bluuebunny/crossref_metadata_2025 huggingface dataset:
Stanford V and Radiotherapy for Locally Extensive and Advanced Hodgkin’s Disease: Mature Results of a Prospective Clinical Trial
Authors: Horning Sandra J. , Hoppe Richard T. , Breslin Sheila , Bartlett Nancy L. , Brown B. William , Rosenberg Saul A.
Published: February 2017

PURPOSE: To provide more mature data on the efficacy and complications of a brief, dose-intense chemotherapy regimen plus radiation therapy (RT) to bulky disease sites for locally extensive and advanced-stage Hodgkin’s disease.

PATIENTS AND METHODS: One hundred forty-two patients with stage III or IV or locally extensive mediastinal stage I or II Hodgkin’s disease received Stanford V chemotherapy for 12 weeks followed by 36-Gy RT to initial sites of bulky (≥ 5 cm) or macroscopic splenic disease. Freedom from progression (FFP), overall survival (OS), and freedom from second relapse (FF2R) were determined using life-table estimates. Outcomes were analyzed according to the international prognostic score. Late effects of treatment were recorded in follow-up.

RESULTS: With a median follow-up of 5.4 years, the 5-year FFP was 89% and the OS was 96%. No patient progressed during treatment, and there were no treatment-related deaths. FFP was significantly superior among patients with a prognostic score of 0 to 2 compared with those with a score of 3 and higher (94% v 75%, P < .0001). No secondary leukemia was observed. To date, there have been 42 pregnancies after treatment. Among 16 patients who relapsed, the FF2R was 69% at 5 years.

CONCLUSION: These data confirm our preliminary report that Stanford V chemotherapy with RT to bulky disease sites is highly effective in locally extensive and advanced Hodgkin’s disease. It is most important to compare this approach with standard doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy in the ongoing intergroup trial (E2496) to determine whether Stanford V with or without RT represents a therapeutic advance.
Does Menopausal Hormone Replacement Therapy Interact With Known Factors to Increase Risk of Breast Cancer?
Authors: Ursin Giske , Tseng Chiu-Chen , Paganini-Hill Annlia , Enger Shelley , Wan Peggy C. , Formenti Silvia , Pike Malcolm C. , Ross Ronald K.
Published: February 2017

PURPOSE: We and other investigators have previously shown that postmenopausal combined estrogen and progestin replacement therapy (EPRT) increases the risk of breast cancer and that the risk associated with EPRT is substantially higher than for estrogen replacement therapy (ERT) alone. The present study was conducted to determine whether any particular subgroup of women are at particularly high risk of breast cancer if they use EPRT and whether tumor characteristics in women who develop cancer while on ERT or EPRT are different from those in women not using ERT or EPRT.

PATIENTS AND METHODS: We conducted a population-based case-control study in Los Angeles, CA, with patients diagnosed with breast cancer in the late 1980s and early 1990s. Control subjects were matched to patients on age, ethnicity, and neighborhood of residence. We present data on 1,897 postmenopausal patients and 1,637 controls aged 55 to 72 years who had not undergone a simple hysterectomy.

RESULTS: Relative risk of breast cancer associated with EPRT use did not vary with body mass index (body mass index at or below v above median [24.6 kg/m2]; P = .98), alcohol intake (≥ one v < one drink per week; P = .16), parity (nulliparous v parous; P = .45), history of benign breast disease (yes v no; P = .99), or family history of breast cancer (first degree v none; P = .57). All of these results were compatible with our previously reported estimate of an increased risk of breast cancer of 5% per year of use of EPRT. Hormone users, principally EPRT users, were more likely to have hormone receptor–positive, especially progesterone-positive, tumors.

CONCLUSION: We found no evidence that the risk of breast cancer associated with EPRT is limited to subgroups of women with specific cofactors. Tumors in EPRT users are more often hormone receptor–positive, indicating that they may have a better prognosis than breast cancer overall.
Association of Angiogenesis and Disease Outcome in Node-Positive Breast Cancer Patients Treated With Adjuvant Cyclophosphamide, Doxorubicin, and Fluorouracil: A Cancer and Leukemia Group B Correlative Science Study From Protocols 8541/8869
Authors: Guidi Anthony J. , Berry Donald A. , Broadwater Gloria , Helmchen Birgit , Bleiweiss Ira J. , Budman Daniel R. , Henderson I. Craig , Norton Larry , Hayes Daniel F.
Published: February 2017

PURPOSE: Increased microvessel density (MVD), a reflection of tumor angiogenesis, is associated with diminished relapse-free and overall survival (OS) in several subsets of breast cancer patients. However, the utility of this assay in node-positive patients treated with adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) has not been well studied.

PATIENTS AND METHODS: Immunostaining for factor VIII–related antigen was performed on tissue sections from a subset of node-positive patients who received one of three dose/schedule regimens of CAF during participation in Cancer and Leukemia Group B protocol 8541. Sections from 577 cancers exhibited acceptable tumor and immunostaining quality and were included in the study. Each section was examined quantitatively for MVD as well as nonquantitatively by scoring the presence or absence of a prominent vascular pattern.

RESULTS: MVD counts were not associated with relapse-free or OS in univariate analysis. The presence of a prominent plexiform vascular pattern was correlated with decreased OS (P = .0085) in univariate analysis, but this pattern was not an independent prognostic indicator of survival in multivariate analysis. No apparent clinically important interactions between measures of angiogenesis, other prognostic factors, administration of tamoxifen, and chemotherapy dose were observed.

