bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of triapine in combination with gemcitabine (G) in patients (pts) with unresectable or metastatic pancreatic cancer (PC)
Authors: Greeno E. , Kindler H. L. , Peeters M. , Trowbridge R. C. , Chong G. , Valle J. W. , Johnson B. , Allain E. L. , Burris H. A.
Published: March 2020

4123

Background: Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone [T]) is a small molecule that inhibits ribonucleotide reductase at a site distinct from G. In tumor cell lines, pre-exposure to T enhances G uptake and DNA incorporation, and yields synergistic cytotoxicity. A phase I trial of T + G showed that the combination was well-tolerated and produced T serum concentrations sufficient to modulate G activity in vitro (Ca Chemother Pharmacol, 2004). Methods: We conducted a phase II trial of T + G in advanced PC pts at 7 centers. Eligible pts were untreated, had measurable disease and ECOG PS 0–2. T was given by 4-hr infusion followed by G 1000 mg/m2 on days 1, 8, and 15 of a 4-week schedule. Since preclinical studies showed longer exposure of T maximized synergy between the agents, the protocol was amended to administer T over 24 hrs continuously (CI) prior to G. Pts were assessed for response q 2 cycles and retreated to progression or toxicity. Results: Sixty pts (median age 62, range 37–88) were treated with T by 4-hr infusion (median 4 cycles, range 1–18). Pt characteristics included M:F 39/21; PS 0/1/2 = 25 (42%)/34 (57%)/1 (2%); metastatic/locally advanced 72/28%. Eight (15%) patients achieved PR; and 32 (60%) had stable disease. Median survival was 8 mos; 13% are alive at 1 yr. The next 6 pts (median age 54, range 50–69, M/F: 3/3) received T at a fixed dose of 400mg CI + G. Two pts were evaluable for response; 1 pt had PD, 1 pt is on treatment after 14 cycles. Due to excessive myelosuppression the dose of T CI was reduced to 105 mg/m2. Of 7 pts (median age 60, range 34–73) treated, 2 had PD, 1 was unevaluable, and 4 remain on tx. T toxicity included hypotension, hypoxia, rash and dyspnea in < 10% of pts. In the 2 CI groups (N=13), the only toxicity attributed to T was excessive myelosuppression, requiring G dose reduction in all pts. Survival data on CI pts pending. Conclusions: T + G shows activity in PC. As predicted by preclinical studies, prolonged exposure (CI) enhances biological effect of T + G evidenced by increased myelosuppression without additional toxicities. Further studies are warranted to define the optimal dose of T CI with G.

[Table: see text]
Image-guided intensity modulated radiation therapy (IG-IMRT) affords increased survival for biliary tract tumors: Results from preliminary analysis
Authors: Starling G. , Fuller C. D. , Thomas C. R. , Fuss M.
Published: March 2020

4131

Background: The purpose of this study is to determine the effect of image-guided radiotherapy on survival in adenocarcinoma of the biliary tract. Methods: Between 1995 and 2005, 43 pts with primary biliary tract (gallbladder or bile duct) neoplasms were treated with radiotherapy. 26 of the pts were female and 17 were male. Their average age at registration was 64, and ranged from 25 to 86. Twenty-five pts (58%) were Hispanic, while 18 (42%) were white. 31 pts (72%) underwent surgical treatment, most having cholecystecomy (50%). 29 pts (67%) had chemotherapy: 21 (72%) were given fluorouracil-based drugs, 2 (7%) received gemcitabine, and 6 (21%) received other agents. 23 pts (53%) received conventional radiation treatment using AP/PA, AP/PA with opposing lateral, or AP with opposing lateral fields. 20 pts (47%) received IG-IMRT using Nomos Peacock and daily ultrasound image guidance (BAT, Nomos, Cranberry, PA). For daily ultrasound-based image-guidance, sagittal and axial ultrasound images were acquired, and used to align pt anatomy through superimposition of CT derived organ and vascular guidance structures. Pts were treated using a boost technique to a reduced volume at gross disease after an initial dose to gross tumor and clinically evident microscopic disease. Results: Median dose to target was 54 Gy, with median conventional and IG-IMRT total doses of 48.6 and 60 Gy respectively (p=0.05). Treatment was well tolerated, with only two patients reporting RTOG grade 3 toxicity. All other patients exhibited Grade ≤2, with 23/43 reporting Grade ≤1 The median survival time from the date of registration for all patients was 8.7 months; conventional RT pts had a median survival of 6.1 months, while the IG-IMRT cohort had a median survival of 11.4 months (p = .02). Conclusions: Ultrasound-based image-guided IMRT is a feasible mechanism of delivering moderate dose escalation in conjunction with tighter safety margins, resulting in acceptable acute toxicities. Early survival data with this novel technique are encouraging and demonstrate a notable survival differential using image guided radiotherapy as component of multi-modaility regimens.

No significant financial relationships to disclose.
A prospective multicenter phase II trial of capecitabine plus oxaliplatin (CapOx) in advanced biliary system adenocarcinomas: The final results
Authors: Nehls O. , Oettle H. , Hartmann J. , Hofheinz R. , Hass H. , Hochhaus A. , Stieler J. , Koppenhöfer U. , Gregor M. , Klump B.
Published: March 2020

