bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of lenalidomide in patients (pts.) with metastatic renal cell carcinoma (MRCC)
Authors: Choueiri T. K. , Dreicer R. , Rini B. I. , Elson P. , Garcia J. , Mekhail T. , Bukowski R. M.
Published: March 2020

4539

Background: MRCC is a disease with susceptibility to immunomodulatory and anti-angiogenic approaches. Lenalidomide (LEN) is a structural and functional analogue of thalidomide with enhanced immunomodulatory properties and unique activity and toxicity profiles. A phase II study of LEN in MRCC was conducted to determine efficacy and safety. Methods: Eligibility included histologically confirmed MRCC, measurable disease, ≤ 1 prior systemic therapy, ECOG PS 0–1, adequate organ function, and no brain metastases. LEN was administered orally at 25 mg daily for the first 21 days of a 28-day cycle. The primary endpoint was objective response rate as determined by RECIST criteria. Patients received treatment until disease progression or unacceptable toxicity. A two-stage design was employed to test the null hypothesis that the true response rate is ≤ 5% versus the alternative hypothesis that the true response rate is ≥ 20% (alpha = 0.05, power = 90%). Results: 28 pts. were enrolled. Median age was 67 years (range, 42–76). All patients had prior nephrectomy and 57% (16/28) received prior therapy. 21 pts. (75%) had clear cell histology. Pts. received a median of 4 cycles of therapy (range, 1–12+) with 21 pts. (75%) completing at least 2 cycles. Three pts. (10.7%; 95% CI = 2.3–28.2 %) demonstrated a partial response (PR) and 8 pts (28.5%) had stable disease (SD). A total of 11 pts. (39%) experienced median tumor shrinkage of 5% (range, 1–72%). Median time to progression (TTP) for the entire cohort was 4 months (m) (range, 0.67–14+). Ten pts (36%) were progression-free for ≥ 6 m and five pts (18%) were progression-free for ≥ 12 m. Previously treated pts had a TTP of 3 m compared to 5 m for pts with no prior therapy (p = .19). 6 pts (21%) continue on-study with a median follow up of 12.6 m (range, 7.3–14.2 m). Toxicities (all grades) included fatigue (93%), skin toxicity (rash, dry skin and pruritus; 68%) and leukopenia/neutropenia (65%). Grade 3/4 toxicities included fatigue/constitutional symptoms (11%), skin toxicity (7%) and leukopenia/neutropenia (29%). Conclusions: LEN demonstrated an anti-tumor effect in MRCC as evidenced by partial responses and additional pts. with tumor shrinkage. LEN was well tolerated with manageable toxicity. Further studies are warranted.

[Table: see text]
Phase II screening study to assess the combination of a LHRH analogue, dexamethasone and a somatostatin analogue versus a LHRH analogue with dexamethasone in hormone refractory prostate cancer patients
Authors: Silva F. , Calais Da Silva F. M. , Gonçalves F. , Oliver T.
Published: March 2020

4565

Background: Hormonal changes and the possible resulting imbalance between androgen and estrogen levels in elderly men may play an important role in prostatic pathogenesis. Androgen suppression can induce regression of prostatic carcinoma. Ample laboratory and clinical research have contributed to evidence that a direct link exists between prostatic cell growth, prostatic carcinoma cell growth and hormones, mainly testicular androgens. As far as prostatic cancer is concerned, we know that SMS blocks GH, PRL, tissular growth factors (TGF) and that it has a direct antiproliferative growth cellular growth effect. The simultaneous administration of depot forms of SMS and LHRH analogues induced the greatest decrease in tumor growth. Methods: A randomized Phase II trial was carried out in M0 (PSA ≥ 20 ng/ml) and M1 patients with hormone refractory prostate cancer to simultaneously screen decapeptyl and dexamethasone, both with and without somatulin (120 mg every 4 weeks), with respect to PSA response rate, time to PSA progression, duration of survival and toxicity. Results: 72 patients with a median time PSA of 77 ng/ml were randomized by 3 institutions, 35 to decapeptyl, dexamethasone and somatulin (DDS) and 37 to decapeptyl and dexamethasone (DD). 21 of 33 (64%) patients on DDS and 21 of 32 on DD (66%) had a PSA response (a decrease of at least 50 % as compared to baseline). The median duration of PSA response was 6.6 months on DDS and 3.4 months on DD. Overall, the median time to PSA progression was 5.8 months on DDS and 1.8 months on DD. The median duration of survival has not yet been reached. Both treatment regimens were well tolerated. The most frequent toxicities on DDS and DD were hot flushes (27%, 10%), gastrointestinal (18%, 20%), and skin complaints (12%, 10%). Conclusions: Both treatment regimens are active and safe in the treatment of hormone refractory prostate cancer. Although the PSA response rate is about 65%, the median duration of response and median time to progression were longer in the somatulin arm; so, the data suggest a possible advantage of DDS with respect to both the duration of the PSA response and the time to PSA progression. Further follow-up is required to assess survival.

No significant financial relationships to disclose.
Long term efficacy of peripheral androgen blockade on prostate cancer: CALGB 9782
Authors: Picus J. , Halabi S. , Small E. , Hussain A. , Philips G. , Kaplan E. , Vogelzang N.
Published: March 2020

