bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of weekly paclitaxel as a second line chemotherapy for metastatic/recurrent gastric carcinoma
Authors: Kodera Y. , Ito S. , Kanyama Y. , Koshikawa K. , Mochizuki Y. , Takase T. , Koike M. , Fujiwara M. , Yamamura Y. , Nakao A.
Published: March 2020

14059

Background: There is currently no standard treatment for gastric carcinoma patients (pts) who failed initial chemotherapy. Since performance status of these pts deteriorates rapidly, moderate and dose-fractionated single agent regimens have been preferred in Japan in the second line setting. Weekly paclitaxel, one of commonly used regimens in this setting, was explored for the first time in a formal phase II study. Methods: Pts with histologically confirmed gastric carcinoma who had unresectable or recurrent disease with ≥1 measurable lesions per RECIST were eligible. Other eligibility criteria included confirmed progressive disease (PD) per RECIST during a front line chemotherapy, PS ≤2, adequate liver, kidney, and marrow functions, no active gastrointestinal bleeding, and written informed consent. Patients received 80 mg/m2 of paclitaxel weekly for 3 successive weeks with one week of rest. The cycle was repeated until objective disease progression or drug intolerance. Results: 35 pts were enrolled: 29 men and 6 women, age 62 (48∼74), 6 unresectable and 29 recurrent cancers, 13 with poorly differentiated phenotype and 20 with differentiated type, 22 PS0, 8 PS1, and 6 PS2. All front line treatments involved oral fluoropyrimidines and had been S-1 in 29, S-1/CDDP in 5, S-1/CPT-11 in one, and UFT in one patient. One pt declined to continue the treatment due to a Grade 2 taste disturbance after a single dose of paclitaxel, and 34 other pts were evaluable for response. Partial response was observed in 6 pts (response rate 17.6%). Median time to progression was 97 days and median survival time was 214 days (467 days among 22 PS0 patients). The incidence of ≥Grade 3 adverse events were as follows: neutropenia in 7 pts, leucopenia in 5, anemia in 4, anorexia in 4, neurological disorder, nausea, diarrhea, asthenia, and dyspnea in one. Conclusions: Activity of weekly paclitaxel was modest for pts with fluoropyrimidine-refractory gastric carcinoma, but median survival time was satisfactory, with a mild toxicity profile. Further phase II study under less strict eligibility criteria (e.g. inclusion of patients with elevated tumor markers or subjective evidence of clinical deterioration during the front line therapy as the sole indication of disease progression) is underway.

No significant financial relationships to disclose.
A phase II study of combination chemotherapy with gemcitabine, 5-fluorouracil, and cisplatin (GFP) for advanced pancreatic cancer
Authors: Kim S. R. , Choi S. B. , Yuh Y. J.
Published: March 2020

14066

Background: Gemcitabine has been the standard regimen for advanced pancreatic cancer, but the effect on the response rate and survival is still disappointing. 5-fluorouracil(5-FU) and cisplatin are synergistic with gemcitabine as well as with each other. This study is aimed to determine the efficacy and safety of combination chemotherapy with gemcitabine, 5-FU and cisplatin for advanced pancreatic cancer. Methods: Patients(pt) with recurred or advanced pancreatic cancer were entered into this study, who had histologically proven adenocarcinoma, no prior radiotherapy, measurable lesion (≥2cm), ECOG performance scale (PS) 0–2, age 18–70, adequate bone marrow, cardiac and renal function, ALT ≤ 3× normal, and total bilirubin ≤ 2mg/dL.The pt were treated every 3weeks with gemcitabine 800 mg/m2, at 10mg/m2/min on days 1 and 8, 5-FU 1g/m2/24 hour continuous infusion from day 1 through 3 for 72 hours (extended to 4 days later in 12 pt due to lack of toxicity), and cisplatin 60 mg/m2 on day 2, 24 hours after the start of gemcitabine. Concurrent chemo-radiotherapy with gemcitabine 250 mg/m2/week was given to the pt with response of stable disease or better after 4 cycles of chemotherapy, if PS ≤1 and age ≤ 65. Results: Characteristics of 25 eligible pt; 17 male/ 8 female, PS 0,1 in 20 pt, 2 in 4 pt, Stage III in 3 pt, IV in 22, age 40–69 (median 62). Five pt had prior 5-FU-based chemotherapy. A total of 109 cycles were given (median 4; 1–10 cycles/person). Response by WHO criteria: 3 PR (14.3%; 95% confidence interval: 0 - 29.6%), 11 SD (52.4%) and 7 PD in 21 assessable pt. The median time to progression was 230 days (48+-478+) and median survival was 322 days (70+-757+). WHO grade ≥3 toxicity: neutropenia 19.3% (/cycle), thrombocytopenia 28.4%, mucositis 1.8%, and nausea and vomiting 5.6%. The clinical benefit response and correlation of tumor response with CA-19–9 level will be detailed on presentation. Conclusions: The chemotherapy with gemcitabine, 5-FU and cisplatin for advanced pancreatic cancer is safe, active and may have better survival benefit than gemcitabine alone. Based on these results, a nationwide phase III trial comparing with gemcitabine alone has been started.

