bluuebunny/crossref_metadata_2025 huggingface dataset:
Interstitial high dose rate (HDR) brachtherapy + IMRT vs. HDR monotherapy for early stage prostate cancer
Authors: Neumann T. , Mark R. , Anderson P. J. , Nair M.
Published: March 2020

14606

Background: Transrectal Ultrasound (TRUS) guided interstitial implant for prostate cancer using High Dose Rate (HDR) + External Beam Radiation Therapy (EBRT) or IMRT has been reported with favorable results. The role of supplemental EBRT or IMRT in brachytherapy is undefined. We compare our results of HDR + IMRT vs. HDR monotherapy. Methods: Between 1997 and 2006, 276 patients with T1 and T2 localized prostate underwent TRUS interstitial implant. After discussion of treatment options, 109 patients elected HDR Implant + IMRT and 167 patients underwent HDR alone. No patient received Hormonal Blockade. Median Gleason Score was 7 (range: 4 to 10). Median PSA was 9.8 (0.60 to 39.8). In patients who received IMRT + HDR, 4500 cGy in 25 fractions was given via IMRT and 1650 cGy in 3 fractions via HDR. Our protocol for HDR alone, has called for two HDR Implants. The treatment volume received 2,250 cGy in 3 fractions prescribed to the 100% Isodose line, given over 24 hours. A 2nd implant was performed 4 weeks later, delivering a further 2,250 cGy in 3 fractions, bringing the final dose to the prostate to 4,500 cGy in 6 fractions. Results: There was no significant difference between the treatment groups with respect to T-Stage, Gleason Score, and PSA. With a median follow-up of 66 months (range: 6 months to 120 months), the overall PSA disease free survival (DFS) was 89.5% (247/276). In patients undergoing IMRT + HDR, PSA DFS was 89.0% (97/109) vs. 89.8% (150/167) for patients undergoing HDR alone (p = 0.6). The 5 year actuarial survival was 86% for the group receiving IMRT + HDR vs. 89% with HDR (log rank = 0.5). Urinary stress incontinence has occurred in 2.5% (7/276). RTOG late bladder toxicities were: 0% Grade 4, 0% Grade 3, and 3.3% (9/276) Grade 2. RTOG late rectal toxicities were: 0.4% (1/276) Grade 4, 0% Grade 3, 3.6% (10/276) Grade 2, and 4.7% (13/276) Grade 1. RTOG late rectal toxicity was higher in patients undergoing HDR + IMRT with 14.7% (16/109) of patients experiencing Grade 2 and 1 symptoms, vs. 3.0% (5/167) receiving HDR alone (p ≤ 0.01). Conclusions: We have observed no difference in PSA DFS in patients undergoing HDR vs. HDR + IMRT. Complications were similar, though RTOG Grade 1 and 2 late toxicity was higher in patients receiving HDR + IMRT. By omitting IMRT, rectal complications may be reduced.

No significant financial relationships to disclose.
A phase I open-label, dose escalation study to determine the maximum tolerated dose and to evaluate the safety profile of lenalidomide with every three week docetaxel in subjects with androgen independent prostate cancer
Authors: Moss R. A. , Shelton G. , Melia J. , Mohile S. G. , Petrylak D. P.
Published: March 2020

14618

Background: Based on the known efficacy of docetaxel (D) in Androgen Independent Prostate Cancer (AIPC), and demonstrated activity of the antiangiogenesis agent thalidomide in combination with docetaxel, a Phase I trial in patients (pts) with AIPC with evidence of progression by unidimensionally measurable disease or rising serum Prostate Specific Antigen (PSA) levels after antiandrogen withdrawal was designed. The study evaluates the combination of escalating doses of D and lenalidomide (Ln), a derivative of thalidomide with immunomodulatory and antiangiogenic properties. Pts were permitted to have no more than two prior chemotherapy regimens. Methods: Pts were given D and Ln on a q3 week dose-escalation schedule. Dose Levels of D (mg/m2): Level (L) 1 = 60 L2-L5 =75, given IVPB over 60 minutes in combination with prednisone 5mg po bid. Decadron 20 mg was given 12, 6 hrs and 15 minutes prior to D on D#1. Dose of Ln (mg/day) on D#1–14 of 21-day cycle: L 1 = 10 mg, L2= 10 mg, L3 = 15 mg, L4–20 mg L5 = 25 mg. Patient Characteristics: L1: N = 5. Median Age 66.2 yrs. Median PSA = 101.9 (range 5.9–164.0). Prior CT: none. Prior palliative RT: none. Patients with unidimensionally measurable disease: 4, all in lymph nodes. Patients with bone metastases: 5. Pre-treatment, 1 patient required narcotic analgesics. Results: Five L1 patients are evaluable for toxicity and response. Median number of cycles administered = 4 (range 2–5). Toxicity: There have been no Grade (G) 3 or 4 toxicities. Anti-tumor activity: Two pts (40%) have had a greater than 50% decline in serum PSA on 2 consecutive measurements at least 2 weeks apart. Of 4 pts with unidimensionally measurable disease, all have stable disease by RECIST criteria. Conclusions: At L1, D + Ln has been well tolerated in AIPC. Further dose escalation to L2 and above is planned.