4136

Background: To investigate the safety and efficacy of capecitabine and oxaliplatin combination therapy (CapOx) in unresectable or metastatic adenocarcinomas of the biliary system. Methods: 65 patients (pts) (27 male, and 38 female) were enrolled (median age, 61 yrs). Major eligibility criteria: histologically proven, measurable disease, age ≤ 75 yrs, ECOG PS 0–2. A total number of 364 cycles (median, 5; range, 1–16) of oxaliplatin (130 mg/m2, d1) plus capecitabine (2 g/m2, d 1–14) were administered 3 weekly for gallbladder carcinoma (GBC) (27 pts), extrahepatic (20 pts), and intrahepatic (18 pts) cholangiocarcinoma (CCC). Response rates were assessed according to WHO criteria. Clinical outcome was determined separately for pts with either GBC/extrahepatic CCC or intrahepatic CCC (mass-forming type). Results: Grade 4 toxicities (WHO): diarrhea in 1 pt (1% of cycles), thrombocytopenia in 1 pt (1%), leukocytopenia in 1 pt (1%), and fever in 2 pts (1%); grade 3 toxicities: nausea/vomiting in 1 pt (1%), diarrhea in 2 pts (1%), thrombocytopenia in 3 pts (2%), and fever in 1 pt (1%). Grade 3/4 peripheral sensory neuropathy (Lévis scale) was found in 13 pts (14% of cycles). Two pts were excluded from study because of oxaliplatin-related allergic reactions. One patient died due to sepsis and another due to cerebral insult during the first treatment cycle. The overall disease control rate in 47 pts with GBC or extrahepatic CCC was 72% (complete response (CR), n = 2 (4%); partial response (PR), n = 11 (23%); stable disease (NC), n = 21 (45%)), whereas progressive disease (PD) was found in 13 pts (28%). In 18 pts with intrahepatic mass-forming CCC, no CR or PR was observed, 5 pts (28%) had SD, and 13 pts (72%) experienced PD. Conclusions: The CapOx protocol is well tolerated and remarkably active for advanced GBC as well as extrahepatic CCC with a disease-control rate of 72%. However, activity appears to be limited in the subset of pts with intrahepatic mass-forming type tumors. Survival data will be presented at the meeting.

No significant financial relationships to disclose.
A proposed staging system for diffuse malignant peritoneal mesothelioma patients undergoing cytoreductive surgery and perioperative intraperitoneal chemotherapy
Authors: Sugarbaker P. H. , Yan T. , Yoo D. , Brun E. , Cerruto C. , Chang D.
Published: March 2020

4150

Background: There is no staging system available for diffuse malignant peritoneal mesothelioma (DMPM). This study evaluated seven clinical, seven radiological and twelve histopathologic prognostic parameters for survival of patients with DMPM. Methods: Between September 1989 and September 2005, sixty-two DMPM patients who were treated in a uniform fashion utilizing cytoreductive surgery combined with heated intraoperative intraperitoneal chemotherapy, with cisplatin and doxorubicin, followed by early postoperative intraperitoneal paclitaxel from postoperative day 1 to day 5 were included in this study. All prognostic parameters were analyzed in univariate and multivariate analyses using overall survival as the endpoint. The clinical and radiological data were obtained prospectively. A review of the histopathological features of DMPM was performed by two experienced pathologists, who individually evaluated each case. The mean number of specimens taken from separate anatomic sites was 11 ± 4 per patient. The mean number of slides studied was 20 ± 8 per patient. Results: The median follow-up was 37 months (range 8 to 143 months). The overall survival was 79 months (range 1 to 143 months) and 5-year survival was 50%. The following 14 prognostic variables were significant for survival in the univariate analysis: gender (p = 0.045), peritoneal cancer index (p = 0.038), completeness of cytoreduction score (p = 0.010), interpretive CT findings of the small bowel (p = 0.001), histologic type (p < 0.001), nuclear size (p < 0.001), nuclear/cytoplasmic ratio (p < 0.001), mitotic count (p < 0.001), atypical mitosis (p < 0.001), chromatin pattern (p < 0.001), cellular necrosis (p < 0.001), perineural invasion (p = 0.037), stroma pattern (p < 0.001) and depth of invasion (p = 0.014). In the multivariate analysis, the only factor that was independently associated with an improved survival was nuclear size. The 3-year survival rates with nuclear size of 10–20 μm, 21–30 μm, 31–40 μm and > 40 μm were 100%, 87%, 27% and 0%, respectively. Conclusions: Nuclear size was the dominant factor determining overall survival in patients with DMPM. A histopathological staging system based on measurement of the nuclear size was proposed.

No significant financial relationships to disclose.
Treatment of HIV positive anal cancer patients with chemoradiation
Authors: Hwang J. M. , Rao A. , Shieh E. , Yao J. , Tome M.
Published: March 2020

4154

Background: Tolerance and outcomes of HIV+ anal cancer patients are questioned, especially since the emergence of High Active Anti-Retroviral Therapy (HAART) in the mid-1990s. Our experience in treating these patients before and during the HAART era is reported. Methods: From 1987–2003, 19 HIV+ invasive anal cancer patients were treated with: 30–60 Gy pelvic RT (2 Gy/d) + Mitomycin C (10 mg/m2 bolus on d1) + 5-FU (1000 mg/m2/d, continuous infusion d1–4 and 28–31). Results: Mean CD-4 count at cancer diagnosis was 311, with 9 on HAART. Mean CD-4 count for HAART was 383 and 247 for non-HAART. Stage distribution: 1 T1, 9 T2, 9 T3, 18 N0, 1 N3. Mean f/u was 40 months. 79% had complete response after chemoRT. 4 had locally persistent disease. There was 1 loco-regional recurrence and 2 distant metastases. 79% of the cohort is colostomy-free. Median OS has not been reached. OS at 2 and 3 years were: 88%and 79%, with 10 Alive and NED, 1 Alive with disease, 3 Dead of disease, 5 Dead from intercurrent disease (all secondary to AIDS). 1.5 year DFS was 74%. Break and CD-4 count < 200 had a statistically significant negative impact on DFS, but not OS. HAART did not affect either factor. 11 had RT break for median of 17 days. There was no Grade 4 skin toxicity. All completed the 2nd 5-FU cycle: 7 had delay (median 7 days) and 3 had dose decrease. There were 6 hospitalizations: 5 neutropenic fevers and 1 perineal abscess rupture. WBC Toxicity: 6-Grade 3 and 2-Grade 4. Platelet Toxicity: 2-Grade 3. Heme toxicity was not affected by HAART or CD4 count < 200. There were no treatment related deaths. Conclusion: HIV+ anal cancer patients have reasonable tolerance and outcomes with chemoRT. CD-4 count < 200 and break were negative prognostic factors for DFS. Our 79% colostomy free survival is similar to RTOG 9208, where suboptimal control was attributed to mandatory RT break. Factors influencing break include heme and skin toxicity. To improve the therapeutic ratio, substitution of Mitomycin-C with Cisplatin, IMRT, and Ethyol are being explored.

