bluuebunny/crossref_metadata_2025 huggingface dataset:
Activity of Vincristine and Irinotecan in Diffuse Anaplastic Wilms Tumor and Therapy Outcomes of Stage II to IV Disease: Results of the Children’s Oncology Group AREN0321 Study
Authors: Daw Najat C. , Chi Yueh-Yun , Kalapurakal John A. , Kim Yeonil , Hoffer Fredric A. , Geller James I. , Perlman Elizabeth J. , Ehrlich Peter F. , Mullen Elizabeth A. , Warwick Anne B. , Grundy Paul E. , Paulino Arnold C. , Gratias Eric , Ward Deborah , Anderson James R. , Khanna Geetika , Tornwall Brett , Fernandez Conrad V. , Dome Jeffrey S. ,   on behalf of the AREN0321 Study Committee
Published: March 2020

PURPOSE

AREN0321 evaluated the activity of vincristine and irinotecan (VI) in patients with newly diagnosed diffuse anaplastic Wilms tumor (DAWT) and whether a regimen containing carboplatin (regimen UH1) in addition to regimen I agents used in the National Wilms Tumor Study 5 (NWTS-5; vincristine, doxorubicin, cyclophosphamide, and etoposide plus radiotherapy) would improve patient outcomes.

PATIENTS AND METHODS

Patients with stage II to IV DAWT without measurable disease received regimen UH1. Patients with stage IV measurable disease were eligible to receive VI (vincristine, 1.5 mg/m2 per day intravenously on days 1 and 8; irinotecan, 20 mg/m2 per day intravenously on days 1-5 and 8-12 of a 21-day cycle) in an upfront window; those with complete (CR) or partial response (PR) had VI incorporated into regimen UH1 (regimen UH2). The study was designed to detect improvement in outcomes of patients with stage II to IV DAWT compared with historical controls treated with regimen I.

RESULTS

Sixty-six eligible patients were enrolled. Of 14 patients with stage IV measurable disease who received VI, 11 (79%) achieved CR (n = 1) or PR (n = 10) after 2 cycles. Doses of doxorubicin, cyclophosphamide, and etoposide were reduced midstudy because of nonhematologic toxicity. Four patients (6%) died as a result of toxicity. Four-year event-free survival, relapse-free survival, and overall survival rates were 67.7% (95% CI, 55.9% to 79.4%), 72.9% (95% CI, 61.5% to 84.4%), and 73.7% (95% CI, 62.7% to 84.8%), respectively, compared with 57.5% (95% CI, 47.6% to 67.4%; P = .26), 57.5% (95% CI, 47.6% to 67.4%; P = .048), and 59.2% (95% CI, 49.4% to 69.0%; P = .08), respectively, in NWTS-5.

CONCLUSION

VI produced a high response rate in patients with metastatic DAWT. AREN0321 treatment seemed to improve outcomes for patients with stage II to IV DAWT compared with NWTS-5, but with increased toxicity. The UH2 regimen warrants further investigation with modifications to reduce toxicity.
Characteristics of a single-centre series of familial testicular germ cell tumours
Authors: Coffey J. , Huddart R. A. , Norman A. R. , Dudakia D. , Stratton M. R. , Rapley E. A.
Published: March 2020

10039

Background: Testicular germ cell tumors (TGCTs) account for 1% of all male cancers with increasing incidence rates documented. A family history of TGCT occurs in 2% of patients, conferring relative risks of 8–10 for brothers and 4–6 for fathers or sons of patients. These risks are high in comparison to other solid cancers and suggest that the risk of developing TGCT may be, at least in part, inherited rather than acquired. Methods: Pedigrees with >1 male family member with TGCT were identified from a tumor database and systematically collected from 1992. Patients donated samples and medical details with full informed consent and under ethical review board approval. Pedigree and medical data were obtained by interview, mail and telephone contact. Results: This series examines 78 pedigrees, containing 160 cases and 170 TGCTs. In the period 1994–2003 6% of all cases had a family history of TGCT. It includes 35 sib-pairs, 12 father-son pairs, 11 uncle-nephew pairs, 10 cousin pairs and 4 pedigrees with ≥ 3 cases of TGCT. The dataset contains 66 seminomas, 56 non-seminomas, 17 mixed histology, 1 CIS and 30 tumors of unconfirmed histology. The median age at diagnosis was 33 (range 17 to 87). The median difference in age at diagnosis between the cases in each pedigree was 6 years (0–58). Histology was concordant between family members in 22 of the 53 (41.5%) 2-case pedigrees. 11 pedigrees contained a case with bilateral TGCTs (6.9% of all cases, compared to 1.1% in the sporadic patient population, p<0.001) with 50% histological concordance. The median age at diagnosis of bilateral tumors was 32 (21–42) for the first tumor and 35 (26–49) for second tumors. 24 TGCT cases (15%, compared to an expected rate of 10%, p=0.045) reported a history of UDT. 9/162 (5.5%) of TGCT cases also developed non-TGCT cancers, including penile, bladder, colorectal, hepatic and pancreatic tumors. Conclusions: When systematic collection is undertaken the incidence of familial TGCT may be higher than previously reported. Familial cases have a higher incidence of UDT and bilateral disease. The majority of this set has been used in an international genome-wide linkage analysis to identify TGCT susceptibility genes.