CONCLUSION: Assessment of angiogenesis does not provide useful information regarding prognosis in node-positive breast cancer patients treated with adjuvant CAF, nor do these measures predict which patients will benefit from dose intensification or addition of tamoxifen.
Practices and Attitudes of Japanese Oncologists and Palliative Care Physicians Concerning Terminal Sedation: A Nationwide Survey
Authors: Morita Tatsuya , Akechi Tatsuo , Sugawara Yuriko , Chihara Satoshi , Uchitomi Yosuke
Published: February 2017

PURPOSE: To clarify the frequency of practice of sedation therapy for terminally ill cancer patients and to identify physicians’ attitudes toward sedation.

METHODS: Questionnaires were mailed to 1,436 Japanese oncologists and palliative care physicians with a request to report their practice of and attitudes toward palliative sedation therapy.

RESULTS: A total of 697 physicians returned questionnaires (response rate, 49.6%). Use of mild, intermittent-deep, or continuous-deep sedation for physical and psychologic distress was reported by 89% and 64%, 70% and 46%, and 66% and 38%, respectively. In vignettes in which physicians were asked whether they would use sedation for a patient with refractory dyspnea or with existential distress, 14% and 15%, respectively, chose continuous-deep sedation as a strong possibility. Those physicians less confident with psychologic care and with higher levels of professional burnout were more likely to choose continuous-deep sedation. In vignettes in which they were asked whether they use sedation for a patient with depression or delirium, 39% and 31%, respectively, considered psychiatric treatment to be a strong possibility, and 42% and 50% regarded continuous-deep sedation as a potential treatment option. Physicians less involved in caring for the terminally ill and less specialized in palliative medicine were significantly less likely to choose psychiatric treatment.

CONCLUSION: Sedation is frequently used for severe physical and psychologic distress of cancer patients. Physicians’ clinical experiences with the terminally ill and their levels of professional burnout influence the decisions. Training and education for physicians in regard to end-of-life care and valid clinical guidelines for palliative sedation therapy are necessary.
Up-to-Date Long-Term Survival Curves of Patients With Cancer by Period Analysis
Authors: Brenner Hermann , Hakulinen Timo
Published: February 2017

PURPOSE: Provision of up-to-date long-term survival curves is an important task of cancer registries. Traditionally, survival curves have been derived for cohorts of patients diagnosed many years ago. Using data of the Finnish Cancer Registry, we provide an empirical assessment of the use of a new method of survival anlysis, denoted period analysis, for deriving more up-to-date survival curves.

PATIENTS AND METHODS: We calculated 10-year relative survival curves actually observed for patients diagnosed with one of the 15 most common forms of cancer in 1983 to 1987, and we compared them with the most up-to-date 10-year relative survival curves that might have been obtained in 1983 to 1987 using either traditional (cohort-wise) or period analysis. We also give the most recent 10-year survival curves obtained by period analysis for the 1993 to 1997 period.

RESULTS: For all forms of cancer, period analysis of the 1983 to 1987 data yielded survival curves that were very close to the survival curves later observed for patients who were newly diagnosed in that period (median and maximum difference of 10-year relative survival estimates: 0.9 and 5.7 percent units, respectively). By contrast, the survival curves obtained by traditional (cohort-wise) survival analysis in 1983 to 1987 would have been much lower for most forms of cancer (median and maximum difference: 5.8 and 18.4 percent units, respectively). The 10-year survival curves for the 1993 to 1997 period are substantially more favorable than previously available, traditionally derived survival curves for most forms of cancer.

CONCLUSION: Period analysis is a useful tool for deriving up-to-date long-term survival curves of patients with cancer.
Association of Preoperative Plasma Levels of Insulin-Like Growth Factor I and Insulin-Like Growth Factor Binding Proteins-2 and -3 With Prostate Cancer Invasion, Progression, and Metastasis
Authors: Shariat Shahrokh F. , Lamb Dolores J. , Kattan Michael W. , Nguyen Cuong , Kim JaHong , Beck Josie , Wheeler Thomas M. , Slawin Kevin M.
Published: February 2017

PURPOSE: We tested the hypothesis that preoperative plasma levels of insulin-like growth factor (IGF) binding protein (BP)-2 or IGFBP-3 would predict cancer stage and prognosis in patients undergoing radical prostatectomy.

MATERIAL AND METHODS: Plasma levels of IGF-I, IGFBP-2, and IGFBP-3 were measured preoperatively in 120 consecutive patients who underwent radical prostatectomy for clinically localized disease, postoperatively in 51 of these patients, in 44 healthy men, in 19 patients with metastases to regional lymph nodes, and in 10 patients with bone metastases.

RESULTS: Plasma IGFBP-3 levels were lowest in patients with bone metastases (P ≤ .043). IGFBP-2 levels were elevated in prostate cancer patients compared with healthy subjects (P ≤ .006). However, within the group of prostatectomy patients, preoperative plasma IGFBP-2 levels were lower in patients with advanced disease (P ≤ .033), were inversely correlated with prostatic tumor volume (P = .037), and declined after prostate removal (P = .044). Lower preoperative IGFBP-2 and IGFBP-3 levels and biopsy Gleason score were independent predictors of biochemical progression (P = .043, P = .040, and P = .020, respectively). In patients with disease progression, preoperative plasma IGFBP-3 levels were lower in those with aggressive than in those with nonaggressive failure (P = .042).

CONCLUSION: Elevation of plasma IGFBP-2 levels in prostate cancer patients apparently is due to increased release directly from the prostate. For patients with clinically localized prostate cancer, preoperative plasma IGFBP-2 levels are inversely associated with biologically aggressive disease and disease progression. Preoperative plasma IGFBP-3 levels were decreased in patients with prostate cancer metastases and were an independent predictor of biochemical progression after surgery, presumably because of an association with occult metastatic disease present at the time of radical prostatectomy.
Induction Chemotherapy Followed by Low-Dose Involved-Field Radiotherapy for Intracranial Germ Cell Tumors
Authors: Aoyama Hidefumi , Shirato Hiroki , Ikeda Jun , Fujieda Kenji , Miyasaka Kazuo , Sawamura Yutaka
Published: February 2017

PURPOSE: To investigate the efficacy of chemotherapy followed by low-dose involved-field radiotherapy for the treatment of intracranial germ cell tumors (GCTs).