4573

Background: The treatment of patients with a rising PSA after definitive local therapy is controversial. Patients are reluctant to undergo androgen suppression due to side effects and interest focuses on the timing and intensity of additional therapy. The use of peripheral androgen blockade in this setting is appealing. Methods: Patients with a rising PSA after definitive local therapy were enrolled in a multi-institutional trial. Accrual of 101 patients lasted from Sept 30, 1998 to July 16, 2001. All patients had undergone previous definitive local therapy at least 1 year, and no more than 10 years prior to enrollment. All patients had a repeated rising PSA, above 1 ng/ml, with no detectable evidence of recurrent disease. CT and bone scans were negative. Patients received a combination of oral therapy consisting of Finasteride, at a dose of 5 mg/day, and Flutamide, at a dose of 250 mg TID. Results: The median age was 71, with a median baseline testosterone level of 322 ng/dl. A >80% PSA decline was seen in 91/94, (97%) of the patients. Three other patients had PSA declines of 77%, 73% and 38%, all of which were maintained for at least 28 days. The median time to PSA nadir was 3.2 months. The current median follow-up is 59 months. To date, only 22 patients have progressed, with 47 patients still on peripheral androgen blockade. Eight patients have died without progression, and 22 patients went off therapy for other reasons not related to progression. Also noted were patients showing PSA responses to Flutamide withdrawal, and per protocol remaining on Finasteride. Toxicity to date remains very mild. Conclusions: Peripheral androgen blockade showed excellent activity produced durable PSA responses in this select group of patients. While the clinical significance of a decline in PSA alone is not fully understood_the durability of these PSA responses is encouraging. The median duration of progression free survival and overall survival has not been reached, and is likely to be longer than five years. Quality of life data is undergoing further analysis. This report supports further study of less aggressive treatments for patients who have only a rising PSA after definitive local therapy.

No significant financial relationships to disclose.
Phase II study of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial carcinoma (UC): Analysis of the second cohort of CALGB 90102
Authors: Philips G. , Sanford B. , Halabi S. , Bajorin D. , Small E. J.
Published: March 2020

4578

Background: The epidermal growth factor receptor (EGFR) is frequently expressed in UC and carries a poor prognosis. C has preclinical synergy with gefitinib and GC plus gefitinib was safe in lung cancer patients (pts). In a UC trial of GC using fixed dose rate infusion of G plus gefitinib, Gr 4 and 5 toxicities led to premature closure of the study after 27 patients. Because toxicity was felt to be related to the fixed dose rate infusion of G, accrual was resumed with a standard G dosing schedule in a second cohort. Methods: Eligible pts had measurable N2, N3 or M1 disease; PS of 0–2; CrCl of > 50 ml/min; adequate organ function; no prior systemic combination chemotherapy. Treatment consisted of C 70 mg/m2 D1, G 1000 mg/m2 D1+8 given over 30 min every 3 weeks concurrent with gefitinib 500 mg/day PO for a maximum of 6 cycles. Responders received maintenance gefitinib 500 mg/day until progression. Results: In 55 eligible pts with a median age of 64 years, 67% (of 49) had visceral metastases and 91% had PS of 0–1. Objective response (CR+PR) was observed in 51% (95% CI = 37–65). With a median follow up of 13.2 mo, the median time to progression was 8 mo (95% CI = 6.8–9.2) on the basis of 45 events, and the median overall survival was 14.4 mo (95% CI = 10.7–20.9) on the basis of 26 deaths. No lethal toxicity was seen. Gr 4 toxicities included Gr 4 neutropenia (20%) and Gr 4 metabolic/electrolyte disorders in 13%. Gr 3 and 4 diarrhea was observed in 25% and 2 % of pts respectively and Gr 3 skin rash in 16% of pts. Conclusions: The combination of GC and gefitinib has acceptable toxicity in advanced UC. However, the relative contribution of gefitinib to the efficacy of this regimen remains uncertain. These preliminary results do not suggest a substantial improvement upon historical results with GC alone in advanced UC.

No significant financial relationships to disclose.
Prognostic significance of the level of serum osteoprotegerin in patients with bladder cancer
Authors: Mizutani Y. , Li Y. N. , Shiraishi T. , Nakamura T. , Nomoto T. , Okihara K. , Ukimura O. , Yoneda K. , Kawauchi A. , Miki T.
Published: March 2020

4581

Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays an important role in cytotoxic T lymphocyte-mediated and natural killer cell-mediated apoptosis against cancer cells. Since Osteoprotegerin (OPG) is a soluble decoy receptor for TRAIL, circulating OPG has been implicated in protection from TRAIL-mediated apoptosis. This possibility was examined in patients with bladder cancer. Methods: Serum OPG levels of 185 patients with bladder cancer were determined by using an enzyme-linked immunosorbent assay. Anti-autologous tumor cytotoxic activity of peripheral blood lymphocytes was assessed by the 12-h Cr release assay. Results: The mean serum OPG level in patients with bladder cancer was approximately 3-fold higher than that in normal donors. The serum OPG level in patients with muscle-invasive bladder cancer was higher than that in superficial bladder cancer. Furthermore, serum level of OPG in patients with metastatic bladder cancer was higher than that in muscle-invasive bladder cancer. Serum OPG level in Grade 2 bladder cancer was higher than that in Grade 1 cancer. Moreover, serum OPG level in Grade 3 bladder cancer was higher than that in Grade 2 cancer. Patients with superficial bladder cancer with low serum OPG level had a longer postoperative tumor-free rate than those with high level in the 5-year follow-up. In addition, patients with muscle-invasive bladder cancer with low serum OPG level had a higher disease-specific survival rate when compared with patients with high level in the 5-year follow-up. There was an inverse correlation between serum OPG level and anti-autologous tumor cytotoxic activity. Conclusions: The present study is the first to demonstrate that the serum OPG level correlates with the stage/grade of bladder cancer, and that elevated level serum OPG predicted early recurrence in patient with bladder cancer. These findings suggest that serum OPG level may be used as a prognostic parameter in patients with bladder cancer, and that OPG may be a molecular therapeutic target in bladder cancer.

