bluuebunny/crossref_metadata_2025 huggingface dataset:
Adult Burkitt's and Burkitt-like non-Hodgkin's lymphoma--outcome for patients treated with high-dose therapy and autologous stem-cell transplantation in first remission or at relapse: results from the European Group for Blood and Marrow Transplantation.
Authors: Sweetenham J W , Pearce R , Taghipour G , Blaise D , Gisselbrecht C , Goldstone A H
Published: February 2017

PURPOSE

To investigate the results of treatment for adult patients with Burkitt's and Burkitt-like non-Hodgkin's lymphoma (NHL) undergoing high-dose therapy and autologous stem-cell transplantation (ASCT), and to determine prognostic factors for this group.

PATIENTS AND METHODS

A retrospective analysis of 117 adult patients reported to the lymphoma registry of the European Group for Blood and Marrow Transplantation (EBMT) between June 1984 and November 1994. Seventy of these patients received high-dose therapy and stem-cell transplantation in first complete remission (CR). Data on all patients were reviewed, and prognostic factors were determined by univariate and multivariate analysis.

RESULTS

The actuarial overall survival (OS) rate for the entire group was 53% at 3 years. The major factor predicting for outcome after transplantation was disease status: the 3-year actuarial OS rate was 72% for patients transplanted in first CR, compared with 37% for patients in chemosensitive relapse, and 7% for chemoresistant patients. For patients transplanted in first CR, disease bulk at the time of ASCT was the only factor predictive of progression-free survival (PFS) and OS.

CONCLUSION

The results of high-dose therapy and ASCT for patients with relapsed disease, particularly chemosensitive relapse, are superior to those reported for conventional-dose salvage regimens. The results for patients transplanted in first CR require comparison with modern dose-intensive regimens.
Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. The Children's Cancer Group.
Authors: Finlay J L , Goldman S , Wong M C , Cairo M , Garvin J , August C , Cohen B H , Stanley P , Zimmerman R A , Bostrom B , Geyer J R , Harris R E , Sanders J , Yates A J , Boyett J M , Packer R J
Published: February 2017

PURPOSE

This study was designed to determine the toxicity, radiographic response rate, and outcome following high-dose thiotepa, etoposide, and autologous bone marrow rescue (ABMR) for young patients with recurrent malignant brain tumors.

METHODS

Eligibility criteria required adequate renal, hepatic, and pulmonary function, and no bone marrow infiltration. Thiotepa 300 mg/m2 and etoposide 500 mg/ m2 were infused on 3 consecutive days, and autologous bone marrow was infused 72 hours following chemotherapy.

RESULTS

Forty-five patients with recurrent high-grade brain tumors, aged 8 months to 36 years (median, 8 years), were treated. Seven patients (16%) died of treatment-related toxicities within 56 days of marrow reinfusion. Delayed platelet engraftment occurred in 44% of patients who survived beyond day 56. Of 35 patients with radiographically measurable disease who survived at least 28 days following ABMR, there were two complete responses (CRs) and six partial responses (PRs), for an overall response (CRs plus PRs) rate of 23% (SE = 7%). Objective responses were observed in four of 14 assessable patients with high-grade glioma and in two of six with primitive neuroectodermal tumors (PNETs)/ medulloblastoma. Survival was significantly improved in patients treated with minimal residual disease (P < .0005). Five of 18 patients (28%) with high-grade gliomas remain free of disease at 39+, 44+, 49+, 52+, and 59+ months post-ABMR.

CONCLUSION

The combination of high-dose thiotepa and etoposide has activity against a variety of recurrent childhood brain tumors. These results merit further evaluation in children and young adults with both recurrent and newly diagnosed high-grade brain tumors.
Use of hematopoietic colony-stimulating factors: the American Society of Clinical Oncology survey. The Health Services Research Committee of the American Society of Clinical Oncology.
Authors: Bennett C L , Smith T J , Weeks J C , Bredt A B , Feinglass J , Fetting J H , Hillner B E , Somerfield M R , Winn R J
Published: February 2017

PURPOSE

Dissemination of use of the hematopoietic colony-stimulating factors (CSFs) is unprecedented in oncology, with almost all physicians having experience with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) shortly after the drugs received Food and Drug Administration (FDA) approval in 1991. The American Society of Clinical Oncology (ASCO) Health Services Research Committee sought to assess patterns of use of CSFs before dissemination of its first-ever publication of ASCO guidelines.

METHODS

A questionnaire describing clinical scenarios was mailed to American oncologists and hematologists who practice medical oncology. In each scenario, the physician was asked whether he would prefer to use a CSF to prevent or treat neutropenia.

RESULTS

The response rate to the mailed survey was 49% (N = 475). Most physicians preferred to use CSFs for secondary prophylaxis in patients receiving chemotherapy at rates of 44% to 85%, rather than reduce doses. Patterns of use did not differ for palliative, curative, or adjuvant chemotherapy. While the majority of CSF patterns of care were similar to those recommended in the ASCO guidelines, more than half of the physicians chose to use CSFs in the treatment of febrile neutropenia, an area not supported in the subsequent guidelines. In general, physicians at academic medical centers and in Health Maintenance Organization (HMO) practices were more likely to prefer dose-reduction strategies over addition of CSFs, while fee-for-service physicians preferred the opposite strategies.

