bluuebunny/crossref_metadata_2025 huggingface dataset:
Pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) in combination in the salvage treatment of epithelial ovarian cancer (OC)—a Danish Gynaecologic Cancer Group (DGC) study
Authors: Mirza M. R. , Lund B. , Bertelsen K. , Lindegaard J. , Keldsen N. , Mellemgaard A. , Depont R.
Published: March 2020

5094

Background: Ovarian cancer patients (pts) recurring with a short treatment-free interval (TFI) after prior chemotherapy (PCT) have a bad prognosis. DGC has conducted a phase II study of PLD-GEM in combination in OC pts recurring with a TFI of less than 12 months (mo). Methods: All pts must have received at least one platinum-paclitaxel containing regimen; no PCT with GEM or anthracyclines. Regimen: GEM 800mg/m2 day 1+8 and PLD 25mg/m2 day 1, q 21 days. GEM dose escalation to 1g/m2 day 1+8 from 2. cycle in the absence of grade 3–4 toxicity. Primary end point: OS, secondary: PFS, response and toxicity. Pts were grouped according to their response to PCT. Group 1: pts with CR on PCT and TFI 3–12 mo; group 2: pts with CR on PCT and TFI 0–3 mo; group 3: pts with PR/SD on PCT and TFI 0–12 mo. 35 pts with ≥2 prior number of treatments. Results: 82 pts were enrolled (May 2003-Aug 2005); the median age was 59 yrs (range 31 to 77 yrs); 15 pts were entered with rising CA125 only (GCIG criteria). Groups according to their response to PCT: group 1: 44 pts; group 2: 5 pts; group 3: 33 pts. TFI ≤ 6 mo 33 pts, TFI > 6 to ≤ 12 mo 49 pts. To date data on 330 cycles (mean 4.7 cycles) is available; 45 pts are evaluable for PFS and OS; 62 pts are evaluable for response and 71 pts for toxicity. Grade 3–4 toxicity: PPE 6/330 cycles; mucosites 8/330 cycles; febrile neutropenia 4%; treatment delay 9%. No dose reductions performed for PLD. GEM dose escalation to 1000 mg/m2 in 31 pts; dose reduction to 650 mg/m2 at any time in 21 pts; skipped dose day 8 in 44 cycles. Response (RESIST): CR 3 pts; PR 17 pts (CR+PR 32%); SD 39 pts; PD 2 pts. Median PFS 212 days, Median OS 234 days. Conclusions: PLD-GEM in combination in the salvage setting is well tolerated, with acceptable toxicity and clear activity.

No significant financial relationships to disclose.
Prediction of long-term survival using expression of FOXA1, a determinant of estrogen response domains in breast cancer
Authors: Badve S. , Turbin D. , Morimiya A. , Nielsen T. , Perou C. , Dunn S. , Huntsman D. , Nakshatri H.
Published: March 2020

539

Background: Recent studies have demonstrated cofactor dependency of estrogen receptor alpha (ERα) in defining specific pattern of estrogen (E2) response in breast cancer. FOXA1, also called HNF3α, a forkhead family transcription factor, has emerged as a major cofactor that is essential for optimum transcription of ∼50% of ERα:E2 responsive genes. FOXA1 is expressed in breast cancer cells and in cDNA microarray cluster analysis segregates with genes that characterize the luminal A subtype such as ERα, GATA3, and XBP-1. Detailed expression analysis of FOXA1 in human breast tumors has not been previously performed and it is not known whether it is an independent prognostic factor in breast cancer. Methods: A tissue microarray comprising tumors from 438 patients with 20 years follow-up was analyzed for FOXA1 expression using goat-anti-human FOXA1 antibody by immunohistochemistry. Percentage (P) and intensity (I) of expression was analyzed to generate numerical score (S= P × I). FOXA1 expression was correlated with tumor grade, nodal status, disease free survival, and expression of ER, PR, GATA3, HER2, p27kip1, phospho-AKT, and luminal A subtype (defined as ER &/or PR+, bcl-2+ and Her-2-neg). Results: FOXA1 expression (score greater than 100) was seen in 187 of 438 breast cancers and correlated with greater likelihood of survival at 20 year (p=0.0114). A significant positive correlation was observed between FOXA1 expression and expression of ERα (p= 0.000001), GATA3 (p= 0.000001), PR (p= 0.00001), phospho-AKT (p= 0.00001). Similarly, a significant correlation was noted with luminal A subtype. An inverse correlation was noted with tumor grade and mdm-2 expression (p=0.00001). HER2 or p27kip1 expression and nodal status showed no correlation with FOXA1. Conclusions: FOXA1 is good prognostic marker predicting disease free survival in patients with breast cancer. Since its expression correlates well with breast cancer of luminal A subtype, it can also be used to identify these good prognosis tumors from the rest of the ER positive breast cancers in archival paraffin embedded breast tissues.