No significant financial relationships to disclose.
Multicenter, randomized, phase III trial comparing radical retropubic prostatectomy with conventional external beam radiotherapy for localized prostate cancer: An interim report
Authors: Di Stasi S. M. , Giannantoni A. , Valenti M. , Storti L. , Attisani F. , Palloni T. , Jannini E. A. , Bibas M. , Zampa G.
Published: March 2020

4607

Background: We report the outcomes of a randomised trial comparing radical retropubic prostatectomy (RP) with conventional external beam radiotherapy (EBRT) in patients with clinically localized prostate cancer. Methods: Between January 1997 and September 2001, 137 patients with clinically localized diagnosed prostate cancer were randomly assigned to RP (n = 70) or EBRT (n = 67). Data collected at follow-up included evidence of clinical disease progression, survival rates and general and disease specific health-related quality of life. All data were measured by physical examination, digital rectal examination, PSA, annual TC and bone scan and questionnaire. Analysis was by intention to treat. Results: After a median follow-up of 67 months (range 24–88) 35 patients (32.8%) had evidence of biochemical disease progression, 22 (31.4%) in RP group and 23 (32.8%) in EBRT group respectively. The median time to biochemical failure was 55.5 months (range 1–86) in RP group and 56 (range 3–88) in EBRT group. A local progression was observed in 11 patients (15.79%) of RP group and 12 (17.9%) of EBRT group. The median time to local progression was 65 months (range 6–86) in RP group and 64 (range 6–88) in EBRT group. Distant metastases were observed in 4 patients (5.7%) in RP group and 6 (8.9%) in EBRT group. The median time to distant failure was 67 months (range 12–86) in RP group and 66 (range 12–88) in EBRT group. Death due to prostate cancer occurred in 3/70 of patients assigned to RP (4.3%) and in 1/67 of those assigned to EBRT (1.5%). A significant decrease in general HRQOL was evident only in the first month after RP (p < 0.001). At 2 years, patients undergoing RP report significantly worse urinary function (p < 0.001), but better bowel function than those treated with EBRT (p < 0.001). Sexual dysfunction was more prevalent in the RP than in the EBRT group (70.2% versus 61.2%). Conclusions: This interim analysis indicates that there was no significant difference between RP and EBRT in terms of clinical disease progression and survival rates in patients with clinically localized prostate cancer. However, additional larger sample size accrual and long-term follow-up data are warranted to confirm these results.

No significant financial relationships to disclose.
A multicentric phase II randomized trial of docetaxel (D) plus estramustine (E) versus docetaxel (D) as first line chemotherapy for patients (pts) with hormone-refractory advanced prostate cancer (HRPC)
Authors: Caffo O. , Sava T. , Comploj E. , Fariello A. , Zustovich F. , Valduga F. , Frisinghelli M. , Segati R. , Sacco C. , Perin A. , Pappagallo G.
Published: March 2020

4625

Background: D is presently considered a standard treatment for HRPC pts. E has shown a synergistic activity with D in vitro, however the role of D+E combination remains to be defined in the clinical practice. We attempted to evaluate the activity, in terms of PSA decline (PSA↓), the safety and quality of life (QoL) of D ± E in HRPC pts. Methods: eligibility criteria were: HRPC diagnosis, hormone-refractory advanced disease (PSA progression after at least two hormonal therapy), ECOG PS ≤ 2, adequate renal, hepatic and hematological functions. Pts were randomized to D 70 mg/m2 IV d1 q3w (arm A) or D 70 mg/m2 IV d1 q3w + E 280 mg/TID PO starting 1 day prior to D, for 5 consecutive days (arm B). The treatments were planned until best PSA response achievement or PSA progression. No anticoagulant prophylaxis was planned in ARM B pts. Qol was assessed by self-filled questionnaires during the treatment. Results: Between 04/2003 and 09/2005, 95 pts (median age 69 years, range 48–86, median PSA 80 ng/ml, range 5–2166 and measurable disease in 45) were randomized to arm A (49) or arm B (46). To date, 9 pts and 6 pts are still on treatment in arm A and B respectively. In arm A, pts received 257 cycles (median 5, range 1–14) with only 10 (3.9%) delays ≥ 7 days. In arm B, pts received 317 cycles (median 7, range 0–20) with only 15 (4.7%) delays. Median follow-up was 19.5 months. Grade 3–4 hematological toxicities consisted of neutropenia, 4% in arm A and 8% in B, anemia, 0% and 2% respectively and 1 pt with febrile neutropenia and grade 3 diarrhea (Arm B). Grade 3−4 non-hematologic toxicities were vomiting (1 pt) in arm A, stomatitis (2 pts) and vomiting (1 pt) in arm B. Two cases of stroke were reported in arm A. Responses, in terms of PSA↓ >50% were: 43% in arm A and 70% in arm B with PSA normalization in 8% and 38% respectively. Progression free survival (biochemical) was 20 weeks in arm A and 31 in B. Analysis concerning QoL outcomes is planned at the treatment completion of all pts. Conclusions: D-based regimens are active in HRPC with a low toxicity profile. From this preliminary data, DE combination appears promising, in terms of activity and tolerability so, front-to-front formal comparison in a phase III trial can be recommended.

No significant financial relationships to disclose.
Assessment of PSA and digital rectal examination (DRE) for the detection of Gleason ≥ 7 prostate cancer in a referral population
Authors: O’Brien C. A. , Mongoue-Tchokote S. , Collins L. , Spurgeon S. , Peters L. , Beer T. M. , Mori M. , Garzotto M.
Published: March 2020

4633

Background: The value of both PSA and DRE for prostate cancer detection have recently been called into question when examined in screening and prostatectomy series (NEJM 350:2239, J Urol 172:1297). The effectiveness of these parameters for detection of clinically significant cancer is not fully characterized. We studied their utility for the detection of aggressive prostate cancer (Gleason Score ≥ 7) in a referral population of men. Methods: Data were collected on 1,699 referred men with a serum PSA of ≤ 10 ng/ml who underwent a prostate biopsy (minimum 6 cores) between 1993 and 2004. Variables analyzed included: age, race, family history, DRE (normal vs. suspicious vs. cancer-likely) and PSA. Thirty percent of the data were randomly reserved for study validation. Logistic regression analysis was performed to estimate the odds ratio and the 95% confidence intervals. Results: Gleason grade ≥ 7 prostate cancer was detected in 157 subjects (9.2%). Using the model building data set (n = 1,184), independent predictors of Gleason ≥ 7 cancer were an elevated PSA and an abnormal DRE only (see table ). Based on these results, a clinically-applicable nomogram was constructed and using the independent validation set (n = 515). The area under the ROC was 0.70 for the model. Conclusions: Although the use of PSA and DRE have recently come under intense scrutiny, they independently predict the presence of aggressive prostate cancer in a contemporary referral population. Improvement in prostate-cancer survival associated with successful treatment of localized disease requires the successful early detection of aggressive prostate cancer. Our results demonstrate that PSA and DRE, currently recommended screening interventions by the ACS and AUA, remain useful for the detection of aggressive prostate cancer in the PSA era.