[Table: see text]
Prognostic factors for the recurrence of renal cell carcinoma after radical nephrectomy
Authors: Ohlmann C. H. , Schneider T. , Wille S. , Engelmann U. , Heidenreich A.
Published: March 2020

14629

Background: Recurrence of renal cell carcinoma depends mainly on tumor stage at the time of radical nephrectomy and increases with increasing T-stage. Up to 30% of patients with T1–2 tumors will experience local or distant recurrence. Recommendations for the follow-up include chest x-ray every 6 months for stages T1–4 and abdominal CT-scan for pT3–4 for the first 3 years. The aim of our study was to identify prognostic factors predicting recurrence of RCC in order to individualize follow up strategies. Methods: We retrospectively analyzed the charts of 177 patients with RCC who underwent radical nephrectomy. In 163/177 (92%) of the patients the histology revealed renal cell carcinoma. The median-follow up was 4.5 (1–6) years. The prognostic significance of histology, gender, age, c-reactive protein, hemoglobin, hematuria, gross hematuria, weight loss, flank pain and metastases at the time of surgery for risk of recurrence was calculated by uni- and multivariate analysis. Cancer specific survival (CSS) was analyzed by the Kaplan-Meir method. Results: Logistic regression analysis identified presence of metastases at time of surgery (p ≤ 0.0005), hematuria (p ≤ 0.0005) and flank pain (p = 0.011) as independent prognostic factors for the recurrence of RCC. The risk of recurrent disease is 33.5% with one, 70 to 83% with two and 95.6% with the presence of all 3 markers. 3-year CSS is 69% vs. 82% in symptomatic vs. asymptomatic patients (p = 0.1352), 45% vs. 90% in M1/N1 vs. M0/N0 (p = 0.0001) and 78% vs. 88% in pT3b vs. <pT3b (p = 0.0102). Conclusions: In our study we were able to identify prognostic factors for the recurrence of renal cell carcinoma. Based on this model the follow-up of patients can be individualized according to the risk for recurrence after radical nephrectomy.

No significant financial relationships to disclose.
Cost-effectiveness of zoledronic acid vs. pamidronate in the management of hormone refractory prostate cancer (HRPC) patients with bone metastases
Authors: Botteman M. , Barghout V. , El Ouagari K.
Published: March 2020

14660

Background: Canadian guidelines recommend zoledronic acid (ZA) (4 mg every 3 weeks) in patients with hormone HRPC and asymptomatic or minimally symptomatic bone metastases to reduce skeletal-related events (SRE). However, IV pamidronate (90 mg every 3 weeks) (PA) is also routinely used in this setting in spite of no significant improvement in occurrence of SRE or pain compared to NT. Objectives: To assess the cost effectiveness of ZA, PA, or no bisphosphonate therapy (NT) in the management of prostate cancer patients with bone metastases in Canada. Methods: A literature-based decision analytic model was developed to estimate the incremental cost and quality-adjusted life years (QALY) associated with the 3 treatment options. The model included assumptions about SREs, mortality, drug and administration costs, cost of SREs, reduced quality of life due to SRE and bone pain, and therapy duration. Sensitivity analyses considered several scenarios in which various assumptions were used regarding treatment efficacy and QALY gains due to pain relief and SRE prevention. All costs were expressed in Canadian dollars (2004). Results: The cumulative number of SREs over a patient’s remaining lifetime (1.9 years) was estimated at 2.69 for PA and NT patients and 1.76 for ZA. Total discounted costs were $11,918 for NT, $17,593 for PA, and $19,312 for ZA. Compared with patients receiving NT or PA, quality-adjusted survival increased by 0.094 (range depending on scenario considered: 0.072 to 0.106) QALY per patient for those on ZA compared to PA or NT. Compared to NT, ZA resulted in a cost per QALY gained of $78,366 (range: $50,717 to $101,831). Compared to PA, ZA resulted in a cost per QALY gained of $18,343 (range: $2917 to $23,835) per QALY gained. PA was more expensive than NT but did not improve patient-related outcomes. Conclusions: For HRPC patients with bone metastasis, zoledronic acid appears to be the only clinically valuable and economically acceptable option in Canada with a cost effectiveness likely better than previously reported.

No significant financial relationships to disclose.
Neoadjuvant chemotherapy in advanced epithelial ovarian oancer (EOC): A phase III randomized study
Authors: Kumar L. , Hariprasad R. , Kumar S. , Bhatla N. , Shukla N. , Thulkar S. , Singh R.
Published: March 2020

15000

Background: We compared upfront surgery to upfront chemotherapy in patients with advanced EOC (stage IIIC and IV (pleural effusion only). Factors- optimum debulking (residual disease ≤1cm) rate, surgical morbidity, chemotherapy toxicity, survival and quality of life (QOL) were analyzed. Methods: Between Oct.2001 and Oct. 2005, 90 newly diagnosed patients with advanced EOC have been randomized to upfront surgery followed by six cycles of paclitaxel + carboplatin (TC) (Arm A) or upfront chemotherapy - 3 cycles (TC) followed by surgery then 3 more cycles of TC. Eligibility criteria included- age 18 to 65 years, biopsy or cytological proven diagnosis of EOC and adequate hematological, renal, liver and cardiac functions. Upper and lower GI endoscopy and serum CEA was done in all patients to rule out GIT primary. QOL was assessed using FACT-O questionnaire at baseline, postop, post 3 cycles and post 6 cycles chemotherapy. Results: 78 of 90 patients have completed the treatment. Among 74 evaluable patients, optimal debulking rate was higher in the neoadjuvant chemotherapy arm (83% vs 13%, p < .001). Blood loss during surgery (340 ml vs.485 ml, p < . 008), mean operating time (69 minutes vs. 77 minutes, p = 0.22), post op infection rate (3% vs 17.5%, p < .07), & hospital stay (9 days vs. 12.4 days, P = 0.04) were lower in the chemotherapy arm. Operative mortality was higher in upfront surgery arm (7.7% vs 3.3%, p = .38). QOL score was higher post 3 cycles and post 6 cycles in the upfront chemotherapy arm (p < . 0001). Grade III-IV GI toxicity (4.5% vs 3.8%) and myelo-suppression (7% vs 9%) was similar in two arms. At a median follow up of 33 months, Overall (41 vs 42 months) & progression-free survival (35.3 vs 29 months,p = ns) are not significantly different in upfront chemotherapy vs upfront surgery arms, respectively. Conclusions: Upfront chemotherapy in advanced EOC results in significantly higher optimum debulking rate with reduced surgical morbidity and mortality, Quality of life score was also higher. Present study favors role of “upfront chemotherapy” in patients likely to have residual disease >1cm and higher morbidity with upfront surgery.