No significant financial relationships to disclose.
Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs placebo) post unblinding
Authors: Robert N. J. , Goss P. E. , Ingle J. N. , Tu D. , Shepherd L. , Palmer M. , Pater J.
Published: March 2020

550

Background: 5187 postmenopausal women were originally randomized to NCIC CTG MA.17 to receive letrozole (LET) or placebo (PLAC) after 5 years of tamoxifen. The hazard ratio (HR) for disease-free survival (DFS) was 0.58 (0.450.76, p=0.00004) after a median follow-up of 30 months (mo). The trial was unblinded in October 2003 after the first interim analysis. Women randomized to PLAC were offered LET at the time of unblinding. The goal of this analysis was to determine whether women switching from PLAC to LET benefit in terms of disease outcome and to evaluate treatment related toxicities. Methods: LET and PLAC-LET have been compared to PLAC, based on the hazard ratio and adjusting for baseline patient and disease variables including, among others, tumor size, nodal status and prior adjuvant chemotherapy. Results: Information about their follow-up treatment after unblinding was available on 2268 women originally assigned to PLAC and who were free of recurrence and alive at the time of unblinding. Among them, 1655 crossed over from PLAC to LET while 613 elected no treatment. With 54 mo f/up the HR for DFS was 0.31 (0.18, 0.55: p<0.0001) favoring patients who crossed over to LET compared to those who stayed on no treatment. The treatment switch was well tolerated with no significant difference in bone fractures or cardiovascular events. An updated analysis of DFS, DDFS and OS by nodal and tumor receptor status, prior chemotherapy, menopausal status at the start of tamoxifen, and duration of prior tamoxifen therapy will be presented at the meeting. Conclusion: Women with hormone dependent breast cancer prescribed LET after a prolonged delay from completing tamoxifen experienced a significant improvement in outcome (DFS, DDFS, OS) and should be considered for this therapy.

[Table: see text]
Gene expression profiling for prediction of distant metastasis and survival in primary nasopharyngeal carcinoma
Authors: Kao K. J. , Cheng S. H. , Huang A. T.
Published: March 2020

5503

Background: Distant metastasis is the major cause of treatment failure for nasopharyngeal carcinoma (NPC). An accurate means to predict potential of distant metastasis before therapy could allow optimization and further improvement of treatment. Gene expression profiling was performed to identify such predictors. Methods: mRNA transcript profiling was performed using Affymetrix U133A GeneChips on 138 biopsy specimens of primary NPC obtained before therapy and stored in liquid nitrogen. The specimens represented two groups of patients: distant metastasis <3 years after initial therapy (high risk group, n = 47) vs no distant metastasis after >3 years of follow-up (low risk group, n = 91). Two thirds of cases in each risk group were randomized to a training set and 1/3 to an independent test set. Supervised analyses were conducted to discover gene expression signatures associated with metastasis in the training set (n = 96). Genes were selected by Kruskal-Wallis test, grouped by self-organizing-map and further selected by logistic regression. Predictive models were established using logistic regression and k-nearest neighbors (kNN). The predictors thus discovered were validated using independent test set (n = 42). Results: Two molecular predictors were established for identification of patients with high or low risk of developing distant metastasis. The first predictor was based on 52 genes and kNN. The second predictor was based on 12 genes and logistic regression. The specificity, the sensitivity and the accuracy determined on the independent test set were 86%, 69% and 81% for the 52-genes predictor, and 72%, 85% and 77% for the 12-genes predictor. The accuracy increased to 85% and the estimated hazard ratio between predicted high and low risk was 11.1 (95% CI=2.4 to 52.4, p = 0.002), when both molecular predictors were used in combination. Log rank test showed significant difference in overall survival between patients predicted with low and high risk for distant metastasis in the test set (p = 0.003). Conclusions: mRNA transcript profiling of primary tumors of NPC can be used to determine the risk of distant metastasis. The method can be used to identify NPC patients at high metastatic risk to undergo trials of new modalities of treatment at the time of diagnosis.

No significant financial relationships to disclose.
Randomized phase III trial comparing induction chemotherapy using cisplatin (P) fluorouracil (F) with or without docetaxel (T) for organ preservation in hypopharynx and larynx cancer. Preliminary results of GORTEC 2000–01
Authors: Calais G. , Pointreau Y. , Alfonsi M. , Sire C. , Tuchais C. , Tortochaux J. , Bourhis J. , Guerrif S. , Garaud P.
Published: March 2020

5506

Background: Induction chemotherapy (CT) with PF followed by RT in case of objective response is an alternative to total laryngectomy (TL) for patients with locally advanced larynx (L) and hypopharynx (H) cancer. Data have suggested that T may add to the efficacy of PF. The objective of this trial was to determine whether the addition of T to PF could increase the L preservation rate. Methods: Patients with L and H cancer for whom surgical procedure required TL were randomized to receive PF or TPF. Inclusion criteria were: adequate organ function, WHO PS 0 or 1, age from 18 to 70, signed informed consent. Treatment arms were PF = P 100 mg/m2/d1 and F: 1000 mg/m2 continuous infusion (CI) d1 to 5, TPF = T: 75 mg/m2/d1, P: 75mg/m2/d1 and F: 750mg/m2 CI d1 to 5 for 3 cycles with 21 days interval. Patients with complete or partial response and who recovered normal L mobility received RT to 70 Gy. Non responders underwent TL followed by RT. The primary endpoint was 3-year larynx preservation rate. To detect an absolute difference of 15% the sample size was 210. Results: 220 patients were randomized (108 to PF, 112 to TPF). Patients characteristics (age, sex, PS, primary site, TN) were well balanced. The TPF arm showed greater grade 3–4 alopecia (19% vs 2%) and neutropenia (57% vs 35%) while the PF arm showed greater grade 3–4 mucositis (9% vs 4%) and febrile neutropenia (6% vs 2%).Compliance to CT was better in the TPF. The specified treatment was delivered in 81.2% of patients in the TPF vs 67.4%. The overall response rate (T and N) was 82.8% in the TPF vs 60.8% (p = 0.0013). 60.6% of patients achieved a complete endoscopic response vs 46.7%. L preservation was offered for 80% of patients in the TPF vs 57.6%. A high hemoglobin level (>14 gr/l) and a compliance to treatment >80% are associated with a better response rate. With a median follow up of 35 months the 3-year actuarial L preservation rate is 73% following TPF vs 63% using the PF regimen. Conclusion: In advanced L and H cancer, TPF demonstrated significantly superior overall response rate compared to the PF regimen. The TPF is better tolerated and preliminary results suggest that L preservation could be achieved for a higher proportion of patients.