No significant financial relationships to disclose.
Comparison of open and closed techniques of delivery of hyperthermic chemotherapy following cytoreductive surgery in patients with peritoneal carcinomatosis
Authors: Sardi A. , Thillainathan V. , Nieroda C. , Merriman B. , Kostuik P. N.
Published: March 2020

14067

Background: Intraperitoneal hyperthermic chemotherapy (IPHC) combined with Cytoreductive surgery (CRS) is an effective approach in the management of peritoneal carcinomatosis. A controversy exists concerning the use of an open or closed technique of delivery of the hyperthermic chemotherapy. A retrospective study of a prospective data base was performed to compare these two techniques with respect to overall survival, disease-free survival, length of hospital stay (LOS), and incidence of complications. Methods: From 1998 to 2005, 64 patients underwent CRS and IPHC. Nineteen patients underwent open technique and forty-five underwent closed technique. The pathological diagnoses included appendiceal carcinoma (35), pseudomyxoma peritonei (10), ovarian carcinoma (7), colon carcinoma (6), mesothelioma (5), and sarcoma (1). Cox Proportional-Hazards Regression analysis was performed. Results: Overall 5- year survival and disease free survival was 46% and 22%, respectively. No significant difference in overall survival (p=0.58), disease-free survival (p=0.37), or incidence of complications (p=0.66) was found between the groups. Open technique patients had a significantly shorter LOS than closed with a mean of 8.7 vs. 11.4 days [p=0.01] and a median of 8 vs.11 days [p=0.002] (Kruskal-Wallis Rank Sum Test). Conclusions: The improved survival seen in patients undergoing CRS and IPHC is not dependent on the choice of technique of delivery of the hyperthermic chemotherapy

No significant financial relationships to disclose.
A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma
Authors: Gruenwald V. , Wilkens L. , Gebel M. , Wirth T. , Greten T. , Kubicka S. , Manns M. P. , Ganser A. , Malek N. P.
Published: March 2020

14079

Background: The majority of hepatocellular carcinomas (HCC) express the epidermal growth factor receptor (EGFR). The monoclonal anti-EGFR antibody cetuximab blocks EGFR activation. In the current study, we tested the activity of cetuximab in this disease. Methods: Pts with advanced or metastatic HCC and measurable disease with adequate renal, hematologic and hepatic function (bilirubin <2×UNL; AST/ALT <3×UNL) were eligible. Prior regional or systemic therapy was permitted. A total of 15 pts have been enrolled to date. Primary endpoint: rate of progression free survival (PFS) at 24 weeks of treatment. Secondary endpoints: overall survival (OS), objective response rate (ORR), tolerability and identification of surrogate markers. Tumor biopsies were performed prior to treatment, after 4 wks and at time of progression. Specimens were analyzed for genetic instability (FISH analyses) and cell cycle regulation (p27Kip1, skp2, EGFR) by immunohistochemistry. Cetuximab was administered 400 mg/m2 iv week 1, and 250 mg/m2 weekly thereafter until disease progression. Demographics: male 14, female 1, age 46–78 yrs (median 65), cirrhosis 13/15 pts, liver transplantion 2/15pts, Childs-Pugh class A: 14/15, B:1/15; distant metastases 6/15; risk factors: hepatitis C virus (HCV) 2/15, HBV 1/15. Contrast enhanced ultrasound examinations were performed on all pts at −2, 4, and at the time of progression to evaluate tumor blood flow. Results: At the time of the first tumor evaluation (8 wks) 2/15 pts (13%) achieved stable disease (SD). Tumor specimens showed a significant increase in copy numbers for centromeric probes against chromosome 1 and 8 in patients with progressive disease. Toxicity: all pts developed skin rash: Grade (Gr) 1 in 12/15 pts, Gr 2 in 3/15. Allergic reaction Gr 1 was seen in 1 pt. 2 pts required dose reduction for drug-related toxicity Conclusions: Cetuximab is well tolerated in pts HCC and liver cirrhosis, without additional toxicity. To date only modest activity has been detected in these unfavorably advanced pts. Accrual will continue to 35 pts total. At time of disease progression tumor specimens showed chromosomal instability with an increase in copy numbers of chr. 1 and 8. Updated results will be presented at the meeting.

[Table: see text]
Oxaliplatin combined with leucovorin plus 5-FU (FOLFOX) in patients with advanced/metastatic biliary tract carcinoma
Authors: Lim J. Y. , Cho J. Y. , Paik Y. H. , Lee S. J. , Won J. Y. , Kim J. H. , Yoon D. S. , Lee D. K.
Published: March 2020

14093

Background: Biliary tract carcinoma is often diagnosed at advanced stage, with median survival rarely exceeding 6 months. There is currently no established palliative standard of care. A phase II trial was conducted to study a FOLFOX regimen as first- or second- line therapy in biliary tract carcinoma. Methods: Patients with unresectable or metastatic intrahepatic or extrahepatic biliary duct carcinoma and gallbladder carcinoma were enrolled. Eligible patients were between 18 and 75 years of age and had histologically confirmed, measurable adenocarcinoma. Patients were stratified according to prior chemotherapy(6) and no prior chemotherapy(15). Treatment consisted of intravenous oxaliplatin (100mg/m2) as a 2 hours infusion on day 1 followed by leucovorin 100mg/m2 on day1 and 5-FU 1000∼1200mg/m2 as a 24 hours infusion on day 1,2. Treatment was repeated every 3 weeks for up to 6 cycles. Tumor response, survival and safety were determined Results: A total of 21 patients were evaluable;12 men and 9 women with a median age of 57(range 37–71). Tumor sites were: intrahepatic (n=7) and extrahepatic biliary duct (n=9); gallbladder (n=4); and ampulla (n=1). Total 115 cycles were administered (median 5 cycles, range 2∼12). According to RECIST criteria, partial response 3(14.3%), stable disease 10(47.7%) and disease progression.8(38%). The overall response rate with and without prior chemotherapy were 0%(0/6) and 20%(3/15), respectively. In patients without prior chemotherapy (15), median progression-free-survival and overall survival were 6.6(range, 1.2∼12.8) and 8.7(range, 3.7∼19.3) months. Grade 1–2 neurotoxicity, fatigue, diarrhea, anorexia, nausea were common. Grade 3 neutropenia and thrombocytopenia occurred in 23% and 4.7% of the patients respectively. There was no treatment related death. Conclusions: FOLFOX should be considered an active and well tolerated first-line combination chemotherapy regimen for patients with advanced/metastatic biliary tract carcinoma.

