bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient Preferences Versus Physician Perceptions of Treatment Decisions in Cancer Care
Authors: Bruera Eduardo , Sweeney Catherine , Calder Kathryn , Palmer Lynn , Benisch-Tolley Suzanne
Published: February 2017

PURPOSE: To examine patient preferences as well as physician perceptions of these preferences for decision making and communication in palliative care.

PATIENTS AND METHODS: Medical decision-making preferences (DMPs) were prospectively studied in 78 assessable cancer patients after initial assessment at a palliative care outpatient clinic. DMPs were assessed with a questionnaire using five possible choices ranging from 1 (patient prefers to make the treatment decision) to 5 (patient prefers the physician to make the decision). In addition, the physician’s perception of this preference was assessed.

RESULTS: Full concordance between the physician and the patient was seen in 30 (38%) of 78 cases; when the five original categories were recombined to cover active, shared, and passive decision making, there was concordance in 35 (45%) of 78 cases. The kappa coefficient for agreement between physician and patient was poor at 0.14 (95% confidence limit, −0.01 to 0.30) for simple kappa and 0.17 (95% confidence interval [CI], 0.00 to 0.34) for weighted kappa (calculated on the three regrouped categories). Active, shared, and passive DMPs were chosen by 16 (20%) of 78, 49 (63%) of 78, and 13 (17%) of 78 patients, and by 23 (29%) of 78, 30 (39%) of 78, and 25 (32%) of 78 physicians, respectively. The majority of patients (49 [63%] of 78; 95% CI, 0.51 to 0.74) preferred a shared approach with physicians. Physicians predicted that patients preferred a less shared approach than they in fact did. Patient age or sex did not significantly alter DMP.

CONCLUSION: An individual approach is needed and each patient should be assessed prospectively for DMP.
Low-Dose Radiation Is Sufficient for the Noninvolved Extended-Field Treatment in Favorable Early-Stage Hodgkin’s Disease: Long-Term Results of a Randomized Trial of Radiotherapy Alone
Authors: Dühmke Eckhart , Franklin Jeremy , Pfreundschuh Michael , Sehlen Susanne , Willich Norman , Rühl Ursula , Müller Rolf-Peter , Lukas Peter , Atzinger Anton , Paulus Ursula , Lathan Bernd , Rüffer Ulrich , Sieber Markus , Wolf Jürgen , Engert Andreas , Georgii Axel , Staar Susanne , Herrmann Richard , Beykirch Maria , Kirchner Hartmut , Emminger Adelheid , Greil Richard , Fritsch Esther , Koch Peter , Drochtert Angelika , Brosteanu Oana , Hasenclever Dirk , Loeffler Markus , Diehl Volker
Published: February 2017

PURPOSE: To show that radiotherapy (RT) dose to the noninvolved extended field (EF) can be reduced without loss of efficacy in patients with early-stage Hodgkin’s disease (HD).

PATIENTS AND METHODS: During 1988 to 1994, pathologically staged patients with stage I or II disease who were without risk factors (large mediastinal mass, extranodal lesions, massive splenic disease, elevated erythrocyte sedimentation rate, or three or more involved areas) were recruited from various centers. All patients received 40 Gy total fractionated dose to the involved field areas but were randomly assigned to receive either 40 Gy (arm A) or 30 Gy (arm B) total fractionated dose for the clinically noninvolved EF. No chemotherapy was given. RT films were prospectively reviewed for protocol violations and recurrences retrospectively related to the applied RT.

RESULTS: Of 382 recruited patients, 376 were eligible for randomized comparison, 190 in arm A and 186 in arm B. Complete remission was attained in 98% of patients in each arm. With a median follow-up of 86 months, 7-year relapse-free survival (RFS) rates were 78% (arm A) and 83% (arm B) (P = .093). The upper 95% confidence limit for the possible inferiority of arm B in RFS was 4%. Corresponding overall survival rates were 91% (arm A) and 96% (arm B) (P = .16). The most common causes of death (n = 27) were cardiorespiratory disease/pulmonary embolisms (seven), second malignancy (six), and HD (five). Protocol violation was associated with significantly poorer RFS. Nonirradiated nodes were involved in 42 of 52 reviewed relapses, infield areas in 18, marginal areas in 17, and extranodal sites in 16.