No significant financial relationships to disclose.
Clinical features of joint symptoms observed in the ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial
Authors: Buzdar A. U.
Published: March 2020

551

Background: Aromatase inhibitors have been associated with higher rates of adverse events associated with the joints, or ‘joint symptoms’ (JS) than tamoxifen. Details of these were reviewed in the ATAC study. JS were reported spontaneously at a higher frequency with anastrozole (A) than with tamoxifen (T), and here we present a detailed assessment of these events. Methods: Adverse events related to the joints were coded into four COSTART terms: arthralgia, arthritis, arthrosis and joint disorder. Time of onset, duration of symptoms and their effect on treatment adherence were reviewed. Results: At 68 months’ median follow-up 1100/3092 (35.6%) patients in the A arm and 911/3094 (29.4%) patients in the T arm experienced JS. Almost half (46%) of patients with JS reported these as an exacerbation of a pre-existing condition in the joints and in most cases the location was generalized. The majority of first events developed within 24 months of initiation of treatment (A 68%, T 59%) with a peak occurrence at 6 months (A 29%, T 20%). Review of all available data showed that half of the patients who recovered from JS were symptom-free within 6 months of onset and in 75%, symptoms resolved within 18 months. Median time to resolution for these events was 5.5 months for the A arm and 5.9 months for the T arm. Sixty percent of patients experiencing JS received treatment, with >90% of these patients managed with an NSAID alone or in combination with mild analgesics. Although the difference in overall prevalence between treatment arms was statistically significant (p<0.0001), a similar occurrence of serious adverse events of JS was reported (A 10.6%, T 10.4%), and only a small number of patients experiencing JS required treatment withdrawal (A 2.1%, T 0.9%). Conclusion: 68-month data from the ATAC trial showed that treatment with A was associated with a modest increase in the incidence of JS compared with T. In most patients the events were mild-to-moderate in intensity and did not lead to withdrawal of treatment.

[Table: see text]
RK-0202 for radiation-induced oral mucositis
Authors: Chambers M. S. , Welsh D. V. , Scrimger R. A. , Zehn W. , Epstein J. B. , Troha J. , Sonis S. T.
Published: March 2020

5523

Background: This study evaluated the effect of RK-0202, administered as an oral rinse, on the incidence of severe oral mucositis in patients being treated with of radiation therapy (RT) for tumors of the head and neck. Methods: This was a prospective, randomized, placebo-controlled, double-blind study that compared the effect of 2 concentrations of RK-0202 with placebo on the incidence of severe oral mucositis at a cumulative RT dose of 60 Gy in 110 subjects. Twenty-seven subjects received RK-0202 5%, 38 received RK-0202 10%, 29 received placebo and 16 received standard of care. Subjects began dosing just prior to RT and continued dosing six times daily throughout RT. Oral mucositis was assessed twice weekly throughout RT by trained oral evaluators. Results: The higher dose of RK-0202 (10%) successfully attenuated severe oral mucositis as measured by WHO or NCI-CTC v.3 criteria. The incidence of WHO grade 3 or 4 oral mucositis by a cumulative RT dose of 60 Gy was 35% in the RK-0202 group vs. 54% in the placebo group (p = NS). By 50 Gy the incidences in the RK-0202 and placebo groups were 25% and 54%, respectively (p = 0.053). Similarly, the incidence of NCI grade 3 or 4 oral mucositis by 60 Gy was 64% in the RK-0202 cohort vs. 92% for subjects being treated with placebo (p = 0.005). Subjects treated with RK-0202 required less feeding tube placement compared to placebo recipients (3% vs. 22%, p = 0.037) and less opiate analgesia. The median percent of time on opiates was 6% on RK-0202 vs. 21% on placebo. The overall incidence of serious adverse events was significantly lower in subjects treated with RK-0202 (8% vs. 31%, p = 0.024). In general, there was no benefit noted among subjects who received RK-0202 as a 5% solution. Conclusions: RK-0202 significantly reduced the incidence of severe mucositis in subjects treated with radiotherapy for head and neck cancer and was not associated with significant adverse events.

[Table: see text]
Neck dissection following organ preservation protocols prolongs feeding tube dependence in patients with advanced head and neck cancer
Authors: Lango M. , Ende K. , Ahmad S. , Feigenberg S. J. , Ridge J. A.
Published: March 2020

5525

Background: Organ preserving strategies employed in the treatment of advanced stage head and neck cancer frequently result in significant organ dysfunction including dysphagia and feeding tube dependence. While the acute and chronic effects of radiation and chemotherapy are known to contribute to swallowing impairment, the effect of a neck dissection, performed 6–8 weeks following the completion of treatment is unknown. Methods: Retrospective review of Stage III/IV squamous carcinoma patients treated with primary radiation with/without chemotherapy and a post-treatment neck dissection, who remain free of locoregional or distant failure for a minimum of two years. Predictors of prolonged feeding tube dependence (>24 months following the completion of treatment) were evaluated using univariate and multivariate analysis. To determine the independent effect of neck dissection on length of feeding tube dependence, patients matched for covariates were also compared. Results: 79 patients treated at the Fox Chase Cancer Center between 1992 to 2003 were included in this study. 61 (77.2%) received chemotherapy and 37 (46.8%) underwent a neck dissection. The surgical specimen was positive for residual carcinoma in 12 patients (33%). 57 patients (71.3%) underwent placement of a feeding tube. The median time to removal of feeding tubes was 12 months [7–17 months, 95% CI]. Feeding tube-free status at 24 months was associated with use of standard radiotherapy (p = 0.031), N0 vs N+ neck stage (p = 0.041) and management without a neck dissection (p = 0.003). There was no association with age, T-stage, tumor site or use of chemotherapy. On multiple regression, only neck dissection remained a predictor of retained feeding tube at 24 months (p = 0.013). In patients matched for N-stage and treatment selection, those who underwent a neck dissections required a feeding tube a median of 36 months compared with 10 months for those without a neck dissection [32–57 months versus 7–13 months, 95% CI, p = 0.021]. The two year frequency of feeding tube dependence was 14/34 (41%) versus 3/30 (10%), respectively (p = 0.005). Conclusions: Neck dissection may contribute dysphagia experienced by head and neck cancer patients treated with organ preservation protocols.