No significant financial relationships to disclose.
First line chemotherapy with FOLFOX 4 in elderly patients (>65 years) with advanced or metastatic gastric cancer (A/MGC): A pilot study
Authors: Azzarello D. , Giuffrè C. , Panuccio V. , Giannicola R. , Del Medico P. , Zavettieri M. , Raffaele M. , Maisano R. , Falzea A. , Nardi M.
Published: March 2020

14095

Background: Cisplatin/5-FU based regimens are considered therapies of choice for the treatment of A/MGC even if severe toxicities are reported especially in elderly pts. FOLFOX 4 regimen is standard chemotherapy in adjuvant and metastatic colorectal cancer and it is effective and well tolerated also in elderly population. Several trials have showed activity and safety of FOLFOX regimen in A/MGC. For these reasons, we carried out this pilot study in order to evaluate the feasibility of FOLFOX 4 in elderly pts (>65 yrs) with A/MGC. Methods: From June 2003 to June 2005 we treated with FOLFOX 4 regimen 31 pts with median age of 70 yrs (range 66–79), 20 males and 11 females, ECOG PS 0–2 with MGC in 19 cases and AGC in 12 cases. All pts had measurable disease according to RECIST criteria, NCI-CTC was employed to grade toxicity except for neurotoxicity graded by specific scale. Results: We recorded 4 CR (13%), 6 PR (19%), 9 SD (29%) and 12 PD for an ORR 32% and median TTP of 6.8 months. A total of 281 courses were delivered with a median of 8 courses (range 4–15) per pt. No toxic deaths occurred and no therapy has been ended for toxicity or pt refusal. Pts did not receive G-CSF support. 43 courses were delayed for toxicity (maximum 2 weeks). Haematological adverse events were: 23 episodes of neutropenia G1/2, 8 episodes of G3 and 3 episodes of G4 neutropenia; G1/2 thrombocytopenia occurred in 15 episodes; anemia G1/2 was reported in 13 episodes. Besides, we recorded 12 episodes of emesis G2 and 2 episodes of G3; 24 episodes of G1/2 and 7 episodes of G3 oral mucositis were recorded; diarrhoea G1/2 was a common event (around 50% of cycles) while severe diarrhoea was a rare. Alopecia G1/2 was registered in 19 pts, G1neurosensorial toxicity (specific scale) occurred in 16 pts, G2 in 7 pts and G3 in one pt. One pt had hypersensitivity reaction at first infusion that did not occurred anyone by prolonged infusion of L-OHP. Conclusions: Our data show that FOLFOX 4 is active in the treatment of A/MGC and that toxicity profile is favourable in elderly population in comparison to standard regimens.

No significant financial relationships to disclose.
Treatment outcomes with first and second line chemotherapy in advanced and metastatic pancreatic cancer patients
Authors: Mancuso A. , Saletti P. , Sacchetta S. , Romagnani E. , Cavalli F. , Sternberg C. N.
Published: March 2020

14107

Background: Recent advances in the treatment of pancreatic cancer might influence the management of locally advanced and metastatic disease, nonetheless prognosis remains dismal (1-year survival rates: 24%). The impact on survival of palliative second-line therapy is hotly debated. Methods: We retrospectively reviewed the clinical records of 103 pancreatic cancer patients admitted to San Camillo/Forlanini Hospital (Rome, Italy) and the Oncology Institute of Southern Switzerland during the period June, 1997 to August, 2005 [60 males, 43 females, median age 65 years (range 43–80); median ECOG performance status (PS): 1]. All patients received Gemcitabine as single agent (90%) or in combination with Oxaliplatin (10%) as upfront therapy. A total of 12 fluoropyrimidine-based salvage regimens were administered to 46 patients in the second line setting. Best supportive care was selected in 57 patients after failing first line therapy. Results: Of 103 evaluable patients, first line chemotherapy produced overall tumor growth control of partial response (PR) and stable disease(SD) by RECIST criteria of 52.4% with a median progression free survival (PFS) of 4.6 months. Multivariate analysis revealed that the most important prognostic factor for PFS was the patient’s PS, as patients with PS of 1–2 at diagnosis had significantly worse results than patients with PS = 0 (First line PFS: 110 days vs 193 days, p<0.05). Baseline CA19–9 and number of metastatic sites were not independent prognostic factors for better first-line PFS. PR was observed in 8/46 patients (17.3%) who received second line chemotherapy, SD in 10 (21.7%), and 28 patients progressed (61%). Median overall second line PFS was 3.2 months. Patients who had responded to first-line Gemcitabine were more likely to respond or attain stable disease with second-line treatment, with a PFS of 5.6 vs 2.85 months (p<0.05). The overall survival for all evaluable patients was 8.4 months. 1-year survival was 52% for patients treated with second line therapy. Conclusions: These results are consistent with historical studies and suggest that fluoropyrimidine-based salvage regimens have marginal but definite activity and should be considered in patients who have responded to first line chemotherapy with an optimal PS.