No significant financial relationships to disclose.
Bevacizumab with or without erlotinib in metastatic renal cell carcinoma (RCC)
Authors: Bukowski R. M. , Kabbinavar F. , Figlin R. A. , Flaherty K. , Srinivas S. , Vaishampayan U. , Drabkin H. , Dutcher J. , Scappaticci F. , McDermott D.
Published: March 2020

4523

Background: Bevacizumab (B) has clinical efficacy in metastatic RCC following cytokine treatment. A single-arm Phase II trial suggested potential clinical benefit of adding erlotinib (E) to B. To further assess this combination in RCC, we conducted a multicenter, randomized, double-blind Phase 2 trial comparing B+E vs B + placebo. Methods: Eligibility criteria included: previously untreated metastatic RCC with >50% clear cell histology; previous nephrectomy; ECOG PS 0 or 1; measurable disease; serum Ca++ ≤ 10 mg/dL; LDH ≤ 1.5 ULN; Hgb ≥ 9 g/dL; and standard exclusion criteria for B. All pts received B 10 mg/kg IV q 2 wk with either E 150 mg po daily or placebo until disease progression or unacceptable toxicity. Tumors were assessed using RECIST every 8 wks. A landmark analysis was performed 9 mo after accrual of the last pt. Objective response rate (ORR) and progression-free survival (PFS) were co-primary endpoints. Secondary endpoints included response duration, overall survival, and safety. Results: 104 pts (53 B, 51 B+E) were enrolled at 20 sites from Mar 2004–Oct 2004. 65 pts have discontinued therapy. 55 have progressed (PFS HR = 0.86, CI 0.5, 1.49). Median follow-up was 9.8 mo. Median survival duration was not reached. Only 1 treatment-related death due to GI perforation occurred (on B+E). Updated safety and survival data will be presented. Conclusions: B+E and B were well tolerated. Adding E does not appear to improve efficacy from B. PFS of 8.5 months with B compares favorably with the historical PFS of ∼ 4.7 mo with interferon alpha (IFN). Results of phase III trials comparing IFN ± B are pending.

[Table: see text]

[Table: see text]
The von Hippel-Lindau gene mutation is associated with the good-prognosis profiling subtype of clear cell renal cell carcinoma
Authors: Tan M. , Teh B.
Published: March 2020

4532

Background: The prevalence of von Hippel-Lindau (VHL) mutations in clear cell renal cell carcinoma (ccRCC) is about 30–50%. The association between VHL mutation and patient prognosis remains controversial, despite extensive in vitro research on its role in hypoxia response. We have previously reported a robust prognostic classification of ccRCC using gene expression profiling. In view of reports of activity of anti-angiogenesis agents, we studied the association of VHL mutation with tumor profiling subtypes, survival and other clinical parameters. Methods: All exons of the VHL gene in 88 ccRCC samples were sequenced. Expression profiling using oligonucleotide arrays (54,675 probe sets) was also performed, and the samples classified using hierarchical clustering. For identification of VHL mutation specific signatures, nearest shrunken centroids with internal validation was used with a 10% misclassification cutoff. Results: 35% of the samples had VHL mutations. Mutation status was not significantly associated with survival on univariate analysis (p = 0.54). Hierarchical clustering yielded two ccRCC subtypes with divergent clinical outcomes (HR = 4.13, p < 0.001). VHL mutations were significantly associated with the good-prognosis profiling subtype of ccRCC tumors (OR 3.3, p = 0.04), but no effect modification between VHL mutation and the prognostic subtypes was found (p=0.31). No standard clinical parameter was associated with VHL mutation. No significant association between VHL mutation and downstream hypoxia response gene expression, including VEGF (p = 0.14), PDGF (p = 0.5), TGF-A (p = 0.24) and GLUT1 (p = 0.45) was found. Conclusion: While VHL mutation is associated with a biologically distinct good-prognosis profiling tumor subtype, its lack of prognostic value on univariate analysis suggests an expanded study to evaluate effect modification. The absence of a specific gene classifier for VHL mutation and the lack of association between VHL gene mutation and known hypoxia response genes suggest that VHL mutations result in heterogenous tissue phenotypes. These results support molecular subtyping of ccRCC in laboratory and clinical studies; in particular, this may be critical for trials involving anti-angiogenesis agents.