[Table: see text]

No significant financial relationships to disclose.
Serum HER-2/neu change predicts clinical outcome to trastuzumab-based therapy
Authors: Ali S. M. , Esteva F. J. , Fornier M. , Gligorov J. , Harris L. , Kostler W. J. , Luftner D. , Pichon M. F. , Tse C. , Lipton A.
Published: March 2020

500

Background: Trastuzumab monotherapy has a 34% objective response rate (ORR) in patients with HER-2/neu IHC 3+ or FISH-positive first-line metastatic breast cancer (C. Vogel et al, JCO 20:719–726, 2002). Predicting response and survival to trastuzumab-based therapy is an unsolved problem. The HER-2/neu extracellular domain (ECD) is released after cleavage by the ADAM metalloproteinases, and the remaining membrane-bound internal domain is constitutively activated. Trastuzumab inhibits cleavage of the HER-2/neu ECD. Methods: A pooled analysis of 7 trials of first-line trastuzumab therapy (with or without chemotherapy) with serial serum HER-2/neu levels were included. The FDA-approved HER-2/neu ELISA (Oncogene Science/Bayer HealthCare) was used to determine serum HER-2/neu levels. A pretreatment and post-treatment serum (16–120 days) from 307 patients was available. 236 patients had data on overall survival. Kaplan Meier Life table analysis was performed to compare duration of response (DRP), time to progression (TTP), and overall survival (OS). Results: The median decrease in serum HER-2/neu levels for all patients was 31.0% (Range: 98% decrease to 239% increase). Patients with > 20% decrease in HER-2/neu levels had a significantly higher objective response rate (ORR, complete + partial response) and longer DRP, TTP and OS. The results were similar regardless of the timing of the second serum draw (≤ 30 days vs. > 30 days) after the start of trastazumab. Conclusion: Patients with < 20% decrease in serum HER-2/neu levels have decreased benefit from trastuzumab therapy. Patients who do not have a significant decrease in serum HER-2/neu levels should be considered for additional HER-2/neu-targeted therapies.

[Table: see text]

[Table: see text]
Surgical staging of uterine cancer: Randomized phase III trial of laparoscopy vs laparotomy—A Gynecologic Oncology Group Study (GOG): Preliminary results
Authors: Walker J. L. , Piedmonte M. , Spirtos N. , Eisenkop S. , Schlaerth J. , Mannel R. S. , Spiegel G.
Published: March 2020

5010

Background: Feasibility of laparoscopy has been demonstrated, but the toxicity, staging, and survival has not been adequately compared to the traditional open approach. A randomized Phase III trial of 2616 patients was conducted by the GOG from 5/1996 to 9/2005. QOL and complications of surgery were previously reported at SGO. FIGO pathologic staging is the basis of this report. Methods: Clinical Stage I-IIA uterine cancer were eligible, consenting to either technique. The randomization procedures yielded two on laparoscopy arm for every one on the laparotomy arm. Scope participants were required to undergo laparotomy if the complete surgical staging was not feasible, or for resection of cancer. The staging results include: FIGO surgical stage, peritoneal cytology, number of nodes per site, and percent positive nodes at each location: right pelvic, left pelvic, right para-aortic, left para-aortic. Results: 2616 were randomized, 403 were excluded for this analysis: 84 ineligible, 76 sarcoma, 198 incomplete data, 45 were stage IV, leaving 2213 evaluable for lymph node staging of endometrial carcinoma (781 open:1432 scope). Conversion to laparotomy from laparoscopy occurred in 23.7%. Positive or suspicious cytology was found in 5.6% of laparotomy and 7.8% of laparoscopy participants (p = 0.055 n.s.). Pelvic nodes were documented (R 98.8% vs 98.9%, L 98.5% vs 98.1% n.s.) and positive pelvics (any positive 8.8% vs 8.7%; R 5.5% vs 5.8%; L 6.9% vs 6.1% n.s.) were similar. Laparoscopic surgical staging cases were less likely to have para-aortic nodes sampled (L 91.3% vs 85.0% p < 0.001; R 96.0% vs 92.5% P = 0.001), but positve nodes were no different (any positive PA 5.0% vs 4.5%; R 4.1%, 3.4%; L 2.3%, 2.7% n.s.). Final FIGO Staging results (III A: 5.5% vs 5.7% n.s.& IIIC: 9.3% vs 9.5% n.s.) were the same by randomization arm. Conclusion: These results demonstrate that laparoscopic surgical staging of endometrial cancer can be completed in 76.3%. No difference in postive cytology, node positivity rate, or FIGO stage could be attributed to the laparoscopic approach. Conversion to laparotomy is advised when incomplete staging results would yield inadequate information for treatment planning. NCI Funding: UO1CA65221, CA 27469.