CONCLUSION

Variations in CSF preferences for use were related to differences in clinical characteristics (history of afebrile v febrile neutropenia), drug characteristics (G-CSF or GM-CSF), and physician practice characteristics (HMO or fee-for-service setting). However, before dissemination of the guidelines, the majority of American oncologists preferred strategies that were subsequently included in the ASCO CSF guidelines. CSF guidelines would be most likely to reduce CSF use for treatment of afebrile and uncomplicated febrile neutropenia.
Phase I trial of recombinant fusion protein PIXY321 for mobilization of peripheral-blood cells.
Authors: Bishop M R , Jackson J D , O'Kane-Murphy B , Schmit-Pokorny K , Vose J M , Bierman P J , Warkentin P I , Armitage J O , Garrison L , Kessinger A
Published: February 2017

PURPOSE

Mobilization of peripheral-blood cells (PBC) with cytokines alone results in rapid hematopoietic recovery and avoids the potential morbidity associated with mobilization by chemotherapy. PIXY321, a fusion protein that consists of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), has enhanced hematopoietic colony-forming activity as compared with individual or equimolar combinations of the two cytokines. A phase I trial of PIXY321 for mobilization of PBC in patients with malignant lymphoma was performed.

PATIENTS AND METHODS

Thirteen patients with malignant lymphoma who were eligible for high-dose therapy (HDT) were enrolled onto the trial. All patients were ineligible for autologous bone marrow transplantation due to overt metastatic disease in the marrow or to severe marrow hypocellularity. PIXY321 was administered at three dose levels of 250, 500, and 750 micrograms/m2/d by continuous infusion until completion of PBC collections. Collections were initiated when the WBC count was greater than 10 x 10(9)/L or 4 days after the initiation of PIXY321, whichever came first. Collections were continued until a minimum of 6.5 x 10(8) mononuclear cells (MNC)/kg patient weight were obtained.

RESULTS

PIXY321 was generally well tolerated. Side effects associated with PIXY321 administration did not exceed grade 2 and included fever (85%), chills/sweats (54%), myalgias (38%), fatigue (31%), nausea/vomiting (31%), headache (31%), edema (23%), and rhinorrhea (23%). The median numbers of colony-forming units-granulocyte/macrophage (CFU-GM) in the graft products for the three dose levels were 0.31, 2.94, and 2.88 x 10(4)/kg, respectively; the median numbers of burst-forming units-erythroid (BFU-e) were 0.20, 6.94, and 12.78 x 10(4)/kg, and the median numbers of CD34+ cells were 2.30, 0.74, and 0.39 x 10(6)/kg. Following transplantation, the median times to an absolute neutrophil count (ANC) > 0.5 x 10(9)/L were 12, 15, and 12 days, respectively, and the median times to platelet transfusion independence were 30, 19, and 15 days.

CONCLUSION

PIXY321 can be safely administered and effectively mobilizes PBC in patients with bone marrow defects. PIXY321-mobilized PBC autotransplants result in rapid and sustained hematopoietic recovery.
Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.
Authors: Flam M , John M , Pajak T F , Petrelli N , Myerson R , Doggett S , Quivey J , Rotman M , Kerman H , Coia L , Murray K
Published: February 2017

PURPOSE

Definitive chemoradiation (CR) has replaced radical surgery as the preferred treatment of epidermoid carcinoma of the anal canal. To determine the importance of mitomycin (MMC) in the standard CR regimen and to assess the role of salvage CR in patients who have residual tumor following CR, a phase III randomized trial was undertaken by the Radiation Therapy Oncology Group (RTOG)/Eastern Cooperative Oncology Group (ECOG).

PATIENTS AND METHODS

Between August 1988 and December 1991, 310 patients were randomized to receive either radiotherapy (RT) and fluorouracil (5-FU) or radiotherapy, 5-FU, and MMC. Of 291 assessable patients, 145 received 45 to 50.4 Gy of pelvic RT plus 5-FU at 1,000 mg/m2/d for 4 days, and 146 received RT, 5-FU, and MMC (10 mg/m2 per dose for two doses). Patients with residual tumor on posttreatment biopsy were treated with a salvage regimen that consisted of additional pelvic RT (9 Gy), 5-FU, and cisplatin (100 mg/m2).

RESULTS

Posttreatment biopsies were positive in 15% of patients in the 5-FU arm versus 7.7% in the MMC arm (P = .135). At 4 years, colostomy rates were lower (9% v 22%; P = .002), colostomy-free survival higher (71% v 59%; P = .014), and disease-free survival higher (73% v 51%; P = .0003) in the MMC arm. A significant difference in overall survival has not been observed at 4 years. Toxicity was greater in the MMC arm (23% v 7% grade 4 and 5 toxicity; P < or = .001). Of 24 assessable patients who underwent salvage CR, 12 (50%) were rendered disease-free.

CONCLUSION

Despite greater toxicity, the use of MMC in a definitive CR regimen for anal cancer is justified, particularly in patients with large primary tumors. Salvage CR should be attempted in patients with residual disease following definitive CR before resorting to radical surgery.
Similar breast cancer cell contamination of single-day peripheral-blood progenitor-cell collections obtained after priming with hematopoietic growth factor alone or after cyclophosphamide followed by growth factor.
Authors: Passos-Coelho J L , Ross A A , Kahn D J , Moss T J , Davis J M , Huelskamp A M , Noga S J , Davidson N E , Kennedy M J
Published: February 2017

PURPOSE

To evaluate tumor-cell contamination of peripheral-blood progenitor-cell (PBPC) collections obtained after priming with granulocyte colony-stimulating factor (G-CSF).

PATIENTS AND METHODS

Immunocytochemical (ICC) and tumor clonogenic (TCA) assays were used to analyze tumor-cell contamination of pretreatment peripheral-blood (PB) and bone marrow (BM) samples, and of PBPC collection samples obtained after priming with G-CSF 5 micrograms/kg/d for 5 or 7 days in 38 women with advanced breast cancer undergoing high-dose chemotherapy (HDC). Results were compared with 37 historical control patients who underwent PBPC mobilization with cyclophosphamide (4 g/m2) followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 micrograms/kg/d for 14 days.