No significant financial relationships to disclose.
Heat shock protein 70 vaccines activate NK cells through NKG2D
Authors: Liu B. , Qaio Y. , Li Z.
Published: March 2020

10044

Background: We have previously reported that vaccination with heat shock protein 70 (HSP70) induced natural killer (NK) cell activity in patients with chronic myelogenous leukemia (CML). The underlying mechanism is unclear. Methods: HSP70 was purified from the peripheral blood mononuclear cells. CD56+ NK cells were enriched by magnetic sorting after staining PBMCs with anti-CD56 monoclonal antibody. Dendritic cells (DCs) were derived from peripheral blood monocytes after culture in the presence of IL-4 and GM-CSF. NK activation was measured by the IFNgamma ELISPOT assay. Results: Unexpectedly, HSP70 of autologous, allogeneic as well as xenogeneic origin was found to stimulate IFNgamma production from peripheral blood mononuclear cells of CML patients as well as normal subjects. Further studies demonstrated that the activity of HSP70 was dependent on both NK cells and DCs. HSP70 did not induce significant IFNgamma production from either NK cells or DCs alone. Mechanistically, we found that HSP70-mediated DC-NK cell crosstalk required cell-cell contact, which could be inhibited completely by neutralizing antibody against NK activating receptor NKG2D. The significance of NKG2D was further corroborated by the finding that HSP70 induced the expression of an NKG2D ligand, the MHC class I chain-related protein A (MICA), on DCs; HSP70-augmented IFNgamma release was abrogated by antibody against MICA. Conclusions: Thus HSP70 may serve as a critical link between NK and DCs in mounting immune responses against infections, cancers and self-antigens. Our novel findings support further studies in the development of HSP70-based vaccines against human malignancies. Acknowledgement: Z.L. is a clinical scholar of the Leukemia and Lymphoma Society.

No significant financial relationships to disclose.
Endothelial progenitor marker CD133 mRNA expression in peripheral blood mononuclear cells predicts outcome of cancer patients
Authors: Mehra N. , Penning M. , Maas J. , Van Daal N. , Voest E.
Published: March 2020

10087

Background: We examined whether expression of CD133, a surface molecule expressed on progenitors of hematopoietic and endothelial lineages, is increased in the peripheral blood mononuclear cells (PBMC’s) of cancer patients. Furthermore we correlated CD133 mRNA expression with tumor prognostication factors and overall survival. Methods: PBMC’s were isolated from the blood of 130 advanced cancer patients (43 renal cell carcinoma, 27 colorectal cancer, 34 prostate cancer, 27 head and neck cancer). Clinicopathological parameters were obtained. Median follow-up time was 16 months after inclusion (range 3–33 months). For the quantification of CD133 mRNA we used a real-time detection and quantification method based on nucleic acid sequence-based amplification (NASBA). Also U1A DNA was quantified as internal control for input and isolation. CD133 mRNA copy numbers were expressed as copies per 10.000 cells, as determined by U1A DNA. Results: Patients with metastasized disease have a significant increase in CD133 mRNA as compared to patients without metastasis. This increase is strongest in patients with bone metastasis. Subgroup analysis in patients with bone involvement show that CD133 mRNA also correlates with PSA (n=34)and inversely with hemoglobin (n=50). CD133 mRNA expression is an independent predictor for overall survival in Cox’s multivariate analysis (variables in the model included age, hemoglobin, metastasis, previous treatment and CD133 as categorical variable). A CD133 mRNA cut-off value was established by Receiver Operating Characteristic analysis of CD133 expression in relationship to survival (sensitivity 64% and specificity 71%). Cancer patients with more than 200 copies of CD133 mRNA, demonstrate a decreased survival compared to patients with lower CD133 expression (median survival 8 and 15.4 months, respectively). In patients with bone metastasis the median survival of high and low expressers is 6.3 months and 21.9 months, respectively. Conclusions: mRNA expression of stem-cell marker CD133 is increased in cancer patients with metastasized disease and an independent prognostic factor for overall survival. Increased CD133 mRNA expression may reflect an activated angiogenic state in these cancer patients.

[Table: see text]
Efficacy of zoledronic acid versus placebo on biochemical markers of bone metabolism in patients with breast cancer metastatic to bone
Authors: Kohno N. , Aogi K. , Minami H. , Takashima S.
Published: March 2020

10559

Background: Zoledronic acid reduces the levels of bone markers and the risk of skeletal complications in patients with bone metastases. Recently, a correlation between the levels of biochemical markers of bone metabolism and the risk of clinical complications (ie, skeletal complications, disease progression, and death) in patients with bone metastases has been reported. The effect of zoledronic acid on bone marker levels was assessed in patients with bone metastases from breast cancer in a multicenter randomized trial conducted in Japan. Methods: Women with bone metastases secondary to breast cancer (N = 228) were randomized to 4 mg zoledronic acid (n = 114) or placebo (n = 114) every 4 weeks for 1 year. Levels of urinary N-telopeptide (NTX), a sensitive marker of bone resorption, were measured at baseline and regularly throughout the study. Results: The table shows that zoledronic acid reduced NTX levels in patients compared with placebo. Patients treated with zoledronic acid had a mean decrease of 61% from baseline NTX levels at week 2. This decrease was maintained throughout the study in this treatment group and was 54% at week 52. In contrast, patients in the placebo group had a mean increase of 27% from baseline NTX levels at week 2, and levels of NTX continued to increase during the study, reaching 146% above baseline at week 52. Conclusions: This analysis shows that treatment with zoledronic acid reduced NTX levels in patients with bone metastases from breast cancer compared with placebo. These results are consistent with published reports in patients with prostate or lung cancer and are consistent with the significant reduction in skeletal morbidity observed in this trial in breast cancer patients. Zoledronic acid demonstrated a 39% reduction in skeletal morbidity in this patient population.