No significant financial relationships to disclose.
The therapeutic benefit of extensive lymphadenectomy in advanced stage ovarian cancer
Authors: Berek J. S. , Karnik Lee N. , Cheung M. K. , Osann K. , Husain A. , Teng N. N. , Kapp D. S. , Chan J. K.
Published: March 2020

15010

Background: To determine if extent of lymphadenectomy affects the disease-specific survival of women with advanced-stage ovarian cancer. Methods: Demographic and clinico-pathologic information were obtained from the Surveillance, Epidemiology and End Results Program from 1988–2001 and analyzed using Kaplan-Meier methods and Cox proportional hazards regression. Results: Of the 15,320 women with stage IIIB-IV disease, 763 (5.0%) had stage IIIB, 5,266 (34.4%) stage IIIC, and 9,291 (60.7%) had stage IV disease. The median age was 66 (range: 1–101). 13,251 (86.5%) were White, 1,049 (6.9%) Black, 716 (4.7%) Asian, and 304 (1.9%) were Other. Of the patients who underwent a lymphadenectomy, the median number of nodes resected was 6 (range: 1–90). We divided our study group 3 groups based on the extent of lymphadenectomy (0, <10, 10–20, and >20). In the overall study group, the extent of lymphadenectomy improved the survival from 21.1%, 40.5%, 45.1% to 46.0%, respectively (p < 0.001). Patients with stage IIIB, IIIC, and IV disease had an improvement in survival associated with lymphadenectomy (see table ). In patients with non-clear cell epithelial carcinoma, the extent of lymphadenectomy was associated with improved survivals 20.9%, 39.8%, 45.4%, and 45.9%, respectively (p < 0.0001). Moreover, those with clear cell cancers (p = 0.0001), germ cell (p = 0.001) and sarcomas of the ovary (p = 0.02) also had a survival benefit; however no benefit was demonstrated in sex cord stromal tumors (p = 0.99). In multivariate analysis, a more extensive lymphadenectomy remained significant as an independent prognostic factor for improved survival after adjusting for all other independent prognostic factors including age, year of diagnosis, surgery, histology, stage, and grade. Conclusions: Our findings suggest that the extent of lymphadenectomy improves the disease-specific survival of women with stage IIIB-IV ovarian cancer. This benefit was demonstrated in epithelial, germ cell, and sarcomas of the ovary.

[Table: see text]

No significant financial relationships to disclose.
Significance of necrosis in grading of anaplastic oligodendroglial tumors: A clinicopathological and genetic study of 916 high-grade gliomas
Authors: Miller C. R. , Dunham C. P. , Scheithauer B. W. , Perry A.
Published: March 2020

1502

Background: High-grade gliomas (HGG, WHO grades III-IV) are morphologically and genetically diverse, with survivals ranging from months to decades. Although WHO 2000 grading criteria are well established for pure astrocytomas [anaplastic astrocytoma (AA) and glioblastoma (GBM)], those for oligodendroglial neoplasms [anaplastic oligoastrocytoma (AOA) and oligodendroglioma (AO)] remain subjective, there being a debate regarding the existence of a grade IV variant based on the finding of necrosis, particularly with pseudopalisading (PPN). Methods: Overall survival of 916 adult (>20 yr) patients diagnosed between 1990 and 2005 with supratentorial HGG (77 AA, 481 GBM, 183 AOA, 175 AO) was analyzed by uni- (log-rank) and multivariate (Cox proportional hazards) models for significance of the following factors: microvascular proliferation, necrosis, patient age, surgery (stereotactic vs. open), location, primary vs. secondary tumor, year of diagnosis, and chromosome 1p and 19q losses by fluorescence in situ hybridization. Results: Necrosis was a statistically significant predictor of poor survival on multivariate analyses in AOA (P=0.035), but not in AO (log-rank P=0.048, Cox P=0.9), while PPN showed a trend towards significance on multivariate analysis only in AOA (P=0.096). Other independent predictors on multivariate analysis included age, grade, surgery type, and year of diagnosis for AA/GBM and age, primary tumor, and 1p/19q codeletion for both AOA and AO (P<0.05). Median survival for AOA patients whose tumors featured necrosis (20.7 mo) was significantly worse than their counterparts lacking necrosis (>104 mo); survival of the latter was more similar to that of AO (83.5 mo), whereas in the former it was better than GBM (10.5 mo) (log-rank P<0.0001). Conclusions: Stratification of oligoastrocytomas, but not of pure oligodendrogliomas, into grades III (AOA) and IV (GBM with oligodendroglial features) on the basis of necrosis is prognostically justified and is more accurate than the current approach of using a single anaplastic grade. These data provide impetus for the modification of present WHO criteria.

No significant financial relationships to disclose.
Concurrent chemoradiation (CCR) for locally advanced or relapsed vulvar carcinoma (VC) treatment: An alternative to pelvic exenteration (PE)
Authors: Porcela H. , Gianni S. , Alvarez A. M. , De Dios D. , Mickiewicz E. , Roth B. , Cinat G. , Menendez P. , Bonomi M.
Published: March 2020

