bluuebunny/crossref_metadata_2025 huggingface dataset:
A new prognostic index of advanced epithelial ovarian cancer (PIEPOC): A JMTO OC01–01 study
Authors: Teramukai S. , Ochiai K. , Tada H. , Fukushima M.
Published: March 2020

5061

Background: The prognostic factors in patients with advanced epithelial ovarian cancer (EpOC) have been identified by many investigators. The purpose of this study was to construct a simple and powerful prognostic index (PI) of EpOC (PIEPOC) by using data from a long-term follow-up study. Methods: Data from 768 women with stage III or IV EpOC from 24 institutions in Japan who were treated between 1994 and 2000 were evaluated for clinical features predictive of overall survival. A PI to predict overall survival after initial surgery was developed using proportional hazards regression model. We selected the best classification in an attempt to separate the prognosis of patients. Results: Out of 768 patients, 408 patients were died and a median follow-up for 360 surviving patients was 4.2 years. We randomly selected 538 (70%) patients as a training sample set. The four prognostic factors that remained independently significant in the analysis of the training sample were age, performance status (PS), cell type, and size of residual disease. After combining levels of factors that appeared to have a similar effect on survival and checking additivity of effects by pooled interaction tests, a linear function based on estimated regression coefficients was as follows: 0.448 (if age 70 and above) + 0.539 (if PS 1 or 2) + 0.980 (if PS 3 or 4) + 0.488 (if mucinous or clear cell) + 0.943 (if residual size 0.1cm and above). From the weight of function, we derived a simplified PI (PIEPOC) = 1 (if age 70 and above) + 1 (if PS 1 or 2) + 2 (if PS 3 or 4) + 1 (if mucinous or clear cell) + 2 (if residual size 0.1 cm and above). The PIEPOC of patients were distributed between 0 and 6. Patients were classified into three risk groups, i.e., low (PI: 0–2), intermediate (PI: 3), and high (PI: 4–6). The PIEPOC was equally predictive in a randomly selected validation sample set (n = 230), identifying three groups (5-year survival: 0.67 in low, 0.43 in intermediate, 0.17 in high risk group, respectively). This predictability was reproducible in Stage IIIc or IV patients. Conclusions: Our PIEPOC is simple and easy to use to discriminate the risk groups among advanced EpOC. Thus PIEPOC should be useful for the selection of appropriate treatment options.

No significant financial relationships to disclose.
Influence of platinum-based chemotherapy on disseminated tumor cells in patients with primary ovarian cancer
Authors: Wimberger P. , Kimmig R. , Schulte A. , Scheulen M. E. , Kasimir-Bauer S.
Published: March 2020

5067

Background: Recent studies in patients (pts) with breast cancer have demonstrated the prognostic significance of disseminated tumor cells (DTC) in the bone marrow (BM) which even can survive high-dose chemotherapy. For ovarian cancer, the impact of chemotherapy on DTC is unknown. Here we evaluated whether first-line chemotherapy with carboplatinum and paclitaxel can eliminate DTC in BM and peripheral blood (PB) of pts with primary ovarian cancer (OC, FIGO IC-IIIC). Methods: PB of 28 pts with OC and bilateral BM aspirates of 18/28 pts were assessed for DTC before and after chemotherapy using density gradient centrifugation and an immunocytochemical cytokeratin (CK) assay with the anti-CK antibody A45-B/B3. Results: We identified CK+ cells in 7/28 blood samples (25%) before therapy with a mean number of 2 cells/20 ml (range 1–3). After chemotherapy, CK+ cells were detected in 3/28 blood samples (11%) with a mean number of 9 cells/20 ml (range 1–18). In 5 out of these 7 CK+ patients prior to therapy, no CK+ cells were found after therapy, a no change and a reduction of DTC could be demonstrated in one patient each. CK+ cells were found in 10/18 BM samples (56%) before therapy with a mean number of 2 cells/9x10E6 BM cells (range 1–7) and in 8/18 BM samples (44%) after therapy with a mean number of 10 cells/9x10E6 BM cells (range 2–35). After chemotherapy, no CK+ cells were found in 6 pts, no change in DTC counts was documented in 2 pts and a significant enhancement of DTC was shown in 6 pts, including 4 pts who had no CK+ cells before chemotherapy. Conclusions: DTC are frequently present in the BM and PB of pts with OC and are not always successfully eliminated after platinum-based chemotherapy. It has to be considered, whether these pts might profit from an additive immunotherapy as already shown by the intraperitoneal application of a trifunctional antibody targeting EpCAM, CD3 and accessory cells (Proc Am Assoc Cancer Res 46: 4260, 2005).

No significant financial relationships to disclose.
Is the adjustment of serum creatinine level < 0.6 mg/dl to 0.6 mg/dl justified in estimates of carboplatin clearance calculated by the Jelliffe formula?
Authors: Nagao S. , Fujiwara K. , Kagawa R. , Kozuka Y. , Oda T. , Maehata K. , Ishikawa H. , Koike H. , Aotani E. , Kohno I.
Published: March 2020