No significant financial relationships to disclose.
Weekly high-dose 5-FU as 24h-infusion and folinic acid (AIO regimen) plus Irinotecan in patients with advanced non-resectable adenocarcinoma or squamous epithelial carcinoma of the oesophagus: Interim analysis of a phase II trial
Authors: Boxberger F. , Wolff K. , Brueckl V. , Brueckl W. M. , Meier C. , Maennlein G. , Horbach T. , Hohenberger W. , Hahn E. G. , Wein A.
Published: March 2020

14109

Background: At the moment of establishing the diagnosis, in approximately 50–60% of the patients with esophageal carcinoma only palliative treatment is possible due to either a locally advanced tumour growth or due to distant metastases. While adenocarcinomas of the esophagogastric junction are increasingly treated like gastric carcinomas, no palliative standard regimen is established for advanced squamous carcinomas of the oesophagus. The question should be answered whether the AIO regimen plus Irinotecan may achieve similarly positive results in esophageal carcinomas as in gastric carcinomas. Methods: Prospective phase II trial, patients: n=20, trial start: 03/2003, chemotherapeutic regimen: Irinotecan (80 mg/m2 i.v. as 1h-infusion; d 1, 8, 15, 22, 29, 36, qd 57) as well as folinic acid (500 mg/m2 i.v.) together with 5-Fluorouracil (2000 mg/m2 i.v.; d 1, 8, 15, 22, 29, 36, qd 57) as 24h-infusion via port catheter. Results: n=16 (adenocarcinomas: n=8, squamous epithelial carcinomas: n=8); median age: 59,3 (44–72) years; men/women: 13/3; ECOG 0/1/2: 4/11/1; chemotherapeutic applications: 314. Evaluable in terms of toxicity: n=16. Higher grade toxicity: grade III diarrhea: n=2, grade III hyponatremia: n=1, thrombosis of the vena subclavia: n=1, grade III stomatitis: n=1, ischemic lesion of the brain stem: n=1. Two patients died after 2 chemotherapeutic applications with known peritoneal carcinomatosis and high tumour burden. Evaluable in terms of response: n=13. PR: n=7 (54%), SD: n=4 (31%), PD: n=2 (15%). Conclusion: The AIO regimen plus Irinotecan is excellently manageable on an outpatient basis in a multimorbid patient group and shows high efficacy in both adenocarcinomas and squamous epithelial carcinomas of the oesophagus. Final results, however, particularly in terms of median survival, still remain to be seen.

No significant financial relationships to disclose.
Phase I/II trial of nemorubicin hydrochloride in combination with cisplatin is supported by new preclinical evidences of its mechanism of action
Authors: Pacciarini M. A. , Geroni C. , Sabatino M. A. , Ciomei M. , Valota O. , Ballinari D. , Capolongo L. , Broggini M.
Published: March 2020

14116

Background: Nemorubicin hydrochloride (nemorubicin) is a non-conventional anthracycline in Phase II evaluation in hepatocellular carcinoma (HCC). Its mechanism of action is not fully elucidated. Although structurally related to doxorubicin, nemorubicin is a topoisomerase I inhibitor, overcomes anthracyclines resistance, is minimally cardiotoxic and is biotransformed by hepatic CYP3A4 into hundred times more cytotoxic metabolite. Phase I and II trials were conducted in Europe and China to test nemorubicin by hepatic intra-arterial (IHA) infusion in HCC patients (pts). The drug was well tolerated up to 600 mcg/m2 q4–6w; DLT was transient liver transaminase elevations. Overall, 57 HCC pts were evaluable for efficacy, with 11/57 confirmed liver CR/PRs (RR = 19.3%; 95% ci 10–31.9%) lasting 1–54+ months. Stable disease ≥ 3 months was observed in 17/57 (29.8%) pts, most with AJCC Stage III, IIIA and IVA. These data supported new trials of nemorubicin in HCC. Methods: To further characterize the mechanism of action of the drug, we generated cells (L1210) resistant to nemorubicin. Since resistant cells were more sensitive than the parental ones to UV irradiation, we reasoned that the nucleotide excision repair (NER) system might be involved in mediating the activity of nemorubicin. To test this hypothesis we used isogenic CHO cells proficient or deficient in excision repair cross-complementing (ERCC) genes, namely ERCC1 and ERCC6 genes. Results: In contrast with what is observed for most DNA damaging drugs that show resistance in the presence of high NER activity, nemorubicin is more cytotoxic in NER proficient than in deficient cells. This suggests that NER pathway plays a role in the cytotoxic effect of nemorubicin. Also, cells resistant to nemorubicin are NER-deficient and are highly sensitive to platinum derivatives and alkylating agents and synergism was found combining cisplatin with nemorubicin. Conclusions: Nemorubicin has a peculiar mechanism of action through the NER system providing the rationale for clinical combination studies with platinum derivatives. A Phase I/II trial of nemorubicin with cisplatin in HCC patients started in Italy at the end of 2005.

No significant financial relationships to disclose.
Chemoradiotherapy in anal carcinoma using cisplatin and 5FU
Authors: Calderillo G. , Cano C. , Ruiz J. M. , Zamora J. , Lopez H. , Martinez J. , Gallardo D.
Published: March 2020

14128

Background: Chemoradiation (CRT) is now established as the primary treatment for anal carcinoma. The original combination was 5Fu and mitomycin C, but the cisplatin may offer better local control than the standar of MMC with toxicity more tolerable. Methods: Between March 2000 and January 2005, 25 patients with anal carcinoma advanced with non pre-treated were enrolled. Eligible patients had an ECOG PS 0–2. They received cisplatin 80–100 mg/m2 day 1 and 5FU 800–1000 mg/m2 day 1–4 every 4 weeks and radiotherapy >45 Gys. Results: 25 patients, 12 male and 13 female, median age 63 (range 36–83 y). 22 with squamous cell carcinoma and 3 adenocarcinoma. (A) 11 patients recieved QT concurrente with RT, median cycles 2 and median of RT 50 Gys and (B) 14 patients recieved QT follow QT-RT concurrent, median cycles 3.5 and median of RT 48 Gys. The toxicity 3–4 were: neutropenia 23%, anaemia 4%, trombocytopenia 8%, diarrhea 15%, vomiting and nausea 19%. The evaluation: (RC) (64%), (RP) (28%) and PD (8%). The median survival 15.5 m (9–42 m), 12 m group A vs 16 m group B. Conclusions: The combination RT-QT with cisplatin and 5FU is feasible and tolerable, and may offer more the secuencie QT follow CRT.