No significant financial relationships to disclose.
Phase II study of letrozole in estrogen receptor (ER) positive relapsed epithelial ovarian cancer (EOC)
Authors: Gourley C. , Smyth J. F. , Mackean M. , Stevenson A. , Williams A. , Rye T. , Reed N. , Vasey P. , Gabra H. , Langdon S.
Published: March 2020

5025

Background: Letrozole is a potent oral aromatase inhibitor which rapidly suppresses circulating estrogen levels by 99% in postmenopausal women. By comparison with cytotoxic agents it is very well tolerated. We previously demonstrated an ‘endocrine sensitive’ subgroup of ovarian cancer patients with ER histoscore cutoff of ≥150 (Bowman et al, Clin Can Res 2002). Methods: This was a phase II study with a planned sample size of 33 patients. Eligible patients had relapsed EOC or primary peritoneal cancer with an ER histoscore of ≥150 and a rising CA125 that had progressed according to Rustin’s criteria. Patients were treated with letrozole 2.5mg daily until clinical or marker evidence of disease progression. The primary endpoint was response according to CA125 and RECIST criteria. Biomarker analysis by tissue microarray is also being performed. Results: 46 patients were accrued, 45 of whom were eligible. The median age was 61 (range 39–81). 24, 10 and 10 patients had received 1,2 and >2 previous lines of chemotherapy respectively. Of 43 patients evaluable for CA125 response, 7 (16%) had a response (decrease of >50%) and 16 (37%) patients had not progressed (doubling of CA125) following 12 weeks on treatment. In the CA125 responders, the nadir CA125 ranged from 0.7–49% of baseline (actual % of baseline: 0.7, 2.6, 11.1, 17.6, 23.6, 42.6, 49). Of the 7 responding patients, 5 had received only one previous line of chemotherapy. The time taken to achieve the nadir CA125 value ranged from 10 to 36 weeks, with a median of 13 weeks. Of 33 patients evaluable for radiological response, 3 (9%) had a PR and 14 (42%) had stable disease at 12 weeks. Overall, 11 patients (26%) had a PFS of >6 months and 2 patients (5%) had a PFS of ≥2 years. Conclusions: To our knowledge this is the first study of a hormonal agent in a selected ER +ve population of ovarian cancer patients. Promising efficacy of the agent is demonstrated in this population of pre-treated patients, many with a considerable bulk of disease. Given the median time of 13 weeks to response, we suggest that this strategy should be tested in ER+ve ovarian cancer patients in the adjuvant setting following first line chemotherapy

No significant financial relationships to disclose.
Phase II open label randomized study of trabectedin (T) given as two different dosing schedules in women with platinum-sensitive, recurrent ovarian carcinoma: Preliminary results
Authors: Del Campo J. , Roszak A. , Ciuleanu T. , Bidzinski M. , Hogberg T. , Wojtukienicz M. , Boman K. , Poveda A. , Westermann A. , Izquierdo M.
Published: March 2020

5031

Background: Trabectedin (Yondelis, ET-743) is a marine derived compound which binds to the minor groove of DNA distorting the DNA structure and induces apoptosis and cell cycle arrest. It has shown clinical activity in soft tissue sarcoma, ovarian, prostate and breast cancer. Methods: Patients (pts) with recurrent platinum sensitive ovarian carcinoma were randomized in a multicenter, open label study to receive T as 1.5 mg/m2 over 24 h infusion (schedule A) or 1.3 mg/m2 over 3 h infusion (schedule B) both every 3 weeks. All pts received dexamethasone premedication. Primary objective is to evaluate the response rate (RECIST) and secondary objectives are response duration, CA-125 response, time to progression and safety. Results: 107 pts were enrolled in 23 centers. Demographic and disease characteristics were well balanced. Toxicity and response data on the first 99 pts are available: median age 57 (25–78) years; ECOG PS=0: 72% and =1: 28%; pts received a median of 4 cycles (range:1–19 in A, 1–13 in B). Relative dose intensity was 84% and 93% respectively. Objective responses due to investigator’s assessment were 29% (8% CR, 21% PR) with 52% SD in A and 28% (11% CR, 17% PR) with 45% SD in B, with 11 pts not yet evaluable for response. CA 125 responses ≥ 50% occurred in 23% in A and 26% in B. TTP data will be presented. Safety: 501cycles were delivered; the most common any grade drug-related AEs per patient were (A and B) fatigue (56% and 47%), nausea (63% and 70%), vomiting (56% and 45%) and constipation (25% and 30%). Consistent with previous experience, alopecia, stomatitis and neurotoxicity were uncommon and mild/moderate. Grade 3/4 fatigue occurred in 15% in A and 4% in B. Grade 3/4 lab abnormalities were non-cumulative neutropenia (50% and 32%) and reversible ALT increase (58% and 53%). G-CSF support was not routinely given. There were 4 deaths <30 days last infusion date (3 in A unrelated to study drug, one in B due to related multiorgan failure). Conclusions: This analysis suggests that both T schedules appear active with manageable toxicity. There was a trend for less neutropenia and fatigue with schedule B. On the basis of these efficacy results, no additional phase III comparisons between these 2 schedules seem warranted

[Table: see text]
Utility of a novel serum tumor biomarker HE4 in patients with uterine cancer
Authors: Moore R. G. , Brown A. K. , Miller C. M. , Badgwell D. , Lu Z. , Verch T. , Allard J. W. , Granai C. O. , Bast R. , Lu K.
Published: March 2020