PATIENTS AND METHODS: Thirty-three patients with GCTs, including 16 pure germinomas, 11 human chorionic gonadotropin-beta (HCG-β)–secreting germinomas, three mixed GCTs composed of immature teratomas plus germinomas (IMT/G), and three highly malignant mixed GCTs, were treated. Etoposide and cisplatin (EP) were used for the treatment of solitary pure germinomas, and ifosfamide, cisplatin, and etoposide (ICE) were used for the treatment of other GCTs. The dose schedule was 24 Gy for germinomas and 40 to 54 Gy for other GCTs. An involved-field set-up was used except for highly malignant GCTs, in which craniospinal irradiation was used. The median follow-up was 58 months (range, 18 to 102 months).

RESULTS: Disease-related, overall, and relapse-free survival rates at 5 years were 100%, 93%, and 69% for all patients, 100%, 100%, and 86% for patients with pure germinomas, and 100%, 75%, and 44% for patients with HCG-β-secreting germinomas, respectively. All six patients with nongerminomatous GCTs were alive at the last follow-up. All eight relapses (one pure germinoma, five HCG-β-secreting germinomas, and two IMT/G), except one in a course of salvage treatment, were salvaged and free of disease at the last follow-up. No decline was observed in the full-scale, verbal, or performance intelligence quotient at 12 to 51 months after the treatment in 11 patients.

CONCLUSION: Our results support an excellent prognosis after EP and ICE regimens followed by radiotherapy. Dose and volume can be reduced to 24 Gy in 12 fractions and involve a field set-up after EP chemotherapy for the treatment of pure germinomas.
Prognostic Significance of Cytokeratin-20 Reverse Transcriptase Polymerase Chain Reaction in Lymph Nodes of Node-Negative Colorectal Cancer Patients
Authors: Rosenberg Robert , Hoos Axel , Mueller James , Baier Patricia , Stricker Dominik , Werner Martin , Nekarda Hjalmar , Siewert Jörg-Rüdiger
Published: February 2017

PURPOSE: Approximately 20% to 30% of patients with curatively resected, node-negative (pN0) colorectal cancer die of tumor recurrence, which can be caused by minimal residual disease. To identify patients with an increased risk of tumor recurrence and evaluate the prognostic value of cytokeratin-20 (CK-20), we detected CK-20–positive cells in histopathologically tumor-free lymph nodes (pN0) of patients with colorectal cancer.

PATIENTS AND METHODS: Two peritumoral lymph nodes each from 85 patients with completely resected (R0) colorectal cancer without lymph node metastases (pN0) by routine examination were analyzed using a CK-20–specific reverse transcriptase polymerase chain reaction (RT-PCR) and compared with CK-20–specific immunohistochemistry (IHC). The results were correlated with histopathologic findings and with survival.

RESULTS: CK-20 RT-PCR was positive in 44 patients (52%) and detected 83% of cancer-related death. Positive RT-PCR was significantly correlated with poorer overall survival (P < .009). Comparing RT-PCR with IHC, 13 patients with positive RT-PCR were identified, where the CK-20 expression was caused by tumor cell contamination located exclusively outside the lymph node capsule and had no prognostic impact. Defining these 13 patients as RT-PCR negative improved specificity of the RT-PCR assay from 57% to 75%. The 5-year overall survival of the 31 RT-PCR–positive patients was 71%, compared with 96% in the 54 negative patients (P < .001). Multivariate analysis showed expression of CK-20 mRNA to be an independent prognostic factor with a relative risk of cancer-related death of 6.1.

CONCLUSION: CK-20 RT-PCR in peritumoral histopathologic tumor-free (pN0) lymph nodes of colorectal cancer is an independent prognostic factor for overall survival. Additional CK-20 IHC improves the specificity and prognostic value of RT-PCR for cancer-related death.
Determination of the Molecular Relationship Between Multiple Tumors Within One Patient Is of Clinical Importance
Authors: van der Sijp Joost R.M. , van Meerbeeck Jan P.A.M. , Maat Alex P.W.M. , Zondervan Pieter E. , Sleddens Hein F.B.M. , van Geel Albert N. , Eggermont Alex M.M. , Dinjens Winand N.M.
Published: February 2017

PURPOSE: To determine the molecular relationship between multiple tumors within one patient and to evaluate the impact of this knowledge on clinical management.

PATIENTS AND METHODS: In 25 consecutive patients with multiple tumors, proven by histology and immunohistochemistry to be identical, molecular aberrations were determined. Each patient had at least one lesion in the lung or head and neck region. Loss of heterozygosity (LOH) and p53 aberration analyses were carried out, and similar aberration profiles suggest clonality and metastasis whereas different profiles suggest independent primary tumors.

RESULTS: The molecular determinations indicated that 12 patients had a probable second primary tumor and 10 patients had a metastasis of the first lesion. In three patients, both an independent primary tumor and a metastasis were present. The molecular findings determined the course of additional treatment in all 10 patients with metastases, in all three patients with both a second primary tumor and a metastasis, and in seven of 12 patients with a second primary tumor.