15021

Background: PE is the standard treatment for locally advanced or relapsed VC that involves the anus or rectovaginal wall, with high morbidity and the consequent loss of Qol. Objective: Locoregional response, toxicity, disease free survival (DFS) and survival (SV) achieved with concurrent chemoradiation in locally advanced or relapsed VC was prospectively evaluated. Methods: From 7/93 to 05/05, 32 pts which would have required some kind of PE were treated with mitomycin C (10 mg./m2 d1) + 5-Fluoruracil (800 mg/m2 d 1–4) IV continuous infusion, plus concurrent external radiotherapy (50 Gy) to the vulva, pelvis and groin. An additional boost (15–20 Gy) was added when a less than complete clinical response (CR) was achieved. Multiple biopsies of the tumor bed were performed to confirm complete pathologic responses (CPR). Results: 30 pts (94%) completed treatment as planned. Overall, locoregional response was obtained in 25/30 (83.3%) pts: 20 (66.6%) CR, 5 (16.6%) partial response (PR). 3 (10%) pts had stable disease and 2 (6.6%) progresive disease. 14/30 (46.6%) had CPR. Radical vulvectomy or radical local excision was performed in 7 pts for residual disease after CCR (4/6 with CR and microscopic residual disease and 3/5 with PR), 2 pts with PR were lost after having completed CCR and 2 pts with CR and microscopic residual disease refused further treatment. None of the responding patients required PE. Treatment was well tolerated with mild to moderate toxicity, attributed to radiotherapy. No treatment deaths were recorded. 28 pts with a median follow-up of 25.5 months (range 6–126) showed a 5-year cumulative DFS (34%) and SV (49%). Conclusion: CCR is a safe therapeutic option with results comparable to those obtained with PE, with significant improvement of Qol. CCR has become the standard treatment for locally advanced or relapsed VC at our center.

No significant financial relationships to disclose.
Docetaxel and cisplatin combination chemotherapy for advanced epithelial ovarian cancer with bulky residual disease
Authors: Shaharyar A. , Shabbir K. , Hafeez M. , Alauddin Z. , Rehman E. U.
Published: March 2020

15030

Background: The combination of docetaxel and cisplatin as an alternative to the gold standard carboplatin and paclitaxel chemotherapy has not been explored in our patients. Docetaxel is more potent of the taxanes, therefore, this combination might yield a better outcome. This phase II study was designed to evaluate the efficacy and toxicity of docetaxel and cisplatin combination in epithelial ovarian cancer with bulky residual disease. Methods: Thirty-two new patients were enrolled between November 2003 and August 2005. Eligible patients had histopatholgically confirmed epithelial ovarian cancer, were older than 18 years and had FIGO stage IIC-IV cancer with bulky residual disease after primary cytoreductive surgery. Patients had a KPS >70 with adequate marrow and hepatic function. Patients with creatinine clearance by Cockroft-Gault formula of >60 ml/min were included. Written informed consent was obtained. Patients with diabetes mellitus, peripheral neuropathy, or cardiac co morbidity were excluded. Docetaxel and cisplatin were given at a dose of 75 mg/m2 each on day-1 of a 21-day cycle. Dexamethasone 8 mg was given thrice before and thrice after and tropisetron 5mg was given one hour before and 12 hours after chemotherapy. Docetaxel was given in 250 ml of NaCl in one-hour followed by cisplatin 75 mg/m2 in 1L of NaCl in 3 hours with pre and post hydration. NCI toxicity criteria version 2.0 and RECIST was used for evaluation. Results: Thirty patients were evaluable for response and toxicity. Final evaluation revealed CR in 12 (40%) (95% CI, 22.7–59.4%), PR in 14 (46.6%) with an ORR of 86.6% (95% CI, 69.3–96.2%). Three (10%) had SD and 1 (3.33) had PD. Grade 2 toxicity included alopecia 18 (60%), vomiting 6 (20%), diarrhea 7 (23.3%) and stomatitis in 5 (16%). Grade 3 and 4 neutropenia were seen in 12 (40%) and 9 (30%) respectively. Sensory neuropathy of grade 1 and 2 was seen in 4 (13.3%) and 2 (6.7%) respectively. Conclusion: Docetaxel and cisplatin combination chemotherapy is an effective and safe regimen in epithelial ovarian cancer with bulky residual disease. It gives a high overall response rate and has a manageable toxicity profile.

No significant financial relationships to disclose.
Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy in carcinoma of uterine cervix
Authors: Goel V. , Singh. J. K. , Pandey M. K.
Published: March 2020

15032

Background: Studies have described decreased pelvic control & survival rates in invasive ca cervix when overall time in definitive RT is prolonged. We evaluated impact of timing of brachytherapy on outcome. Methods: Retrospective analysis of 338 patients of ca cervix treated with radical RT from Jan 2002 to Dec 2002 at Mahavir Cancer Sansthan Patna. The median age was 50 yrs (23–80 yrs). 73% patients were postmenopausal. Histopathology was Squamous Cell in 97% patients. Most common presenting complaints were bleeding P/V (92%) & discharge P/V (82%); with stage I (3%), II (35%), III (43%), IV (5%), unknown stage in 14% cases. Results: Records of 338 patients (Stage IB to III) treated with definitive irradiation (combination of EBRT & ICRT) were reviewed with reference to loco regional control, distant failure and its correlation with patient and tumor variables including OTT. Out of 302 patients who received complete RT, 24 received 60 Gy in 30 fractions as they were found to be unsuitable or were unwilling for ICRT. The rest received a dose of 50 Gy/25 Fr to 50.4 Gy/28 Fr over a median duration of 37 days. 30 patients received concomitant chemo radiation (cisplatin 40 mg/m2/4 cycles). 276 patients received ICRT (dose 21 Gy in 3 Fractions with a median gap of 43 days (range 5–111) after completion of ERT. The median OTT for completion of ERT & ICRT was 75 days (range 54–177). At an average follow up of 18- 24 months residual disease was seen in 2 cases (0.6%), local recurrence in 14 cases (4%) & distant failure in 14 cases (4%). Post RT complications were seen in 4.7% cases and included small bowel obstruction in 6 cases, VVF in 4 & RVF in 6 cases. Significant correlation was seen between OTT and rate of loco regional recurrences. All local recurrences were seen when OTT was more than 75 days. No significant correlation could be drawn between age, Hemoglobin, tumor histology, & bulky vs. non bulky tumor on loco regional and distant failure. Conclusions: Longer radiotherapy completion time was found to be associated with diminished survival outcomes for patients treated radically for carcinoma cervix. The significance of this observed association requires further investigation & correction to keep OTT as short as possible.