No significant financial relationships to disclose.
The mechanisms of apoptosis induced by artistical composition of Chinese medicinal herbs in gastric cancer metastasis
Authors: Li J. , Sun G.
Published: March 2020

14147

Background: In China, gastric cancer has been treated by Chinese medicinal herbs to prevent relapse and metastasis for decades. The purpose of this study is to investigate the effectiveness and the mechanism of artistical composition of Chinese medicinal herbs (YWKL) in preventing gastric cancer metastasis. Methods: The herbs, after decoction, were administered by feeding 615 mice, which is a proventriculus cancer (FC) transplanted model, the rate of its lung metastasis rate is 70–80%. The inhibitory effect of artistical composition of Chinese medicinal herbs on FC spontaneous lung metastasis was evaluated by histological classification method. Apoptosis were determined through TUNEL technique. The expression of apoptosis relative gene was determined by immunohistochemical methods. Results: It has been found that YWKL can significantly decrease the tumorous node numbers in the lung, while increase the apoptosis cell index (AI) of tumor cell metastasizing to lung. We found the expression of Fas,Bax were much higher than that of control group, FasL and Bcl2 were no significantly different between the two groups. Conclusions: The oral application of the herbs after decoction was demonstrated to prevent gastric cancer metastasis mice model. The mechanism of YWKL-induced apoptosis in FC cancer cell might through regulating the expression of Fas and Bax genes.

No significant financial relationships to disclose.
The importance of etoposide dose intensity in the management of metastatic germ cell tumours and the role of paclitaxel in salvage treatment of relapsing patients
Authors: North S. A. , Marwaha S. , Venner P. M.
Published: March 2020

14502

Background: The primary objective was to evaluate the effect of etoposide dose intensity in the standard cisplatin/etoposide/bleomycin (PEB) regimen on progression free (PFS) and overall survival (OS). Secondary objectives were and to determine how the addition of paclitaxel in salvage regimens impacts OS and to compare the risk distribution of germ cell patients seen at a tertiary care centre to that quoted in the International Germ Cell Consensus Classification (IGCCC). Methods: A retrospective chart review of all 302 germ cell patients requiring cisplatin-based chemotherapy between January 1980 and December 2004 was conducted. Data collected on initial treatment included the dose of etoposide: 500 mg/m2/cycle (E500) or 360 mg/m2/cycle (E360) and whether the salvage treatment contained paclitaxel or not. PFS and OS were calculated. Patients were risk stratified as per IGCCC variables. Results: In the PEB regimen, E500 is superior to E360 as it results in a relapse rate of only 3% and an overall survival of 97% compared to a relapse rate and survival of 29% and 80% respectively. The addition of paclitaxel to salvage chemotherapy regimens for patients relapsing results in 1/5 (20%) of patients dying compared to 26/39 (67%) for those receiving a non-paclitaxel based salvage regimen. The distribution of seminoma patients was similar to the IGCCC (90% good risk, 10% intermediate risk). Non-seminoma (NS) patients were skewed to the good-risk category: 71% good risk, 10% intermediate risk and 18% poor risk as compared to 56%, 28% and 16% respectively as reported by the IGCCC. 5-year PFS and OS were comparable to those documented by the IGCCC with the exception of the intermediate risk NS patients where our 5 year PFS was 48% compared to 75% expected but 5 year OS was similar in these patients (75% Vs. 80%). Conclusions: This review demonstrates that PEB treatment containing higher dose etoposide is superior in terms of PFS and OS. Although the sample size is small it appears that Paclitaxel containing salvage regimens results in superior outcomes compared to previously used salvage regimens. Our centre has a similar risk distribution of patients as that quoted by the IGCCC.

No significant financial relationships to disclose.
National study of patients, caregivers and physicians reveals pain associated with advanced prostate cancer as the primary concern
Authors: Moyad M. A. , Kirk T. A.
Published: March 2020

14505

Background: Over 50,000 men developed hormone refractory prostate cancer (HRPC) in 2005 (CancerMetrics 2005). The objective of this study is to compare attitudes of patients, caregivers and physicians on the effects of advancing disease on patients. Methods: Respondents indicated attitudes towards 18 PC symptoms. Responses were analyzed by a division of Yankelovich. Grant funding from Abbott.Us TOO International conducted an online survey of HRPC patients, caregivers, and physicians in 2005. Patients and caregivers were recruited from NexCura’s database of users of the Treatment Profiler Options Tool for PC and links from PC websites (UsTOO, PCRI, PCF and PAACT). Board certified physicians who treat HRPC were recruited by J. Reckner & Associates. Respondents indicated their attitudes towards 18 symptoms of advancing PC. Responses were analyzed by TSC, a division of Yankelovich. Results: 409 HRPC patients (P), 236 caregivers (C), and 204 physicians (MD) (100 urologists/104 oncologists) participated in the study. Mean patient age was 65.7 and age at diagnosis was 60.2. Patients were identified as non-metastatic (M0) or metastatic (M+). 46% of patients were M+; 60% of caregivers are caring for M+ patients. 51% of M+ patients and 74% of M+ caregivers’ patients experienced bone pain. The most common symptom concerns were bone pain, other pain and mental changes. Conclusions: Over half of the M+ patients experienced bone pain related to PC in this survey. Once HRPC becomes M+, bone pain significantly affects the quality of life of patients and caregivers. It is the highest rated concern of patients, caregivers and physicians. Bone pain significantly alters the lives of those with advancing HRPC. New options are needed for patients with advancing PC. [Table: see text]