No significant financial relationships to disclose.
Outcomes of radical conformal radiotherapy and concomitant cisplatin chemotherapy for olfactory neuroblastoma—Review of a single centre experience
Authors: Nikapota A. D. , Sevitt T. , Lund V. J. , Howard D. , Spittle M. F. , Prior T. , Saunders M. I. , Varughese M. , Carnell D. M.
Published: March 2020

5555

Background: Olfactory neuroblastoma is rare with 25 new cases annually in the UK. Cranio-facial resection and post operative radiotherapy is standard treatment. The use of concomitant chemotherapy has not been fully evaluated, although chemo-sensitivity has been demonstrated by retrospective series. This study evaluates the use of radical radiotherapy and concomitant chemotherapy. Methods: Since 1978 more than 70 patients have been seen at the Institute of Otology and Laryngology. Eighteen patients treated with radiotherapy between 1999 and 2005 were reviewed. These were all CT planned and treated with conformal radiotherapy ± cisplatin chemotherapy 100 mg/m2 D 1, 22 and 43. The radiotherapy prescribed dose varied from 50Gy to 62 Gy in 1.8 to 2 Gy fractions, 10 (56%) received 60Gy in 30 fractions. Overall survival, disease free survival and treatment related morbidity were assessed. Results: Seventeen patients were post operative and 1 was neo-adjuvant. Mean age was 46 years (range 20–83) and the majority were Kadish stage C. Of the 17 post-operative patients, 13 (76%) had surgery as primary treatment and 4 (24%) for recurrence. Eight patients (44%) received concomitant chemotherapy. At the time of analysis follow up ranged from 4 months to 72 months (median 17.5, mean 28.2), 16 (88.9%) patients were alive and 14 (77.8%) disease free. Four (22.2%) patients developed recurrence and 2 died of disease. Of the 4 patients with recurrence, 3 did not receive concurrent cisplatin chemotherapy and the fourth patient did not undergo radical surgery. No patients reported deterioration in vision or significant morbidity following treatment. Conclusions: Post operative radiotherapy with concurrent cisplatin chemotherapy is effective and well tolerated in the management of olfactory neuroblastoma. Where concurrent chemotherapy was not given, relapse rates were high. Our results, although immature, suggest disease free survival superior to published data. A prospective multi-centre study to evaluate concomitant treatment schedules is required.

No significant financial relationships to disclose.
Derangement of p53 and MDM2 is involved in transformation of differentiated into anaplastic thyroid cancer
Authors: Wiseman S. M. , Masoudi H. , Niblock P. , Turbin D. , Rajput A. , Hay J. , Filipenko D. , Melck A. , Gilks B. , Huntsman D.
Published: March 2020

5556

Background: Anaplastic thyroid cancer arises as a consequence of tumor progression, or transformation, from pre-existing differentiated thyroid cancer. Mutation of the p53 tumor-suppressor gene represents a common event in thyroid tumor progression. MDM2 encodes a protein that complexes with p53, downregulates its function, and leads to its degradation via a ubiquitin-proteasome pathway. The objective of this study was to evaluate the change in p53 and MDM2 expression in the transformation of differentiated to anaplastic thyroid carcinoma. Methods: Of 94 cases of anaplastic thyroid cancer diagnosed and treated in British Columbia Canada over a 20 year period (1984–2004) 32 cases (34%) had adequate tissue available for evaluation and 12 of these cases had associated foci of differentiated thyroid carcinoma. A tissue microarray was constructed from these 12 anaplastic thyroid tumors and their associated differentiated foci. Immunohistochemistry was utilized to evaluate expression of p53 and MDM2 by these tumors. Results: There was decreased expression of p53 and MDM2 by the anaplastic tumors when compared to the differentiated thyroid tumors from which they evolved. The expression of p53 and MDM2 was 17% and 8%, respectively, by the differentiated thyroid carcinoma, and 83% and 25%, respectively, by the anaplastic tumors. Evaluating the anaplastic cancers and the differentiated foci from which they evolved, p53 overexpression developed in 8 (67%) of tumors and MDM2 overexpression developed in 3 (25%) of tumors. All the anaplastic tumors that developed MDM2 overexpression also concurrently developed p53 overexpression. Conclusions: This report is the first to demonstrate derangement of p53, and its regulator, MDM2, is involved in the transformation of a subset of differentiated into anaplastic thyroid tumors. Isolated MDM2 overexpression does not appear to play an important role in anaplastic transformation of thyroid cancer.