No significant financial relationships to disclose.
Perioperative chemotherapy treatment patterns in stage III transitional cell carcinoma (TCC) (1998–2003): A report from the National Cancer Data Base (NCDB)
Authors: David K. A. , Nanus D. M. , Milowsky M. I. , Ritchey J. , Stewart A. , Carroll P. R.
Published: March 2020

4540

Background: Studies have demonstrated benefits of perioperative chemotherapy in locally advanced TCC. We reviewed chemotherapy treatment patterns in patients with stage III TCC of the bladder and upper urinary tract (UUT) between 1998–2003 to investigate the use of perioperative chemotherapy. Methods: The NCDB collects data on approximately 75% of all newly diagnosed cancer cases annually in the U.S. We queried for all treatments in male and female (≥18 years old) TCC cases diagnosed between 1998 and 2003. Cancer stage (1998–2002) was forward converted to AJCC 6th edition. A total of 223,050 bladder and 11,625 UUT TCC cases were found. Results: Treatment patterns were analyzed in 11,328 patients with stage III bladder TCC and 1,840 patients with stage III UUT TCC, representing 5.0% and 15.8% of all cases, respectively (Table). Satisfactory follow-up was available for approximately 51% of patients. 5.4% (bladder) and 3.5% (UUT) of patients received pre-operative or adjuvant (within 4 mos of surgery) chemotherapy. No significant difference was seen comparing 1998 and 2003 perioperative chemotherapy use for bladder or UUT cancers. Conclusions: No increase in perioperative chemotherapy use occurred over the 5-year period (1998–2003), suggesting chemotherapy is underutilized in the management of surgically resectable stage III TCC of the bladder or UUT. This may reflect a delay in implementing the results of randomized trials recently reported or a low incidence of referral by urologists for perioperative chemotherapy. Further follow-up will determine if this pattern changes over the next 5 years.

[Table: see text]

No significant financial relationships to disclose.
Predictors of clinical outcome in patients with bone metastases from prostate cancer
Authors: Saad F. , Coleman R. E. , Cook R. , Smith M. R. , Brown J. E. , Hei J. Y. , Chen Y. M.
Published: March 2020

4555

Background: Bone metastases are a significant cause of morbidity in patients with prostate cancer (PC). To assess the predictive value of bone markers and fractures for clinical outcome in patients with bone metastases from PC, we conducted a retrospective analysis of patients in a large, randomized, controlled trial of zoledronic acid. Methods: Data were analyzed in patients treated with 4 mg zoledronic acid or placebo who had bone marker (n = 411) or fracture (n = 640) information. Cox regression models, adjusted for treatment group, were used to assess the association between bone markers (urinary N-telopeptide [NTX] and bone alkaline phosphatase [BALP]) or fractures (time-dependent variable) and the risk of death or of experiencing a first skeletal-related event (SRE) on study. For bone marker analyses, patients were grouped by low (< 50 nmol/mmol creatinine), moderate (50 to 99), or high (≥ 100) NTX levels and by low (< 146 U/L) or high (≥ 146) BALP. Results: Patients who experienced a fracture on study (19%) had shorter survival compared with patients who did not; the hazard ratio for death was 1.29 (95% CI = 1.01, 1.65; P = .04), suggesting 29% increased risk of death among these patients. When adjusted for previous SRE and baseline ECOG performance status ≥ 2, the risk for death associated with fractures was increased by 23% and trended toward statistical significance (P = .10). Patients with high NTX levels had significantly increased risk of SREs and disease progression (P < .001) compared with patients with low NTX. Relative to low NTX levels, high and moderate NTX levels were associated with a 5.72-fold (95% CI = 4.04, 8.11; P < .001) and 4.10-fold (95% CI = 2.81, 5.97; P < .001) increased risk of death, respectively. High BALP also significantly correlated with an increased risk of a first on-study SRE (P = .028) and bone lesion progression (P < .001). Conclusions: These analyses suggest that pathologic fractures are associated with increased risk if death and that high bone marker levels are associated with increased risk of SREs, bone lesion progression, and shorter survival in patients with PC and bone metastases. The results support appropriate treatment for the prevention of fractures and to decrease bone marker levels.

[Table: see text]
CALGB 90207: Phase II trial of bortezomib in patients with previously treated advanced urothelial tract transitional cell carcinoma (TCC)
Authors: Rosenberg J. E. , Halabi S. , Sanford B. L. , Himelstein A. L. , Atkins J. N. , Hohl R. , Seagren S. L. , Bajorin D. F. , Small E. J.
Published: March 2020

4582

Background: No standard 2nd-line chemotherapy exists for metastatic TCC. Response rates to 2nd-line chemotherapy for advanced TCC are low and response duration tends to be short. Bortezomib is a proteasome inhibitor with preclinical activity against TCC. Methods: Twenty-five patients with advanced TCC who had been previously treated with combination chemotherapy were enrolled in a multi-institutional single-arm trial from December 2003 through April 2005. Treatment consisted of bortezomib 1.3 mg/m2 intravenously twice weekly for two consecutive weeks, followed by a 1-week rest period. The primary endpoint was objective response rate by RECIST criteria. Secondary endpoints included safety, toxicity, progression-free survival, and overall survival. Results: The median age was 65.5 yrs (59–7-74.9) and the median number of years since diagnosis was 1.4 (0.9–3.6). 72% of patients were male. 65% of patients had visceral metastases, and 20% of patients had lymph node-only metastases. Prior chemotherapy regimens included gemcitabine/cisplatin (50%), gemcitabine/carboplatin (25%), paclitaxel/carboplatin (5%), single agent paclitaxel (5%), and other multi-agent regimens (15%). Median hemoglobin was 11.4 g/dL (inter-quartile range 10.6–12.3). No objective responses were observed. The median time to progression was 2.1 months (95% CI= 1.4–5.5). Median overall survival was 5.5 months (95% CI= 3.6–8.1). Toxicity was modest. Grade 3/4 drug-related toxicities included thrombocytopenia (6%), sensory neuropathy (6%), hyperglycemia (6%), neuropathic pain (6%), dehydration (6%) and vomiting (6%). There were no treatment-related deaths. Conclusions: Although bortezomib is well tolerated in patients with previously treated advanced TCC, it does not have anti-tumor activity as 2nd-line therapy in TCC.