RESULTS

Before PBPC priming with G-CSF, only one of 37 (3%) PB and four of 36 (11%) BM samples had tumor cells detected by ICC. Tumor-cell contamination of PBPC collections obtained after 5 or 7 days of G-CSF priming was observed in only three of 38 patients (8%). All patients with tumor cells detected in the PBPC collection had stage IV disease. Cells with in vitro clonogenic potential were detected only in the pretreatment BM sample in one patient, and another two patients had ICC- and TCA-positive PBPC samples despite tumor-negative PB and BM before priming. These results are similar to those previously reported for PBPC primed with cyclophosphamide and GM-CSF.

CONCLUSION

In patients with advanced breast cancer responsive to cytotoxic chemotherapy, tumor-cell contamination is not increased in PBPC collected after 5 or 7 days priming with G-CSF and appears similar to that seen when PBPC are primed with cyclophosphamide followed by GM-CSF.
Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy.
Authors: Kuukasjärvi T , Kononen J , Helin H , Holli K , Isola J
Published: February 2017

PURPOSE

Up to 30% to 40% of metastases from hormone receptor-positive primary breast cancer do not respond to endocrine therapy. We studied how often hormone receptor status changes between primary and recurrent tumors and whether such a change might explain unresponsiveness to endocrine therapy.

PATIENTS AND METHODS

Primary breast cancer samples and matched asynchronous recurrences were studied from 50 patients who had not received any adjuvant therapy. Estrogen receptor (ER) and progesterone receptor (PR) status was determined immunohistochemically from histologically representative formalin-fixed paraffin-embedded tumor samples. ER status was ascertained by mRNA in situ hybridization.

RESULTS

Thirty-five (70%) of 50 primary tumors were positive for ER and 30 (60%) for PR. Hormone receptor status of the recurrent tumor differed from that of the primary tumor in 18 cases (36%). Discordant cases were due to the loss of ER (n = 6), loss of PR (n = 6), or loss of both receptors (n = 6). Receptor-negative primary tumors were always accompanied by receptor-negative recurrences. Among 27 patients with ER-positive primary tumors, loss of ER was a significant predictor (P = .0085) of poor response to subsequent endocrine therapy. Only one of eight patients (12.5%) with lost ER expression responded to tamoxifen therapy, whereas the response rate was 74% (14 of 19) for patients whose recurrent tumors retained ER expression.

CONCLUSION

Loss of ER expression in recurrent breast cancer should be considered as a cause for poor response to endocrine therapy in primarily ER-positive patients. We conclude that analysis of recurrent tumor samples may improve the predictive value of ER and PR assays.
Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial
Authors: O'Shaughnessy J. , Osborne C. , Pippen J. , Yoffe M. , Patt D. , Monaghan G. , Rocha C. , Ossovskaya V. , Sherman B. , Bradley C.
Published: February 2017

3

Background: TNBC is an aggressive breast cancer subtype that shares molecular and pathologic features with BRCA1-related breast cancers. BRCA-deficient cells are sensitive to inhibition of PARP1, a critical enzyme of cell proliferation and DNA repair, and thus represent a rational target of PARP inhibitor-based cancer therapy. The objectives of this study were to evaluate BSI-201, a potent PARP1 inhibitor, in combination with gemcitabine/carboplatin (G/C) in subjects with metastatic TNBC. Methods: Eligible subjects had measurable disease and had ≤2 prior cytotoxic regimens for ER-, PR-, and HER2-negative metastatic breast cancer. Patients were randomized (1:1) to G/C alone or G/C + BSI-201. Gemcitabine (1000 mg/m2) and carboplatin (AUC=2) were given on days 1 and 8, and BSI-201 (5.6 mg/kg; iv; biweekly) on days 1, 4, 8, and 11 every 21 days. Endpoints were clinical benefit rate (CBR = CR + PR + SD ≥6 months), progression-free survival (PFS) and overall survival (OS). Results: Analyses of the first 86 of a planned 120 patients showed that BSI-201 + G/C had improved CBR, median PFS, and median OS, compared with G/C alone. The frequency and nature of adverse events (AEs) did not differ between arms. Conclusions: This preliminary analysis demonstrates that BSI-201 + G/C significantly improves CBR, PFS, and OS, compared with G/C alone. BSI-201 + G/C was well tolerated, with BSI-201 adding no significant toxicity to G/C. Updated CBR, PFS, and OS for all 120 patients and exploratory correlative analyses of PARP expression and clinical response will be presented.

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Prevalence and predictors of posttraumatic stress disorder in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study
Authors: Stuber M. , Meeske K. , Zebrack B. , Krull K. , Stratton K. , Leisenring W. , Robison L. , Zeltzer L.
Published: February 2017