No significant financial relationships to disclose.
Peripheral blood quantitative PCR analysis of EBV DNA in nasopharyngeal carcinoma
Authors: Sirachainan E. , Trachu N. , Wisetpanit Y. , Panvichian R. , Ratanavila A. , Udomsubpayakul U. , Chintrakarn C. , Sirisinha T. , Ativitavas T. , Ratanatharathorn V.
Published: March 2020

5557

Background: Epstein-Barr virus (EBV) is the major etiology of WHO type 2, 3 nasopharyngeal carcinoma (NPC). Almost every tumor cell contains EBV genome. Correlation between prognosis, disease status and serum EBV DNA level was recently reported. Methods: We conducted a cross-sectional study to determine the correlation between the EBV DNA level from circulating tumor cells and the status of disease. The subjects were classified into 4 groups: new diagnosis, in remission, recurrent disease and control (healthy volunteers). The number of subjects/group was calculated to be at least 32, using proportion of P0 = 40%, P1 = 10% at α = 0.05 and Power = 80%. Genomic DNA was isolated from buffy coat of peripheral blood sample. Using Taqman probes for latent membrane protein 2 (LMP2) gene in EBV genome and beta actin gene as internal control, real-time quantitative PCR was performed. The LMP2 copy number was adjusted according to the beta actin copy number from the same sample. Results: The LMP2 gene can be quantified in the samples from new diagnosis, in remission, recurrent disease and control groups as following: 11/33 (33.3%), 10/29 (34.5%), 19/33 (57.6%) and 0/32 (0%) respectively. Among the patients with measurable LMP2, the median (range) of LMP2 copy numbers of each patient group are 12.97 (1.89–118.41), 18.75 (11.79–92.08) and 38.26 (2.41–642.76) copies/500 ng DNA respectively. Using Chi-Square test, all three patient groups have significantly higher LMP2 copy number than the control group (p < .001). The recurrent disease group has significantly higher LMP2 copy number than the new diagnosis group (p=.048). There is no significant difference between the in remission group and the other patient groups. The sensitivity of this test is 42.1% and the specificity is 100%. Conclusions: The peripheral blood EBV DNA copy number, determined by Real-time quantitative PCR, may be a potential molecular marker in the screening for NPC.

No significant financial relationships to disclose.
Squamous cell carcinoma of the head and neck (SCCHN) in patients reporting human immunodeficiency virus (HIV) infection: A retrospective case series
Authors: Haigentz M. , Jung G. , Garg M. , Owen R. , Schiff B. , Smith R. V.
Published: March 2020

5570

Background: Although Squamous Cell Carcinoma of the Head and Neck (SCCHN) is a non-AIDS defining malignancy, its risk is greater in HIV-positive populations for unclear reasons. Very limited data exist on the clinical presentation, treatment toxicities and outcomes of HIV infected pts with SCCHN, a population frequently excluded from participation in clinical trials. Methods: We present a large case series of HIV infected pts with SCCHN who were recently treated at a single institution. Retrospective chart reviews were performed by treating physicians. Results are reported with descriptive statistics. Results: Thirty individuals with SCCHN reporting HIV infection have been treated by the collaborating physicians from 1997–2005; all were smokers. The average age at diagnosis of SCCHN was 49.3 years (range 33–62), and interestingly, a relatively large number were female (13 of 30, 43%). The median CD4 count of pts was 374/μL, and most pts reported a history of antiretroviral therapy. The most frequent sites of primary disease were the larynx (13 pts, 43%, mostly supraglottic) and oropharynx (13 pts, 43%). Although most patients (87%) presented with advanced (stage III and IV) disease, a few (4 pts, 13%) had stage II disease. Although 12 pts underwent surgical resections for primary treatment, 16 pts underwent primary nonsurgical therapy, including 8 pts treated with chemoradiotherapy. Therapy related toxicities were expected and did not appear different from those observed in immunocompetent individuals. Eight pts had recurrence (7 locoregional/1 distant), and 5 pts died from recurrent/metastatic disease. Three pts had second primary cancers. Conclusions: HIV-infected individuals with SCCHN are generally young smokers, both male and female, receiving active treatment against HIV. The detection of a proportion of pts with early stage disease further supports the role for aggressive smoking cessation counseling and screening efforts for SCCHN in HIV infected populations. Additionally, HIV infection is not a contraindication to aggressive organ-preserving regimens for SCCHN pts with otherwise good functional status. A case-control clinical and pathologic study of SCCHN in HIV infection is planned.

No significant financial relationships to disclose.
A phase II trial of docetaxel and cisplatin combination in patients with locally advanced undifferentiated carcinoma of nasopharyngeal type (UCNT): Study update
Authors: Yamouni M. , Benhadji K. A. , Beldjilali Y. , Lahfa I. , Yekrou D. , Djellali L. , Brahimi M. , Bouzid K.
Published: March 2020

5579

Background: The standard treatment of locally advanced undifferentiated carcinoma of nasopharyngeal type (UCNT) is cisplatin based chemotherapy followed by locoregional radiotherapy. The purpose of this study is to assess the antitumor activity and toxicity of a new neoadjuvant chemotherapy regimen combining docetaxel (D) and cisplatin (C). Patients and Methods: Previously untreated patients (pts) with histologically diagnosed locally advanced UCNT (Stages IVa and IVb TNM/UICC 1997) received D 75 mg/m2 and C 75 mg/m2 both on day 1, cycles were repeated every 21 days. Every pts received three cycles in a neoadjuvant setting before radiotherapy (4 to 6 weeks after the third cycle of DC). Pts were evaluated by clinical examination, CT scan of nasopharynx and nasofibroscopy with biopsy. Primary end point was tumor response. Secondary end points were disease free survival (DFS), toxicity and overall survival. Results: 75 pts were enrolled in this trial, 54 males and 21 females with a median age of 41 years (range 18–69), WHO performance status of 0–1 in 71 pts and 2 in 4 pts. 19 pts had stage IVa and 56 pts had stage IVb. Toxicity, tumor response and survival over tree years were assessable in 75 pts. After 225 cycles, grade 3 & 4 toxicity (NCI-CTC 2.0) were: neutropenia (12%), febrile neutropenia (2%), anemia (1%), nausea and vomiting (23%), diarrhea (8%), mucositis (1%), reversible alopecia (70%). Two pts had onycolysis. Response rates for the 75 pts were: complete pathologic response 37% (28 pts), partial response 52% (39 pts), stable disease 8% (6 pts) and progression 3% (2 pts). The overall response rate was 89%. 74 pts (98%) had complete response after radiotherapy and one patient had stable disease. 31 patients had recurrence: 25 locoregional, and 6 metastatic (3 with bone metastasis, 2 hepatic metastasis and 1 cerebral metastasis). DFS and overall survival at 3 years were respectively 57% and 65%. Conclusion: DC chemotherapy followed by radiation therapy is an effective regimen for the treatment of advanced UCNT. This treatment has an acceptable safety profile. These data need to be compared to concurrent chemoradiotherapy to assess the best strategy for the management of advanced UCNT.