[Table: see text]

No significant financial relationships to disclose.
Fulvestrant (F) in metastatic breast cancer: Standard dose (Std) vs loading dose (Ld)—A retrospective study
Authors: Moussallem C. D. , Lopez A. , Gauthier A. , Moore S. , Johnson M. , Murray J. L. , Ibrahim N. K.
Published: March 2020

10575

Background: Fulvestrant is shown to be an effective hormonal agent in menopausal hormone-receptor positive metastatic breast cancer (MBC) patients. This study aimed at showing if Ld of fulvestrant will improve its efficacy over the FDA approved Std schedule. Methods: We retrospectively reviewed our pharmacy electronic database over a period of two years to identify MBC patients who were treated with fulvestrant. Patients received either Std of 250 mg IM on day (d) 1 and repeated Q28d or Ld of 500 mg IM d1 and 15 and Std on d28 which was repeated every 28 days until evidence of progression. All medical records were reviewed and responses were recorded as improved disease (ID), stable disease (SD), or progressive (PD) as documented by the treating oncologist. Time to response (TTR) (the interval from first injection until response) as well the duration of response (DR), was determined. Results: Medical records of 157 consecutive, evaluable patients who received F for their MBC were identified and reviewed. Group 1 (Gp1) received std (N = 122) and Group 2 (Gp2) received loading dose (N = 35). There were no significant differences between the two groups in relation to age, pathology, grade, Her-2, ER and PR status or number of prior chemotherapy regimens (p > 0.05). Gp2 had statistically significant more prior hormone therapies (p = 0.0159). Median number of doses for Gp2 was 5 (R: 1–18) compared to 3 (R: 1–25) for Gp1 (p = 0.0169). Responses (ID) 14% for Gp1 and 18% for Gp2; clinical benefits (ID + SD) were 37.7% and 38%, respectively, NSS (p = 0.9550). TTR was 10 (R: 6–32) wks for Gp1 and 8 (R: 4–20) wks for Gp2; the DR was 15.5 (R: 4- 84) weeks for Gp1, and 12 (R: 2- 96) for Gp2. No statistical significance was detected between the 2 groups. Conclusions: This study showed there is no significant difference between the 2 dose schedules, either in the response rate or its duration. Prospective studies are needed to prove the equivalence of the Std and Ld of F.

No significant financial relationships to disclose.
Phase II trial of gemcitabine and carboplatin, plus trastuzumab in HER2+ patients as first line therapy in metastatic breast cancer
Authors: Yardley D. A. , Peacock N. W. , Shipley D. , Waterhouse D. , Landgdon R. , Simons L. , Thomas S. , Hainsworth J. D. , Spigel D. R. , Burris H. A.
Published: March 2020

10590

Background: Gemcitabine (G) and carboplatin (C) demonstrate significant preclinical synergy together as well as in combination with trastuzumab (H) in metastatic breast cancer (MBC) pts. This multicenter phase II trial evaluates the efficacy and safety of G + C with trastuzumab in HER2 + pts as 1st line therapy in MBC. Methods: Eligibility requirements: females > 18 with no prior regimens for MBC, ECOG 0–2, RECIST bidimensional disease, and adequate organ function. FISH HER2 + pts received H with GC. Treatment: G 1,000 mg/m2 D1& 8 with C AUC 5 D1 in the first 20 pts. Following a toxicity assessment revealing significant myelosuppression, C was administered in subsequent pts at AUC 4. 14 HER2+ pts received H 8 mg/kg loading dose followed by 6 mg/kg q21 days. Pts were evaluated for response after 9 weeks; treatment continued until progression or toxicity except in HER2+ pts who received up to 6 cycles GCH followed by single agent H. Results: Between 11/03 & 11/05, 45 pts have been treated: median age 55 for GC, 65 for GCH, ECOG 0/1 22/23. 19 pts were chemonaive. 26 pts received prior adjuvant chemotherapy: 20 pts adjuvant anthracyclines (A) & taxanes (T), 3 only prior A and 3 prior T. 73% had 2 or more metastatic sites of disease. 31 pts received GC & 14 pts received GCH. 18 of 41 evaluable pts (44%) had objective responses (PR 16, CR 2) with 17 pts (42%) exhibiting SD & 6 pts PD (15%). 91% of AT pretreated pts demonstrated SD or better. 9 remain on study. 6 went off study due to heme related toxicities and 9 due to MD discretion [4 max benefit, 3 XRT]. Median # of cycles was 5. Combined G3/4 hematologic toxicity was notable for 66% neutropenia (only 1 FN), 55% thrombocytopenia, and 32% anemia, predominately occurring at the carboplatin AUC 5 dose level. Transfusions of PRBCs and plts were administered in 14 and 8 pts respectively. Nonhematologic toxicity was minimal and remarkable for G3/4 fatigue in 20%. Conclusions: In FISH HER2+ pts, the addition of trastuzumab to GC yielded a 50% RR, with no evident cardiotoxicity. The combination of gemcitabine with carboplatin AUC 4 is active, albeit with moderate hematologic toxicity, warranting further exploration of alternate GC ± H schedules in breast cancer.

[Table: see text]
Every-other week capecitabine (C7) combinations: An active and well tolerated treatment in heavily pretreated patients (p) with advanced solid tumours
Authors: Chacon J. , López L. , Quintanar T. , Rubio G. , Blanca M. , Andrade J. , Carbonero I. , G Esteban C. , Cruz M. A.
Published: March 2020