5072

Background: The Jelliffe formula (JF) does not include body surface area (BSA) or body weight to adjust the body size. We demonstrated that estimates of carboplatin clearance calculated by the JF tend to have greater positive bias compared to other formulae. The JF has been used to estimate carboplatin clearance in Gynecologin Oncology Group studies. In patients with serum creatinine level <0.6 mg/dl, it is adjusted to 0.6 mg/dl in estimates of carboplatin clearance (Adjusted-Jelliffe formula (AJF)). The purpose of this study is to evaluate whether this adjustment is suitable. Methods: Carboplatin clearance was estimated in 115 patients with serum creatinine <0.6 mg/dl who received carboplatin-based chemotherapy for gynecologic malignancies between January 1996 and August 2004. Creatinine clearance was estimated using the Cockroft-Gault formula (CGF), JF, and AJF. The median percent error (MPE) and the median absolute percent error (MAPE) were evaluated by comparing carboplatin clearance. The relationships between BSA and ratios of estimated carboplatin clearance (JF/CGF, AJF/CGF) were evaluated by using simple regression. Results: The estimated carboplatin clearances were: CGF, 126.7 ± 27.7; JF, 148.2 ± 20.5; AJF, 130.5 ± 14.3. Comparing the results of the CGF with the JF, AJF yielded MPEs of +20%, +6%, and MAPEs of 21%, 14%, respectively. There were the linear correlations between ratio of estimated carboplatin clearances and BSA (Y1 = −1.141X + 2.830, Y2 = -1.061 X + 2.581, Y1: ratio of carboplatin clearance (JF/CGF), Y2: ratio of carboplatin clearance (AJF/CGF), X: BSA). Conclusions: As expected, carboplatin clearance was decreased by adjusting serum creatinine to 0.6 mg/ml, but it did not adjust the bias by BSA. Estimates of carboplatin clearance calculated by the AJF tend to have greater negative bias, particularly when the BSA of the patient is large.

No significant financial relationships to disclose.
ER+ PR- breast cancer defines a unique subtype of breast cancer that is driven by growth factor signaling and may be more likely to respond to EGFR targeted therapies
Authors: Finn R. S. , Dering J. , Ginther C. , Press M. , Forbes J. , Mackey J. , French T. , South M. , Rupin M. , Slamon D. J.
Published: March 2020

514

Background: Hormonal based therapy has long been the mainstay for treatment of ER+ breast cancer. ER+ PR- disease is now known to exhibit different clinical behavior compared to ER+PR+ disease. Recent data indicate that ER+PR- disease is characterized by a lower response rate to estrogen deprivation, has a worse prognosis compared to ER+ PR+ disease, and may be dependent on other signaling pathways. To evaluate the role of the EGFR tyrosine kinase inhibitor gefitnib in the treatment of breast cancer, we conducted a pre-surgical study in women with operable disease. Methods: Frozen core biopsies were obtained at baseline. Patients then received a short-term exposure to gefitinib (at least 2 weeks) prior to definitive surgery when a frozen tumor specimen was obtained. Tissue integrity and composition was verified by H and E and RNA was isolated for microarray analysis. 59 women were enrolled in the study of which 43 were evaluable for molecular analysis. Baseline microarrays were performed on the initial biopsies to classify the ‘subtype‘ of breast cancer (e.g. basal, luminal, HER2 amplified). To analyze the genetic changes that occur in breast cancer tissue with exposure to gefitinib, a direct comparison of the baseline sample and post-treatment tumor was performed. In addition, ER and PR status were determined by immunohistochemistry and compared to the microarray findings. Changes in Ki67 and a set of cell cycle genes were used to define ‘molecular response” to gefitinib. Of the 43 samples evaluated by microarray, 11 patients were categorized as exhibiting molecular growth inhibition, 10 patients as molecular growth proliferation, and 22 did not have a significant change in Ki67 and the cell cycle gene set to assign a response. When grouped by subtype, ER+PR- and HER2 amplified tumors define a subgroup more likely to show molecular growth inhibition with gefitinib. Conversely, ER+PR+ tumors were more likely to show molecular growth proliferation. Conclusions: These results support the hypothesis that ER+PR- breast cancer is growth factor dependent and constitutes a unique subgroup of ER+ patients which may be more likely to benefit from EGFR inhibition.

[Table: see text]
Epirubicin/paclitaxel (EP) vs. capecitabine/paclitaxel (XP) in first-line metastatic breast cancer (MBC): A prospective, randomized multicentre phase III study of the AGO breast cancer study group
Authors: Lueck H. , Minckwitz G. V. , Du Bois A. , Schrader I. , Huober J. , Heilmann V. , Beckmann M. , Stähle A. , Jackisch C. , Marth C. , Richter B.
Published: March 2020

517

Background: Anthracyline-taxane combinations have the highest response rates in high risk MBC. Recently, anthracyclines and taxanes have become standards for adjuvant breast cancer chemotherapy. The addition of capecitabine to docetaxel improved overall survival in MBC. This regime was associated with a high rate of side effects (actually FN was not different from Taxotere mono - it was more the addition of cape AEs to Taxotere AEs). Earlier phase II studies with XP are able to show efficacy with better tolerability including less febrile neutropenia. Methods: Our aim was to show non-inferiority of XP to EP. The primary endpoint was progression-free survival (PFS). Secondary endpoints were toxicity and overall survival (OS).Patients (pts) were treated with 6x E 60 mg/m2 and P 175 mg/m2 d1 q21d, or with 6× X 2×1000 mg/m2 d1–14 q 21d and P 175 mg/m2 d1 q21d. Results: During a period of 2.5 y the planned 340 pts (170 in each arm) in 63 centres were recruited. The median number of cycles was 6 in both arms. The median PFS for EP was 11.8 months, and 12.3 for XP (p=ns). OS also was not different between the arms. The response rate (RECIST) was 41.0% (CR 6.6%, PR 34.4%) for EP and 41.5% (CR 8.5%, PR 33.1%) for XP. The main toxicity was myelosuppression (10% of cycles grade 3/4). Febrile neutropenia was seen in 5 cases in EP and in 1 case in XP. Skin toxicity grade 3 was observed in 5 of XP pts. Two patients stopped treatment for cardiological reasons in EP, and 4 patients for GI reasons in XP. Conclusions: This first analysis shows a comparable efficacy of the non-anthracycline regimen XP to the EP combination in first-line MBC. The toxicity is relatively low compared to other non-anthracycline containing combination therapies. XP is therefore an appropriate option for pts with anthracycline pretreated first line MBC.