[Table: see text]
Retrospective analysis of renal toxicity in breast cancer patients following zoledronic acid or pamidronate treatment
Authors: Chen L. , Nikolas T. L. , Markowitz G. , Green J. , Wintfeld N. , Neary M. , Duh M.
Published: March 2020

564

Background: In breast cancer (BC) patients (pts), reports suggest that some i.v. bisphosphonates (BPs) are associated with an incremental renal toxicity risk. Few studies have investigated this risk in clinical practice. We retrospectively analyzed rates of renal toxicity in BC pts treated with zoledronic acid (ZO), pamidronate (PA), or no BP treatment (NT). Methods: Pts were identified through medical and pharmacy claims and laboratory data from >35 managed care plans between 01/2000 and 12/2004. Inclusion criteria: female pts with ≥2 claims for BC, no gap in health plan coverage, and serum creatinine measurements available from before and after first ZO or PA infusion. BC pts receiving NT provided a separate reference group. Observations were analyzed from first infusion to health plan disenrollment (BP monotherapy) or before BP switch. Renal impairment was defined as a ≥25% decrease in glomerular filtration rate (GFR,abbreviated MDRD formula) from baseline. Andersen-Gill model, adjusted for demographics and baseline comorbidities, was used to analyzer multiple events in a given pt, as physician practice patterns indicate that administration of both BPs continues even after the development of a first nephrotoxic event. Results: 312 ZO pts, 166 PA pts, and 2,862 NT pts were included. ZA and PA groups had comparable baseline characteristics, renal-related comorbidities, and baseline GFR. Both BP groups were more frequently exposed to chemotherapies and nephrotoxic drugs than the NT group (p<0.0001). ZO and PA groups had similar renal impairment rates that were significantly higher than the NT group and increased with treatment duration (ZO 15.8%, PA 15.6%, NT 7.3% in pts treated for <6 months, increasing to ZO 42.0%, PA 40.0%, NT 16.9% in pts treated for ≥18 months). Mean renal impairment events per person-year were significantly higher for ZO than PA (0.93 vs 0.81, p=0.019). Multiple-event analysis showed a significantly higher renal impairment risk for ZO than PA (hazards ratio=1.4, p<0.0001). Conclusions: In this study on BC pts, renal impairment was more commonly seen in ZO and PA pts than in NT pts. ZO and PA pts have similar renal impairment risk, but ZO pts are more likely to experience multiple impairment events after repeated administrations.

[Table: see text]
Randomized trial of sequence vs. combination of capecitabine (X) and docetaxel (T): XT vs. T followed by X after progression as first-line therapy for patients (pts) with metastatic breast cancer (MBC)
Authors: Beslija S. , Obralic N. , Basic H. , Tatarevic A. , Naila M. , Banjin M. , Cardzic A. , Sosevic A. , Pasic A. , Ceric T. , Salkic B.
Published: March 2020

571

Background: Capecitabine (Xeloda [X]) and docetaxel (Taxotere [T]) are highly active single agents in MBC. The XT combination leads to superior overall survival (OS), time to progression (TTP) and response rate (RR) vs. T alone in anthracycline-preatreated MBC [O’Shaughnessy et al. J Clin Oncol 2002], although only one third of pts in the T group received X after progression. We designed this study to determine whether XT is better than sequential T→X in first-line MBC. Methods: 100 pts with measurable MBC, prior adjuvant anthracyclines (100%) but no prior chemotherapy for MBC and KPS ≥70 received 3-weekly cycles of either XT (X 1250mg/m2 bid d1–14 + T 75mg/m2 d1) or T→X (T 100mg/m2 d1 followed after progression by X 1250mg/m2 bid d1–14). X monotherapy data were not considered in the RR or TTP analyses but were included for OS and safety. Results: The XT and T→X arms were well balanced for prognostic factors: median age 48 (29–59) vs. 51 (31–64) years; median KPS 100 (70–100) in both arms; hormone-responsive disease 20 vs. 16%; dominant metastatic sites (liver 42 vs. 44%, lymph nodes 34 vs. 36%, lung 28 vs 24%, bone 20 vs 18%); number of involved organs (1 = 58 vs. 52%, >1 = 42 vs. 48%); median interval since prior adjuvant anthracyclines (18.5 vs. 17.0 months). Efficacy findings are shown in the table . 74% of the pts in the T→X arm crossed-over to X on progression. The post-study treatment rate was similar in both arms. The most common grade 3/4 adverse events (>5% of pts) with XT vs. T→X were: hand-foot syndrome 18 vs. 4%; stomatitis 16 vs. 8%; neutropenia 12 vs. 14%; neutropenic fever 12 vs. 14%; diarrhea 12 vs. 8%; fatigue 8 vs. 12%; alopecia 6 vs. 8%; edema 4 vs. 8%. Dose reductions were necessary for 52% of pts on XT and 36% of pts on T→X. Conclusions: XT provides significant RR, TTP and OS advantages over T→X. XT should be the standard therapy in fit poor-prognosis pts with aggressive disease.