10649

Background: Standard C schedule is 14 days every 3 w (C14). However, data have shown that C7 schedule is as effective as and significantly less toxic than C14. The objective is to evaluate retrospectively the response rate and toxicity of C7 as single agent or in combination in heavily pretreated p with advanced solid tumours. Methods: p with advanced solid tumour, age ≤ 75 years, ECOG PS <2 and adequate bone marrow, renal and hepatic functions were analyzed. p received C7: 1250 mg/m2/12 h x 7 days every-other week. The combination drugs doses were adjusted to be used days 1 and 15. Cycles every 28 days. Response was evaluated every 3 cycles according to RECIST criteria Results: 20 p received C7. Cancer type: 11 breast (BC), 7 colo-rectal (CRC), 1 H&N and 1 gastric (GC). Median age 56 y (33–75). M/F: 8p/12p. ECOG 0/1: 39%/61%. 19 p stage IV and 1 (H&N) stage III. The most frequent metastatic site was liver 42.2%. 90% p had been heavily pretreated with chemotherapy (CT): 55% p had received ≥ 2 CT lines. 15% p had been treated with taxanes, 45% p taxanes + anthracyclines, 10% p 5-FU, 15% p oxaliplatin (Oxa) and/or raltritexed. 2 BC p had also received herceptin (Her) and 2 p (1BC/1CRC) had been previously treated with C14. Median nº cycles: 6 (1–19). C7 combinations were: 5/7 CRC p Oxa or CPT-11 and 11/11 BC p docetaxel (1p) or gemcitabine (1 p) or carboplatin (9 p) ± Her. 4 p received C7 alone. Toxicity (20 p). Grade I/II: HFS 55%, diarrhoea 25%, nausea/vomiting 15%, mucositis 5%, skin 5% and parestesias 5%. Grade III/IV: diarrhoea in 2 p (1CRC and 1 BC). Response (20 p): 2 CR (10%) both CRC p; 6 PR (30%) 5 BC p and 1 CRC p; 4 SD (20%) and 8 PD (40%). 40% ORR rate and 60% TGC. Median response duration: 37 w (22–44 w). 2 p who achieved CR received C7 combined with CPT-11. C7 combination in p with PR were Oxa (1 CRC p) and carboplatin ± Her (5 BC p). Conclusions: C7 schedule is an active regimen in patients with advanced CRC and BC heavily pretreated with CT and it shows a very favourable toxicity profile. These results warrant a phase II trial of carboplatin-C7 in MBC as front line therapy that will by lauched by Feb-2006.

No significant financial relationships to disclose.
Updated results of a multicenter phase II trial of neoadjuvant docetaxel, carboplatin and capecitabine for inflammatory and locally advanced breast cancer (LABC)
Authors: Franco S. X. , Perez A. , Tan-Chiu E. , Gokce F. , Frankel C. , Schwartzberg L. S. , Krill E. , Jakub J. , Abramson N. , Vogel C.
Published: March 2020

10685

Background: Neoadjuvant chemotherapy for the treatment of LABC has become the standard of care but the best combination is not established. The combination of docetaxel and capecitabine demonstrates synergism in patients(pts) with metastatic breast cancer (MBC). Recent studies support the value of platinum salts in LABC and MBC. Methods: pts with stage IIA-IIIC or inflammatory BC, EGOG PS 0–1, are eligible.We are evaluating the combination of weekly docetaxel 30mg/m2, carboplatin AUC2 on D1, 8,15 of a 4-week cycle plus capecitabine 625 mg/m2 BID given on days 5–18 (based on the upregulation of thymidine phosphorylase) for 4 cycles prior to surgery. The primary objective of this phase II trial is pCR rate in breast. Results: 39 of 48 pts have been enrolled from 7 centers. Median age 46 (range 26–75), stage II 41%, stage III 59%. Median baseline tumor is 5.4cm (range 2.1–15); 1pt inflammatory BC; 10 pts N2 disease (36%); 12 tumors were ER+, 20 ER-, and 5 Her-2+. To date, 2,377 doses (including daily capecitabine doses) were administered out of a total of 2,560 (93% of intended doses) with only 10 dose delays and 8 dose reductions. 37 pts are evaluable for toxicities. No grade IV toxicities were seen, grade III neutropenia was seen in 3/37(8%) and grade III fatigue in 1/37(3%). There were no episodes of neutropenic fever.The most common grade I/II toxicities were nausea in 57%, diarrhea 38%, fatigue 43%, epiphora 24%, mucositis 24% and hand-foot syndrome 3%. No death related treatments have been reported. 32 pts have completed definitive surgery. Objective clinical response is 94% with 53% cCR. 5 patients had pCRs in breast(16%) and 5 pCR in breast and axilla(16%). 9 pts (28%) have microscopic residual disease in the breast (<3mm). 14 pts had complete axillary clearance (44%). Conclusions: The preoperative combination of docetaxel, carboplatin and capecitabine is feasible with very good response rate and a very acceptable toxicity profile. Accrual is ongoing.

No significant financial relationships to disclose.
Open labeled phase II observation study of gemcitabine plus cisplatin plus trastuzumab (GCT) in metastatic breast cancer patients with prior anthracyclines and taxanes exposures: Preliminary results
Authors: Demiray M. , Evrensel T. , Kanat O. , Kurt E. , Arslan M. , Gokgoz S. , Tolunay S. , Manavoglu O.
Published: March 2020

10720

Background: Trastuzumab provides significant clinical benefit in HER2 positive metastatic breast cancer. Gemcitabine and cisplatin (GC) combination is attractive treatment options for anthracyclines-taxanes-pretreated metastatic breast cancer. These agents demonstrated synergistic activity and minimal overlapping toxicity. On the other hand, additional synergistic activity was observed with trastuzumab and GC. Methods: Histologically confirmed metastatic breast cancer patients with FISH positive tumors (HER2/choromosome 17 ≥2) were eligible if they were at least one measurable disease; ≥18 and ≤70 years; life expectancy >3 month; ECOG 0–2; prior anthracyclines and taxanes treatment but no prior trastuzumab therapy; adequate marrow, renal and hepatic function. Treatment schedule was as follows: Gemcitabine 1000 mg/m2 and cisplatin 30 mg/m2 d1, 8 every 3 weeks conjunction with trastuzumab 4 mg/kg d1 and 2 mg/kg for weekly. Chemotherapy was scheduled for up to eight cycles. Treatment was discontinued in case of progression or prohibitive toxicity. After progression additional regimen was administered with trastuzumab. Results: Eleven women were enrolled. All patients were eligible for toxicity and efficacy evaluations. Median age was 48 (range 28–64) years and median ECOG performance status was 0. Ten patients (90.9%) had visceral metastases, most commonly located in the liver (8 pts) and lung (4 pts). Estrogen receptor positivity was 63.6% (7 pts). A total of 80 cycles were delivered with a median of 8 cycles. Objective response rate was 54.5% (6 pts) with 27.2% (3 pts) complete response and 27.2% (3 pts) partial response. Stabile disease was achieved 36.3% (4 pts). Median time to progression and overall survival were 8 (95% CI: 3.97–12.02) and 18 months (95% CI: 15.89–20.10) respectively. Grade 3–4 toxicity was observed in 18.1% (2 pts). Treatment of one patient was discontinued due to grade 4 thrombocytopenia. Dose reductions due to myelotoxicity were performed in 1 (9.0%) patients. Conclusions: Our preliminary data shows that gemcitabine and cisplatin and trastuzumab combination regimen is effective and has manageable toxicity profile.