No significant financial relationships to disclose.
Evaluation of prognosis in relapsed germ cell tumors: Identification of patients who profit from high dose chemotherapy (HDCT)
Authors: Sammler C. , Beyer J. , Bokemeyer C. , Hartmann J. , Siegert W. , Rick O.
Published: March 2020

4585

Background: To identify prognostic variables in patients (pts) with metastatic germ cell tumors (GCT) and relapse or progression after first-line chemotherapy (FLC). Methods: In our database of 257 GCT pts treated with HDCT, 176/257 (67.4%) pts with first relapse or progression were identified. All patients had received platinum-based FLC. As salvage treatment all pts had received 1–3 cycles of conventional-dose salvage chemotherapy (CDCT) followed by one cycle HDCT. First, pts were retrospectively classified according to a prognostic score developed for CDCT by Fossa et al. [Br J Cancer 1999,80:1392], based on variables present at the time of relapse. Thereafter, a multivariate analysis was performed to evaluate further risk factors. Results: After a median follow up of 9 years the event-free survival (EFS) and overall survival (OS) for all 176 patients was 34% and 38%, respectively. Patients with good (n= 100/176, 57%) and poor (n = 76/176, 43%) prognosis in accordance to Fossa et al. showed an EFS of 41% and 26% (p < 0.01) and an OS of 47% and 26% (p < 0.01). Thus, in contrast to the data of Fossa et al, long-term survival could be demonstrated even in the poor prognosis subset. In the multivariate analysis, the level of elevated tumor markers alfa-fetoprotein and human chorionic gonadotrophin (p < 0.01), the presence of extrapulmonal visceral metastases (p < 0.01) and refractoriness to cisplatin (p < 0.01) adversely influenced OS after HDCT significantly. Based on these latter factors three different groups with increasingly poor OS could be identified: none factor (n = 39/176, 22%) 4 year OS of 59%, one factor (n = 78/176, 44%) 6 year OS of 42% and more than one factor (n = 59/176, 34%) 4 year OS of 17%. Conclusion: In pts with first relapse or progression after platinum-based FLC high serum tumor markers, presence of extrapulmonal visceral metastases and cisplatin refractoriness proved to be independent prognostic significance for OS after salvage HDCT. However, even in the poor prognosis subset long-term survival could be demonstrated.

No significant financial relationships to disclose.
Salvage chemotherapy with paclitaxel, ifosphamide and nedaplatin for cisplatin refractory germ cell tumors
Authors: Miki T. , Mizutani Y. , Nomoto T. , Nakamura T. , Kawauchi A. , Oka D. , Nishimura K. , Nonomura N. , Okuyama A.
Published: March 2020

4587

Background: Only 20–30 % of patients with cisplatin (CDDP) refractory germ cell tumor (GST) will remain continuously disease free with salvage chemotherapy. The present study investigated the chemotherapy with paclitaxel (TXL) in combination with ifosphamide (IFM) and nedaplatin (NDP), which is a derivative of CDDP, as salvage chemotherapy for CDDP refractory GCT. Methods: Between 2000 and 2005, 33 patients with CDDP refractory GCT were enrolled. All patients were male, with median age 30 (range: 17–45). Median number of previous regimens was 2 (range: 1–4). The combination chemotherapy consisted of TXL: 200 mg/m2 on day 1, NDP: 100 mg/m2 on day 2 and IFM: 1.2 g/m2 on day 2–6 every three weeks. Results: A median of 5 cycles was administered to 33 patients. Grade 3/4 toxicity were reported as follows: neutropenia: 90%, thrombocytopenia: 70%, anemia: 70%, nausea/vomiting: 90%, diarrhea: 6%, alopecia: 97%. No treatment related death was observed. Response rate was 82% (CR: 9%, PRm−: 67%, PRm+: 6%, NC: 6%, PD: 6 %). Nineteen (58%) patients achieved a no evidence of disease status with a median duration of follow-up of 18 months (7–60 months). Six patients (18%) remain alive with disease. However, 8 patients (24%) died of the disease. Conclusions: This study demonstrates that the chemotherapy with TXL in combination with IFM and NDP showed a significant anticancer activity for patients with CDDP refractory GCT. These findings suggest that the combination chemotherapy may be one of the options of salvage chemotherapy for CDDP refractory GCT.

No significant financial relationships to disclose.
POMB-ACE therapy for patients with international germ cell cancer collaborative group (IGCCCG) poor risk germ cell tumors (GCT): The USC experience
Authors: Dorff T. B. , Rupani R. , Wei D. T. , Groshen S. , Pinski J. , Raghavan D. , Quinn D. , Aparicio A.
Published: March 2020