CONCLUSION: By comparing DNA alterations of multiple tumors within one patient, the relationship between the tumors can be assessed. This study shows that in 20 of 25 patients, knowledge of the nature of both lesions was essential in clinical decision making. Furthermore, after thorough analysis of the five cases where clinical decision making was not influenced, there was in retrospect no clear indication for LOH or p53 analysis. Because these molecular analyses can be performed on routine specimens, they can be applied in almost all patients.
Postchemotherapy Ejaculatory Azoospermia: Fatherhood With Sperm From Testis Tissue With Intracytoplasmic Sperm Injection
Authors: Damani M. N. , Masters V. , Meng M. V. , Burgess C. , Turek P. , Oates R. D.
Published: February 2017

PURPOSE: To define the success of testis sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) in azoospermic men with a history of chemotherapy.

PATIENTS AND METHODS: In a retrospective study, 23 men with ejaculatory azoospermia and a history of chemotherapy underwent TESE in a search for usable spermatozoa. In six patients cryopreserved tissue and in nine patients fresh tissue provided sperm for an ICSI cycle. Histologic analysis of the testis was performed in all patients. The presence or absence of sperm, fertilization rates with ICSI, and final outcomes of pregnancy were recorded.

RESULTS: Spermatozoa were found on TESE in 15 (65.2%) of 23 men. On histopathology, the predominant pattern observed was Sertoli cell only (47.8%), followed by hypospermatogenesis (30.4%), mixed (17.4%), and late maturation arrest (4.3%). The fertilization rate was 65.2%, and ongoing/delivered pregnancies occurred in 30.8% of cycles. Six healthy boys and four healthy girls have been born to date.

CONCLUSION: Men who are azoospermic and have had prior cytotoxic therapy make up a small subgroup of males with nonobstructive azoospermia. It is important to define and characterize this subgroup and better define their true fertility potential. Approximately two thirds of these men have retrievable testis sperm, which may be used with ICSI to have healthy offspring. This exciting avenue for paternity has heretofore not been available to such patients.
Adrenocortical Carcinoma: Clinical, Morphologic, and Molecular Characterization
Authors: Stojadinovic Alexander , Ghossein Ronald A. , Hoos Axel , Nissan Aviram , Marshall David , Dudas Maria , Cordon-Cardo Carlos , Jaques David P. , Brennan Murray F.
Published: February 2017

PURPOSE: To define multimolecular phenotypes of adrenocortical carcinoma (ACC) and to correlate outcome with morphologic and molecular parameters.

PATIENTS AND METHODS: Clinical data were analyzed for 124 patients, histopathologic slides for 67 primary tumors, and tissue specimens for 74 patients (38 primary and 36 metastatic tumors) with ACC and for 38 normal adrenal tissue samples. Molecular expression profiles were investigated by immunohistochemistry. The prognostic significance of 12 gross and histologic parameters in 67 primary ACCs was evaluated. Morphologic and protein expression patterns were correlated with disease-specific survival (DSS). Univariate influence of prognostic factors on DSS was analyzed by log-rank test and multivariate analysis by Cox regression.

RESULTS: The median follow-up period was 4.7 years. Significant predictors of DSS included distant metastasis at time of initial presentation; venous, capsular, and adjacent organ invasion; tumor necrosis, mitotic rate, atypical mitosis, and mdm-2 overexpression. Five-year DSS by number (one to six) of adverse histologic parameters was as follows: one to two, 84%; three to four, 37%; more than four, 9% (P = .005).The phenotype Ki-67(−)p53(−)mdm-2(+)cyclinD1(−)Bcl-2(−)p21(−)p27(+) was observed in 83% of normal and 3% of malignant adrenal tissue (P = .01). Molecular phenotypic expression was more heterogeneous in malignant than in normal (10 v five phenotypes) adrenal tissue.

CONCLUSION: Meticulous morphologic evaluation, mitotic count, and tumor stage are essential in determining prognosis for patients with ACC. Multimolecular phenotyping demonstrates that the molecular complexity and heterogeneity of these neoplasms are such that targeted therapy needs to be patient specific.
Validation Study of the Accuracy of a Postoperative Nomogram for Recurrence After Radical Prostatectomy for Localized Prostate Cancer
Authors: Graefen Markus , Karakiewicz Pierre I. , Cagiannos Ilias , Klein Eric , Kupelian Patrick A. , Quinn David I. , Henshall Susan M. , Grygiel John J. , Sutherland Robert L. , Stricker Phillip D. , de Kernion Jean , Cangiano Thomas , Schröder Fritz H. , Wildhagen Mark F. , Scardino Peter T. , Kattan Michael W.
Published: February 2017

PURPOSE: A postoperative nomogram for prostate cancer was developed at Baylor College of Medicine. This nomogram uses readily available clinical and pathologic variables to predict 7-year freedom from recurrence after radical prostatectomy. We evaluated the predictive accuracy of the nomogram when applied to patients of four international institutions.

PATIENTS AND METHODS: Clinical and pathologic data of 2,908 patients were supplied for validation, and 2,465 complete records were used. Nomogram-predicted probabilities of 7-year freedom from recurrence were compared with actual follow-up in two ways. First, the area under the receiver operating characteristic curve (AUC) was calculated for all patients and stratified by the time period of surgery. Second, calibration of the nomogram was achieved by comparing the predicted freedom from recurrence with that of an ideal nomogram. For patients in whom the pathologic report does not distinguish between focal and established extracapsular extension (an input variable of the nomogram), two separate calculations were performed assuming one or the other.

RESULTS: The overall AUC was 0.80 when applied to the validation data set, with individual institution AUCs ranging from 0.77 to 0.82. The predictive accuracy of the nomogram was apparently higher in patients who were operated on between 1997 and 2000 (AUC, 0.83) compared with those treated between 1987 and 1996 (AUC, 0.78). Nomogram predictions of 7-year freedom from recurrence were within 10% of an ideal nomogram.