[Table: see text]
Mifepristone (RU-486) in androgen independent prostate cancer
Authors: Hayes J. H. , Oh W. K. , Kantoff P. W. , Manola J. B. , Smith M. R. , Gelmann E. P. , Bubley G. , Balk S. P. , Taplin M.
Published: March 2020

14508

Background: The androgen receptor (AR) plays a critical role in the development and progression of prostate cancer, and available antiandrogens do not turn off AR transcription completely. Mifepristone (RU-486) is a potent inhibitor of AR and acts by both competing with dihydrotestosterone (DHT) and binding with the AR co-repressor nuclear receptor co-repressor (NCoR), converting AR from a transcriptional activator to a transcriptional repressor. Methods: 22 patients with AIPC, PSA ≥5 ng/mL, and documented bone metastases were treated with mifepristone 200 mg PO QD until disease progression. Correlative studies include measurement of testosterone, cortisol, androstenedione, DHT, DHEA (dehydroepiandrosterone), and DHEA sulfate levels at baseline and during therapy. Results: Patients were treated a median of 84 days (range 10–182 d). Median PSA at time of enrollment was 41.9 ng/mL (range 5.2–1930.9 ng/mL). No patients demonstrated a PSA response. 13 patients have discontinued treatment, 12 for progressive disease (11 PSA progression and 1 bony progression) and 1 for grade 3 toxicity (GI bleed after 10 d on treatment). 6 patients are still on therapy with stable disease after a median 98 d. In 11 patients, baseline testosterone levels were mean 28.4 ng/dL (range <20–49 ng/dL). After one month of therapy, testosterone increased to mean 66.6 ng/dL (range 16–104 ng/dL) (p = 0.001). Compared to baseline, one month androstenedione and DHEAS levels were elevated in the majority of patients. Conclusions: Mifepristone demonstrated limited activity in AIPC patients. Potential efficacy was most likely limited by a rapid elevation in testosterone levels. We hypothesize that inhibition of glucocorticoid receptor led to an increase in ACTH with subsequent elevation of adrenal androgens and conversion to DHT. These preliminary data suggest that even moderate increases in systemic testosterone levels may stimulate tumor growth. These data also emphasize the continued importance of adrenal androgens and AR transcription in prostate cancer biology.

No significant financial relationships to disclose.
Role of prognostic factors in patients with metastatic renal cell carcinoma (MRCC) eligible for treatment with interleukin (IL2)
Authors: Muniswamy H. , Dutcher J. P. , Mannam P. , Malik S. , Rusciano V. , Paul L. , Wiernik P. H.
Published: March 2020

14514

Background: Motzer (JCO1999) defined 5 factors that predict for poor survival of patients with MRCC: low Karnofsky scale (<80%), high LDH (>1.5 times upper limit), low Hb (<lower limit of normal), elevated corrected calcium (10 mg/dl) and absence of nephrectomy. Method: We retrospectively evaluated 124 patients with MRCC (81 male/43 female, median age 54 years, range (R) 27 to 79 years) treated in our center from 10/98–12/05 with IL2 based therapy. Patients eligible for IL2 study were included. Patients were categorized into favorable (F - 0 risk factors), intermediate (I - 1–2 risk factors) and poor (P - 3 or more risk factors) groups. 89 patients had high dose (HD) IL2 (600,000 u/kg/dose every 8 hours up to 14 doses), and 35 patients had moderate dose (MD) IL2 (5 mu/m2/day for 5 days continuous infusion or 72,000 u/kg every 8h up to 14 doses). 26 patients had prior treatment. Prognostic factors were identified at the start of IL2 therapy. Primary endpoint was survival time defined as the time from initiation of IL2 treatment to time of death or December 2005 as the last follow up for all patients. Results: Analyzed using Kaplan-Meier method. Conclusions: 1. These prognostic factors apply to IL2 treated patients and separate them into prognostic groups. 2. HD IL2 treated patients have ≥ 6 months greater survival compared to MD IL2 treated patients or historical data. [Table: see text]

No significant financial relationships to disclose.
Phase II trial of motexafin gadolinium (MGd) for treatment of metastatic renal cell carcinoma (MRCC)
Authors: Misellati A. , Phan S. , Amato R. J.
Published: March 2020

14518

Background: MGd inhibits thioredoxin reductase. Thioredoxin is implicated in activation of hypoxia-inducible factor-1 alpha, which is overexpressed in >85% of renal cell carcinomas (RCC). We evaluated anti-tumor and safety activity of MGd in patients (pts) with progressive MRCC. Methods: Eligibility included: measurable MRCC, adequate organ/marrow function, zubrod performance status (ZPS) ≤2, life expectancy ≥12 weeks, ≤2 prior therapies and no active CNS involvement. MGd was infused intravenously over 30 minutes at 5mg/kg on days 1–5 and 15–19 of each 28-day cycle. Evaluation was performed after every 3 cycles. RECIST criteria were utilized to determine response rate. Time to progression (TTP) is determined from time of study entry. Results: 25 evaluable pts were enrolled 19 male/6 female, median age 63 years (range 38–76). All pts had histologic confirmed RCC; 9 pts had clear cell carcinoma, 9 pts with predominant clear cell carcinoma component, 2 pts with papillary and 1 pt with collecting duct. 23 pts received prior systemic therapy, median 2 treatments. 16 pts had ZPS of 0, 8 pts had ZPS of 1, and 1 pt had ZPS of 2. All pts had progressive MRCC. Sites of disease included: lung, nodal, bone, adrenal, kidney and liver. 7 pts had 1 metastatic site, 6 pts had 2 and 12 pts had 3 or more. 20 pts have completed at least 12 weeks of therapy. 5 pts progressed within 3 months. 1 pt had a complete response of lung metastasis but progressed in the CNS. Median TTP is 12 weeks (3–69). Median overall survival is 10.1+ months (1–19+). Grade 1/2 toxicity consisted of: skin discoloration, fatigue, nausea, and headache. Grade 3/4 toxicity consisted of: blisters of the digits and hypophosphatemia. Conclusions: MGd was well tolerated and stabilization of disease was observed in pts with progressive disease. These results show promise for MGd in the previously treated MRCC population and potentially can be used in combination with other MRCC agents.