No significant financial relationships to disclose.
FEC 60 adjuvant chemotherapy (AdCT) in breast cancer (BC) patients (Pts): 10-year follow-up results
Authors: Moura Silva F. , Tosello C. , Laloni M. T. , Andrade C. M. , Bertozzi A. , Vernaglia P. , Correa F. M. , Moraes R. P. , Goes J. S.
Published: March 2020

10725

Background: To evaluate the efficacy of the Epirubicin as a part of the FEC60 AdCT in operable BrC patients in a Brazilian single-center. Methods: We verified retrospectively our experience with FEC 60 as AdCT in pre and postmenopausal, node positive and negative, pathologic stage I, II and III patients with BrC. Pts were submitted after surgery to receive Fluorouracil 600 mg/m2, Epirubicin 60 mg/m2 and Cyclophosphamide 600 mg/m2 every 28 days for 6 cycles. Pts who were ER+ and/or PR+ received Tamoxifen (TMX) 20 mg/day for 5 years after AdCT. Radiotherapy was also offered at the end of AdCT if indicated. All patients were evaluated in terms of 10 year (y) Disease Free Survival (DFS) and Overall Survival (OS). The most common toxicities (acute and chronic) and metastatic sites will also be reported. Results: Between July 1983 and December 1995 a total of 752 patients (ranging from 22 to 77 years old - median 47.7) were encountered and all of them were evaluated to 10 year (y) DFS and OS. Approximately 61% of these patients received adjuvant TMX. Pts in premenopausal and postmenopausal represented 62.5% and 37.5% respectively. 72 (11%) pts had pathological stage I; 353 (46%) pts had stage II and 327 (43%) had stage III. The 10y DFS was 70%, 46% and 19% for stage I, II and III respectively. The 10y OS after a minimal follow-up of 122.98 months was 74%, 48% and 20% for stage I, II and III respectively. Conclusions: Our results demonstrated that FEC 60 regimen is active and well tolerated in the adjuvant treatment for BrC pts. We had about 89% of stage II and III pts and in this population FEC60 regimen add benefit. Nevertheless, the randomized studies indicate that the greatest anticancer effect of Epirubicin requires doses ranging from 75 to 120 mg/m2, but due to economic reasons (we integrate the brazilian public healthy system) we could not offer dosages greater than 60 mg/m2. FEC 60 was feasible and offered reasonable results in our population in terms of 10y DFS and OS.

No significant financial relationships to disclose.
Glioma patterns of care in Victoria from 1998–2000
Authors: Rosenthal M. , Drummond K. , Dally M. , Murphy M. , Cher L. , Ashley D. , Thursfield V. , Giles G.
Published: March 2020

11521

Background: The management of Gliomas is complex and requires a multidisciplinary approach. The care of such patients (pts) may be variable. The State of Victoria has a population of approximately 4 million people and over 300 new glioma cases diagnosed annually. Methods: This was a retrospective cohort study conducted by surveying doctors involved in managing incident adult glioma cases identified from the population based Victorian Cancer Registry during 1998–2000. The survey was conducted in 2004–5 obtaining at least four years follow-up data on all pts. Results: 828 pts were considered eligible for this study. 264 pts (32%) were aged over 70 years and 92 (11%) were aged over 80 years. 105 (13%) did not have a histologic diagnosis and 473 (57%) had glioblastoma multiforme (GBM). Complete macroscopic resection was performed in 209 pts (25%). Of all pts with a glioma, 612 (74%) and 326 (54%) were referred at initial diagnosis for consideration of radiotherapy and chemotherapy respectively. In 473 pts with GBM, 406 (86%) and 147 (31%) pts were initially referred for consideration of radiotherapy and chemotherapy respectively. Only 39 pts(5%) were enrolled on a clinical trial. The median survival for pts with a GBM was 7.4 months with a 3% five-year survival. Conclusions: This is one of the largest ever-reported glioma management surveys. Much of the patient demographics and approach to treatment were expected and represent a reasonable “standard of care”. Importantly, this study emphasises the elderly nature of this patient population and identifies areas of concern including: absence of histologic diagnosis, lack of multi-disciplinary care and low clinical trial enrolment.