CONCLUSION: The postoperative Baylor nomogram was accurate when applied at international treatment institutions. Our results suggest that accurate predictions may be expected when using this nomogram across different patient populations.
BRCA1 and BRCA2 Mutation Frequency in Women Evaluated in a Breast Cancer Risk Evaluation Clinic
Authors: Shih Helen A. , Couch Fergus J. , Nathanson Katherine L. , Blackwood M. Anne , Rebbeck Timothy R. , Armstrong Katrina A. , Calzone Kathleen , Stopfer Jill , Seal Sheila , Stratton Michael R. , Weber Barbara L.
Published: February 2017

PURPOSE: To determine the prevalence of BRCA1 and BRCA2 mutations in families identified in a breast cancer risk evaluation clinic.

PATIENTS AND METHODS: One hundred sixty-four families seeking breast cancer risk evaluation were screened for coding region mutations in BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis and DNA sequencing.

RESULTS: Mutations were identified in 37 families (22.6%); 28 (17.1%) had BRCA1 mutations and nine (5.5%) had BRCA2 mutations. The Ashkenazi Jewish founder mutations 185delAG and 5382insC (BRCA1) were found in 10 families (6.1%). However, 6174delT (BRCA2) was found in only one family (0.6%) despite estimates of equal frequency in the Ashkenazi population. In contrast to other series, the average age of breast cancer diagnosis was earlier in BRCA2 mutation carriers (32.1 years) than in women with BRCA1 mutations (37.6 years, P = .028). BRCA1 mutations were detected in 20 (45.5%) of 44 families with ovarian cancer and 12 (75%) of 16 families with both breast and ovarian cancer in a single individual. Significantly fewer BRCA2 mutations (two [4.5%] of 44) were detected in families with ovarian cancer (P = .01). Eight families had male breast cancer; one had a BRCA1 mutation and three had BRCA2 mutations.

CONCLUSION: BRCA1 mutations were three times more prevalent than BRCA2 mutations. Breast cancer diagnosis before 50 years of age, ovarian cancer, breast and ovarian cancer in a single individual, and male breast cancer were all significantly more common in families with BRCA1 and BRCA2 mutations, but none of these factors distinguished between BRCA1 and BRCA2 mutations. Evidence for reduced breast cancer penetrance associated with the BRCA2 mutation 6174delT was noted.
Phase II Trial of Chronomodulated Infusion of High-Dose Fluorouracil and l-Folinic Acid in Previously Untreated Patients With Metastatic Colorectal Cancer
Authors: Curé H. , Chevalier V. , Adenis A. , Tubiana-Mathieu N. , Niezgodzki G. , Kwiatkowski F. , Pezet D. , Perpoint B. , Coudert B. , Focan C. , Lévi F. , Chipponi J. , Chollet P.
Published: February 2017

PURPOSE: To study tolerability and efficacy of an intensified chronomodulated schedule of fluorouracil (5-FU) and l-folinic acid (l-FA) as first-line treatment of metastatic colorectal cancer, 5-FU was given near individually determined dose-limiting toxicity in a multicenter phase II trial.

PATIENTS AND METHODS: One hundred patients (68 men and 32 women, median age 62 years, World Health Organization performance status ≤ 2) with previously untreated and inoperable metastases received chronomodulated daily infusion of 5-FU/l-FA (from 10:00 pm to 10:00 am with peak at 4:00 am). 5-FU dose was escalated from 900 to 1,100 mg/m2/d with fixed dose of l-FA at 150 mg/m2/d for 4 days every 14 days.

RESULTS: 5-FU dose escalation was achieved in 66% of the patients. Grade 3 to 4 toxicities mainly consisted of nausea or vomiting (14% of patients and 1.5% of courses), hand-foot syndrome (38% of patients and 8% of courses), mucositis (26% of patients and 4% of courses), and diarrhea (21% of patients and 2.3% of courses). Objective response rate (ORR) was 41% (95% confidence interval, 31.5% to 50.5%). Twenty patients underwent metastases surgery; among these, 12 had a complete resection. Median progression-free survival was 7 months. Median survival was 17 months; 28% of the patients were alive at 2 years and 18.6% at 3 years.

CONCLUSION: The ORR achieved with intensified chronomodulated delivery of 5-FU/l-FA was nearly twice as high as that earlier obtained by our cooperative group using less intensive 5-FU/FA chronotherapy.
Survival Effect of Maximal Cytoreductive Surgery for Advanced Ovarian Carcinoma During the Platinum Era: A Meta-Analysis
Authors: Bristow Robert E. , Tomacruz Rafael S. , Armstrong Deborah K. , Trimble Edward L. , Montz F. J.
Published: February 2017

PURPOSE: To evaluate the relative effect of percent maximal cytoreductive surgery and other prognostic variables on survival among cohorts of patients with advanced-stage ovarian carcinoma treated with platinum-based chemotherapy.

MATERIALS AND METHODS: Eighty-one cohorts of patients with stage III or IV ovarian carcinoma (6,885 patients) were identified from articles in MEDLINE (1989 through 1998). Linear regression models, with weighted correlation calculations, were used to assess the effects on log median survival time of the proportion of each cohort undergoing maximal cytoreduction, dose-intensity of the platinum compound administered, proportion of patients with stage IV disease, median age, and year of publication.

RESULTS: There was a statistically significant positive correlation between percent maximal cytoreduction and log median survival time, and this correlation remained significant after controlling for all other variables (P < .001). Each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time. When actuarial survival was estimated, cohorts with ≤ 25% maximal cytoreduction had a mean weighted median survival time of 22.7 months, whereas cohorts with more than 75% maximal cytoreduction had a mean weighted median survival time of 33.9 months—an increase of 50%. The relationship between platinum dose-intensity and log median survival time was not statistically significant.