5036

Background: Approximately 40,880 new cases of uterine cancer are diagnosed in the U.S. annually resulting in 7,310 deaths. Uterine cancer is surgically staged and 75% of patients present with stage I disease. Patients with stage I tumors with intermediate to high risk factors have a recurrence rate of 20 to 30%. Serum CA125 is elevated in 75% of patients with advanced stage disease and in only 17% of patients with early stage disease. The use of CA125 for the detection of recurrent disease is limited at best. Only 25% of patients with asymptomatic recurrent disease have an elevated CA125. A better marker indicating early recurrent disease is needed. The objective of this study was to examine the value of a novel serum tumor marker HE4 in endometrial cancer. Methods: Serum samples from two prospective IRB approved studies at two institutions were analyzed to compare HE4 with CA125 in patients who had surgical staging for uterine cancer. Normal controls were obtained from healthy patients. Informed consent was obtained from all patients and blood samples were drawn pre-operatively. HE4 and CA125 levels were determined using assays from Fujirebio Diagnostic Inc. ROC curves were constructed for each tumor marker and the sensitivity at a set specificity of 95% was determined. Results: Serum from 156 controls and 233 patients with surgically staged endometrial cancer; (151 stage I, 21 stage II, 47 stage III and 14 stage IV) were examined. The area under the ROC curves (ROC-AUC) for HE4 and CA125 were determined and compared ( Table1 ). At 95% specificity, the sensitivity for differentiation of controls versus all stages was 44.9% for HE4 compared to 25.2% for CA125 (p = 0.0001). For stage I cases, HE4 showed an improvement in the sensitivity of 20.5% compared to CA125 (37.1% vs 16.6%, p = 0.0001). Conclusions: HE4 is elevated in all stages of endometrial cancer and has a greater sensitivity for discrimination from normal controls compared to CA125. As well, HE4 is elevated in early stage endometrial cancer and should be investigated as a marker for early recurrent disease.

[Table: see text]

[Table: see text]
In vitro drug resistance profiles correlate with DNA ploidy and p53 expression in 3,106 endometrioid and papillary serous adenocarcinomas of the uterus
Authors: Yu I. , Huang W. , Mechetner E.
Published: March 2020

5037

Background: Although chemotherapy is widely used to treat advanced and recurrent endometrial cancer, no patient-tailored protocols were developed, resulting in intermittent and incomplete clinical response. The utility of the Extreme Drug Resistance (EDR) assay to predict clinical resistance to chemotherapy was proven in several cancer types, including ovarian cancer. This study is the first attempt to evaluate the efficacy of the EDR assay in endometrioid (E) and papillary serous (PS) tumors and correlate it with the expression of two major biomarkers, DNA ploidy and p53. Methods: 2520 E and 586_PS adenocarcinomas were tested in the EDR assay using in vitro incubation in suprapharmacologic exposures of 4-HC (the active species of cyclophosphamide), cisplatin, carboplatin, and doxorubicin. The results were defined as EDR (one standard deviation more resistant than the database median), intermediate drug resistance (IDR - between the median and EDR), and low drug resistance (LDR - lower than the median). DNA ploidy was assessed in flow cytometry; p53 expression was quantitated on paraffin sections by immunohistochemistry. Results: Compared to E, the more clinically aggressive PS tumors were significantly associated with high (IDR + EDR) in vitro resistance to all EDR-tested drugs: 4-HC (p = 0.0010; χ2 statistics), cisplatin (p = 0.0064), carboplatin (p = 0480), doxorubicin (p = 0.0001). PS tumors showed significantly higher non-diploid status (p < 0.0001) and p53-positivity (p < 0.0001). For all EDR-tested drugs, increased in vitro resistance closely correlated with the non-diploid and high p53 status. Conclusions: These data document close correlation between the EDR assay results and biological behavior of endometrial tumors in terms of their clinical aggressiveness and biomarker expression and justify further studies on combined EDR and biomarker testing in assay-guided chemotherapy.

[Table: see text]

No significant financial relationships to disclose.
An RT-PCR-based multi-gene prognostic signature predicts distant metastasis of node negative, ER positive breast cancer from FFPE sections
Authors: Lau K. F. , Wang A. , Chew K. , Dai H. , Hastie T. , Brandt B. , Waldman F. , Sninsky J.
Published: March 2020

506

Background: Gene expression profiles have been shown to predict distant metastasis risk in breast cancer patients. For routine medical practice, molecular prognostic tests need to be able to quantify metastasis risk with readily available samples and optimally employ regulatory-approved platforms. Methods: 142 early stage, N-, ER+, untreated breast cancer patients were chosen. Mean age was 61.8 (31 - 89) yrs with 72% > 55 yrs. RNA was isolated from 4×10 μm FFPE sections. Using real-time RT-PCR, 200 genes selected from van ‘t Veer et al, Dai et al, Paik et al and additional candidate genes were profiled. Primary endpoint was distant metastasis free survival. A prognostic signature was identified using semi-supervised principal component method. Metastasis score (MS) was calculated from gene expression levels. Results: We identified a unique 15-gene prognostic signature and 3 normalization genes. Probability of metastasis for any time period can be calculated from MS and was evaluated for 2, 5, and 10 yrs. Using median of MS to stratify patients, the high-risk group had a hazard ratio (HR) of 4.1 (95%CI 1.77–9.54, p = 0.001) vs. the low-risk group. 5-yr and 10-yr metastasis free survival rates (std. error) were 0.76 (0.053) and 0.62 (0.064) in the high-risk group and 0.96 (0.025) and 0.90 (0.038) in the low-risk group. Multivariate Cox regression analyses indicated that molecular signature had independent prognostic value with HR of 2.97 (95%CI 1.17 - 7.52, p = 0.022) after adjusting for age, tumor size and grade. Molecular signature was more prognostic in the low-grade subgroup (HR = 6.85, 95%CI 1.81–25.88) than an unstratified analysis. AUC at 5 yr was 0.65 and 0.60 for molecular signature and Adjuvant Online (AO) respectively. The prognosticator combining both had AUC of 0.67. 10-yr metastasis probabilities from MS and AO have low correlation (R2=0.17). Conclusions: A prognostic signature based upon mRNA expression of 15 genes has been identified using FFPE sections with RT-PCR for early stage, N-, ER+ patients. Metastasis score that quantifies distant metastasis risk for any time period, not confounded with any treatment effect, can help clinicians and patients to choose among different therapeutic options. (Lau and Wang contribute equally)

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Topotecan (T) and carboplatin (C) in the treatment of platinum sensitive relapsed ovarian cancer (ROC): Results of a multicenter phase I/II study
Authors: Koensgen D. , Belau A. , Klare P. , Steck T. , Camara O. , Sommer H. , Oskay-Oezcelik G. , Coumbos A. , Lichtenegger W. , Sehouli J.
Published: March 2020