No significant financial relationships to disclose.
A comparative study on capecitabine (Cape) pharmacokinetics (PK) in elderly or younger patients with metastatic breast (MBC) or colo-rectal cancer (CRC)
Authors: Longobardi C. , Strocchi E. , Di Fabio F. , Camaggi C. M. , Zoli N. , Martoni A. A.
Published: March 2020

12003

Background: Cape is an efficient oral prodrug of 5FU in MBC and CRC. Unexpected severe toxicity in older patients (pts) was reported after standard dose of 2500mg/sm/day. About 70% of drug and metabolites are excreted with the urine and a 25% reduction of the dose is recommended if the pt has a creatinine clearance (CrCl) <50ml/min. However no prospective study has been done on Cape PK in the elderly pts. Methods: Between Oct 2004 and Nov 2005, 21 pts with MBC or CRC and age ≥70yrs or ≤60yrs who received Cape (1000 mg/sm bid for 14 days every 21 days) entered the study after giving signed informed consent. CrCl was calculated according to the Cockcroft-Gault method. Patient characteristics: 15 elderly pts (median 78 range71–84yrs), 6 younger pts (median 50.5 range 43–57yrs); 9 (42.9%) males and 12 (57.1%) females; median KPS 90 (range 70–100); 8 MBC pts (38%), 13 CRC pts (62%). Blood samples were taken on the first day of treatment at time 0 and at 0.25,0.5,1,2,3,4,5,6,8 hrs after the first drug administration and on 4th, 8th, 12th and 14th days in the morning. Plasma levels of Cape, 5DFUR, 5DFCR and 5FU were determined by a validated HPLC method and UV detection. Results: At present PK data after the first administration of Cape are available for 13 pts (9 elderly; 4 younger). The mean Cape and 5DFCR AUC0–8hr are higher in older patients (Cape 6653±2564.8 vs. 4427±2714.5; P=0.09; 5DFCR 8635±5197.1 vs. 6292±3813.6; P=0.26), while no evident differences are present for 5DFUR and 5FU. The same results are obtained both in pts with CrCl < and ≥ 50 ml/min. The ratios of DFUR_AUC to Cape_AUC and 5FU_AUC to Cape_AUC are conversely higher in younger than in older pts (mean: 2.2 vs 1.62). A large interindividual variability in the concentration/time curves is present for Cape and metabolites. Cape dose reduction because of G3 toxicity (2 hand-foot syndrome, 1 stomatitis) was performed in 3 elderly pts. Drug systemic exposure was higher in 2 of these pts independently of CrCl. Conclusions: The preliminary results of this PK study suggest that elderly patients treated with Cape at 1000 mg/sm/bid are more drug-exposed than younger patients, independently of renal function. PK analysis is ongoing for the remaining patients.

No significant financial relationships to disclose.
Evaluation of 5-FU metabolism-relating enzyme gene expression levels using quantitative real-time RT-PCR from formalin fixed parafine embedded samples
Authors: Terashima M. , Odashima Y. , Ohtani S. , Soeta N. , Ohsuka F. , Kashimura S. , Hoshino Y. , Kogure M. , Gotoh M. , Danenberg K. D. , Danenberg P. V.
Published: March 2020

13034

Background: We have previously reported that tumors with high orotate phosphoribosil transferase (OPRT) and low dihydropyrimidine dehydrogenase (DPD) mRNA expression levels showed remarkable sensitivity to 5-fluorouracil (5-FU) by real-time RT-PCR using fresh frozen (FF) tumor samples. However, the use of fresh frozen samples has some limitations. The use of formalin fixed parafine embedded (FFPE) samples has great advantage to apply these technologies for clinical settings. In order to investigate the feasibility of real-time RT-PCR from FFPE samples to predict sensitivitiy to 5-fluorouracil (5-FU), we investigated the gene expression levels of 5-FU metabolism-relating enzymes by real-time RT-PCR from FFPE samples and compared the results from FF samples in gastric and colorectal cancer. Methods: FFPE samples and FF samples were obtained from 46 patients with gastric cancer and 29 patients with colorectal cancer. Gene expression levels of tymidylate synthase (TS), OPRT, thymidine phosphorylase (TP) and DPD were determined by quantitative real-time RT-PCR. In FFPE samples tumor tissue was obtained using laser captured microdissection (LCM). Tumor sensitivity to 5-FU was evaluated by in vitro ATP assay. Results: Gene expression levels of TS, TP, DPD determined from FFPE samples significantly correlated with those from FF samples. Although respective gene expression levels alone failed to show signifcianct correlation with the in vitro 5-FU sensitivity, statistically significant correlation was noted either from the samples of FF or FFPE in both gastric (FF: r = 0.660, FFPE: r = 0.780) and colorectal cancer (FF: r = 0.780, FFPE: r = 0.660), when OPRT/DPD mRNA ratio was applied for comparison with the results of 5-FU sensitivity. Thus, high OPRT/DPD ratio determined from FFPE samples resulted in high sensitivity to 5-FU. Conclusions: From these results, it is suggested that sensitivity to 5-FU is predictable by quantitative RT-PCR using FFPE samples. Measurement of 5-FU metabolism-relating enzyme gene expression level from FFPE samples appeared to be feasible for predicting 5-FU sensitivity and to have great advantage to apply the molecular predicting assay in clinical settings.

[Table: see text]
Sequence specificity of docetaxel (Doc) and the proteasome inhibitor PS-341 combinations in androgen-independent (AI) prostate cancer (CaP)
Authors: Holland W. S. , Lara P. N. , Kimura T. , Kenosi T. , Gandara D. R. , Devere White R. W. , Gumerlock P. H.
Published: March 2020