CRA10002

Background: This study examined prevalence and demographic- and disease-related correlates of posttraumatic stress disorder (PTSD) among 6,542 adult childhood cancer survivors and 368 siblings from the Childhood Cancer Survivor Study. Methods: Subjects were dichotomized based on full PTSD criteria, using the Foa PTSD self-report measure to assess posttraumatic stress symptoms of intrusion of unwanted memories, avoidance of event reminders, and increased startle response, and the Brief Symptom Inventory-18 and the SF-36 subscale, role limitation due to emotional health, to evaluate clinical distress or impaired function. A self-report questionnaire provided demographic information and medical abstraction provided cancer reatment data. Multivariable generalized linear models were used to compare prevalence of PTSD among cancer survivors to siblings and to examine relationships between PTSD and demographic and disease-related factors. Relative risks (RR) were calculated based on a Poisson distribution with robust error variances. Results: Five hundred eighty-nine (9%) childhood cancer survivors and 8 (2%) siblings met criteria for a diagnosis of PTSD (RR = 3.83, 95% CI 1.96–7.48, p < 0.0001). Among cancer survivors, there was significantly more PTSD reported by women from minority backgrounds (p < 0.05). Other demographic factors associated with PTSD were having less than a college education (p < 0.05), being unmarried (p < 0.001), having an annual income less than $20,000 (p < 0.05) and being unemployed (p = 0.001). Risk of PTSD was significantly higher for survivors diagnosed at ages 15 to 20 years (p < 0.05). PTSD was more common among survivors treated with intensive chemotherapy (p < 0.05) or radiation therapy (p < 0.001) and who relapsed or developed a second malignant neoplasm (p < 0.001). Neuroblastoma and Wilms tumor survivors had a significantly lower risk of PTSD than did leukemia survivors (p < 0.05). Conclusions: While the majority of childhood cancer survivors did not demonstrate PTSD, a clinically significant number did meet diagnostic criteria. Prospective assessment of survivors with high risk demographic-, diagnosis-, and treatment-related characteristics should be considered as part of long-term health screening.

No significant financial relationships to disclose.
Final STEPP results of prophylacatic versus reactive skin toxicity (ST) treatment (tx) for panitumumab (pmab)-related ST in patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Mitchell E. P. , Lacouture M. , Shearer H. , Iannotti N. , Piperdi B. , Pillai M. , Xu F. , Yassine M.
Published: February 2017

CRA4027

Background: Pmab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is approved as monotherapy in the US for mCRC following disease progression (PD) and in the EU and Canada for tumors bearing wild-type (WT) KRAS. The most common toxicity with anti-EGFR inhibitors are ST. This study of pmab+ chemotherapy (CT) estimates the difference in the incidence of specific ≥ grade 2 ST of interest between pts receiving prophylactic (P) or reactive (R) skin tx. Methods: Pts had unresectable mCRC after PD with 1st-line fluoropyrimidine and oxaliplatin-based CT ± bevacizumab. Pts received either pmab 6.0mg/kg/FOLFIRI Q2W or pmab 9 mg/kg/irinotecan Q3W. Within each stratum, pts were randomized 1:1 to either P ST tx 24 hrs before the 1st dose daily for 6 wks or R ST tx after ST occurred. Tx for ST included: moisturizers, sunscreen, topical steroid, and doxycycline. Efficacy and safety were evaluated by P vs R tx groups, KRAS status (mutant [MT] vs WT), and chemotherapy status. Responses were assessed using modified RECIST with confirmation. Quality of life was assessed using the Dermatology Life Quality Index at screening, wks 2–7, and follow-up. Results: 95 pts were enrolled and randomized: 48 pts to P and 47 pts to R. During the 6 wk ST tx period, 29% of pts in the P group vs 62% of pts in the R group had protocol-specified ≥grade 2 ST. Of the 87 KRAS evaluable pts, 49 (56%) pts had WT KRAS and 38 (44%) pts had MT KRAS. Efficacy and safety are shown. Mean (SD) change in DLQI from baseline was 1.3 (2.6) for P and 4.2 (5.8) for R at wk 3 (when the median time to 1st ≥grade 2 ST was reached in the R group) and was 2.0 (2.8) for P and 2.6 (4.4) for R at wk 7. Conclusions: Prophylactic use of the skin tx regimen resulted in >50% reduction in the rate of specific ≥ grade 2 STs and improved QOL during the 6-week skin tx period vs R use. Numerical differences in favor of the P group were observed for all endpoints.

[Table: see text]

[Table: see text]
Partial breast irradiation or whole breast radiotherapy for early breast cancer: A meta-analysis of randomized controlled trials
Authors: Valachis A. , Mauri D. , Polyzos N. P. , Mavroudis D. , Georgoulias V. , Casazza G.
Published: February 2017

CRA532

Background: The purpose of the study was to compare treatment outcomes in patients with breast cancer treated with partial breast irradiation and of those treated with whole breast radiation therapy. Methods: We conducted a systematic review and meta-analysis of published. Randomized clinical trials comparing partial breast irradiation versus whole breast radiation therapy. Primary outcome was overall survival and secondary outcomes were locoregional, distant and supraclavicular recurrences. Results: A search of the literature identified 3 trials with pooled total of 1,140 patients. We found no statistically significant difference between partial and whole breast radiation arms associated with death (OR 0.912, 95% CI 0.674–1.234, p = 0.550), distant metastasis (OR 0.740, 95% CI, 0.506–1.082, p = 0.120), or supraclavicular recurrences (pooled OR 1.415, 95% CI 0.278–7.202, p = 0.560). However, partial breast irradiation was statistically significantly associated with an increased risk of both local (pooled OR 2.150, 95% CI, 1.396–3.312; p = 0.001) and regional disease recurrences (pooled OR 3.430, 95% CI, 2.058–5.715; p < 0.0001) compared with whole breast radiation. Conclusions: Partial breast irradiation does not jeopardize survival and may be used as an alternative to whole breast radiation. Nevertheless, the issue of locoregional recurrence needs to be further addressed.