4591

Background: Patients with poor-risk GCT have low rates of cure with standard therapy, with 3 year overall survival (OS) reported at 50% (IGCCCG, JCO 1997). POMB-ACE is a rapidly alternating, dose dense chemotherapy regimen developed to improve outcomes in this population, with reported 3 year OS of 75% (Bower et al, Ann Oncol 1997). We report our experience with this regimen, including analysis of acute and long-term toxicity. Methods: Subjects with poor-risk GCT, defined by IGCCCG criteria as AFP >10,000, bHCG >50,000, LDH > 10 × ULN, non-testicular primary, or non-pulmonary visceral metastases, who were diagnosed at Los Angeles County General Hospital and USC/Norris Cancer Center between 1998 and 2005 were identified using pathology and admission records. All clinical notes and laboratory data were reviewed. Results: Of 23 poor-risk GCT patients identified, 21 received POMB-ACE; 16 were treated at the county facility. 15 patients were Hispanic. 5 had primary mediastinal tumors. 16 were stage IIIC, 4 stage IIIB, and 1 stage IIIA. The median number of cycles was 8 (range 4–12), with a median interval between treatment cycles of 14 days (range 10–39). There were no treatment-related deaths. Febrile neutropenia occurred in 5.9% of treatment cycles, grade 3/4 hematologic toxicity in 19%, and other Grade 3/4 non-hematologic toxicities in 9.8%. G-CSF support was used with 24% of cycles. Nineteen patients (90%) had a partial response, of whom 8 underwent surgery for residual disease; only 1 had residual active tumor, 4 teratoma. Marker-negative status was achieved in 5 patients (23.8%). With median follow-up of 28 months, 9 subjects have recurred (43%) and 4 have died of disease progression. The estimated 2 year disease-free survival is 54%, and 3 year OS 75%. At the end of treatment, residual neuropathy persisted in 2 patients (9.5%), renal compromise in 2 (9.5%), pulmonary toxicity in 3 (14%), and otoxicity in 1 patient (4.7%). Conclusions: In our modern North American experience, POMB-ACE is feasible to administer, even in an uninsured population. This is an effective option in poor-risk GCT patients, with 3 year OS exceeding that achieved with standard therapy. Acute toxicity is modest, however persistent adverse sequelae are common.

No significant financial relationships to disclose.
Observational study in patients with pulmonary metastases of renal cell carcinoma receiving inhaled recombinant interleukin-2 (rIL-2)
Authors: García A. G. , Esteban E. , Girón C. G. , Maroto P. , Andrés R. , Canelas A. , Caballido J. , Carles J. , Espinosa E. , Lacave A. J.
Published: March 2020

4603

Background: Patients with metastatic renal cell carcinoma have a poor prognosis, including those with pulmonary metastases (PMRCC). The objective of this study was to obtain efficacy and safety data on inhaled rIL-2 used in clinical practice in PMRCC patients. Methods: Data provided from 107 PMRCC patients from 48 centres in Spain and 6 in Portugal, treated with inhaled rIL-2 between 2000 and 2005 were evaluated. Data were analyzed by ITT, considering a valuable patient when receiving the first dose of inhaled rIL-2. The treatment schedule was: 3 cycles of 36 MIU rIL-2 per day for 5 days/week for 12 weeks (with one week treatment free between cycles) in Spain and for 3 weeks (out of each 4 weeks) for 12 weeks in Portugal. Efficacy was assessed by best response following each treatment cycle and overall (WHO criteria). The Kaplan-Meier method was used to estimate progression free survival (PFS) and overall survival (OS) that were measured from the time of administration of the first dose of inhaled rIL-2 until progression or death. Safety data were analysed using descriptive statistics, with toxicities expressed as number of weeks in which each toxicity was reported by cycle and by grade. Results: After 1902 treatment weeks administered (median 17.8), the overall objective response rate (complete and partial response,) was 12.2% (95% CI: 6.0–18.4) and a stable disease rate of 22.45% (95% CI: 14.5–30.3). Median PFS and OS were 3.72 (95% CI: 2.86–4.57) and 18.5 (12.69– 23.61) months, respectively. Non-haematological toxicities were the most notable adverse events observed, especially in terms of cough (20.4% of weeks) and fatigue (4.4%) being grade 1 or 2 in severity and reversible by removing the treatment in all cases. Conclusions: This study provides data of efficacy and mild toxicity of inhaled rIL-2. On the basis of these findings inhaled rIL-2 might be considered as an alternative to its systemic administration to treat patients with PMRCC.

No significant financial relationships to disclose.
Comparative expression profiling with kinetic RT-PCR in paired fresh frozen and archived formalin-fixed, paraffin-embedded renal cell cancer and normal tissue
Authors: Hennig G. , Paus H. , Atkins D. , Störkel S.
Published: March 2020

4606

Background: It would be a substantial progress if gene expression of tumor markers could be accurately analyzed on RNA isolated from formalin fixed paraffin-embedded (FFPE) tumor tissue which is routinely collected. To prove equivalence between fresh frozen and archived FFPE tissue RNA profiles, we quantified 12 different genes with kinetic RT-PCR in renal tumor and paired adjacent normal tissue archived for 8–14 years. Methods: We had access to a set of 32 clear cell renal cell cancers and its adjacent normal tissue (HELIOS Clinic, Wuppertal). Each sample existed as a FFPE tissue block and as paired fresh frozen tissue both stored over 8–14 years at RT or -80oC, respectively. RNA from FFPE tissue was isolated with a Bayer HealthCare internal silica bead-based isolation method. Each sample was analyzed with kinetic one-step RT-PCR for the gene expression of 3 housekeepers (RPL37A, GAPDH, CD63) and 9 candidate genes (EGFR, Her2/neu, Her3, Her4, EGF, TGFα, NRG1, HIF1α, VEGFα). Results: The comparative FFPE/fresh frozen expression data showed a good correlation over all data points (r = 0.87 for Ct values) and the tumor specific up- and down regulation of EGFR family genes and its ligands could be detected in both tissue types equally. We could clearly demonstrate the tumor specific up-regulation of EGFR (2-fold), TGFα (2-fold), VEGFα (4-fold) and down-regulation of EGF (60-fold), Her2/neu (4-fold), Her3 (2-fold) and Her4 (30-fold) in renal cell cancer for both tissue entities (fixed and fresh frozen). In addition a 3-dimensional Principal Component Analysis completely separated the renal tumor population from paired normal tissue in both tissue entities based on the differential gene expression. Conclusions: Here we demonstrate that a small set of genes from the EGFR family and their ligands is specifically up-/down-regulated in renal cell cancer tissue and therefore can be clearly distinguished from normal renal tissue. Furthermore, these data prove that the internal Bayer HealthCare isolation/kinetic RT-PCR detection protocol for RNA from FFPE tissue allows accurate retrospective expression profiling and validation of marker panels in archived tissue material stored for more than a decade.