[Table: see text]
Insulin resistance, estimated by serum C-peptide level, is associated with reduced event-free survival for postmenopausal women in NCIC CTG MA.14 adjuvant breast cancer trial
Authors: Pollak M. N. , Chapman J. W. , Shepherd L. , Meng D. , Richardson P. , Wilson C. , Orme B. , Pritchard K. I.
Published: March 2020

524

Background: NCIC CTG MA.14 is a randomized multi-centre trial of tamoxifen versus combined tamoxifen and octreotide LAR therapy in the adjuvant treatment of breast cancer in post-menopausal women. Planned secondary analyses included investigation of baseline metabolic factors that might influence survival. Laboratory and clinical studies indicate that insulin resistance is associated with adverse outcome in breast cancer. Insulin resistance elevates C-peptide levels. Methods: In MA.14, trial patients with stage I or II postmenopausal breast cancer were randomized from September, 1996 until July, 2000 to receive 20 mg tamoxifen PO daily for 5 years with/without the administration of the somatostatin analogue Octreotide LAR 90 mg depot injection monthly for 2 years. Event-free survival (EFS), the trial’s primary outcome measure, was defined as time from randomization to time of recurrence of primary disease, time of second malignancy or death due to any cause. We investigated the effect of baseline IGF-I, IGFBP-3, and C-peptide levels on EFS. Kaplan-Meier univariate and Cox step-wise multivariate regressions were performed with/without adjustment for the stratification factors of adjuvant chemotherapy, nodal status, and hormone receptor status, and included patient age (years) and tumour size (T-status). Results: These results are based on analysis of patient serum for the trial’s 667 patients. Median follow-up for those alive is 6.1 years; patients experienced 165 events. Higher C-peptide levels were associated with significantly worse EFS in adjusted, and unadjusted, univariate and multivariate analyses. Final efficacy analyses are expected within a few months. Updated analyses for the effects of baseline metabolic markers and body mass index on EFS will be presented. Conclusions: This is the largest data set, and the first clinical trial, linking higher serum C-peptide levels to adverse outcome in patients with early breast cancer. These results raise concern in the context of increasing population prevalence of insulin resistance. Potential novel adjuvant therapies exist as insulin resistance is modifiable.

[Table: see text]
Multivariate analysis of expression of the microtubule-associated protein, tau, predicts improved progression free and overall survival in patients with metastatic HER-2-negative breast cancers treated with docetaxel and vinorelbine plus filgrastim
Authors: Gown A. M. , Goldstein L. C. , Porter P. L. , Livingston R. B. , Tam S. , Yeh I. , Barlow W. E. , Gralow J. R. , Hayes D. F.
Published: March 2020

543

Background: Drugs that poison the mitotic spindle, including taxanes and vinca alkaloids, are active agents against breast cancer. Preliminary evidence showed that high expression levels of tau predicted improved PFS and OS in patients with metastatic HER-2-negative breast cancers treated with docetaxel and vinorelbine plus filgrastim. We now tested whether levels of tau and another microtubule associated protein, beta-tubulin, could predict PFS and OS in multivariate analysis using other prognostic marker studies, including ER, PR, p53 and Ki-67 on a tissue microarray (TMA) obtained from patients in the SWOG S0102 trial. Materials and Methods: Immunohistochemistry (IHC) using antibodies to tau, beta-tubulin, ER, PR, p53, and Ki-67 was performed on a TMA constructed from the S0102 paraffin blocks. All markers were scored semiquantitatively from 0 to 3. Progression free survival (PFS) and overall survival (OS) were evaluated using multivariate analysis. Results: A total of 38 patients (41.3%) were evaluated. Tau was positively correlated with ER (r=0.36; p=0.0325) and PR (r=0.63; p<0.0001), but not with beta tubulin (p=0.34), Ki-67 (p=0.58), or age (p=0.73). Beta tubulin was not significantly correlated with any other markers. Adjusting for age, there was a significant effect of tau expression on OS (HR=0.667, p= 0.0193) and PFS (HR=0.653; p=0.0035), with higher tau associated with longer survival. When adjusted for both age and PR, there was a marginally significant effect of tau on OS (HR=0.582; p=0.056) and PFS (HR=0.604; p= 0.065). Beta tubulin was not associated with OS (HR=0.909; p=0.66) and PFS (HR=0.904; p=0.58) adjusted for age. Conclusions: In multivariate analysis, identification of breast cancer specimens showing high expression levels of tau predicts improved PFS and OS in patients with metastatic HER-2-negative breast cancers treated with docetaxel and vinorelbine plus filgrastim. High expression of tau also correlated with PR and ER expression. These results confirm and expand earlier studies of the predictive power of tau in a multivariate analysis using a panel of IHC markers for breast cancer.

No significant financial relationships to disclose.
Impact of age on treatment effect in locally advanced head and neck cancer (HNC): Two individual patient data meta-analyses
Authors: Bourhis J. , Le Maı̂tre A. , Pignon J. , Ang K. , Bernier J. , Overgaard J. , Tobias J. , Saunders M. , Adelstein D. , O’Sullivan B.
Published: March 2020

5501

Background: The Meta-Analysis of Radiotherapy in Carcinomas of Head & Neck (MARCH; Bourhis J, ASTRO 2002) showed that altered fractionation radiotherapy (Alt-RT) could improve survival as compared to standard RT in patients with locally advanced HNC (pooled hazard ratio - HR -: 0.92, 95% confidence interval: 0.86–0.97). The Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC; Bourhis J, ASCO 2004) demonstrated that concomitant chemotherapy (CT), added to RT, improved survival (HR: 0.82, 95% CI: 0.78–0.86). This study considers age as a potential modifier of the treatment effect. Methods: 15 randomized trials with 6,515 patients were included in MARCH (median follow up: 6.0 years), and 50 with 9,471 patients in concomitant part of MACH-NC (median follow up: 5.6 years). The interaction between age and treatment effect, using HR of death, was tested with heterogeneity test. Effect of prognostic factors on the interaction was analysed using Cox model. Results: The effect of Alt-RT in MARCH and of concomitant CT in MACH-NC on overall survival decreased with increased age ( table ). Patients aged 71+ had a lower performance status, less advanced stage, and more often laryngeal cancer than the younger patients; there were more women in the oldest patients group. However, adjusting on covariates did not modify the results. Causes of death was available in MARCH and in recent (1994–2000) trials of MACH-NC. The proportion of deaths not due to HNC increased with age, from 18% at age 50 to 41% at age 71+ in MARCH, and from 15% to 39% in MACH-NC. Conclusions: Treatment benefit decreases with increasing age. Patients aged 71+ did not benefit from Alt- RT nor from concomitant CT. The increasing risk of death from other causes with age may explain part of these observations. Supported by PHRC, ARC, LNCC