No significant financial relationships to disclose.
A phase II study of combination CPT-11 and docetaxel in patients with ovarian carcinoma refractory or resistant to combination paclitaxel and carboplatin
Authors: Enomoto T. , Yoshino K. , Yamasaki M. , Nishio Y. , Wakimoto A. , Miyake T. , Fujiwara K. , Takemura M. , Ito K.
Published: March 2020

15036

Background: To investigate the efficacy and toxicity of combination irinotecan and docetaxel in patients with ovarian carcinoma refractory (not responded) or resistant (relapsed within 6 months after the last chemotherapy) to the first line chemotherapy with combination paclitaxel (175mg/m2) and carboplatin (AUC=5). Methods: 30 refractory patients and 28 resistant patients with measurable disease were treated with combination irinotecan (60 mg/m2) and docetaxel (30 mg/m2) at days 1 and 8 every 3 weeks for more than 2 courses. Results: The average number of courses administered was 2.6 for refractory cases and 3.4 for resistant cases. The average number of courses administered was 2.6 for refractory cases and 3.4 for resistant cases. Using RECIST criteria, 2/28 (7%) resistant cases responded completely, 6/30 (20%) of refractory cases and 6/28 (21%) resistant cases were responded partially. 16/30 refractory cases and 14/28 cases progressed. Grade 3–4 toxicities were leukopenia (31%) neutropenia (36%) thrombocytopenia (8%) and diarrhea (6%). Conclusions: Combination chemotherapy of CPT-11 and Docetaxel at days 1 and 8 every 3 weeks is a regimen with moderate toxicity and good compliance, and shows some response to those patients who are refractory or resistant to the first-line chemotherapy with paclitaxel and carboplatin with a response rate of 20% and 29%, respectively.

No significant financial relationships to disclose.
Analysis of third-line and fourth-line chemotherapy for recurrent ovarian cancer treated with first-line platinum/taxane regimens
Authors: Nishio S. , Katsumata N. , Matsumoto K. , Tanabe H. , Kato Y. , Yonemori K. , Kouno T. , Shimizu C. , Ando M. , Fujiwara Y.
Published: March 2020

15045

Background: Limited information is available regarding to the usefulness of third-line chemotherapy (TLC) and forth-line chemotherapy (FLC) for recurrent ovarian cancer treated with first-line platinum/taxane (PT) regimens. Methods: We retrospectively reviewed the medical records of patients (pts) with ovarian cancer treated with PT regimens at the National Cancer Center Hospital from 1998 to 2004. The aim of this study is to investigate the important clinical factor such as response rate (RR), time to treatment progression (TTP), overall survival (OS) and predictor of response to TLC and FLC. Kaplan-Meier method was used for estimating TTP and OS. Wilcoxon test was performed for survival times and p-values < 0.05 were considered to be statistically significant. Results: There were 183 pts received first-line PT regimens in study period, 77 of 183 pts received second-line chemotherapy (SLC), 61 of 77 progressed after SLC and 55 of 61 pts received TLC. The RR to TLC was 34.5%. The median TTP was 5 months (mo) (range; 1–19 mo) and the median OS was 12 mo (range; 2–38 mo). The TLC regimen was consisted of P and/or T regimens of 36 pts and the other regimens of 19 pts. The RR according to the duration of response of previous chemotherapy (DRPC) (< 6 mo and ≥ 6 mo) were 31.4% and 37.3%, respectively. The median OS of DRPC (< 6 mo and ≥ 6 mo) were 8 mo (range; 2–33 mo) and 12 mo (range; 2–38 mo), respectively (p = 0.002). After TLC 47 pts progressed and 29 pts received FLC. The RR to FLC was 27.5%. The median TTP was 3 mo (range; 0–11 mo). The median OS of 18 pts who didn’t receive FLC and 29 pts received FLC were 2 mo (range; 2–16 mo) and 7 mo (range; 2–25 mo), respectively (p = 0.01). The RR according to DRPC (< 4 mo and ≥ 4mo) were 22.2% and 30%, respectively. The median OS of DRPC (< 4 mo and ≥ 4 mo) were 3 mo (range; 2–23 mo) and 6 mo (range; 2–25 mo), respectively (p = 0.4). Conclusions: The DRPC is considered to be predictor of response to TLC but not to FLC. Giving TLC and FLC if the pts have tolerable may improve OS, however this analysis is prone to several well-established potential biases and limitations. Further prospective study is warranted.

[Table: see text]
Diagnostic and prognostic significance of a t(1;19)(q10;p10) in patients (pts) with low-grade oligodendroglioma and astrocytoma: NCCTG 94–72–53
Authors: Jenkins R. B. , Ballman K. V. , Giannini C. , Arusell R. M. , Blair H. , Passe S. , Flynn H. , Brown P. , Shaw E. G. , Buckner J. C.
Published: March 2020

1505

Background: Combined deletion of chromosomes 1p and 19q is associated with improved prognosis in pts with anaplastic oligodendroglioma. We recently discovered that the combined deletion is mediated by a chromosome 1;19 translocation: t(1;19)(q10;p10). The prognostic significance of this alteration in pts with low-grade gliomas is not known. Methods: Paraffin-embedded tumor tissue was obtained from 134 pts enrolled in two NCCTG trials for newly-diagnosed low-grade glioma: 86–72–51: a randomized phase III trial of 50.4 Gy vs 64.8 Gy radiation therapy (RT) and 93–72–02: a phase II trial of PCV for 6 cycles followed by RT. Interphase fusion of a CEP1 probe and a BAC contig probe for 19p12 was used to detect the 1;19 translocation. Analysis of 1p and 19q deletions had been previously performed by FISH. Kaplan-Meier distributions of overall survival (OS) and progression-free survival (PFS) for pts whose tumors did or did not exhibit CEP1/19p12 fusion were compared using the Wilcoxon test. Results: Of 134 pts, CEP1/19p12 fusion testing was informative for 92. CEP1/19p12 fusion prevalence was 55% among 42 oligodendrogliomas, 47% among 30 mixed oligoastrocytomas, and 5% among 20 astrocytomas. 91% of gliomas with and 11% without 1p/19q deletion had CEP1/19p12 fusion (p<0.0001, chi-square test). The frequency of the t(1;19) by tumor histology, as well as median and 5-year progression-free and overall survival are provided in the table . Conclusions: Our results strongly suggest that a t(1;19)(q10;p10) mediates the combined deletion of 1p and 19q in human gliomas. Like combined 1p and 19q deletion, the 1;19 translocation is associated with superior progression-free and overall survival in low-grade oligodendroglioma patients. FISH analysis of the t(1;19) will likely be a more sensitive and specific means to assess 1p and 19q status in patients with gliomas. (Supported in part by CA85799, CA108961 and NCCTG grants CA25224 and CA114740)