13150

Background: AI CaP is an invariably fatal disease. While treatment with Doc, a microtubule-stabilizing taxane, improves survival, patient outcomes remain suboptimal. PS-341 inhibits degradation of cell cycle and tumor suppressor proteins resulting in cycle arrest and apoptosis. We hypothesized that the combination of Doc with PS-341 would abrogate the abnormal survival response seen in AI CaP and lead to improved tumor cell kill, but that results would be dependent on administration schedule due to interactive cell cycle kinetics. Methods: The PC3 cell line model of AI CaP was evaluated in vitro and in vivo to determine response to Doc or PS-341 alone, and in combination in sequences of PS-341→Doc, Doc→PS-341, and simultaneous (PS-341 + Doc). Cell cycle and protein analyses were performed by flow cytometry and Western blotting, respectively. For nu/nu mouse xenografts, 5 × 106 cells were injected subcutaneously into each flank. The agents were administered either together or 24hr apart, with all regimens given weekly [IP doses: Doc: 10 mg/kg; PS-341: 0.5 mg/kg]. Results: in vitro: Each combination showed an increased apoptotic sub-G1 population versus untreated cells, in addition to altered cell cycling in a sequence-specific manner. Of the combinations, PS-341 + Doc showed the largest sub-G1 while Doc→PS-341 had the lowest sub-G1 but the largest S-phase content; in vivo: PS-341 + Doc showed a cytotoxic effect (reduction in tumor volume) while the combinations of Doc→PS-341 and PS-341→Doc both showed growth inhibition (stabilization of tumor growth) as best response. Conclusions: Combinations of PS-341 and Doc have sequence specific cell cycle effects leading to increases in apoptosis (PS-341 + Doc) or cell cycle arrest (Doc→PS-341). Clinical validation of these findings is warranted. (ACS: CRTG-0019701-CCE)

No significant financial relationships to disclose.
Radiotherapy plus concurrent irinotecan (CPT-11) and capecitabine (CAP) as preoperative downstaging treatment for locally advanced inoperable rectal cancer: A phase I/II study
Authors: Gollins S. W. , Myint S. , Levine E. , Bishop J. , Haylock B. , Susnerwala S. , Saunders M. , Biswas A.
Published: March 2020

13519

Background: Preoperative downstaging chemoradiation has become standard treatment for locally advanced unresectable rectal cancer. Oral CAP is potentially more convenient as a radiation sensitiser than infusional fluoropyrimidine regimes. This study evaluated the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of daily CAP plus weekly i.v. CPT-11 when used in combination with RT in locally advanced rectal cancer. Methods: Patients had an adenocarcinoma of the rectum (lower limit within 12 cm of the anal verge) which on MRI was T3 within 2 mm of the mesorectal outer edge, T4, or any T3 within 5 cm of the anal verge. There were no distant metastases on staging investigations. Patients received planned pelvic RT to 45 Gy in 25 daily fractions over five weeks, concurrent with oral CAP daily throughout RT (including weekends) and a 60 minute infusion of i.v. CPT-11 weeks 1, 2, 3 and 4. Doses of CAP and CPT-11 were gradually escalated in cohorts of three patients. Results: The most common DLT was diarrhoea. Initially dose level (D/L) 3 was chosen as the recommended dose for phase II. However, unacceptable toxicity was encountered in the first 12 patients treated at D/L 3 (see Table). Thus D/L 2 is now being expanded to 60 patients for phase II. 40 patients have thus far potentially been eligible for resection: 5 (13%) could not be resected (2 deteriorated, 2 developed metastases, 1 died during treatment), 32 (80%) had R0 and 3 (7%) R1 resection. 9 (25%) had a pathological complete response (pCR) and 7 (20%) ‘near’ pCR. 5 (9%) of 57 patients had a defunctioning stoma pre-RT. Conclusions: The RD for this regime is 60 mg/m2 i.v. CPT-11 weeks 1, 2, 3, 4 and 650 mg/m2 bd of oral CAP daily. This demonstrates promising signs of efficacy. The RD is currently being studied in an expanded phase II cohort of 60 patients. D=diarrhea; F=febrile neutropenia; A=anorexia; L=lethargy; N=nausea/vomiting. [Table: see text]

No significant financial relationships to disclose.
The therapeutic effect of radiofrequency ablation(RFA) combining with/without chemotherapy in treating inoperable liver metastases of colorectal cancers
Authors: Pan H. , Wang S. , Zheng Y. , Jin W.
Published: March 2020

13581

Background: Patients (pts) with colorectal cancer often develop metastases to the liver without extra hepatic spread. Surgery is the mainstay of treatment in these pts, but only 20% of pts are suitable for a surgical approach and some pts are reluctant to receive surgery. This study is to compare the therapeutic effect of RFA combining with chemotherapy and RFA alone in treating inoperable liver metastases of colorectal cancers. Methods: From May 2001 to July 2005, 26 patients have inoperable liver metastases derived from colorectal cancer whose primary tumors were resected. Among them, 14 pts received chemotherapy from 3 months before RFA to 3 months after RFA (13 pts received systemic chemotherapy with FOLFOX4, 1 pt received FOLFIRI), 12 pts didn’t receive any chemotherapy. The metastatic lesions in liver were evaluated by CT scan every 3 months. Results: Pts’ characteristics: m/f 18/8; median age 57 yrs (range, 31–68); primary tumor: colon 15, rectum 11; karnofsky’s score≥60. Median no. of LM: 2.2 (range, 1–7), mean size of LM: 24mm (range, 12–97 mm). The last time of follow-up visit is Nov 2005, 11 pts has been dead because of tumor progression, 14 pts is still living, and 1 patient is lost to follow-up. The main complication of RFA is fever, local pain and elevation of hepatic enzyme. Reactive pleural effusion occurred in 1 patient which disappeared after thoracentesis. No RFA related bleeding,pneumathorax,perforation of digestive tract,infection and needle track implantation occurred. The median survival,1-year survival rates and 2-year survival rates in all pts were 33 months, 83.8% and 64.1% respectively. The median time to local progression in all pts is 346 days. In the pts treated with RFA alone, the median survival,1-year survival rates and 2-year survival rates were 18 months, 71.3% and 38.2% respectively; in the pts treated with RFA and chemotherapy, they were 36.5 months, 92.9% and 85.1% respectively (P=0.0210). In the pts treated with RFA alone, the median time to local progression is 346 days; in the pts treated with RFA and chemotherapy, it is 317 days (P>0.05). Conclusions: RFA Combining with chemotherapy is safe and may be more effective than RFA alone in treating inoperable liver metastases of colorectal cancer.