5089

Background: Despite of the effectiveness of radical surgery and first-line chemotherapy, most patients (pts) with advanced ovarian cancer will relapse. Paclitaxel (P) in combination with C as second-line treatment improves the outcome of pts with platinum-sensitive ROC in comparison to C monotherapy. Due to polyneuropathy and alopecia this regimen can not be offered to all pts. Therefore, other platinum-combinations are required. We conducted a phase I/II study to define the dose limiting toxicities (DLT) and the tolerability of combination therapy with T and C. Methods: Pts with platinum-sensitive ROC and primary standard therapy were stratified according to treatment-free interval (TFI): 6–12 months (A) and ≥12 months (B). Following dose regimens were analysed: T 1mg/m2/d1–3 + C AUC5/d3 and T 0.75 mg/m2/d1–3 + C AUC5/d3, q21d. DLT was based on the first 4 courses and defined as: CTC grade 3/4 hematological and grade 2 non-hematological toxicity (excepted alopecia, vomiting), treatment delay >7d. Primary endpoints were DLT and tolerability. Secondary endpoints were remission rate (RR) and progression-free survival (PFS). Results: From 06/04 to 08/05, 28 pts were enrolled, 26 pts (A:13 pts, B:13 pts) were eligible. Median age was 61.5 years. A total of 141 cycles were analysed, median number of cycles was 6 (range A:2–8, B:1–10). DLTs were: leucopenia (n = 5) and thrombocytopenia (n = 1). MTD was reached at dose: T: 0.75mg/m2 and C: AUC5. Overall, grade 3/4 hematologic toxicities (in% of all cycles), for (A) and (B) respectively, were: anemia 4% vs. 4%, leucopenia 34% vs. 13%, neutropenia 30% vs. 31%, thrombocytopenia 7% vs. 6%. Febrile neutropenia 4.3% vs. 0%. Darbepoetin alfa was given in 13.5% of all cycles. Overall, grade 3/4 non-hematologic toxicities were infrequent (< 5%). Overall RR (95% CI) was 50% (29.7–70.1) [A: 30.8% (0.1–61.1), B: 69.3% (38.7–90.9)]. Median follow-up was 5.8 mo, median PFS (95% CI) was 7.7 mo (1.3–9.4) [A: 6.2 (1.3–7.2), B: 8.0 (7.3–9.4)]. Median overall survival was not reached. Conclusions: TC is a feasible and effective chemotherapy regimen for platinum sensitive ROC. Tolerability is not associated to TFI. The recommended dose for subsequent studies is T:0.75 and C:AUC5.

No significant financial relationships to disclose.
Clinical activity of imatinib mesylate in combination with docetaxel in patients with advanced, platinum-resistant ovarian cancer—Hoosier Oncology Group GYN03–62
Authors: Matei D. , Emerson R. E. , Menning N. , Schilder J. , McClean J. , Sutton G. , Stephens D. , Whalen C. , Baldridge L. , Moore D.
Published: March 2020

5091

Background: Ovarian tumors harborc-Kit and PDGF receptors. We showed in an in-vitro model that Imatinib (G) inhibits the growth of ovarian cancer cells. We hypothesized that G in combination with chemotherapy inhibits the growth of ovarian tumors. Data from a phase II clinical trial utilizing G in combination with Docetaxel (D) in patients with advanced ovarian cancer (OC) are presented. Methods: This was an open label, one stage, multi-center phase II clinical trial. Planned sample size was 23. Patients with relapsed, platinum-resistant or refractory OC expressing PDGFR or c-kit were eligible. PDGFR and c-kit expression was assessed prior to enrollment by IHC using archival tumor tissue. G was administered at 600mg/d continuously and D was given weekly (30mg/m2) for 4 weeks, with 2 weeks break. Each cycle was 6 weeks, with a maximum of 6 cycles allowed. Tumor assessments were obtained after 2, 4 and 6 cycles. Response rate by RECIST was the primary endpoint. Results: 34 patients were screened. 17 tumors were c-kit + and 25 were PDGFRα +. 23 patients were enrolled. Of those, 4 patients had c-kit+/PDGFR- tumors, 12 were PDGFR+/c-kit- and 7 were c-kit+/PDGFR+. Median age was 55 (range 33–76) and median PS was 0 (range 0–2). Median number of prior treatments was 3 (range 1–9). Efficacy and toxicity data are available for 20 and 14 patients, respectively. Based on RECIST, there were 3 patients with PR and 3 patients with SD lasting at least 12 weeks. Of these 6 patients, 2 pts were c-kit+, 2 were PDGFR+ and 2 were PDGFR and c-kit+. All 6 patients had carboplatin and taxane resistant disease. Grade 3–4 toxicities were: neutropenia (2), thrombocytopenia (1), fatigue (1), dehydration (1), constipation (1), cardiac ischemia (1), nausea/vomiting (2), urinary frequency (1). Other G1–2 toxicities were: N/V (9), diarrhea (7), fatigue (8), mucositis (4), anemia (4), hypocalcemia (5), rash (6), anorexia (7), edema (5), hemolysis (1), non-neutropenic infections (7). Additional data will be available in May 2006. Conclusions: The combination G+D is tolerated well. Clinical activity consisted of 3 PRs (15% response rate) and 3 SD > 3 months in pts with heavily pre-treated, platinum resistant OC expressing c-kit or PDGFRα.