[Table: see text]

No significant financial relationships to disclose.
Eukaryotic elongation factor 1 alpha 2 alone is not sufficient to cause tumorigenicity in immortalized and neoplastic ovarian cell lines
Authors: Leiser A. L. , Rosales N. , Spriggs D.
Published: March 2020

15051

Background: EEF1a2 is amplified and overexpressed in 25% of ovarian tumors. Previous studies have shown EEF1a2 to have oncogenic and tumorigenic properties in rodent fibroblasts. However, its role in the tumorigenesis and behavior of human ovarian carcinomas is not known. Methods: Stable expression of EEF1a2 cDNA in both T80 immortalized human ovarian surface epithelial cells and SKOV-3 cell line was followed by standard proliferation assays, soft agar assays for anchorage independent growth, cell cycle analysis, mouse xenograft injections, evaluation for changes in factors such as VEGF and ras and susceptibility to CDDP. Transient transfections with 3 different siRNA’s to EEF1a2 were performed in both cell lines. Results: Stable expression of EEF1a2 was detected by Western Blot and IP. Compared to vector only control, transfection with pCMVTag2B EEF1a2 vector did not change proliferation in either cell line. Anchorage independent growth was slightly higher in the T80 transfected cells. Cell cycle and expression of VEGF and ras were not different than control. IC50 of CDDP was similar between the transfected and control cell lines. No size difference was seen in SKOV transfected and control xenografts. T80 controls grew larger and more frequent tumors than transfected controls. Transient transfection of T80 with siRNA did not result in changes in anchorage independent growth. Conclusion: EEF1a2 alone is not sufficient to act induce tumorigenicity, affect tumor growth rate or drug susceptibility in human ovarian epithelial cells. Experiments utilizing stable siRNA vectors specific to EEF1a2 are underway, as well the combination of EEF1a2 with recognized ovarian tumor oncogenes.

No significant financial relationships to disclose.
Control of acute toxicity with amifostine and pelvic chemoradiotherapy
Authors: Tate M. , Wilson L. , Silverman C. , Helm W. , Parker L. , Metzinger D. , Paris K. , Carrascosa L. , Yashar C.
Published: March 2020

15058

Background: Amifostine is an FDA approved normal tissue radioprotector for head and neck carcinoma. Several studies have also demonstrated a radioprotective role in pelvic malignancies. However, literature also shows that amifostine has substantial toxicity. We examined patient compliance with combined chemoradiotherapy and daily amifostine subcutaneous injections, the incidence of acute toxicity, and the efficacy of interventions. Methods: Patients undergoing pelvic radiotherapy and concurrent chemotherapy were eligible. Patients received daily subcutaneous injections of 500 mg amifostine 30 to 60 minutes before radiotherapy. Injection pain, erythema, and rash were recorded daily, as was patient blood pressure before and after receiving amifostine and radiotherapy. Treating physicians evaluated patients at least weekly. Symptoms were recorded and graded using the NCI Common Toxicity Criteria. The protocol was amended early in accrual to include nausea prophylaxis guidelines. Results: Nineteen patients have been entered into this study. Fourteen had cervix cancer, four had rectal cancer, and one had anal cancer. Four patients (21%) received <1 week of amifostine. Seven (37%) received <50% of their planned injections. Fifty three percent received >80% of their injections, while 32% received the full course of amifostine. Of those that prematurely discontinued amifostine, 1 withdrew before receiving any injections, 1 transferred to another facility, 6 withdrew because of nausea, 2 secondary to rash, 2 secondary to injection pain. One developed paresthesias. Of those that withdrew because of nausea, all but one received >50% of the planned injections. Twenty six percent experienced grade 3 nausea. When comparing patients that did not receive nausea prophylaxis with those that did, grade two or three nausea dropped from 100% to 29%. No patients developed grade 3 rash. Two patients experienced hypotension. Nine patients (47%) complained of injection site pain. Conclusions: Subcutaneous amifostine is reasonably well tolerated when used with pelvic radiotherapy. Nausea was a significant side effect seen in this study. Assuring adequate hydration and use of prophylactic antiemetic medication significantly decreased nausea.

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Lessons from ovarian cancer patients with more than 10 years survival
Authors: Kudoh K. , Takano M. , Kita T. , Yoshikawa T. , Furuya K. , Kikuchi Y.
Published: March 2020

15059

Background: Purpose of this retrospective study is to explore predictive factors for long-term survival in patients with primary epithelial ovarian carcinoma. Methods: Total 161 patients treated from March 1983 to December 1994 at the National Defense medical College hospital were enrolled in this study. Profiles and characteristics of patients with long-term survival were retrospectively examined. Results: All patients with stage IA-B or IIA-B survived more than 10 years although 2 of patients with stage IA and IB tumor were dead of primary disease and one patient was dead of other disease after more than 10 years follow-up. More than half of patients with stage IC, IIC or IIIA-B survived more than 10 years, while 10-years’ survival rates of patients with stage IIIC or IV were only 10% with marked increase of death by primary disease. All patients with stage I or IIA-B without residual tumor after initial surgery survived more than 10 years. Although long-term survival rates of patients with stage IIC or IIIA-B were higher in patients without residual tumor after initial surgery, 6 out of 7 patients with stage IIIC or IV had residual tumor. Analysis of 70 patients with stage III or IV ovarian cancer revealed that residual tumor size, histologic types and response to initial chemotherapy affected significantly long-term survival. Conclusions: We demonstrated that predictors for long-term survival were stage, residual tumor size after initial surgery, histology and response to initial chemotherapy.