[Table: see text]

No significant financial relationships to disclose.
Weekly cisplatin-epirubicin-paclitaxel (PET) with granulocyte-colony stimulating factor support versus tri-weekly epirubicin-paclitaxel in locally advanced breast cancer: Final comprehensive and subgroup analysis of a SICOG phase III study
Authors: Frasci G. , D’Aiuto G. , Comella P. , Thomas R. , Botti G. , Rubulotta M. , Iodice G. , Costanzo R. , Di Bonito M. , Comella G.
Published: March 2020

572

Background: We previously reported the preliminary pathological response data of a phase III trial comparing a weekly dose-dense approach (PET) to a standard epirubicin-paclitaxel q3wk combination, in LABC pts. (ASCO 2004; abstr.511). In the present abstract, we report the final data on response and PFS, and a subgroup analysis according to the hormone-receptor, and HER2/neu status. Methods: Overall, 200 patients with stage IIIB disease were randomised to receive either 12 weekly cycles of cisplatin 30 mg/m2, epirubicin 50 mg/m2, and paclitaxel 120 mg/m2 (PET) plus granulocyte-colony stimulating factor support, or 4 cycles of epirubicin 90 mg/m2 + paclitaxel 175 mg/m2 (ET) every 3 weeks. Results: Overall, a pCR in both breast and axilla occurred in 16 (16%) PET patients and in 6 (6%) ET patients (P=0.02). The higher activity of PET was evident only in ER negative (27.5% vs 5.4%; P=0.026), and in HER/neu 3+ (31% vs 5%; P=0.037) tumours. The 2 arms yielded similar pCR rate in ER positive (PET/ET=7.5%/7.1%) and HER/neu negative (PET/ET=10%/6%) patients. At a 45 months median follow-up, 78 patients showed a progression or relapse (PET= 32 vs ET= 46). The 5-year Failure-free survival rates in PET/ET arms were: Total =27%/21%; ER+= 26%/23%; ER- =25%/9%; HER2+=.18%/11%; HER2- =29%/25%. Conclusions: The PET weekly regimen is superior to ET in terms of pCR rate in LABC patients. The advantage of such an aggressive approach is limited to ER negative and HER2 positive pts. A large randomised trial comparing weekly PET to a standard regimen in ER- LABC pts., with FFS as the main end-point, is highly recommendable.

No significant financial relationships to disclose.
Comorbidity and outcomes in elderly women treated with breast-conserving therapy
Authors: Harris E. E. , Urtishak S. L. , Hwang W. , Kinosian B. , Solin L. J.
Published: March 2020

599

Background: Breast cancer incidence increases with age and is a major cause of morbidity and mortality among elderly women. Co-morbidities are often considered in treatment management of elderly women. Methods: Between 1979 and 2002, 238 women age 70 or older with unilateral stage I or II invasive breast cancer underwent conventional breast conservation treatment with radiation. The age distribution was 122 women (51%) age 70–74 years, 71 women (30%) age 75–79 years, and 45 women (19%) age ≥80 years. Surgical axillary staging was performed in 73% (n= 173) of patients, of which 73% (n=126) were N0, and 27% (n=47) were N1. Co-morbidities were scored using the Charlson Comorbidity Index and Cumulative Illness Rating Scale (CIRS). Median follow-up was 6.2 years. Results: On analysis by age groups, the 10-year cancer specific outcomes were not significantly different (see Table ). However, distant metastases were the most common site of first failure in all age groups: 9% for age 70–74; 12% for age 75–79 and 11% for age >/= 80. Second malignancies were the second most common cause of first failure in all age groups. Death from intercurrent disease was significantly more likely in the older age groups. In this cohort, moderate and severe co-morbidities were not significantly more common in the older age groups, and CIRS score did not correlate with overall survival. Conclusions: Breast conserving surgery and definitive breast irradiation provide excellent outcomes in appropriately selected elderly women. Older age itself is not a contraindication to breast conserving therapy. Women of any age with lower co-morbidity indices should be offered standard treatment.

[Table: see text]

No significant financial relationships to disclose.
Model-based predictions of expected anti-tumor response and survival in phase III studies based on phase II data of an investigational agent
Authors: Claret L. , Girard P. , O’shaughnessy J. , Hoff P. , Van Cutsem E. , Blum J. , Zuideveld K. , Jorga K. , Fagerberg J. , Bruno R.
Published: March 2020

6025

Background: Decision making during early oncology drug development remains very empirical. A drug-disease simulation model to predict expected clinical response and survival in phase III studies from observed longitudinal tumor size in phase II trials offers a science-based alternative. Methods: We developed the following: 1) longitudinal exposure-response models of drug effect (and resistance) on tumor growth dynamics based on phase II data on capecitabine (X) in metastatic breast (MBC) and colorectal cancer (MCRC) and on historical phase III data on docetaxel (T) in MBC and 5-FU in MCRC; and 2) a survival model relating change in tumor size and patient characteristics to survival time in MBC and MCRC based on phase III data. The models were validated and used to predict expected anti-tumor response and survival in phase III studies of XT vs. T alone in MBC and X vs. 5-FU in MCRC. Multiple replicates (n = 1000) of simulated phase III studies were compared to actual results. Results: Change of tumor size and survival time distributions in X arms were well predicted. In MBC, expected median (90% prediction interval) survival for patients treated with XT was 412 (range 330 to 526) days (vs. 431 days observed) with an improvement over T of 57 days (range -17 to 148) (vs. 78 days observed). For MCRC patients, X treatment resulted in a potential survival improvement of 39 (range -21 to 110) days (vs. 35 days observed) compared to patients treated with 5-FU. Conclusions: The dose-tumor size-survival model succeeded in predicting survival in phase III trials based on X phase II data in MBC (in combination with T) and as a single agent in MCRC. This model is a useful tool to compare expected clinical response of new compounds to various competitors and to support end-of-phase II decisions and design of phase III studies.