CONCLUSION: During the platinum era, maximal cytoreduction was one of the most powerful determinants of cohort survival among patients with stage III or IV ovarian carcinoma. Consistent referral of patients with apparent advanced ovarian cancer to expert centers for primary surgery may be the best means currently available for improving overall survival.
Increasing Single Epirubicin Doses in Advanced Soft Tissue Sarcomas
Authors: Lopez Massimo , Vici Patrizia , Di Lauro Luigi , Carpano Silvia
Published: February 2017

PURPOSE: To evaluate the maximum-tolerated dose and the clinical efficacy of epirubicin in patients with advanced soft tissue sarcoma.

PATIENTS AND METHODS: Sixty-one patients were treated at three different epirubicin dose levels: 140 mg/m2 (six patients), 160 mg/m2 (52 patients), and 180 mg/m2 (three patients). Cycles were repeated every 3 weeks for a maximum of eight cycles. The first two dose levels proved to be feasible and safe without dose-limiting toxicity (DLT). Because the first three patients entering the third dose level experienced DLT, subsequent patients received the next lower dose level.

RESULTS: The overall response rate was 44% (95% confidence interval, ± 12%), with six complete (10%) and 21 partial (34%) responses. Responses seemed related to epirubicin dose level, because the response rate was 17%, 44%, and 100% for the three dose levels (χ2 test for trend, P = .02). Median response duration, median time to progression, and median overall survival were 10, 8, and 15 months, respectively. Myelosuppression was the most frequent side effect, with grade 3 or 4 neutropenia occurring in 79% of the patients; 31% of patients were febrile. Nonhematologic toxicity was mainly grades 1 and 2. The mean epirubicin dose-intensity was 49 mg/m2 per week.

CONCLUSION: The third epirubicin dose level (180 mg/m2) was the maximum-tolerated dose. The recommended drug dose for clinical use is 160 mg/m2 every 3 weeks with hematopoietic support. Single high-dose epirubicin is effective as first-line treatment and should be preferentially used whenever a high response rate is important to allow the resection of an otherwise unresectable disease or whenever it might result in a significant symptomatic benefit.
Economic Analysis of the TAX 317 Trial: Docetaxel Versus Best Supportive Care as Second-Line Therapy of Advanced Non–Small-Cell Lung Cancer
Authors: Leighl Natasha B. , Shepherd Frances A. , Kwong Rita , Burkes Ronald L. , Feld Ronald , Goodwin Pamela J.
Published: February 2017

PURPOSE: To determine the cost-effectiveness (CE) of second-line docetaxel compared with best supportive care (BSC) in the TAX 317 trial, a randomized clinical trial of second-line chemotherapy in non–small-cell lung cancer.

METHODS: A retrospective CE analysis of the TAX 317 trial was undertaken, evaluating direct medical costs of therapy from the viewpoint of Canada’s public health care system. Costs were derived in 1999 Canadian dollars, and resource use was determined through prospective trial data.

RESULTS: The incremental survival benefit in the docetaxel arm over BSC was 2 months (P = .047). The CE of docetaxel was $57,749 per year of life gained. For patients treated with docetaxel 75 mg/m2, the CE was $31,776 per year of life gained. In univariate sensitivity analyses, CE estimates were most sensitive to changes in survival, ranging from $18,374 to $117,434 with 20% variation in survival at the recommended dose. The largest cost center in both arms was hospitalization, followed by the cost of drugs, investigations, radiotherapy, and community care. BSC patients had fewer hospitalizations than patients in the chemotherapy arm and were more often palliated at home.

CONCLUSION: Although the decision to treat should not be based on economic considerations alone, our CE estimate of $31,776 per year of life gained (at the currently recommended dose of docetaxel) is within an acceptable range of health care expenditures, and the total costs of therapy are similar to those of second-line palliative chemotherapy for other solid tumors.
Phase II Trial of Temozolomide Plus the Matrix Metalloproteinase Inhibitor, Marimastat, in Recurrent and Progressive Glioblastoma Multiforme
Authors: Groves Morris D. , Puduvalli Vinay K. , Hess Kenneth R. , Jaeckle Kurt A. , Peterson Pamela , Alfred Yung W.K. , Levin Victor A.
Published: February 2017

PURPOSE: Novel therapies are needed for patients with recurrent glioblastoma multiforme (GBM). Because there is evidence that temozolomide (TMZ) has some activity in GBM and is well tolerated, and because of laboratory evidence that metalloproteinases are important in glioma cell invasion, the combination of TMZ and the matrix metalloproteinase inhibitor marimastat (MRM) in patients with recurrent GBM was studied.

PATIENTS AND METHODS: Forty-four patients with recurrent GBM after standard radiotherapy were enrolled. For 19 patients, this therapy was their first chemotherapy after tumor progression after irradiation; 25 others had received chemotherapy previously. TMZ 150 to 200 mg/m2 days 1 to 5 and MRM 50 mg days 8 to 28 was administered at 28-day intervals for two cycles; then patients were reevaluated. Treatment continued until progression of tumor or toxicity developed.

RESULTS: Joint and tendon pain was the major therapy-related toxicity and was reported in 47% of patients. Five patients (11%) were removed from the study because of intolerable joint pain. For all patients, the progression-free survival (PFS) at 6 months was 39%. Median PFS was 17 weeks, median overall survival was 45 weeks, and 12-month PFS was 16%.