[Table: see text]

No significant financial relationships to disclose.
EGFr expression and clinical outcome in head and neck cancer patients treated with radiotherapy with or without cetuximab
Authors: Bonner J. A. , Harari P. M. , Giralt J. , Cohen R. B. , Baselga J. M. , Spencer S. A. , Azarnia N. , Rowinsky E. K. , Amellal N. , Ang K. K.
Published: March 2020

5510

Background: Increased expression of epidermal growth factor receptor (EGFr) has been correlated with poor outcome for patients with squamous cell carcinoma of the head and neck (SCCHN). This analysis was performed to examine the prognostic significance of EGFr expression in patients with locoregionally advanced SCCHN treated with radiotherapy (R) with or without cetuximab (C, an IgG1 anti-EGFr monoclonal antibody). Methods: This correlative study was performed on tumor biopsy samples from patients with locoregionally advanced SCCHN who were randomized to R with or without C as previously described (ASTRO Abstract #120, 2005). Immunohistochemistry was utilized to assess the percentage of tumor cells that stained for EGFr (JCO 23:5568, 2005). Kaplan-Meier estimates of locoregional control and survival were derived, and Cox regression was used to adjust for differences in prognostic factors. Results: Tumor specimens were evaluated from 339 of the 424 randomized patients. The median percentage of EGFR-detectable tumor cells (EDTC) was 50%. 183 patients had ≤50% EDTC, whereas 156 patients had >50% EDTC. The addition of C to R resulted in improved locoregional control (LRC, p = 0.005) and survival (p = 0.03) in the overall study. The LRC and survival results are summarized for patients with ≤50% EDTC and patients with >50% EDTC. Medians are measured in months. These findings were not altered after adjusting for imbalances in known prognostic factors of Karnofsky score (90–100 vs. 60–80) and primary site (Oropharynx or Larynx vs. Hypopharynx). Conclusions: A high positive EGFr expression in SCCHN, as determined by current methodology, is not necessary for response to radiotherapy and cetuximab. These results warrant further evaluation.

[Table: see text]

[Table: see text]
Randomized phase II/III clinical trial of induction chemotherapy (ICT) with either cisplatin/5-fluorouracil (PF) or docetaxel/cisplatin/5-fluorouracil (TPF) followed by chemoradiotherapy (CRT) vs. crt alone for patients (pts) with unresectable locally advanced head and neck cancer (LAHNC)
Authors: Hitt R. , Grau J. , Lopez-Pousa A. , Berrocal A. , García-Giron C. , Belon J. , Sastre J. , Martinez-Trufero J. , Cortés-Funes H. , Cruz-Hernandez J.
Published: March 2020

5515

Background: we have previously reported that ICT plus CRT is more active than CRT alone in pts with unresectable LAHNC (Hitt et al: ASCO 2005, abstract 5578). Here we present new data of efficacy and time to progression (TTP) in this trial. Methods: Patients: eligible pts included those with unresectable LAHNC, measurable disease, adequate organ function and ECOG 0–1. Pts were stratified according to primary tumor site. Treatment: Induction chemotherapy regimens (3 cycles): PF : P 100 mg/m2 day (d) 1, then F 1000 mg/m2 c.i. d1–5 q 21d; TPF: T 75 mg/m2 d1, P 75 mg/m2 d1, F 750 mg/m2 c.i. d 1–5 q 21 d plus G-CSF and ciprofloxacin. Chemoradiotherapy: conventional RT up to 70 Gy plus P 100 mg/m2 d 1–22–43 Results: Patients: a total of 310 pts have been accrued. Pts/tumor characteristics (ECOG, age, primary site, T/N stage) were well balanced among the three arms. T/N stage: T3–4 (88%); N2–3 (63%); pharynx-oropharynx site (62%). Treatment: Median number of cycles of ICT: 3; median dose of RT: 70 Gy, median number of cycles of P during RT in three arms: 3. Efficacy: Complete Response: 70% (ICT + CRT) vs. 49% (CRT alone) (p = 0.01). The response rate was similar between TPF and PF. Time to progression (TTP) in months: 16 (TPF + CRT); 12 (PF + CRT) vs 8 (CRT alone) (log-Rank= 0.02). G 3/4 toxicity (NCI criteria): Febrile neutropenia: 21% (TPF); mucositis: 10% (PF). Mucositis was observed in 55% (TPF + CRT), 60% (PF + CRT) and 36% (CRT alone) of the pts, respectively Conclusions: The results of the present randomised clinical trial demonstrate that the combination of ICT + CRT significantly increases the complete response rate and prolongs TTP when compared to CRT alone in patients with unresectable LAHNC.