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Burden of illness analysis of renal cell carcinoma
Authors: Lang K. , Danchenko N. , Gondek K. , Schwartz B. , Thompson D.
Published: March 2020

14548

Background: There were over 36,000 new cases of kidney cancer reported in the US in 2004, the most common being renal cell carcinoma (RCC). RCC patients have limited treatment options and low survival rates, particularly for advanced-staged patients. Despite the growing importance of RCC, data on its economic burden are limited. Methods: A prevalence-based approach was used to estimate the aggregate annual cost burden from a societal perspective, including costs of medical treatment and lost productivity, due to RCC in the U.S. Key relationships represented in the model include the annual number of patients treated for RCC by age group and cancer stage; utilization of cancer specific treatments; unit costs of these treatments; work-days missed by these patients, and wage rates. Data sources included the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, the Bureau of Labor Statistics, and the published literature. Results: The annual prevalence of RCC in the US was estimated to be 109,500 cases. The associated annual burden of RCC (US $2005) was approximately $4.8 billion ($43,749 per patient). Healthcare costs and lost productivity accounted for 84.9% ($4.1 billion) and 15.1% ($726 million) of the total, respectively. Reflecting its higher prevalence, the total cost associated with localized RCC accounted for the greatest share (78.2%) followed by regional, distant and unstaged RCC, which accounted for 18.3%, 2.8% and 0.7%, respectively. Sensitivity analyses resulted in a range in the estimated annual burden from $3.9 to $5.2 billion. Focusing only on newly diagnosed RCC cases (approximately 25,000 per year), the annual burden was estimated at $1.5 billion, with a per-patient cost of $62,340. Conclusions: The economic burden of RCC in the US is substantial. New therapies for RCC have the potential to yield considerable economic and societal benefits.

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The treatment of primary and metastatic renal cell carcinoma (RCC) with stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS)
Authors: Teh B. S. , Bloch C. , Paulino A. C. , Doh L. , Chiang S. , Shen S. , Baskin D. , Jac J. , Amato R. J.
Published: March 2020

14572

Background: RCC is often regarded as a radio-resistant tumor. However, brain metastases from RCC have been successful treated with SRS. Therefore, metastases to extra-cranial sites may be treated with similar success using stereotactic body radiation therapy (SBRT), where image-guidance allows for the delivery of precise high dose radiation in a few fractions. We report our experience with SRS/SBRT in the management of primary and metastatic RCC. Methods: The image-guided Novalis radiation therapy system was used. Thirty patients with brain metastases were treated with SRS (16–22 Gy in a single fraction). Five of these patients underwent resection of their metastatic lesions after SRS and their pathology were reviewed. Twenty patients with extra-cranial metastatic lesions (orbits, head and neck, lung, mediatinum, sternum, clavicle, scapula, humerus, rib, spine, abdomen) and 2 patients with biopsy proven primary RCC (not surgical candidates), were treated with SBRT (24–32 Gy in 3–4 fractions over 1–2 weeks). All patients were immobilized in body cast and image-guidance was used for all fractions. 4D-CT was utilized in the treatment planning to assess tumor motion. Results: Of the 30 patients who received SRS to brain metastases, 25 showed decreasing or stable lesion size. Five patients showed an increase in size and underwent resection. Their pathology revealed necrosis in >99% of the specimen, with no viable RCC. Nineteen patients who received SBRT to extra-cranial metastases achieved symptom relief. One patient had local progression, yielding a local control rate of 95%. In the 2 patients with primary RCC, tumor size remained unchanged but their pain improved, and their renal function was unchanged post SBRT. There was no significant treatment related side-effect. Conclusions: Precise high dose radiation can cause significant tumor cell death in “radio-resistant” metastases from RCC. It also offers excellent local control and symptom palliation, without significant toxicity. Therefore, SBRT may represent a novel non-invasive, nephron-sparing option for the treatment of primary RCC as well as extra-cranial metastatic RCC. A prospective clinical trial using SBRT for primary and metastatic RCC is on-going.

No significant financial relationships to disclose.
Phase II trial of gemcitabine and cisplatin as neoadjuvant chemotherapy for invasive bladder cancer: Preliminary results
Authors: Dienstmann R. , Herchenhorn D. , Peixoto F. A. , Campos F. , Santos V. O. , Moreira D. M. , Moreira D. M. , Small I. A. , Cardoso H. , Ferreira C. G.
Published: March 2020