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A phase II trial of docetaxel and samarium in patients with bone metastases from castration-refractory prostate cancer (CRPC) and a response or stabilization after induction docetaxel-estramustine
Authors: Laplanche A. , Beuzeboc P. , Lumbroso J. , Di Palma M. , Theodore C. , Prapotnich D. , Escudier B. , Bouzy J. , Haddad V. , Fizazi K.
Published: March 2020

4608

Background: Most patients (pts) with disseminated CRPC have bone metastases. Samarium is a radio-isotope with a high affinity to bone. Docetaxel is currently the standard of care in CRPC. We assess the efficacy of combining docetaxel and samarium as consolidation treatment after docetaxel-estramustine in pts with CRPC. Methods: This is a prospective, bi-center phase II trial. Pts with bone metastases from CRPC received docetaxel 70 mg/m2 day 2 + estramustine 10 mg/Kg/day, day 1–5 (1 cycle every 3 weeks). Pts with a response or stabilization after 4 cycles were given consolidation therapy: docetaxel 20 mg/m2/week x 6 weeks + samarium 1 injection during week 1 (37 MBq/Kg). Zoledronic acid was routinely used and was stopped 1 month before samarium infusion. This study used a Simon two-step design with a final target of 39 pts receiving the consolidation treatment. Biological responses were defined according to the working group criteria (Bubley, J Clin Oncol 1999). The primary endpoint was progression-free survival (PFS). Results: From 01/2004 to 12/2005, 43 pts were included in the trial and the accrual is over. Of the 39 pts currently fully evaluable after induction treatment, 28 (72%), 10 (26%) and 1 (3%) achieved a PSA response, stabilization, and progression, respectively. Of 30 pts currently evaluable after consolidation treatment, 20 (65%), 5 (16%) and 5 (16%) achieved a PSA response, stabilization, and progression, respectively. A pain response (defined as a decrease in pain intensity by at least 2/10 on a pain analog visual scale in pts with a baseline pain level ≥ 2/10) was achieved in 89% (16/18) after consolidation treatment. The consolidation docetaxel-samarium regimen was feasible with most pts experiencing a mild (grade 1–2) and rapidly reversible thrombocytopenia at week 5. Data on PFS and overall survival are pending. Conclusions: Combining docetaxel and samarium is feasible and well-tolerated. It yields a high PSA response rate and a major pain improvement in pts with bone metastases from CRPC.

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Predictors of overall and cancer-specific survival in patients with clinically localized prostate cancer (PC) treated with primary androgen deprivation therapy (PADT): Results from the Prostate Cancer Outcomes Study
Authors: Graff J. , Mori M. , Li H. , Garzotto M. , Penson D. , Potosky A. , Beer T. M.
Published: March 2020

4610

Background: Use of PADT as sole therapy for clinically localized PC is rapidly increasing, despite little evidence to support this approach. We examined predictors of overall survival (OS) and cancer-specific survival (CSS) using the data available from the Prostate Cancer Outcome Study (PCOS). Methods: PCOS recruited 5,672 patients between 1994 and 1995, within 6 months of PC diagnosis. Vital status was last updated in 12/02. 276 patients had clinically localized PC and received PADT. We examined the relationship between baseline demographic, socio-economic, and tumor factors and OS and CSS using Kaplan-Meier and Cox regression methods implemented in the SUDAAN software. Results: Of 276 patients, 148 patients have died, 35 from PC. The median age at diagnosis was 75 (50–88). The average follow-up of censored subjects was 7.6 yrs (1.1–8.1). 5-year OS was 66% (95% CI: 69–72), while the 5-year CSS was 91% (95% CI: 86–94). In the multivariate analysis (see Table), age, serum PSA at diagnosis, and Gleason score were the only independent predictors of OS. Abnormal DRE was marginally significant. The Gleason score (≥7) was the only independent predictor of CSS (HR 4.0, p = 0.04); PSA ≥ 20 (HR 2.38, p = 0.09) approached significance. This analysis was limited by a smaller number of deaths due to prostate cancer (n = 35). Conclusions: In an analysis that included a broad range of demographic and socio-economic factors, overall survival of patients with clinically localized prostate cancer treated with PADT was predicted by age and measures of tumor biology (Gleason score) and tumor mass (serum PSA). Thus, cancer remains an important contributor to overall mortality in these patients, particularly those with high Gleason score and high serum PSA. These data can be used to inform patients regarding their individual 5-year survival if they choose PADT for the treatment of their clinically localized prostate cancer.

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No significant financial relationships to disclose.
Evaluating high-grade prostatic intraepithelial neoplasia as a predictor of outcome following radical prostatectomy
Authors: Pierorazio P. M. , Lambert S. M. , McCann T. R. , Katz A. E. , Olsson C. A. , Benson M. C. , McKiernan J. M.
Published: March 2020