No significant financial relationships to disclose.
A phase I study of bevacizumab (B) with fluorouracil (F) and hydroxyurea (H) with concomitant radiotherapy (X) (B-FHX) for poor prognosis head and neck cancer (HNC)
Authors: Seiwert T. Y. , Haraf D. J. , Cohen E. E. , Stenson K. , Mauer A. M. , Dekker A. , Bajda C. , Weichselbaum R. R. , Chen H. X. , Vokes E. E.
Published: March 2020

5530

Background: Increased VEGF levels are found in HNC. Preclinical data suggest synergistic antitumor activity of B with radiation and chemotherapy. We conducted a Phase I dose escalation study to determine the maximum tolerated dose and dose limiting toxicity (DLT) of B, when added to infusional 5-FU, Hydroxyurea (HU), and daily radiotherapy administered every other week in patients (pts) with poor prognosis HNC. Methods: Eligible pts had recurrent, or newly diagnosed HNC with high risk of recurrence, ± metastatic disease requiring local control, ECOG PS ≤2, and life expectancy >12 weeks. Two week cycles were repeated 6–7 times (see table ). Results: 43 pts were treated (34 completed). DLT was reached at level 3 with 2 pts having gr 3 transaminase elevations and one pt gr 4 neutropenia. Treatment of 7 (6 evaluable) pts on level 4 resulted in one DLT (SMV thrombosis) and this dose level was chosen for expanded evaluation. In all level 4 pts (N = 27) gr 3 mucositis occured in 73.1% and gr 3 hand-foot syndrome in 15.4%. Additional gr 3 or worse toxicities in the expanded level 4 included: esophageal bleed (tumor bed, grade 5), stroke (grade 4), carotid rupture (3 wks post RT, grade 5), and neck ulceration with need for carotid stent (3 months post RT, grade 4). One sudden death of unclear etiology occurred. Median overall survival is 389 days. One/two year survival is 52.1/26%. Median survival for patients treated with re-irradiation for recurrent, non-metastatic HNC is 314 days; one/two year survival is 45.9/17.2%. With a median follow-up of 317 days 13 patients are still alive (12 are cancer free). Conclusions: B can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m2 every 2 weeks. While B related toxicities are seen, there appears to be no major synergistic toxicity. Long term activity is observed in this very high risk patient population. A randomized phase II trial of FHX with or without B in a lower risk population is ongoing.

[Table: see text]

No significant financial relationships to disclose.
Vitamin D deficiency: A threat to bone health in breast cancer patients during adjuvant treatment with aromatase inhibitors
Authors: Lonning P. , Geisler J. , Krag L. E. , Løkkevik E. , Risberg T. , Hagen A. I. , Schlichting E. , Eide G. E. , Di Salle E.
Published: March 2020

554

Background: To evaluate potential detrimental effects of the aromatase inactivator exemestane on bone, 147 postmenopausal women with early breast cancer were randomised to receive either exemestane for 2 years or placebo (J. Clin. Oncol. 23 [22], 5126–5137, 2005). Exemestane increased the annual bone loss from the femoral neck (2.72%) compared to placebo (1.48%; P = 0.024) with a non-significant increase in the lumbar spine (exemestane 2.17% versus placebo 1.84%). The annual bone loss was higher than expected in the placebo arm. Methods: Various biomarkers involved in bone metabolism (25-hydroxyvitamin D, parathormone, calcium, estrogens, androgens) were analysed to elucidate their influence on bone status at baseline and BMD loss during treatment with exemestane compared to placebo. Results: Using a cut-off value of 30 ng/ml for 25-hydroxyvitamin D (J. Clin. Endocrinol. Metab. 90 [6], 3800–3801, 2005), the majority of study participants suffered from vitamin D deficiency (56 of 62 patients in the placebo group and 52 of 59 in the exemestane group). The mean levels (95% confidence interval) of vitamin D were 22.6 ng/ml (21.2 - 24.1) in the placebo group and 21.6 ng/ml (20.0 - 23.3) in the treatment group, revealing no differences between these groups. Low serum calcium levels at baseline were found to be significantly correlated to low BMD in the femoral neck in the exemestane group. However, individual levels of vitamin D, parathormone and estradiol at baseline were not correlated significantly to BMD. Conclusions: Considering an annual bone loss of 0.5% to be representative for postmenopausal women (Osteoporos. Int. 15, 881–886, 2004), our data indicate that vitamin D deficiency could be the most important factor elevating bone loss among patients treated with exemestane as well as in the placebo group. These findings, together with the observation of a moderate additional effect of exemestane on bone loss, underlines the need for proper vitamin D substitution of postmenopausal women in general and in breast cancer patients during treatment with aromatase inhibitors in particular.

[Table: see text]
Accelerated fractionated radiation by concomitant boost (AFX-CB) with concurrent cis-platinum (CDDP) for advanced nasopharyngeal carcinoma
Authors: Choi W. , Huang H. , Sachdeva G. , Culliney B. , Malamud S. , Blum R. , Schantz S. , Li J. , Nishihori T. , Chow  , Harrison L. B. , Hu K.
Published: March 2020

5540

Background: Recent data (RTOG 90–03 and RTOG 99–14) strongly suggest that concomitant boost radiation (AFX-CB) and concurrent chemoradiation offer a local control advantage in advanced head and neck cancer patients. Based on our previous experience treating unresectable head and neck cancer, we initiated a phase II trial delivering CDDP concurrent with AFX-CB for advanced nasopharyngeal carcinoma (NPC). Methods: From 2/99–7/05, 44 patients with newly diagnosed stage IIa-IV NPC were treated with AFX-CB to 70Gy/6 weeks (BID RT last 2 weeks with a 3D-conformal plan, 6 hr interfraction interval) with 2–3 cycles of concurrent CDDP (100mg/m2) on day 1, 22, 43 of radiation followed by adjuvant 5-Fluorouracil/CDDP. The median age was 46 (24 to 83) and 20 patients were male. Disease characteristics were as follows: 1997 AJCC stage: II-7; III-14 and IV-23, T3/T4 66%, N2/N3 55%. Results: With a median follow-up of 30 mo. (3–78 mo.), the crude local control rate (LC) was 93%, regional control (RC) was 98%, locoregional control (LRC) 91%, freedom from distant metastasis (FFDM) was 86%, disease-free survival (DFS) was 82%, and overall survival (OS) was 89%. Eighty-six percent of patients were able to receive 2–3 cycles of adjuvant chemotherapy. Four of the 6 distant metastases occurred after 3 years post-treatment. One of the 3 local failures was salvaged with additional chemoradiation and is without evidence of recurrence 23 months later. Thus, the total crude local control is 95%. Among 29 T3/T4 patients, local control was 93%. For all patients, the three year actuarial LC, RC, LRC, FFDM, DFS and OS were 95%, 98%, 93%, 94%, 86% and 87%, respectively. Major grade 3 acute toxicities include mucositis (59%), dysphagia (41%), vomiting (20%) and anemia (4.5%). Average hemoglobin drop was 2.3 gm (17.7%). Ninety percent of patients received erythropoietin support and near 20% required blood transfusion. Late toxicities included grade 3 tinnitus in 1, grade 2 serous otitis in 1, osteoradionecrosis in 1 and brain necrosis in 2. Conclusions: AFX-CB with concurrent and adjuvant chemotherapy for advanced NPC provides excellent locoregional control and acceptable toxicity. Future efforts will focus on decreasing toxicity and increasing systemic control.