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No significant financial relationships to disclose.
Temozolomide (TMZ) 3 weeks on/1 week off in the treatment of progressive low grade gliomas: A phase II GICNO study
Authors: Brandes A. A. , Tosoni A. , Cavallo G. , Scopece L. , Gardiman M. , Berti F. , Pasetto L. M. , Ferrarese F. , Blatt V. , Ermani M.
Published: March 2020

1514

Background: Encouraging results have been obtained inlow grade glioma (LGG) patients (pts) following TMZ therapy at the standard schedule of 200 mg/m2 for five-days every 28 days. A continuous dose TMZ schedule leads to DNA repair enzyme AGAT level depletion in tumor cells. By removing TMZ-produced methyl adducts, AGAT contributes to the development of resistance to alkylating agents. Methods: Pts with a diagnosis of LGG received TMZ 75 mg/m2/d for 21 days every 28 days at clinical or radiological progression. MiniMax Simon’s design with P0=0.2, P1=0.4, α=0.1, β=0.1 was used and a sample size of 36 pts was planned. The primary end-point was to assess the response rate (RR=CR+PR), and the secondary end-point to investigate the correlations between 1p/19q deletions by FISH and MGMT promoter methylation by methylation specific PCR (MSP). Results: 22 oligodendroglioma (O), 4 oligoastrocytoma (OA) and 10 astrocytoma pts (A) were enrolled (median age of pts 47 years, range 24–69 years; median KPS 90, range 50–100). Eleven pts were pre-treated with radiotherapy; 5 (13.5%) had enhancing lesion at MRI scan. RR was 30.5% (11 PR), all RR being obtained in pts with non-enhancing lesions; 20 pts (55.5%) had disease stabilization; 8/11 responders were assessable for 1p/19 q deletions and, of these, 6 pts (75%) had combined 1p/19q deletion. Median PFS was 17.4 months (interquartile ranges, 9.3–25). PFS at 1 year was 73% (SE 8%). Preliminary data on molecular assessment are: 29 pts were assessable for 1p and 19q deletions, both being present in 19 pts (65.5%). 1p/19 q loss was significantly greater in pts with O/OA than A (p=0.01). Of 11 assessable pts, 7 (63.6%) presented MGMT promoter gene methylation and all 7 pts presented 1p and 19q deletions (p=0.03). Grade 3 lymphopenia was observed in 4 pts (11.1%) and 1 patient had G2 reversible renal toxicity. Conclusion: TMZ for 21 days every 28 is an active and well tolerated regimen in pts with LGG. The analysis to verify any correlation between molecular markers and clinical outcome is ongoing.

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An update of phase II results from RTOG 0211: A phase I/II study of gefitinib with radiotherapy in newly diagnosed glioblastoma
Authors: Chakravarti A. , Berkey B. , Robins H. I. , Guha A. , Curran W. J. , Brachman D. , Shultz C. , Mehta M.
Published: March 2020

1527

Background: The epidermal growth factor receptor (EGFR) pathway is commonly deregulated in GBMs and its activity has been associated with treatment resistance in preclinical models. Accordingly, the Radiation Therapy Oncology Group (RTOG) recently conducted a Phase I/II study of Gefitinib, an EGFR tyrosine kinase inhibitor, in combination with radiotherapy for newly-diagnosed glioblastoma (GBM) patients. Methods: 178 GBM patients were entered on RTOG 0211 (Phase I: 31 patients and Phase II: 147 patients). The maximum tolerated dose (MTD) of Gefitinib was determined to be 500mg in non-EIACD patients, and the Phase II component of RTOG 0211 was continued at this dose level during radiation and as maintenance for 18 months afterward or until disease progression. Results: 119/147 patients completed treatment per protocol and/or with acceptable deviation. The median survival time for all patients in the study was 11.0 months. Progression-free survival was 5.1 months for all patients. When considering only patients who were treated per protocol, the median survival of RTOG 0211 patients was 11.5 months, compared to 11.0 months for historical controls treated in previous RTOG studies (p=0.14). RPA Class IV patients appeared to derive the greatest benefit from Gefitinib when combined with radiotherapy compared to historical controls, although not reaching statistical significance. Molecular and genetic profiling efforts are underway to determine which GBM patients derive greatest benefit from Gefitinib in the upfront setting, which will be reported at the time of the annual meeting. These include markers such as EGFRvIII and PTEN, which have been recently reported to be associated with response to anti-EGFR agents in the recurrent setting, and members of key signal transduction pathways regulated by EGFR. Conclusions: The observed survival advantage of newly-diagnosed GBM patients treated with Gefitinib in combination with radiotherapy compared to historical controls treated on previous RTOG studies does not reach statistical significance. Molecular and genetic profiling efforts are underway to identify subsets of GBM patients who might derive the greatest benefit from Gefitinib in the upfront setting.