No significant financial relationships to disclose.
A phase III study comparing concurrent gemcitabine (Gem) plus cisplatin (Cis) and radiation followed by adjuvant Gem plus Cis versus concurrent Cis and radiation in patients with stage IIB to IVA carcinoma of the cervix
Authors: Dueñas-González A. , Zarba J. J. , Alcedo J. C. , Pattarunataporn P. , Beslija S. , Patel F. , Casanova L. , Barraclough H. , Orlando M.
Published: February 2017

CRA5507

Background: Cervical cancer is the second-most common cancer among women worldwide, in both incidence and mortality. Current standard therapy for locally advanced disease consists of concurrent Cis and external-beam radiation (XRT). This multicenter, open-label, randomized, phase III trial aimed to improve outcomes, capitalizing on the synergistic activity of Gem, Cis, XRT, and the potential value of adjuvant therapy. Methods: Eligible patients (pts) with bulky stage IIB to IVA, 18–70 years of age, chemotherapy- and radiotherapy-naive, with a Karnofsky Performance Status score ≥70, were randomized to Arm A: Cis 40 mg/m2 followed by Gem 125 mg/m2 weekly × 6 doses with concurrent XRT (50.4 Gy: in 28 fractions: 1.8 Gy/day, 5 days/week), followed by brachytherapy (brachy) (30–35 Gy) and then 2 adjuvant 21-day cycles of Gem (1,000 mg/m2 on Days 1 and 8) plus Cis (50 mg/m2 on Day 1); or Arm B: Cis 40 mg/m2 weekly × 6 doses with concurrent XRT followed by brachy, given as in Arm A. Primary endpoint was progression-free survival (PFS) at 3 years, compared between arms using Kaplan-Meier methods and a Z-statistic. Results: 515 pts were enrolled between 5/02 and 3/04 (259 pts Arm A, 256 pts Arm B). Median age was 46 years; stage IIB/IIIB/IVA in 61/37/2% of pts. Compliance in the concurrent and brachy phase was >90% for both arms; adjuvant cycles were completed by >75% of pts in Arm A. PFS at 3 years was 74% in Arm A compared to 65% in Arm B, resulting in a statistically significant improvement (p = 0.029). Overall survival (log-rank p = 0.0224) and time to progressive disease (log-rank p = 0.0008) were also significantly improved. Significantly more pts in Arm A experienced grade 3/4 toxicities (86.5%), compared to pts in Arm B (46.3%; Fisher's p < 0.001). In Arm A, 2 pts died due to causes probably related to treatment compared to 0 pts in Arm B. Conclusions: This novel regimen of concurrent Gem plus Cis and XRT followed by brachy and adjuvant Gem plus Cis significantly improved outcomes in pts with locally advanced carcinoma of the cervix, at the expense of increased but acceptable toxicity, compared to the current standard of care.

[Table: see text]
MSH2 and adjuvant cisplatin-based chemotherapy in non-small cell lung cancer
Authors: Fouret P. , Planchard D. , Mendiboure J. , Kamal N. S. , Olaussen K. A. , Bertrand P. , Pirker R. , Dunant A. , Le Chevalier T. , Soria J. C. ,   IALT-Bio Investigators
Published: February 2017

CRA7502

Background: Adjuvant cisplatin-based chemotherapy improves survival among patients with non-small cell lung cancer. The human MutS homolog 2 (MSH2) protein is required to repair cisplatin-DNA lesions. Methods: We used immunohistochemistry to determine MSH2 expression in specimens from patients who had been enrolled in the International Adjuvant Lung Trial. The long-term (median follow-up 7.5 years) overall survival benefit was evaluated in a Cox model adjusted on clinical and pathological variables. Results: Among 673 evaluable tumors, 257 (38%) were MSH2 positive and 416 (62%) were MSH2 negative. The long-term survival benefit of chemotherapy was likely different according to MSH2 expression (test for interaction, P=0.06): chemotherapy compared with observation prolonged survival in the MSH2 negative group (adjusted hazard ratio for death, 0.76; 95%CI, 0.59 to 0.97; P=0.03), but not in the MSH2 positive group (adjusted hazard ratio for death, 1.12; 95%CI, 0.81 to 1.55; P=0.48). In the control arm, the adjusted hazard ratio for death associated with MSH2 positivity compared to MSH2 negativity was 0.66 (95%CI, 0.49 to 0.90; P=0.01). Among 658 patients with available excision repair cross-complementing group 1 (ERCC1) data, the benefit of chemotherapy decreased with the number of positive markers among MSH2 and ERCC1 (P=0.01). Chemotherapy compared with observation prolonged survival in the combined MSH2 negative/ERCC1 negative subgroup (adjusted hazard ratio for death, 0.65; 95%CI, 0.47 to 0.91; P=0.01). Conclusions: MSH2 appears to predict a long-term benefit from adjuvant cisplatin-based chemotherapy in patients with non-small cell lung cancer and may be combined with ERCC1.

[Table: see text]
A randomized trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II)
Authors: James R. , Wan S. , Glynne-Jones R. , Sebag-Montefiore D. , Kadalayil L. , Northover J. , Cunningham D. , Meadows H. , Ledermann J. ,   National Cancer Research Institute (NCRI) ACT II Trial Management Group
Published: February 2017