No significant financial relationships to disclose.
A pilot phase II study of consolidation chemotherapy with docetaxel and cisplatin following concurrent chemoradiotherapy (CCRT) for locoregionally advanced head and neck squamous cell carcinoma (HNSCC)
Authors: Lee Y. , Lee S. , Lee K. , Park S. , Cho E. , Shin D.
Published: March 2020

5549

Background: With the improvement seen with CCRT in the management of locoregionally advanced HNSCC, distant failures have become a more relevant problem in terms of survival. As a consequence, more effective strategies including consolidation chemotherapy are warranted. The primary objective of this pilot phase II study was to assess the feasibility and efficacy of docetaxel and cisplatin consolidation following primary CCRT for HNSCC. Methods: Thirty-three patients with previously untreated, stage III/IV HNSCC participated in this study. CCRT consisted of cisplatin 100 mg/m2 on day 1, 22 and 43. Concurrent radiotherapy (70 Gy) to the primary tumor and neck was performed over a period of 7 weeks. After completion of CCRT, patients with no evidence of disease progression received an additional 4 cycles of consolidation chemotherapy with docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks. To minimize the expected accrual into unacceptable treatment, either in terms of clinical response or toxicity, a total of 35 patients would be required in a two-stage design. Results: Baseline characteristics were: male (22), median age (60 years), ECOG performance status 0/1 (15/18), stage III/IV (10/23). Of these, 27 (81%) patients completed CCRT. After CCRT, 3 complete and 19 partial responses were recorded, giving an overall response rate of 67% (95% CI, 51–83%). Of the 19 patients who went to consolidation phase, only 4 (21%) completed all 4 cycles of docetaxel and cisplatin. Failure to consolidation chemotherapy was attributed to the following causes: toxicity (11 including 3 treatment-related deaths), disease progression (4). During consolidation chemotherapy, 13 patients (68%) had grade 3/4 neutropenia and febrile neutropenia occurred in 6 (32%). With consolidation chemotherapy, one patient with initial stable disease achieved a partial response. Median survival in all patients was 11.0 months, and 8.3 months for those treated with consolidation chemotherapy. Conclusions: The poor compliance and the high incidence of severe toxicities, including 3 treatment-related deaths, prompted no further evaluation of this consolidation chemotherapy following CCRT.

No significant financial relationships to disclose.
Quality of life assessment in patients above 60, below 50 years of age during and after curative radiotherapy in head and neck cancers
Authors: Turaka A. , Mohanti B. K. , Chander S. , Deo S. V. , Jena R. , Rath G. K.
Published: March 2020

5552

Background: To evaluate the Quality of life in patients above 60 and below 50 years during and after curative radiotherapy in head and neck cancers. Methods: Head and Neck cancer patients who are to undergo curative radiotherapy (RT) were divided into two groups, 49 patients (Group A,above 60 years) and 40 patients (Group B,below 50). Quality of life assessment was done using EORTC QLQ C-30 version-2 at 4 phases;Pretreatment-Phase I,during RT-Phase II,1-month post RT-Phase III and 6 months post RT-Phase IV.Statistical analysis was done with mean scores using ’t’ test. Results: Physical functioning (PF)scores in both groups were highest in phase I (69.4;77.5, p < 0.035) and lowest in phase II (40; 50, p < 0.008) and the difference was statistically significant. Although PF scores declined in both groups in phase II, overall PF score remained higher in group B than in group A in all phases.Role functioning score remained low in both groups and the difference were not statistically significant at all phases. Emotional functioning score was highest in phase I (68.37; 69.15), but declined as treatment progressed, consequent to depression.The values improved over time, restored to near pretreatment values at phase IV. Cognitive functioning scores in both groups was also highest in phase I (70.07; 79.17). Social functioning of both groups declined during RT (42.52; 45)compared to pre RT values (73.47; 77.09). The mean Global Health Status score was higher in group B compared to group A at all phases, yet there was no statistical significance.The scores declined during RT (66.87 vs 35.62 & 64.79 vs 34.01), improved overtime but did not reach pre RT scores.The symptom scores were all higher for elderly patients compared with younger patients at all phases, implying elderly patients experienced more symptoms, with greater experience of symptoms during RT. Conclusions: Quality of Life of elderly patients was lower compared to younger patients at phase II in terms of physical functioning, social and emotional functioning. Global Health Status score was higher for younger patients than elderly at all phases, and declined in phase II.