CONCLUSION: The combination of TMZ and MRM resulted in a PFS at 6 months that exceeded the literature target by 29%. This drug combination met phase II study criteria; further study in recurrent patients with GBM might be warranted. Further study of therapy-induced joint pain is necessary.
Protracted Intermittent Schedule of Topotecan in Children With Refractory Acute Leukemia: A Pediatric Oncology Group Study
Authors: Furman Wayne L. , Stewart Clinton F. , Kirstein Mark , Kepner James L. , Bernstein Mark L. , Kung Faith , Vietti Teresa J. , Steuber C. Philip , Becton David Lee , Baruchel Sylvain , Pratt Charles
Published: February 2017

PURPOSE: To determine dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of a protracted, intermittent schedule of daily 30-minute infusions of topotecan (TPT) for up to 12 consecutive days, every 3 weeks, in children with refractory leukemia.

PATIENTS AND METHODS: Forty-nine children were enrolled onto this phase I trial (24 with acute nonlymphoblastic leukemia [ANLL] and 25 with acute lymphoblastic leukemia [ALL]). TPT dosage was escalated from 2.0 to 5.2 mg/m2/d for 5 days and 2.4 mg/m2/d from 7 days to the same dose for 9 and 12 days in cohorts of three to six patients when no DLT was identified. TPT pharmacokinetics were studied in 33 children once or twice (first and last doses in patients who received TPT for > 7 days).

RESULTS: Seventy assessable courses of TPT were administered to 49 children who had refractory leukemia. DLTs were typhlitis, diarrhea, and mucositis, and the MTD was 2.4 mg/m2/d for 9 days in this group of heavily pretreated children. In 33 patients, the median TPT lactone clearance after the first dose was 19.2 L/h/m2 (range, 9.4 to 45.9 L/h/m2) and did not change during the course. There were significant responses (one complete response [CR] and four partial responses [PR] in patients with ANLL and one CR and two PRs in patients with ALL), and all but one were at dosages of TPT given for at least 9 days.

CONCLUSION: The MTD was 2.4 mg/m2/d for 9 days. Further testing is warranted of TPT’s schedule dependence in children with leukemia.
Adjuvant Radiation for Stage II-B Soft Tissue Sarcoma of the Extremity
Authors: Alektiar Kaled M. , Leung Dennis , Zelefsky Michael J. , Brennan Murray F.
Published: February 2017

PURPOSE: Adjuvant radiation therapy (RT) has been shown to improve local control in patients with high-grade soft tissue sarcoma (STS) of the extremity. This study sought to define the optimal management in patients with stage II-B (high-grade, size ≤ 5 cm) tumors.

PATIENTS AND METHODS: Between July 1982 and December 1998, 204 adult patients with primary stage II-B STS underwent limb-sparing surgery with negative microscopic margins. Eighty-eight patients (43%) received RT; 116 (57%) did not. The RT and no-RT groups were balanced with regard to age, site (upper v lower extremity), whether patients had prior unplanned excision, and location (central, ie, shoulder/groin v noncentral). The RT group had more deep tumors (P = .03). Adjuvant RT was delivered with brachytherapy in 60% and external-beam radiation in 40% of patients.

RESULTS: With a median follow-up of 67 months, the 5-year local control, distant relapse-free survival, and disease-specific survival rates were 82%, 80%, and 88%, respectively. There was no significant difference in local control between the RT and no-RT groups (84% v 80%, respectively, P = .3). Tumor depth, site, and prior unplanned excision did not correlate with local control. The only independent predictors of poor local control were central tumor location (relative risk [RR] = 3; 95% confidence interval [CI], 2 to 7; P = .005) and age more than 50 years (RR = 6; 95% CI, 2 to 13; P = .001).

CONCLUSION: In this retrospective study, adjuvant RT did not significantly improve local control in patients with stage II-B STS of the extremity. The outcome of patients with central tumor location was poor, and efforts to identify the optimal local treatment approach for such patients are warranted.
Long-term follow-up results of EORTC 26951: A randomized phase III study on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors (AOD).
Authors: Van Den Bent Martin J. , Hoang-Xuan Khê , Brandes Alba Ariela , Kros Johan M , Kouwenhoven Mathilde C.M. , Taphoorn Martin J. B. , Delattre Jean-Yves , Bernsen Hans J.J.B. , Frenay Marc , Tijssen Cees , Grisold Wolfgang , Sipos Laszlo , Enting Roelien H. , Dinjens Winand N.M. , French Pim , Vecht Charles J , Allgeier Anouk , Lacombe Denis A. , Gorlia Thierry
Published: February 2017

2

Background: AOD are chemotherapy-sensitive tumors especially if 1p/19q co-deleted. Between 1995 and 2002 the EORTC Brain Tumor Group conducted a prospective phase III study on adjuvant procarbazine, CCNU and vincristine chemotherapy (PCV) in AOD. We now present long-term follow-up. Methods: Patients (pts) with locally diagnosed newly diagnosed AOD were randomized between radiotherapy (RT, 33 x 1.8 Gy) and the same RT followed by 6 cycles of standard PCV (RT/PCV). Primary endpoints were overall survival (OS) and progression-free survival (PFS). 1p/19q status, IDH status and MGMT promoter methylation were determined in 300, 167, and 186 pts respectively. Results: Between 1996 and 2002, 368 pts were included. At the time of analysis 281 pts (76.4%) had died. Median PFS after RT/PCV was significantly longer compared to RT alone (24.3 months versus 13.21 months, hazard ratio [HR] 0.66, [95% confidence interval (95% CI) 0.52, 0.83]). More RT arm patients received chemotherapy at progression (75% vs 53%). Median OS was also significantly prolonged in the RT/PCV arm (42.3 months vs 30.6 months for the RT arm, HR 0.75 [95% CI 0.60, 0.95]). 1p/19q co-deleted patients (n = 76) treated with RT/PCV had improved OS compared to RT arm pts (median OS not reached vs 113 months; HR 0.54, p = 0.0487). In the 224 patients without 1p/19q co-deletion the difference in OS was non-significant (OS RT/PCV arm 25 months vs 22 months in the RT arm, HR 0.82, p = 0.18; test for interaction p = 0.22). There was a slight trend towards improved OS in MGMT methylated and IDH mutated tumors versus unmethylated and IDH wild type tumors (Table). Conclusions: The addition of PCV to RT increases PFS and OS in AOD. Pts with 1p/19q co-deletion appear to benefit most from the addition of PCV, with a trend for improved OS in pts with MGMT methylation and IDH mutations. [Table: see text]
CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC).
Authors: Rugo Hope S. , Barry William Thomas , Moreno-Aspitia Alvaro , Lyss Alan P. , Cirrincione Constance , Mayer Erica L. , Naughton Michael , Layman Rachel M. , Carey Lisa A. , Somer Robert A. , Perez Edith A. , Hudis Clifford , Winer Eric P.
Published: February 2017