LBA4009

Background: Chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and mitomycin-C (MMC) is standard treatment for anal cancer. This trial addresses two questions: whether (i) replacing MMC with cisplatin (CDDP) improves the complete response (CR) rate, and (ii) two cycles of maintenance chemotherapy after CRT reduces recurrence. Methods: Between 2001 and 2008, 940 patients (pts) were recruited to a multicenter, randomized factorial trial. Pts received 5-FU (1,000mg/m2/day on d1–4 and 29–32), radiotherapy (RT) (50.4Gy in 28 fractions), and either MMC (12mg/m2, d1; n=471) or CDDP (60mg/m2 on d1 and 29; n=469). Pts were also randomized to receive maintenance therapy (n=448) 4 weeks after CRT (two cycles of CDDP and 5-FU weeks 11 and 14) or no maintenance (n=446). Maintenance randomization was not considered appropriate in 46 pts. Statistical power was ≥80% to detect a difference in the CR rate of 5% (CDDP vs MMC), and 30% reduction in recurrence (maintenance vs no maintenance). Results: Median age 58 yrs; 62% male, 38% female; tumor site - canal (81%), margin (15%); stage T1-T2 (50%), T3-T4 (43%); node negative (62%), positive (30%). Median follow-up was 3 yrs. The CR rate was 94% MMC and 95% CDDP (p=0.53). MMC pts had more acute grade 3/4 haematological toxicities (25 vs 13%, p<0.001) but this did not result in an increase in neutropaenic sepsis (3.1 vs 3.2%, p=0.93). Non-haematologic grade 3/4 toxicities were similar (61 vs 65%, p=0.22). Preliminary analysis shows no statistically significant difference in recurrence free survival (RFS) (HR 0.89, 95% CI 0.68, 1.18; p=0.42) or overall survival (HR 0.79, 95% CI 0.56,1.12; p=0.19) for the maintenance comparison. The number of pre-treatment colostomies not reversed were similar between treatments (18 MMC vs 14 CDDP, p=0.65, Maint/No maint, p=0.23) and only 9 disease-free pts had colostomies performed (5 MMC, 4 CDDP). Conclusions: ACT II is the largest trial conducted in anal cancer. High CR (95%) and RFS (75% at 3 yrs) rates were achieved with this CRT. This excellent outcome may have been influenced by the absence of a gap in the RT schedule. There was no difference in CR rates between MMC and CDDP or in RFS rates with or without maintenance chemotherapy. 5-FU, MMC with RT remains the standard of care.

[Table: see text]
A randomized, phase III study of carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in relapsed platinum-sensitive ovarian cancer (OC): CALYPSO study of the Gynecologic Cancer Intergroup (GCIG)
Authors: Pujade-Lauraine E. , Mahner S. , Kaern J. , Gebski V. , Heywood M. , Vasey P. , Reinthaller A. , Vergote I. , Pignata S. , Ferrero A.
Published: February 2017

LBA5509

Background: This multicenter phase III study was designed to compare efficacy and safety of carboplatin-pegylated liposomal doxorubicin (PLD) (C-D) and carboplatin-paclitaxel (C-P) in relapsed platinum-sensitive OC patients (pts). Methods: Pts with recurrent OC > 6 months after first-line or second-line platinum-based therapy who had been pretreated with a taxane were randomized by stratified blocks to either C-D [C AUC 5 IV + PLD 30 mg/m2 IV] d1 q4 wk, or C-P [C AUC 5 IV + P 175 mg/m2 IV] d1 q3 wk × ≥ 6 cycles. The primary endpoint was progression-free survival (PFS), with secondary endpoints of toxicity, QoL and survival. The non-inferiority design required 745 events with 90% power, 95% confidence interval (CI). Results: From 4/05 to 09/07, 976 pts were enrolled, 467 to C-D arm and 509 to C-P arm. Pt parameters were well balanced. 85% of C-D and 78% of C-P pts received ≥ 6 cycles. Median follow-up is 21mo. Overall survival is still too early to be reported (n=308 deaths). This is the final analysis for PFS and toxicity. Results are below. Conclusions: This trial, the largest in relapsed OC, showed significant superiority of PLD-carboplatin combination in terms of PFS. In addition, compared to paclitaxel-carboplatin, PLD-carboplatin was well tolerated with lower rates of severe and long-lasting (neuropathy) toxicities.

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No significant financial relationships to disclose.
A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC)
Authors: Miller V. A. , O'Connor P. , Soh C. , Kabbinavar F.
Published: February 2017

LBA8002

Background: B when added to chemotherapy, and E alone, each lead to improved survival in the treatment of patients (pts) with NSCLC (Sandler et al, NEJM 2006, 355:2542–2550; Shepherd et al, NEJM 2005, 353:123–132). Pre-clinical and clinical data (Herbst, J Clin Oncol 2007, 25: 4743–4750) suggest that the combination of B and E may improve the efficacy of NSCLC treatment. This potential was demonstrated in the BETA (B in combination with E compared with E alone for treatment of advanced NSCLC after failure of standard first-line chemotherapy) trial, a phase III trial in which progression free survival (PFS) was improved for patients treated with B + E (Hainsworth, Thoracic Oncol 2008, 3(11) Supp. 4:S302). Methods: The ATLAS study was designed to evaluate B + E (150 mg daily) versus B alone, following B + platin-containing doublet chemotherapy, in pts with stage IIIb/IV NSCLC. Enrolled pts were B-eligible, including pts with treated brain metastases, and pts anticoagulated with low molecular weight heparin(s). Pts with peripheral and/or extra-thoracic squamous tumors were also eligible. Pts received 4 cycles of B (15 mg/kg every 3 weeks) with chemotherapy. Pts who had not experienced disease progression (DP) or significant toxicity were then randomized to receive B + E or B + placebo (P). The primary objective of ATLAS was to compare PFS in pts receiving B + E versus B + placebo. Secondary objectives included the assessment of safety, and overall survival. A data safety monitoring committee (DSMC) monitored safety and efficacy. Results: 1,160 patients were enrolled and 768 randomized from May 2005 to May 2008. The DSMC recommended stopping the trial at the second planned interim efficacy analysis, because it met the primary endpoint. The median PFS after randomization was 4.8 mos for (B + E) vs. 3.7 mos for (B + P), HR= 0.722 (95% CI: 0.592–0.881), p = 0.0012. The safety profile for B + E was consistent with known profiles for B and E. Conclusions: E added to B treatment after chemotherapy with B significantly improves the PFS of patients treated in the first-line setting for locally advanced, recurrent, or metastatic NSCLC.