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End of life treatments and events in ovarian cancer: A comparison of short versus long-term outcomes
Authors: Von Gruenigen V. E. , Daly B. , Frasure H. , Hutchins J. , Green A.
Published: March 2020

5096

Background: To identify the aggressiveness of treatment and events in ovarian cancer patients during the last year of life based on survival time. Methods: Patient charts of deceased epithelial ovarian cancer patients were retrospectively reviewed from 2000–2005. All patients included had debulking surgery and received adjuvant chemotherapy. Patients were separated into groups based on survival quartiles. Aggressiveness of care was measured by chemotherapy regimens, ER visits and hospitalizations. Significant clinical events (SCE) were defined as ascites, bowel obstruction, and pleural effusion. Comparison of quartiles was done using chi-square and t-test statistic. Multiple regression analysis was done using survival duration as a dependent variable. Results: 97 patients with epithelial ovarian cancer were reviewed. There was no difference in patterns of hospitalizations and SCE between the top and bottom survival quartiles. Patients with a shorter survival time received more chemotherapy during their last 3 months of life and had increased overall aggressiveness of care measures (Table). In patients who had a remission, regression analysis revealed length of initial remission time was significant in predicting survival (p < 0.01). Time to 2nd relapse was also significant in predicting survival time (p < 0.01). Number of SCE during the last year of life events trended for predicting survival (p = 0.10). Conclusions: Duration of ovarian cancer remission is predictive of survival. Those patients with a short trajectory of disease receive more aggressive care, chemotherapy at the end of life, less hospice care; however, they die similarly to those with longer survival duration. Those patients with short remissions and / or SCE during recurrence should receive less aggressive care at the end-of-life.

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No significant financial relationships to disclose.
HER2 predicts benefit from adjuvant paclitaxel after AC in node-positive breast cancer: CALGB 9344
Authors: Hayes D. F. , Thor A. , Dressler L. , Weaver D. , Broadwater G. , Goldstein L. , Martino S. , Ingle J. , Henderson I. C. , Berry D.
Published: March 2020

510

Background: CALGB 9344 showed 4 cycles of paclitaxel (T) after 4 cycles of doxorubicin/cyclophosphamide (AC) improved disease-free (DFS) and overall survival (OS) compared to 4 cycles of AC. Higher dose of A had no benefit (Henderson JCO ’03). Prior studies suggest HER2 is associated with benefit from standard vs low dose of C&A (Dressler JCO ’05). We hypothesized that HER2 might predict benefit from higher dose of A or from T, and that HER2 might refine the observed negative interaction of T with estrogen receptor (ER). Methods: 3121 node + women in CALGB 9344 received 4 q3wk cycles of AC (A: 60, 75, or 90 mg/m2) and then 4 cycles of T (175 mg/m2 q3wk) or no T. Blocks were collected from ∼2800 subjects. 2 sets of 750 patients each were randomly selected from these cases: Set 1 to develop hypotheses; Set 2 for validation. Tissue specimens were available from 643 (set1) and 679 (set2) cases (20% & 22% total enrolled in 9344 respectively). HER2 was evaluated by FISH and by IHC (by antibody cb11 and by Herceptest). Statistical analyses used Cox proportional hazards models, including interaction terms, and Kaplan-Meier estimates for comparing 5-yr DFS by treatment group. Results: In Set 1, all 3 assays suggested that T improved DFS for HER2+ but not for HER2-. For this single set the interaction was not statistically significant. There appeared to be an interaction of HER2, T and ER. IHC using cb11 was applied to Set 2, revealing nearly identical results. In the two sets combined (n=1322), the interaction between HER2 and T was statistically significant (p=0.013). The 3-way interaction of HER2, ER and T was hypothesis-generating and not tested statistically. Differences in 5-yr DFS rates (95% CI) for T vs. no T by HER2 and ER (both sets combined) There was no interaction between HER2 and dose of A. Conclusions: These results suggest that the benefit of adding T to AC is greater for HER2+ tumors, even if ER+, while T was of no apparent benefit in the ER+, HER2- group. Further validation is needed from remaining cases in 9344 and from other trials involving T.

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Survival benefit of switching to anastrozole after 2 years’ treatment with tamoxifen versus continued tamoxifen therapy: The ARNO 95 study
Authors: Kaufmann M. , Jonat W. , Hilfrich J. , Eidtmann H. , Gademann G. , Zuna I. , Von Minckwitz G.
Published: March 2020

547

Background: Initial adjuvant treatment with anastrozole has significant efficacy and tolerability advantages over tamoxifen in postmenopausal women with hormone-sensitive early breast cancer (EBC) (ATAC Trialists’ Group. Lancet 2005; 365: 60–62). The ARNO 95 study evaluated prospectively switching to anastrozole from tamoxifen after 2 years, compared with continuing tamoxifen therapy. Here, we present an interim efficacy and safety analysis. Methods: This was a prospective, randomized, open-label study conducted in 54 centers in Germany. Postmenopausal women (≤75 years) with hormone receptor-positive, invasive EBC, who had received 2 years of adjuvant tamoxifen without recurrence, were randomized to switch to anastrozole (1 mg/day) or continue on tamoxifen (20 or 30 mg/day) for a further 3 years. No adjuvant chemotherapy was given. The primary end point was disease-free survival (DFS; time to earliest occurrence of local or distant recurrence, new primary breast cancer, or death from any cause); secondary end points included overall survival (OS), safety, and tolerability. Data were analyzed using a log-rank test; a second analysis used a Cox proportional hazards model with covariates of age, tumor size, nodal status, grade, and type of surgery. Results: Overall, 979 patients (mean age 60 years; 74% node-negative; 97% hormone receptor-positive) were enrolled, 489 were randomized to switch to anastrozole, with 490 continuing on tamoxifen. Median follow-up was 30.1 months. Switching to anastrozole significantly improved DFS and OS compared with continuing on tamoxifen ( Table ). Fewer patients who switched to anastrozole reported serious adverse events (22.7%) compared with those who remained on tamoxifen (30.8%). Conclusions: Switching endocrine treatment improved DFS and OS in this well-defined population. Postmenopausal women with hormone-sensitive EBC who have already received 2 years’ adjuvant tamoxifen therapy should be switched to anastrozole.

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