No significant financial relationships to disclose.
Performance and side effect evaluation of sequentially reduced radiotherapy doses in a phase II trial of induction chemotherapy (IndCT) followed by concomitant chemoradiotherapy (CTX) for advanced head and neck cancer (HNC)
Authors: List M. A. , Vokes E. E. , Cohen E. W. , Stenson K. M. , Karrison T. , Bruce B. E. , Witt M. , Haraf D. J.
Published: March 2020

5558

Background: CTX regimens are often limited by severe acute toxicities and long-term functional impairment. This paper presents patient (pt) reported side effects and performance outcome in 3 sequential groups of stage IV HNC pts treated at the University of Chicago with IndCT and lowering radiation doses with the goal of maintaining survival while minimizing negative sequelae. Methods: Pts. were treated with IndCT followed by alternating weeks of concurrent CTX with lowering doses of radiotherapy to gross disease/ high risk microscopic/low risk microscopic disease: Group A - 75/60/45 Gy (n = 36 pts); Group B - 75/54/39 Gy (n = 34 pts); Group C - 72/51/36 Gy (n = 60 pts), respectively (treatment details & survival analyses presented separately). Pts were assessed for quality of life, performance (Performance Status Scale for HNC) and side effects (Radiotherapy Questionnaire) pretreatment, during CTX, at 3 & 12 months and annually thereafter. Controlling for baseline scores, differences between the groups were examined on- treatment and at 12-months. Results: Baseline and 12-month data were available for 81/114 pts. While all pts declined in performance (e.g., diet) and reported increased side effects (e.g., dry mouth, mouth pain, swallowing problems) on CTX, there were no statistically significant differences based on radiation dose. Similarly, there was improvement in most symptoms by 12 months with little difference among groups. In contrast, on normalcy of diet, fewer patients in Group C (20%) showed declines of more than 20 points from baseline compared to A (46%; p = .085) and B (45%, p = .09). Overall, 4% of patients were unable to take anything orally at 12-months with no difference among groups. Conclusions: This study showed no differences in pt reported symptoms on-treatment or at 12-months based on lowered radiation doses during CXT. On the other hand, while there continued to be some restriction in long-term diet, pts in the lowest radiation dose group showed somewhat less decline from baseline. These findings suggest the continued need to explore ways of decreasing both acute and long term toxicities in the use of CTX regimens.

[Table: see text]
Intensity-modulated radiation therapy for head and neck cancer of unknown primary
Authors: Klem M. L. , Wolden S. L. , Zelefsky M. J. , Su Y. B. , Singh B. , Kraus D. , Shaha A. , Shah J. , Pfister D. G. , Lee N.
Published: March 2020

5565

Background: Unknown primary head and neck cancers often require comprehensive mucosal and bilateral neck irradiation. With conventional techniques, significant toxicity can develop. Intensity modulated radiation therapy (IMRT) has the potential to minimize toxicity. Methods: From 2000–2005, 21 patients received IMRT for unknown primary head and neck cancer at our center. Median age was 57. Clinical stages were: TxN1: 43%; TxN2b:38%; TxN2c:5%; TxN3:14%. Five patients received IMRT with primary intent and 16 as postoperative therapy. Fourteen received concurrent chemotherapy, most with cisplatin (100mg/m2/cycle) or carboplatin (70mg/m2)/ 5FU (600mg/m2) every 3 weeks for 2–3 cycles. Seven received IMRT alone. Median dose was 66 Gy. PEG tube was placed in 13 patients. Toxicities were evaluated. Regional progression free survival (RPFS), distant metastases free survival (DMFS) and overall survival (OS) were calculated with Kaplan Meier curves. Results: Grade 1 and 2 xerostomia was seen in 57% and 43%. Salivary function improved with time. By 6 months, no patient had greater than grade 1 xerostomia. Grade 1, 2, and 3 acute skin toxicity and mucositis were seen in 67%, 29%, 5% and in 33%, 52%, 14%, respectively. PEG tube was required in 72% who had combined modality and 43% with IMRT alone. Of the 13 with PEG tubes, only 3 required PEG support at the time of last follow up. For those who had PEG removed, median time with PEG was 3.8 months from the end of RT. Two patients treated with combined modality and 1 treated with IMRT alone developed esophageal strictures, but all had improvement or resolution with dilation. Two patients had persistent disease after RT and 1 had late regional failure at 39 months. Two patients developed distant metastases and died. With a median follow up of 14.3 months (5.4–73.4), 2 year RPFS, DMFS, and OS were 88.9%, 89.4%, and 84.0%. Conclusions: Preliminary analysis of IMRT for unknown primary head and neck cancer shows acceptable toxicity and encouraging efficacy. Xerostomia was a common acute complication but patients had marked improvement by 6 months. Esophageal strictures were seen but effectively treated with dilation. Techniques to limit esophageal dose may help further minimize this complication.

No significant financial relationships to disclose.
A phase II trial of PS-341 (bortezomib) followed by the addition of doxorubicin at progression in incurable adenoid cystic carcinoma of the head and neck: An Eastern Cooperative Oncology Group study
Authors: Argiris A. , Goldwasser M. A. , Burtness B. , Deconti R. , Axelrod R. , Van Waes C. , Forastiere A.
Published: March 2020