No significant financial relationships to disclose.
Tinzaparin prophylaxis against thromboembolic complications in brain tumor patients
Authors: Vredenburgh J. J. , Bohlin C. , Reardon D. A. , Desjardins A. , Quinn J. , Rich J. , Sathornsumetee S. , Marks L. B. , Friedman A. H. , Friedman H. S.
Published: March 2020

1539

Background: Thromboembolic complications are common in brain tumor patients, contribute to the morbidity and mortality and complicate treatment. Twenty to 40% of brain tumor patients develop a deep venous thrombosis and/or pulmonary embolus during their course. Thromboembolic complications are the second leading cause of death in brain tumor patients. One of the low molecular weight heparins, tinzaparin, has increased factor Xa activity as opposed to thrombin inhibition, which may improve the therapeutic:toxicity ratio. Methods: We report a phase II trial of prophylactic tinzaparin for newly diagnosed brain tumor patients. Twenty-seven of the planned 40 patients have been accrued. Patients received daily tinzaparin at a fixed dose of 4500 IU subcutaneously beginning a minimum of 48 hours post-operatively and a maximum of 4 weeks post-operatively. Patients were scheduled to receive tinzaparin for 12 months. During chemotherapy cycles, the blood counts were monitored weekly. If the platelet count was <50,000, the tinzaparin was held until the platelets were >100,000. Results: One of the patients developed a grade 3 CNS hemorrhage, necessitating cessation of the tinzaparin, there have been no grade 4 or 5 CNS hemorrhages or treatment associated mortality. Also, there have been no ≥ grade 2 systemic hemorrhages. One patient developed a deep venous thrombosis while taking tinzaparin, and three patients developed thromboembolic complications while off tinzaparin secondary to thrombocytopenia. One patient was taken off study for increased liver function tests, possibly secondary to tinzaparin. The patients have taken the tinzaparin for 4–52 weeks, with a median of 18 weeks. Conclusions: Tinzaparin at a fixed prophylactic dose is safe and may decrease the incidence of thromboembolic complications in brain tumor patients. If the completed phase II study yields similar results, a phase III trial is warranted.

No significant financial relationships to disclose.
Induced fluorescence of medullary carcinoma of the thyroid: A technology with potential to improve visualization of malignant tissue at the time of surgical resection
Authors: Johnson T. E. , Luiken G. A. , Quigley M. M. , Xu M. , Hoffman R. M.
Published: March 2020

15503

Background: Surgery for medullary carcinoma of the thyroid can at times be technically challenging to the surgeon. Inducing the cancer cells to be fluorescent would have the potential to improve the surgeon’s ability to quickly and accurately identify and excise all of the malignant tissue. We have previously demonstrated the feasibility of induced tumor fluorescence with fluorophor-tagged anti-tumor antigen antibodies using human colon and breast cancer cell lines. We present here our results using a human medullary carcinoma of the thyroid cell line in the nude mouse model. Methods: A human medullary carcinoma of the thyroid cell line that was demonstrated to express CA 15–3 was used. Thyroid carcinoma cells were subcutaneously implanted in 4 nude mice (3 study mice and 1 control mice). Three weeks after injection, tumor nodules were easily detectable. Using the tail vein method, 3 study mice were injected with fluorophore-tagged anti-CA 15–3 and 1 control mouse with fluorophore-tagged IgG. Mice were examined using a small animal imaging system with a 470 nm light source and appropriate filters. They were also examined using a simple blue LED flashlight fitted with a fixed 470 nm band pass filter for illumination and were observed through filtered goggles. Results: Fluorescence of tumor nodules in the study mice could be seen through the skin. On dissection and exposure of the tumor nodules, this fluorescence was intense and clearly distinguishable from the surrounding normal tissue using either the imaging system or the blue LED. The control mouse injected with fluorophore-tagged IgG and examined in a similar manner revealed no tumor fluorescence. Conclusions: When tumor antigens are known, fluorophore-tagged antibody induced fluorescence is simple, easy to perform, requires no technically complex equipment or operator expertise and could be adapted to thyroid cancer surgery in the academic or community hospital setting. This technology would be indicated in those patients undergoing initial resection of medullary carcinoma of the thyroid as well as in those patients undergoing resection of recurrent disease where accurate identification of tumor tissue may be more difficult and time consuming.

No significant financial relationships to disclose.
Daily concurrent chemoradiotherapy with docetaxel (D) and cisplatin (C) using new superselective intra-arterial infusion via the superficial temporal artery (HFT method) for stage III, IV head and neck cancer—Preservation of the primary lesion
Authors: Tohnai I. , Fuwa N. , Mitsudo K. , Nishiguchi H. , Fukui T. , Yamamoto N. , Ueda M. , Ito Y.
Published: March 2020

15513

Background: We previously developed a new method of superselective intra-arterial infusion via the superficial temporal artery (HFT method; Hattori, Fuwa and Tohnai). Our previous study involved preoperative daily concurrent radiotherapy and chemotherapy with docetaxel (D) and cisplatin (C) using the HFT method for 41 patients with stage III, IV oral cancer. Clinical effects were complete response (CR) in 29 (82.9%) and partial response (PR) in 6 (17.1%) patients and pathological effects of the resected tumor were CR in 31 (88.6%) and PR in 4 (11.4%) patients, with a 5-year cumulative survival rate (overall rate) of 78.8%. Thus, the present study investigated the effectiveness of chemoradiotherapy using the HFT method without surgery for stage III, IV oral cancer. Methods: Patients (n = 16) with stage III, IV oral cancer were treated. A new catheter was prepared by modifying a 1.35-mm diameter angiographic catheter and inserting it superselectively using a guide wire to the feeding artery of the tumor via the superficial temporal artery. Long-term catheterization is possible by this method. Radiotherapy (total dose: 60 Gy) and superselective intra-arterial infusion chemotherapy using D (total dose: 60 mg/m2) and C (total dose: 100 mg/m2) were concurrently performed daily. Radical neck dissection was performed after chemoradiotherapy, but the primary lesions were preserved. Results: Toxicities over grade 3 were leukopenia (6.3%), mucositis (25.0%), and dermatitis (18.8%). No infection was associated with catherization. No major complications were observed. The clinical effects were CR in 13 (81.5%) patients, with recurrences in 3 patients. Salvage operations were performed in these 3 patients. The 3-year cumulative survival rate (overall rate) of 87.5% is higher than that of conventional therapy. Conclusions: Our HFT method, unlike the Seldinger method, allows for long-term catheterization, enabling daily concurrent chemoradiotherapy to be performed. This method promises to be the strategy of choice for the treatment of stage III, IV head and neck cancer.

No significant financial relationships to disclose.