No significant financial relationships to disclose.
Expression of thymidylate synthase in primary colorectal carcinoma and their corresponding metastases
Authors: Bendardaf R. , Elzagheld A. , Ristamäki R. , Syrjänen K. , Pyrhonen S.
Published: March 2020

13587

Objective: Thymidylate synthase (TS) is the rate-limiting enzyme in the synthesis of pyrimidine nucleotides required for DNA synthesis and is a critical target for fluoropyrimidines, which are widely used in the treatment of gastrointestinal tumours. Tumour TS expression was analysed in a series of 39 patients diagnosed and treated for Duke’s B, C and D colorectal cancer between January 1996 and August 2003 to investigate the role of TS in the development of metastatic phenotype in CRC. Methods: TS expression was determined immunohistochemically in 39 paraffin-embedded primary and metastatic tumour sections and the overall staining index was calculated according to the intensity of the cytoplasmic staining (0, 1, 2, 3) and the fraction of the corresponding tumour cells in the sample. Results: Tumours were classified as showing either lower or higher TS expression, i.e. below- or above the mean. In 29/39 (74.3%) pairs, the primary tumours and their metastases are concordant. In 10 out of 39 (25.7%) discordant pairs, TS expression was high in the primary tumours and low in the metastasis in 9/10 cases, and opposite in the remaining one case. Using the absolute staining index values, TS expression in the primary tumours and in the metastases was also significantly correlated (Pearson R=0.501, p=0.001). Conclusion: Between the paired primary tumours and distant metastatic lesion, the TS expression is in the majority higher in primary tumours compared to the metastasis and more concordant cases showed compared to discordant cases and in 9/10 discordant cases, TS expression in the primary tumours was above the mean and below the mean in their corresponding metastases compare to only one case showing the opposite pattern.

No significant financial relationships to disclose.
Clinical application of immunoreactivity of dihydropyrimidine dehydrogenase (DPD) using highly specific antibody against recombinant human DPD (rhDPD) in gastric scirrhous cancer treated with S-1, new DPD inhibitory fluoropyrimidine
Authors: Shimizu T. , Yamada Y. , Shirao K. , Yasui H. , Morita H. , Tamura K. , Ozaki T. , Fukuoka M.
Published: March 2020

14053

Background: Highly specific antibody against recombinant human dihydropyrimidine dehydrogenase (DPD) has been developed to assess immunohistochemically DPD expression in tumors. A new oral DPD inhibitory fluoropyrimidine (DIF), S-1, is reportedly effective against gastric scirrhous cancer. Objective of this study was to assess intra-tumoral levels of DPD immunohistochemically using highly specific anti-DPD polyclonal antibodies, and investigated the relationship between the immunoreactivity of DPD and the anti-tumor effects of S-1 as a DIF in gastric scirrhous cancer patients. Methods: The relationship between immunoreactivity to DPD in biopsy specimens and the effects of chemotherapy was investigated in 61 patients treated with first-line fluoropyrimidine-based chemotherapy (S-1:DIF, 5-FU:non-DIF) for gastric scirrhous cancer. Immunohistochemical staining intensity was semiquantitatively graded (− to 3+) on the basis of the proportion of positively stained cancer cells in the lesions. Results: Total 61 gastric scirrhous cancer patients (M/F: 34/27) were analyzed to date with a median age of 56 (range 30–73). Response rate (partial response) was significantly higher in patients with DPD positive tumors than in those with negative in S-1 group (45.5%, 10.0% : p<0.05), as compared with in 5-FU group (0%, 5.6%: p=0.398). According to median survival time, there was no significant difference between patients with DPD positive tumors (364 days) and those with negative (406 days; p=0.626) in S-1 group or in 5-FU group (181 days and 256 days, respectively; p=0.543). Conclusions: This study indicates that S-1 is effective even in gastric scirrhous cancer with the high level of DPD activity. Further immunohistochemical studies using DIF-based regimens are needed to confirm these results with larger numbers of patients.

No significant financial relationships to disclose.
Treatment of cancer of the anal canal. The Hamburg experience
Authors: Rudat V. , Streller S. , Rades D.
Published: March 2020

14062

Background: To compare surgical and non-surgical treatment approaches for anal cancer and to identify prognostic factors. Methods: Survival data of 214 patients with cancer of the anal canal were reviewed who were referred for radiotherapy to the Department of Radiation Oncology of the University of Hamburg, Germany between 1/88 and 3/05. 75 patients received a definitive radiochemotherapy (RCT) with 5-FU and MMC according to international standards, 43 an operation followed by RCT (OP+RCT), 37 an operation followed by irradiation (OP+RT), 25 an irradiation alone (RT) and 34 an operation alone because they refused a planned adjuvant RCT or RT. The operations had been performed by different referring hospitals in and around Hamburg. Results: The median follow-up time of the living patients was 67 months (1–200 months). The 10 year overall survival rate for RCT was 0.62 (95%CI 0.46–0.77), for OP+RCT 0.65 (95%CI 0.47–0.83), for OP+RT 0.55 (95%CI 0.37–0.74), for OP alone 0.51 (95%CI 0.26–0.75) and for RT alone 0.27 (95%CI 0.05–0.48). There was no statistical difference between the overall survival of patients who received RCT, OP+RCT and OP+RT according to Kaplan Meier analysis (log rank test, p = 0.71). Cox regression analysis was used to examine the simultaneous influence of the prognostic factors T, N, age, haemoglobin concentration before radiotherapy, gender, and grading on the survival of patients who were treated with RCT. The model (p = 0.015) revealed T and N to be the only statistically significant prognostic factors. Conclusions: The different surgical and non-surgical approaches to treat cancer of the anal canal in Hamburg obviously reflect the individual preferences of the different physicians. Statistical analysis did not show a benefit of an OP added to RCT. Prognostic factors for survival after RCT were the T- and N-stage.

No significant financial relationships to disclose.