in the majority of cases. Changes in volume are more sensitive because they exhibit a wider dynamic range. Ratios of size changes volumetrically appears to better discriminate RECIST responders from those with stable disease. Further work is needed to define the biologically relevant cut-off value for volume change, and to correlate volume change with other biomarkers.

No significant financial relationships to disclose.
18-FDG-PET and somatostatin receptor scintigraphy (SRS) can predict disease progression and survival in patients with metastatic endocrine tumors: Results of a prospective study
Authors: Raoul J. , Devillers A. , de Lajarthe A. , Cuggia M. , Boucher E. , Garin E.
Published: March 2020

4577

Background: Appropriate treatment for metastatic endocrine tumors (MET) depends on the aggressiveness of the disease. We wanted to know whether PET and SRS can predict early disease progression and patient survival. Methods: A prospective exploration protocol was applied for new cases of untreated MET diagnosed between September 2003 and January 2006 who gave their written informed consent. Explorations included: computed tomography (CT), SRS, PET, review of histological data (WHO grade, p53 and Ki67 IH); CT was repeated every three months to assess: disease-free survival (PFS), the risk of early (first 6 months) progressive disease (PD6m)and overall survival (OS). Results: The series included 38 patients (60±15y) with a primary digestive tract (n=24), lung (n=2) or unknown (n=12) tumor. Histologically, 4 patients had a high-grade tumor and 34 a low-grade tumor. Visual analysis of PET and SRS was positive in 15 and 27 patients respectively. The 2-year OS and DFS were 73% and 45%; 16 patients had PD6m. PET exhibited an excellent positive predictive value for PD6m (14/15 PET+ and 2/23 PET- were PD6m) and was correlated with DFS (p<0.0001; at 2 yr 75% DFS for PET- and 0% for PET+) and OS (p<0.0001; at 2 yr 95% vs 42%) even when considering only low-grade tumors. Positive SRS was associated with DFS (p<0.001) and OS (p<0.03). Among patients with positive PET, the SRS-positive patients had a better DFS than the SRS-negative patients. At univariate analysis DFS and OS were correlated with: PET, SRS, WHO grade, Ki67 and p53. At multivariate analysis only PET was predictive of DFS. Conclusions: PET and SRS exhibit excellent predictive value for rapid tumor progression. There results are correlated with DFS and OS even for histologically low-grade tumors. Tumors progressed within 6 months in 14/15 patients with a positive PET. These explorations should be included in the initial work-up for MET.

No significant financial relationships to disclose.
NCCTG phase I/II trial (N9943) of gemcitabine and pemetrexed in patients with biliary tract or gallbladder carcinoma: Phase II results
Authors: McWilliams R. R. , Foster N. R. , Quevedo F. J. , Marschke R. F. , Kugler J. W. , Friedman E. L. , Jaslowski A. J. , Sande J. R. , Alberts S. R.
Published: March 2020

4578

Background: Gemcitabine is commonly used in patients with cholangiocarcinoma with a response rate of 20–30% and median overall survival of 6–10 months. Pemetrexed’s mechanism of action and tolerability in patients with hepatic dysfunction makes it a potential agent for cholangiocarcinoma. Methods: Patients with unresectable, previously untreated biliary tract cancers were eligible for participation. Patients received pemetrexed 500 mg/m2 IV over 10 minutes and gemcitabine 800 mg/m2 IV at 10 mg/m2/minute on days 1 and 15 of an every 4 week schedule with vitamin B12 and folate supplementation. The primary end-point is 6-month survival with a planned accrual of 59 patients. Results: 58 eligible patients are included in this analysis. 93% had metastatic disease. Median age was 61 (range: 40 - 81). Median follow-up was 6.5 months (range: 3.3 - 23.2). Median of 3 cycles of treatment was given (range: 1 - 10). Reasons for stopping treatment included disease progression (57%), adverse events (20%), refusal (17%), death on- study (4%), and other medical problems (2%). 6-month survival was 52% (95% CI: 40 - 68%). Median survival was 6.3 months (95% CI: 5.4 - 8.0 months) and median time-to-progression was 3.8 months (2.4 - 5.0). 46 of 58 patients (79%) experienced at least one grade 3+ AE (at least possible attribution), and 26 patients (45%) experienced at least one grade 4 AE (at least possible attribution), most of which were due to grade 4 neutropenia. Conclusions: This study shows similar results to what would be expected with gemcitabine alone. The addition of pemetrexed, as with other agents, has not significantly enhanced the activity of gemcitabine. Supported by NIH Grant CA25224- 18.

[Table: see text]

No significant financial relationships to disclose.
Pancreatic endocrine tumors (PETs): Incidence and recent trend toward improved survival
Authors: Halfdanarson T. R. , Rabe K. , Rubin J. , Petersen G. M.
Published: March 2020

4584

Background: PETs (islet cell tumors) are uncommon and often indolent tumors, but little is known about the incidence of PETs in the US and trends in survival. Methods: The SEER registry was used to identify cases of functional PETs (fPETs) and non-functional PETs (nfPETs) diagnosed from 1973–2000. Benign insulinomas were excluded. Incidence rates were age adjusted to the standard US population for 2000. Results: Of 971 patients with PETs, 824 (85%) were nfPETs, 37 (4%) were malignant insulinomas, 88 (9%) were fPETs other than insulinoma, and data were missing for 22 (2%). The crude annual incidence of PETs (per 100,000) for all ages was 0.1 in females and 0.2 in males. The incidence was highest in the age group >70 years (0.4, Table ). Tumors were localized in 109 (11%), regionally advanced in 228 (23%), and distant metastases were present in 545 (56%). Patients with fPETs were younger than patients with nfPETs (mean age 54.2 vs. 57.6, p=0.038) and had a longer median survival (MS) (47 vs. 30 months (mos), p=0.001) but were as likely to have advanced disease (p=0.50). The 5 and 10 year overall survival was 45.3% vs. 32.7% and 31.7% vs. 18.1% for fPETs vs. nfPETs, respectively. MS was 95 mos for localized PETs, 66 mos in regionally advanced PETs and 19 mos for distant metastases (p<0.001). Race did not influence incidence and survival. On multivariate analysis, only age (p<0.0001) and stage (<0.0001) were independently associated with prognosis but the functional status of the tumor approached significance (p=0.053). Survival has improved over time with longer MS in patients diagnosed in later quartiles of the observation period (p<0.001, Table). This difference is not explained by stage migration, as patients in all four quartiles had a similar stage distribution (p=0.79). Conclusions: PETs are uncommon tumors and the prognosis is highly dependent on the stage and the age of the patients. Patients with fPETs may have a better prognosis than nfPETs. Survival has improved over time.

[Table: see text]

No significant financial relationships to disclose.