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Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-positive patients with non-small cell lung cancer (NSCLC).
Authors: Bang Y. , Kwak E. L. , Shaw A. T. , Camidge D. R. , Iafrate A. J. , Maki R. G. , Solomon B. J. , Ou S. I. , Salgia R. , Clark J. W.
Published: February 2017

3

Background: PF-02341066 (PF-1066) is a selective, ATP-competitive, small molecule, orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases. EML4-ALK fusion oncogenes have been reported in approximately 4% of NSCLC. Patients with NSCLC harboring an ALK fusion were recruited into an expanded cohort at the recommended phase II dose within the first-in-patient monotherapy trial of PF-1066.

Methods: Patients with ALK fusions, as determined by FISH using a break-apart probe to ALK, were enrolled into the expanded cohort irrespective of prior therapy. Treated brain metastases were allowed. PF-1066 was given orally at a dose of 250 mg BID. Responses were determined using RECIST with radiographic studies repeated every 8 weeks. The disease control rate (DCR) was determined based on the frequency of patients with RECIST CR, PR and stable disease at 8 weeks.

Results: To date, 76 ALK+ NSCLC patients have been treated. The median number of prior treatments was 3 (range, 0-7). Most patients had adenocarcinoma histology and were never or former smokers. Mean plasma Ctrough was 292 ng/mL, which was above the predicted efficacious concentration from preclinical models (120 ng/mL). The median t1/2 was ∼53 hours. To date, 50 patients are evaluable for response; ORR is 64% and DCR 90%. The median progression-free survival is not yet mature. The median duration of treatment is 25.5+ weeks. Radiological responses typically were observed at the first or second restaging CT scan. Gastrointestinal toxicities, including nausea (55%) and vomiting (39%), were the most frequent adverse events.

Conclusions: The oral ALK inhibitor, PF-1066, demonstrated a high response rate in patients selected for ALK fusions and was associated with a good safety profile. A phase III study has been initiated. This study supports the concept of molecular selection of NSCLC patients for appropriately designed treatment.

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Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study.
Authors: Burger R. A. , Brady M. F. , Bookman M. A. , Walker J. L. , Homesley H. D. , Fowler J. , Monk B. J. , Greer B. E. , Boente M. , Liang S. X.
Published: February 2017

LBA1

Background: BEV, a humanized anti-VEGF monoclonal antibody, has demonstrated single-agent activity in patients with recurrent EOC, or PPC. The therapeutic impact of concurrent ± maintenance BEV with standard chemotherapy (CT) was evaluated in an international, double-blind, placebo-controlled phase III trial.

Methods: Eligible patients had newly diagnosed, previously untreated EOC, PPC or FTC following abdominal surgery for staging and maximal effort at tumor debulking; stage III (macroscopic residual disease) or stage IV disease. The randomly allocated regimens were (1) CT (IV paclitaxel 175 mg/m2 + carboplatin AUC 6 cycles 1-6) + placebo cycles (C)2-22 (R1) (2) CT + concurrent BEV (15 mg/kg) C2-6 + placebo C7-22 (R2) (3) CT + concurrent BEV C2-6 + maintenance BEV C7-22 (R3) Infusions were administered d1 of a 21d cycle. The primary endpoint is progression-free survival (PFS) (radiographic, CA125, clinical criteria or death); secondary endpoints include overall survival, safety, and QoL.

Results: 1,873 patients, median age 60, were enrolled from 9/05 - 6/09. Stage III optimally debulked (34%), stage III sub-optimally debulked (40%), and stage IV (26%) patients were similarly distributed in each treatment group. Grade 3 - 4 hypertension was reported in 1.6% (R1), 5.4% (R2), and 10.0% (R3). Grade ≥ 3 GI perforation, hemorrhage or fistula occurred in 0.8% (R1), 2.6% (R2) and 2.3% (R3). Relative to R1, the hazard of first progression or death for R2 was 0.908 (95% CI: 0.795 – 1.04, p=0.16) and for R3 was 0.717 (95% CI: 0.625 – 0.824, p<0.0001).

Conclusions: This study demonstrates that front-line treatment of EOC, PPC, and FTC patients with CT plus concurrent and maintenance BEV prolongs PFS. This is the first anti-angiogenic agent to demonstrate benefit in this population.

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A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): Survival results of CALGB 90401.
Authors: Kelly W. K. , Halabi S. , Carducci M. A. , George D. J. , Mahoney J. F. , Stadler W. M. , Morris M. J. , Kantoff P. W. , Monk J. P. , Small E. J. ,   Cancer and Leukemia Group B
Published: February 2017

LBA4511

Background: The preclinical activity of vascular endothelial growth factor (VEGF) blockade, the inverse relationship of plasma and urine VEGF levels and survival in mCRPC patients (pts), and encouraging phase II data testing estramustine and docetaxel with bevacizumab suggested that VEGF blockade was an appropriate potential strategy in mCRPC. A phase III study testing the effect of adding bevacizumab to standard docetaxel and prednisone therapy administered every 3 weeks in pts with mCRPC was conducted.

Methods: 1050 pts with chemotherapy naïve, mCRPC with evidence of progressive disease despite castrate testosterone levels and anti-androgen withdrawal, ECOG performance status ≤ 2, and adequate bone marrow, hepatic and renal function were eligible. Pts were prospectively randomized with equal probability to receive docetaxel (D:75 mg/m2 IV over 1 hour q 21 days), plus prednisone (P) 5 mg po BID with either bevacizumab (B:15 mg/kg given intravenously q 3 weeks following D) or placebo. All patients received dexamethasone 8 mg PO 12, 3 and 1 hour prior to D. Randomization was stratified by predicted 24 mo survival probability, age and history of prior arterial thrombotic event. The primary endpoint was overall survival (OS). The trial was designed with 86% power to detect a 21% decrease in the hazard rate of death (equivalent to an increase in median OS from 19 months to 24 months) assuming a two-sided significance level of 0.05. The primary analysis was based on the stratified log-rank statistic adjusted for the stratification factors following observation of 748 deaths.