4612

Background: The presence of high-grade prostatic intraepithelial neoplasia (HGPIN) has been associated with future development of prostate cancer. High-grade intraepithelial neoplasia in other malignancies is associated with adverse outcome. This study examines the relationship between the presence of HGPIN in prostatectomy specimens, biochemical disease free survival (bDFS) and other cancer specific outcomes following radical retropubic prostatectomy (RRP). Methods: The Columbia University Urologic Oncology Database was reviewed and 2,522 were identified who had undergone radical prostatectomy from 1988 to 2005; 2,133 patients with or without HGPIN were included. Two-sample proportion analysis of means with 95% confidence intervals and ANOVA techniques were used to evaluate the relationship between HGPIN and pathologic stage, Gleason sum, perineural invasion, multifocality, extracapsular extension (ECE), margin status, and nodal status. Kaplan-Meier analysis with log-rank test and a multivariate Cox proportional hazard model controlling for preoperative PSA, Gleason sum and pathologic stage were used to assess differences in bDFS. Results: 1,885 of 2,133 (88.4%) patients demonstrated HGPIN. There was no significant difference in the distribution of pathologic stage or Gleason sum between the patients with and without HGPIN. The HGPIN-positive group had higher rates of perineural invasion (69.9 vs. 57.5%; p = 0.003), multifocality (63.0 vs. 38.4%; p = 0.000) and ECE (56.4% vs. 48.4%; p = 0.059). There was no statistically significant difference observed in nodal status or margin status between the two groups. Patients without HGPIN had an increased bDFS demonstrated by a predicted disease free survival of 73.6% versus 67.0% at 9 years (p = 0.045) with a median follow-up of 50 months. In the multivariate Cox hazard model HGPIN, PSA, Gleason sum and pathologic stage were validated as independent predictors of failure (p < 0.001). The risk of failure was 1.9 × greater in the HGPIN-positive group than the HGPIN-negative group (p=0.006). Conclusions: The presence of HGPIN in the radical prostatectomy specimen denotes a significantly higher rate of tumor multifocality, perineural invasion, ECE, and ultimately biochemical recurrence.

No significant financial relationships to disclose.
Routine interval computed tomography in detecting new soft tissue disease in patients with androgen-independent prostate cancer (AIPC) and only bone metastasis
Authors: Wu S. , Jones E. , Gulley J. , Arlen P. , Chen C. , Figg W. , Dahut W.
Published: March 2020

4621

Background: Bone is the most common metastatic site in AIPC and the only site of metastasis for many patients. However, some pts with only bone metastasis will eventually develop soft tissue disease. Thus many clinical trials include CT monitoring to exclude new soft tissue disease as the only manifestation of disease progression. The true incidence of the asymptomatic development of soft tissue metastases without PSA or bone scan progression is unknown. Here we have identified pts with bone metastasis only at the time of protocol enrollment. We analyzed their disease progression pattern to determine the utility of routine interval CT scans. Methods: We reviewed 100 pts with metastatic AIPC from three phase II clinical trials (docetaxel/thalidomide, docetaxel/vaccine, and ketoconazole/alendronate) between 1995 and 2004. Pts were assessed every 4 weeks with PSA measurement. CT and bone scans were performed 2 months after start of the trial and then at least every 3 months. Median follow-up time was 8 months (1–44 months). The pts with bone metastasis only were examined for the occurrence of soft tissue diseases by subsequent CT scans in association with bone scan and PSA. Results: Of 100 pts with metastatic AIPC, 33% had soft tissue disease alone or soft tissue and bone disease. 67% had no soft tissue involvement identified by CT but had bone metastasis revealed by bone scan. Of the pts with only bone metastasis, 3% (2 pts) developed new soft tissue disease. One pt developed new right illiac fossa lymphadenopathy after 8 months, and another a peri-rectal mass after 12 months. The one with new lymphadenopathy also had multiple new bone lesions identified by bone scan and PSA progression. The one with a peri-rectal mass had PSA progression and a palpable abnormality. Conclusions: The incidence of asymptomatic new soft tissue disease as the only manifestation of disease progression appears to be quite low in pts with only bone metastasis. Scheduled interval examination with CT to exclude new soft tissue disease does not appear to be warranted. CT scans should probably only be done at the time of disease progression shown by bone scan/PSA or when there are clinical signs or symptoms of new soft tissue disease.

No significant financial relationships to disclose.
Delaying metastatic disease progression in locally advanced disease − Results from the Early Prostate Cancer program at a median follow-up of 7.4 years
Authors: Wirth M. P. , See W. A. , McLeod D. G. , Iversen P. , Morris T. , Armstrong J.
Published: March 2020

4629

Background: Progression of prostate cancer to bone metastases impacts seriously on patients (pts)’ quality of life and increases treatment costs. The 3rd analysis of the Early Prostate Cancer (EPC) program revealed that bicalutamide (CASODEX) 150 mg plus standard care (radiotherapy [RT], radical prostatectomy [RP] or watchful waiting [WW]) significantly improved progression-free survival (PFS) vs standard care alone in locally advanced disease. Adjuvant bicalutamide 150 mg also improved overall survival for RT pts with locally advanced disease. Here, we report an exploratory analysis of the effect of bicalutamide on delaying bone metastases in pts with locally advanced disease in the EPC program. Methods: The EPC program comprises 3 trials in which pts (n = 8113) were randomized to standard care plus bicalutamide 150 mg or placebo. This exploratory analysis included only pts with locally advanced disease (T3–4, any N; or any T, N+; bicalutamide n = 1367, placebo n = 1315). Distant metastases were assessed by bone scan. Metastatic PFS was defined as time from randomization to either first bone scan-confirmed progression or death in the absence of bone-scan data. A Cox proportional hazards regression model was used for the WW and adjuvant subgroups; each was analyzed separately with covariates for trial, treatment, prior therapy, baseline prostate-specific antigen level, and tumor grade. Results: At 7.4 years’ median follow-up, bicalutamide significantly improved metastatic PFS vs placebo (hazard ratio [HR] 0.64, p < 0.001 for WW; HR 0.77, p = 0.005 for RT/RP; table). The most common adverse events were gynecomastia and breast pain. Conclusion: Addition of bicalutamide 150 mg to standard care significantly reduced the risk of distant metastases in locally advanced prostate cancer, irrespective of standard care. Both the efficacy and tolerability of treatment must be considered, and therefore, bicalutamide is an option for men with locally advanced prostate cancer.

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