CRA1002

Background: Weekly P is superior to q 3 week (wk) dosing, and adding B improves progression free survival (PFS) (E2100). Ix is a potent epothilone that can be effective after microtubule inhibitor resistance. NP is a novel albumin-bound formulation of P with promising activity in the first-line MBC setting. In this phase III trial, the efficacy of weekly Ix or NP is compared to P, in combination with B in patients (pts) with chemotherapy (CTX) naïve MBC. Toxicity including >Grade 2 sensory neuropathy (SN) is compared to P. Methods: Pts were randomized 1:1:1 to receive P (90 mg/m2), Ix (16 mg/m2) or NP (150 mg/m2) on a 3 wk on, 1 wk off schedule, stratified by prior adjuvant taxane use and hormone receptor status. B was initially given to all pts, but became optional in 3/2011 and was added to stratification. The primary end point of PFS is defined as time from randomization to progression or all-cause death. With a target N=900 pts, the study was powered to detect a hazard ratio (HR) of 1.36 (median PFS 10 vs 13.6 mos). Eligibility included no prior CTX for MBC, >12 mos from adjuvant P and measurable disease. Results: 799 pts were enrolled between 11/08-11/11 (283 to P, 271 to NP, 245 to Ix); 98% received B. 72% had ER+ disease, 44% received adjuvant P. At the 1st interim analysis (165 events) the comparison of Ix to P crossed the futility boundary (FB) and accrual to Ix was closed. At the 2nd interim analysis (236 events), NP to P crossed the FB and the study was closed on 11/30/11. Median PFS was 10.4, 9.6 and 7.6 mos for P, NP and Ix, with HRs (95% CIs) of 0.94 (0.73-1.22) and 0.66 (0.51-0.84) for P to NP and Ix respectively. Grade 2+ SN was 48% for NP, 44% for Ix and 37% for P; Grade 3+ hematologic toxicity was 49% for NP, 20% for Ix, and 12% for P. Conclusions: In pts with CTX naive MBC, both NP and Ix are highly unlikely to be superior to P for PFS (when all are combined with B), and in combination with B, weekly P is the better tolerated drug. Toxicity including SN was greater in each experimental arm compared to P. Updated data will be presented, and correlative studies will be reported at a future date.
Regional screening network for characterization of the molecular epidemiology of non-small cell lung cancer (NSCLC) and implementation of personalized treatment.
Authors: Zander Thomas , Heukamp Lukas Carl , Bos Marc Christiaan Allardt , Fassunke Jana , Mattonet Christian , Merkelbach-Bruse Sabine , Ko Yon-Dschun , Schlesinger Andreas , Brockmann Michael , Serke Monika , Gerigk Ulrich , Hekmat Khosro , Engel-Riedel Walburga , Stoelben Erich , Reiser Marcel , Schulz Holger , Schmitz Stephan H. , Frank Konrad , Buettner Reinhard , Wolf Juergen
Published: February 2017

CRA10529

Background: Personalized treatment of genetically stratified subgroups has the potential to substantially improve outcome in NSCLC. A major challenge now is to implement high-quality molecular diagnostics and personalized treatment strategies in routine clinical practice also outside of highly specialized academic centers. Methods: We have established a molecular screening network in the catchment area of our comprehensive cancer center encompassing about 2.5 million inhabitants in March 2010 after review of the local ethics committee (10-242). Lung adenocarcinoma (AD) was screened centrally for ALK translocations, mutations in KRAS, EGFR, BRAF and PIK3CA and for amplification of ERBB2. Squamous cell carcinoma (SQ) was analyzed for FGFR1 amplifications. Results: 2032 NSCLC samples were acquired of which 1782 in the Cologne-Bonn area indicating a capture rate of 60-70% of all NSCLC samples in the area. Material was suitable for molecular analysis in 77%. Distribution of histological subtypes was as expected (AD 63.4%, SQ 26.7, large cell carcinoma 1.4%, adenosquamous cell carcinoma 1.8%, carcinoid 0.1%, NSCLC NOS 6.7%. In AD the following frequencies of genetic lesions were detected: KRAS (32%), EGFR (13%), ALK (3%), BRAF (2%), PIK3CA (2%), ERBB2 (2%). EGFR mutations were highly enriched in the lepidic and micropapillary subtype of AD (30-32%), whereas the solid subtype only harboured a very small amount of the tested oncogenic lesions. In SQ FGFR1 amplification was detected in 78/500. Overall 40% of all NSCLC samples harboured potentially tractable oncogenic lesions. All patients with ALK translocations received crizotinib when clinically indicated. 75% of the stage IIIB/IV patients with activating EGFR mutations received EGFR-TKI treatment. In addition, clinical trials have been initiated to provide personalized treatment options to all patients with tractable genetic lesions. Conclusions: High-quality molecular diagnostics and identification of patients for personalized treatment approaches is feasible in daily clinical routine for the majority of diagnostic samples also in a non-academic setting.