Results: See Table .

Conclusions: Despite an improvement in PFS, measurable disease response and post-therapy PSA decline, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC, and was associated with greater morbidity and mortality. The median OS of pts treated with standard DP (21.5 m) was longer than previously reported (19 m).

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Primary outcome results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection (SNR) to conventional axillary dissection (AD) in clinically node-negative breast cancer patients.
Authors: Krag D. N. , Anderson S. J. , Julian T. B. , Brown A. , Harlow S. P. , Costantino J. P. , Ashikaga T. , Weaver D. , Mamounas E. P. , Wolmark N.
Published: February 2017

LBA505

Background: NSABP B-32 is the largest prospective randomized phase III trial designed to determine in SN negative patients that SNR alone results in the same survival and regional control as SNR + AD while reducing morbidity. It was designed to detect a survival difference of 2% between the 2 groups at 5 years.

Methods: 5,611 women with operable, clinically N0, invasive breast cancer were randomized to SNR + AD (Group 1) or to SNR alone with AD only if SNs were positive (Group 2). 3,989 (71.1%) of the 5,611 patients were SN negative and followed for events. 99.9% of these SN negative patients had follow-up information: 1,975 in Group 1 and 2,011 in Group 2. Median time on study was 95.3 months. Patients were well balanced across clinical strata. Log-rank tests for unadjusted analyses and Cox proportional hazard models adjusting for study stratification variables were used to compare overall survival (OS) and disease-free survival (DFS) between the two groups. Two-sided p-values were used. HR values > 1 indicate a more favorable outcome in Group 1 (SNR + AD).

Results: Comparisons of OS (Group 1 vs. Group 2) yielded an unadjusted HR of 1.20 (p = 0.12) and an adjusted HR of 1.19 (p=0.13). Five-year Kaplan-Meier estimates for OS are 96.4% in Group 1 and 95.0% in Group 2 and the 8-year estimates are 91.8% and 90.3%, respectively. Comparisons of DFS (Group 1 vs. Group 2) yielded an unadjusted HR of 1.05 (p=0.54) and an adjusted HR of1.07 (p=0.57). No substantial differences could be seen across sites for first treatment failure. Five-year Kaplan-Meier estimates for DFS are 89.0% in Group 1, and 88.6% in Group 2 and the 8-year estimates are 82.4% and 81.5%, respectively. Local and Regional Recurrences: There were 54 local recurrences in Group 1 and 49 in Group 2 (p=0.55). There were 8 regional node recurrences as first events in Group 1 and 14 in Group 2 (p=0.22).

Conclusions: No significant differences were observed in OS, DFS, or regional control between the trial groups. Within the limits of this trial, SNR without AD is validated as a safe and effective method for regional node treatment of SN negative breast cancer patients.

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ACOSOG Z1031: A randomized phase II trial comparing exemestane, letrozole, and anastrozole in postmenopausal women with clinical stage II/III estrogen receptor-positive breast cancer.
Authors: Ellis M. J. , Babiera G. , Unzeitig G. W. , Marcom P. K. , Guenther J. M. , Deshryver F. K. , Allred D. C. , Suman V. , Hunt K. , Olson J. A.
Published: February 2017

LBA513

Background: Neoadjuvant aromatase inhibitor (AI) therapy is a rational and effective approach to improving the breast conservation surgery (BCS) rate for postmenopausal patients with large, estrogen receptor (ER) rich breast cancers. Barriers to adopting this strategy include lack of experience in this management approach in the US and uncertainty regarding the comparative effectiveness of the three approved aromatase inhibitors for this indication.

Methods: ACOSOG Z1031 is a multicenter, open-label, neoadjuvant phase III screening study that randomized postmenopausal women with clinical stage II/III ER rich (Allred score 6-8) breast cancer to 16 weeks of either exemestane (EXE) 25 mg daily, letrozole (LET) 2.5 mg daily, or anastrozole (ANA) 1 mg daily. At baseline study participants were either marginal for BCS (MBCS), candidates for mastectomy only (MO), or inoperable (IO). Planned enrolment was 125 patients per arm in order that the likelihood of the treatment with the “best” 16-week clinical response rate (based on caliper measurements) by WHO criteria (cRR) was included among the subset of treatments with “similar” cRR (90% power). Secondary endpoints included: extent of surgery, radiologic and pathologic response rates.

Results: From 4/1/2006 to 10/1/2009, 377 postmenopausal women with clinical stage II or III ER rich breast cancer were enrolled. 374 women began treatment and were included in an intent-to-treat analysis. Median age was 66 yrs (range: 43-90 yrs), Median tumor size was 4.0 cm (range: 2-13 cm). The 16-week cRR was 60.5% (95%CI: 51.3-69.1%) for EXE; 70.9% (95% CI: 62.2-78.6%) for LET, and 66.7% (95% CI: 57.6-74.9%) for ANA. Seventeen patients did not have surgery due to refusal (12 pts), progression (3 pts) or other medical conditions (2 pts). The BCS rate was 78% (163/207) in MBCS group; 42% (77/163) in MO group; and 75% in IO group (3/4). Surgeons made the decisions regarding procedure choice 75% of the time in both the MBCS and the MO categories.

Conclusions: This large multicenter screening trial selected non-steroidal AIs for further development due to their higher observed cRR. The study demonstrates that high response and breast conservation rates and low rates of disease progression can be achieved through patient selection based on high ER expression. We are currently refining our approach for early detection of poor response to AIs through an assessment of the tumor Ki67 proliferation index at 2 to 4 weeks (Z1031 Cohort B).

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