14590

Background: Gemcitabine and cisplatin (GC) is an active and well tolerated combination in the treatment of metastatic bladder cancer (BC). Studies of neoadjuvant chemotherapy in BC suggest improved survival, especially for patients with complete pathologic response. We have prospectively analyzed the tolerability and efficacy of GC as neoadjuvant treatment of invasive BC. Methods: in this single-institution, one-stage phase II trial, patients (pts) with histologically verified muscle-invasive transitional cell carcinoma received 3 cycles of gemcitabine 1200 mg/m2 on days 1 and 8 with cisplatin 75 mg/m2 on day 1 prior to surgery. Radiologic response was evaluated with computed tomography and magnetic resonance imaging. Planned accrual was 35 pts. Primary endpoint was clinical and pathological response rate. Results: between Jun 2002 and Mar 2005, 22 pts (19 males) were enrolled. Accrual was poor due to a higher percentage of superficial tumors than expected. Median age was 61 years. All pts had Performance Status 0 or 1. Initial stage was II (T2) in 11 and III (T3–4) in 11 pts. Chemotherapy was well tolerated with infrequent grade III/ IV toxicity (nausea/ vomiting in 27%, neutropenia in 23% and neutropenic fever in 1 patient). Median follow-up is 26 months (6–40). Partial radiologic response rate was documented in 15 out of 19 assessable pts (79%). One patient was excluded due to renal toxicity in the first chemotherapy cycle and other had sarcomatoid carcinoma at definitive pathologic examination. By Dec 2005, 14 pts underwent radical cystectomy, 4 pts pelvic radiotherapy, 1 is waiting surgery and 1 had systemic progression before surgery. Nine out of 20 pts (45%) relapsed (8 systemic and 1 local) and 4 (20%) are dead (3 with confirmed disease progression). Complete pathologic response was observed in 3 pts (21.5% of 14) and local progression during chemotherapy in another 3 pts. Median estimated progression-free survival by Kaplan-Meier is 27 months (CI 95% 20.5–33.5) with median overall survival not reached. Conclusions: the combination of gemcitabine and cisplatin is effective and tolerable when used as neoadjuvant therapy in muscle-invasive bladder cancer. Longer follow-up is necessary to evaluate its impact in the overall survival of these pts.

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Chemotherapeutic management of adrenocortical carcinoma: The M. D. Anderson Cancer Center experience
Authors: Fareau G. G. , Vassilopoulou-Sellin R.
Published: March 2020

14592

Background: Adrenocortical carcinoma (ACC) is a rare cancer associated with a poor prognosis. We describe our experience with the effectiveness of various chemotherapies in the treatment of ACC. Methods: We performed a detailed retrospective review of every patient diagnosed with ACC at the M.D. Anderson Cancer Center between the years 1980 and 2000. We included only those patients with a histological diagnosis of ACC who had radiologically measurable disease and received chemotherapy followed by post-treatment imaging. Patients without a pathological diagnosis, serial imaging studies, or adequate follow-up were excluded from our study. In each case, we compared radiological tumor burden after a given drug or drug combination to the radiological tumor burden preceding the treatment session. Radiologist reports were used to categorize post-treatment imaging studies as showing either a decrease in tumor burden, no change in tumor burden, or an increase in tumor burden. Patients who did not have post-treatment imaging due to rapid progressive clinical deterioration were regarded as having increased tumor burden. Results: 224 patients with a diagnosis of ACC were identified in our database, of which 62 had histological confirmation and received chemotherapy with documented radiological follow-up. 38 different chemotherapeutic regimens were reviewed. Patients given single agent fluorouracil, taxol, taxotere, trimetrexate, navelbine, and patients given combination treatment with cyclophosphamide/adriamycin/cisplatin, gemcitabine/taxotere, and mitotane/cisplatin/taxol did not show any improvement. Treatment with single agent mitotane and combination VP-16/cisplatin resulted in either no change or decrease in tumor burden in over 50% of sessions. Promising trends were seen in patients treated with single agent VP-16 and carboplatinum, and with combination adriamycin/cisplatin/ifosfamide, mitotane/cisplatin, and VP-16/adriamycin/cisplatin. Conclusions: We have identified specific drugs and drug combinations of no apparent benefit in this cohort, and have also identified select agents and combinations which offer benefit. Further prospective clinical trials should focus on the use of those agents and combinations which offer benefit.

No significant financial relationships to disclose.
Phase II study of intravenous vinorelbine plus hormone therapy in hormone-refractory prostate cancer
Authors: Silva E. , Silva F.
Published: March 2020

14601

Background: Vinorelbine (VRL) has been shown to be active in hormone-refractory prostate cancer (HRPC) in Phase II studies, alone or in combination. Its moderate toxicity profile is well tolerated in elderly patients. The purpose of this study was the investigation of the efficacy of vinorelbine and its toxicity. Methods: Patients with metastatic prostate cancer, progressive after hormonal therapy, receive intravenous VRL 30 mg/m2 on days 1 and 8 every 3 weeks, and hydrocortisone 40 mg/day. Previous chemotherapy was allowed if stopped 6 months before. 44 received VRL according to the protocol. Inclusion criteria: hormone refractory prostate cancer patients PSA >20; performance status WHO < 2. The primary endpoint was prostate specific antigen (PSA) levels, pain, and WHO performance status. Their mean (range) age was 71 (45–80) years, their median prostate specific antigen (PSA) level was 286 (38–950) ng/ml, and the median Gleason score was 8 (7 to 9). 38 patients had had previous chemotherapy. Results: Among the 44 patients, 7 with less than 3 cycles were not evaluated. Patients received a mean (range) of 9 (3–44) cycles of therapy. 6 patients (14%) had not been dispensed prior chemotherapy and 38 (86%) had; 19 (43%) had 2 lines of chemotherapy and 19 (43%) had 1 line. The median follow-up was 13 months. There were no reported drug related Grade 3 toxicities. Only 2 patients required a blood transfusion. Tumour responses: 7 (16%); 17 (39%) PSA stable; 13 (29%) PSA progression, 7 not evaluated. Time of PSA response was 7 months; time to progression: 7 months. Conclusions: Vinorelbine (VRL) is a safe regimen in previous poly-chemotherapy treated hormone-refractory prostate cancer elderly patients and even with response and efficacy.

No significant financial relationships to disclose.