[Table: see text]
Understanding of prognosis among parents of children with cancer: Parental optimism and the role of the parent-physician interaction
Authors: Mack J. W. , Cook E. F. , Wolfe J. , Grier H. E. , Cleary P. D. , Weeks J. C.
Published: March 2020

6033

Background: Patients often overestimate their chances of surviving cancer. Factors that contribute to accurate understanding of prognosis among parents of children with cancer are not known. Methods: We conducted a cross-sectional survey of 194 parents of children with cancer (overall response rate 70%), treated at the Dana-Farber Cancer Institute and Children’s Hospital, Boston, Mass, and the children’s physicians. Our main outcome measure was agreement between parent and physician ratings of the child’s likelihood of cure. Results: The majority of parents (61%) were more optimistic about the likelihood of their child’s cure than their child’s physician was. Most parents, however, believed that their opinions about prognosis either matched (70%) or were more pessimistic (26%) than those of their physicians. When physicians were confident in their knowledge of the child’s prognosis, parent and physician perceptions of prognosis were more likely to agree (OR 2.55, P = .004). Parents whose role in decision-making matched their ideal role were more likely to give prognostic estimates that agreed with physician perceptions of prognosis (OR 1.89, P = .019). In contrast, parent confidence in knowledge (OR .07, P < .0001), coping strategies (disengagement, OR .31, P = .007; reliance on emotional support from others, OR .31, P = .029), and use of intuition to understand prognosis (OR .51, P = .012), were associated with overestimation of likelihood of cure. Conclusions: Many parents overestimate their children’s chances of being cured of cancer. Neither physician nor parent attributes alone account for this finding; rather, successful communication about prognosis requires that physicians relate to parents’ individual communication and decision-making needs.

No significant financial relationships to disclose.
Social and racial disparities in the use of non-standard breast cancer adjuvant chemotherapy regimens
Authors: Griggs J. J. , Culakova E. , Sorbero M. E. , Crawford J. , Dale D. C. , Wolff D. A. , Poniewierski M. S. , Lyman G. H.
Published: March 2020

6036

Background: Economically disadvantaged and black women have worse stage-specific breast cancer outcomes than other women, even after controlling for tumor histologic features. Disparities quality of chemotherapy may contribute to differences in outcome. The purpose of this study was to investigate the use of non-standard breast cancer adjuvant chemotherapy regimens in black women and those of lower socioeconomic status (SES). Methods: Detailed information on patient, disease, and treatment factors was collected prospectively on 1,006 patients receiving adjuvant chemotherapy for early-stage breast cancer in 115 oncology practices throughout the US. All patients signed informed consent. Regimens included in the guidelines of the National Comprehensive Cancer Network were considered standard regimens; all others were considered non-standard. Receipt of non-standard regimens was examined according to clinical and non-clinical factors. Differences between groups were assessed using a chi-square test. Multivariate logistic regression was used to identify factors associated with use of non-standard regimens. Results: Non-standard regimens were used in the treatment of 136 (14%) of the participants. Black patients were twice as likely to receive a non-standard regimen as whites (23% vs. 12%, p = .0014). Patients with less than a high school education were twice as likely to receive a non-standard regimen compared with those with a college education (21% vs. 8%, p = 0.0011). Other factors associated with non-standard chemotherapy regimens were past chemotherapy exposure (p < .0001), higher stage disease (p < .0001) and geographic location (p = 0.0059). Age, comorbidity, body mass index, type of insurance, and employment status were not associated with receipt of non-standard chemotherapy. In multivariate analysis, all variables that were significant in the bivariate analysis remained independently associated with receipt of non-standard chemotherapy. Conclusions: The more frequent use of non-guideline concordant adjuvant chemotherapy regimens in black women and women with lower SES may contribute to their less favorable outcomes. These findings offer an opportunity to improve patient care and perhaps cancer outcomes.

[Table: see text]
Complementary systems: Quality and timeliness of passive vs. active adverse event reporting and regulatory vs. peer-reviewed adverse drug reaction (ADR) dissemination
Authors: Bennett C. L. , Angelotta C. , Lurie A. J. , Lyons E. A. , Yarnold P. R. , Raisch D. W.
Published: March 2020

6062

Background: RADAR, a NIH funded R01 project, obtains reports of serious ADRs by conducting hypothesis-driven active surveillance efforts in hematology/oncology. The FDA and pharmaceutical sponsors conduct passive surveillance efforts based on review of reports voluntarily submitted by health care workers. Methods: Completeness and timeliness of ADR reports and dissemination efforts by RADAR versus the FDA/pharmaceutical sponsors were compared. Results: Individual reports were more complete in RADAR databases with fewer total reports (341 versus 1,341). Pharmaceutical sponsors disseminated ADR data 1 year (median) earlier as revised package inserts (PIs), but RADAR publications were more complete. Conclusion: Compared to pharmacovigilance efforts by the FDA/pharmaceutical suppliers, RADAR is more complete but less timely.

[Table: see text]

No significant financial relationships to disclose.