5573

Background: Adenoid cystic carcinoma (ACC) is usually resistant to chemotherapy. Bortezomib (B) is a highly selective inhibitor of the 26S proteasome which is central for the ubiquitin-proteasome degradation pathway. Inhibition of NF-κB activity achieved by B may be important for inhibition of the growth of ACC. Preclinical studies have shown synergy between B and doxorubicin (D). Methods: Eligibility criteria included incurable ACC, any number of prior therapies but without an anthracycline, unidimensionally measurable disease, ECOG performance status 0–2, ejection fraction within normal limits (WNL), absolute neutrophil count >1500/μL, platelets >100,000/μL, and total bilirubin WNL. Patients (pts) with stable disease (SD) for 9 months or more were excluded. Pts received B 1.3 mg/m2 IV push on days 1,4,8, and 11, every 21 days, until progression. Doxorubicin 20 mg/m2 IV on days 1 and 8 was added at the time of progression. Response assessment was performed after every 2 cycles using RECIST. Immunohistochemistry for biomarkers affected by the ubiquitin-proteasome pathway on baseline tumor and measurement of serum inflammatory and angiogenic cytokines before and in response to therapy were performed. Results: 25 pts were enrolled; 18 were females; median age was 56 years (26–73); distant metastatic sites: lung (21), liver (4), bone (2). Best response to single-agent B: 16 pts (64%) had SD, 7 progressed, and 2 were unevaluable (1 with symptomatic deterioration). The median progression-free survival was 8.5 months. In 4 evaluable pts who received B plus D, 1 partial response and 2 SD were observed. 1 pt died 7 months after starting treatment without documented progression. Worst grade (G) 3/4 toxicities with B alone in 22 evaluable pts were: G3 neutropenia 5%, G4 neutropenia 5%, G3 thrombocytopenia 5%, G3 sensory neuropathy 14%; G3 generalized weakness 5%, G3 fatigue 9%, G3 anorexia 5%, G3 diarrhea 5%, G3 hyponatremia 5%, G3 dyspnea 5%. Conclusions: B was well tolerated and resulted in disease stabilization in a high percentage of pts but no objective responses. Updated response data with the addition of D will be available.

No significant financial relationships to disclose.
Acute myeloid leukemia (AML) in older women after adjuvant breast cancer therapy
Authors: Patt D. A. , Duan Z. , Hortobagyi G. , Giordano S. H.
Published: March 2020

560

Background: Adjuvant chemotherapy for breast cancer is associated with the development of secondary AML, but this risk in an older population has not been previously quantified. Methods: We queried data from the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database for women who were diagnosed with nonmetastatic breast cancer from 1992–1999. We compared the risk of AML in patients with and without adjuvant chemotherapy (C), and by differing C regimens. The primary endpoint was a claim with an inpatient or outpatient diagnosis of AML (ICD-09 codes 205–208). Risk of AML was estimated using the method of Kaplan-Meier. Cox proportional hazards models were used to determine factors independently associated with AML. Results: 36,904 patients were included in this observational study, 4,572 who had received adjuvant C and 32,332 who had not. The median patient age was 75.3 (66.0–103.3). The median follow up was 63 months (13–132). Patients who received C were significantly younger, had more advanced stage disease, and had lower comorbidity scores (p<0.001). The unadjusted risk of developing AML at 10 years after any adjuvant C for breast cancer was 1.6% versus 1.1% for women who had not received C. The adjusted HR for AML with adjuvant C was 1.72 (1.16–2.54) compared to women who did not receive C. HR for radiation was 1.21 (0.86–1.70). HR was higher with increasing age but p>0.05. An analysis was performed among women who received C. When compared to other C regimens, anthracycline-based therapy (A) conveyed a significantly higher hazard for AML HR 2.17 (1.08–4.38), while patients who received A plus taxanes (T) did not have a significant increase in risk HR1.29 (0.44–3.82) nor did patients who received T with some other C HR 1.50 (0.34–6.67). Another significant independent predictor of AML included GCSF use HR 2.21 (1.14–4.25). In addition, increasing A dose was associated with higher risk of AML (p<0.05). Conclusions: There is a small but real increase in AML after adjuvant chemotherapy for breast cancer in older women. The risk appears to be highest from A-based regimens, most of which also contained cyclophosphamide, and may be dose-dependent. T do not appear to increase risk. The role of GCSF should be further explored.

No significant financial relationships to disclose.
Effect of treatment with sunitinib malate, a multitargeted tyrosine kinase inhibitor, on circulating plasma levels of VEGF, soluble VEGF receptors 2 and 3, and soluble KIT in patients with metastatic breast cancer
Authors: Deprimo S. E. , Friece C. , Huang X. , Smeraglia J. , Sherman L. , Collier M. , Baum C. , Elias A. D. , Burstein H. J. , Miller K. D.
Published: March 2020

578

Background: Sunitinib malate (SU11248) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity that specifically inhibits VEGFR, PDGFR, KIT, RET and FLT3. In a phase II trial of 64 patients with refractory, metastatic breast cancer, sunitinib treatment resulted in an ∼11% objective response rate (Miller et al, ASCO 2005). To characterize potential biomarkers of biological response to sunitinib, we analyzed plasma levels of a panel of soluble proteins from patients in this trial. Methods: Patients received sunitinib in 6-week cycles comprised of 50 mg/day for 4 weeks followed by 2 weeks off treatment. Pre-dose plasma samples from 62 patients were obtained on days 1, 14, and 28 of the first cycle and days 1 and 28 of subsequent cycles. Plasma levels of VEGF, soluble VEGF receptor 2 (sVEGFR-2), soluble KIT (sKIT), and a novel biomarker, sVEGFR-3, were measured via ELISA analysis. Results: Plasma levels of each protein were modulated in most patients during the course of treatment. At the end of the first cycle, VEGF levels were increased more than 3-fold relative to baseline in 73% of cases, while sVEGFR-2 levels decreased by at least 30% in 88% of cases, and by >20% in all but 4 cases. In addition, levels of sVEGFR-3 were decreased by >30% in 82% of cases during the first cycle. For each of these markers, levels tended to return to near-baseline after 2 weeks off treatment. Longitudinal decreases in sKIT were also observed; decreases >50% by the end of cycle 2 were correlated with treatment outcomes for time-to-progression (P < 0.001) and survival (P = 0.03). Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: Sunitinib therapy is associated with increases in plasma VEGF and decreases in soluble VEGFRs and KIT. This panel of circulating proteins may have utility as pharmacodynamic biomarkers of sunitinib activity in patients with metastatic breast cancer. sVEGFR-3 may be a novel biomarker of the biological activity of sunitinib, while sKIT may be correlated with clinical response. Analysis of these and other biomarkers in larger studies of sunitinib in breast cancer may be warranted.

[Table: see text]