CONCLUSION: EF-RT alone attains good survival rates in favorable early-stage HD. The 30-Gy dose is adequate for clinically noninvolved areas. Protocol violation worsens the subsequent prognosis. Relapse patterns suggest that systemic therapy can reduce the 20% long-term relapse rate.
Intergroup Rhabdomyosarcoma Study-IV: Results for Patients With Nonmetastatic Disease
Authors: Crist William M. , Anderson James R. , Meza Jane L. , Fryer Christopher , Raney R. Beverly , Ruymann Frederick B. , Breneman John , Qualman Stephen J. , Wiener Eugene , Wharam Moody , Lobe Thom , Webber Bruce , Maurer Harold M. , Donaldson Sarah S.
Published: February 2017

PURPOSE: The study goal was to improve outcome in children with rhabdomyosarcoma by comparing risk-based regimens of surgery, radiotherapy (RT) and chemotherapy.

PATIENTS AND METHODS: Eight hundred eighty-three previously untreated eligible patients with nonmetastatic rhabdomyosarcoma entered the Intergroup Rhabdomyosarcoma Study-IV (IRS-IV) (1991 to 1997) after surgery and were randomized treatment by primary tumor site, group (1 to 3), and stage (I to III). Failure-free survival (FFS) rates and survival were the end points used in comparisons between randomized groups and between patient subgroups treated on IRS-III and IRS-IV. Most patients were randomized to receive vincristine and dactinomycin (VA) and cyclophosphamide (VAC, n = 235), or VA and ifosfamide (VAI, n = 222), or vincristine, ifosfamide, and etoposide (VIE, n = 236). Patients with group 3 tumors were randomized to receive conventional RT (C-RT) versus hyperfractionated RT (HF-RT).

RESULTS: Overall 3-year FFS and survival were 77% and 86%, respectively. Three-year FFS rates with VAC, VAI, and VIE were 75%, 77%, and 77%, respectively (P = .42). No significant difference in outcome was noted with HF-RT versus C-RT (P = .85 and P = .90, respectively). Overall, patients with embryonal tumors benefited from intensive three-drug chemotherapy in IRS-IV (3-year FFS, 83%). The improvement was seen for patients with stage I or stage II/III, group 1/2 disease, many of whom received VA chemotherapy on IRS-III. Patients with stage 2/3, group 3 disease had similar outcomes on IRS-III and IRS-IV. Three-year FFS for the nonrandomized patient subsets was 75% with renal abnormalities; 81% for paratesticular, group 1 cases; and 91% for group 1/2 orbit or eyelid tumors. Patients with paratesticular primaries had poorer outcomes if they were more than 10 years old (3-year FFS, 63% v 90%). Myelosuppression occurred in most patients, but toxic deaths occurred in less than 1%.

CONCLUSION: VAC and VAI or VIE with surgery (with or without RT), are equally effective for patients with local or regional rhabdomyosarcoma and are more effective for embryonal tumors than therapies used previously. Younger patients with group 1 paratesticular embryonal tumors and all patients with group 1/2 orbit or eyelid tumors can usually be cured with VA chemotherapy along with postoperative RT for group 2 disease.
Phase I Trial of Pegylated Liposomal Doxorubicin and Docetaxel in Advanced Breast Cancer
Authors: Sparano Joseph A. , Malik Umekalsoom , Rajdev Lakshmi , Sarta Catherine , Hopkins Una , Wolff Antonio C.
Published: February 2017

PURPOSE: To develop a combination of pegylated liposomal doxorubicin (Doxil; Alza Pharmaceuticals, Palo Alto, CA) and docetaxel (Taxotere; Aventis Pharmaceutical, Parsipanny, NJ) that can be safely used for the treatment of advanced breast cancer.

PATIENTS AND METHODS: Forty-one patients with locally advanced (n = 10) or metastatic (n = 31) breast cancer received Doxil (30-, 40-, or 45-mg/m2 intravenous [IV] infusion over 30 to 60 minutes), followed 1 hour later by docetaxel (60 or 75 mg/m2 by IV infusion over 1 hour) in cohorts of three to six patients. Dose-limiting toxicity (DLT) was defined as febrile neutropenia, prolonged neutropenia, or grade 3 to 4 nonhematologic toxicity that occurred during cycle 1.

RESULTS: In conjunction with docetaxel 75 mg/m2 every 4 weeks, the MTD of Doxil was 30 mg/m2 and required granulocyte colony-stimulating factor (G-CSF) to prevent febrile neutropenia. Without G-CSF, the MTD was docetaxel 60 mg/m2 and Doxil 30 mg/m2 every 3 weeks; only 1 (7%) out of 15 patients treated at this dose level had cycle 1 DLT. Infusion reactions were common with Doxil with the recommended infusion schedule during the first cycle (55%) but were reduced with a modified schedule (7%). There was no clinically significant cardiac toxicity. Objective response occurred in eight of nine assessable patients with stage III disease and in 16 (52%) of 31 patients (95% confidence interval, 34% to 70%) with stage IV disease.

CONCLUSION: The recommended dose and schedule of this combination for further evaluation is Doxil 30 mg/m2 and docetaxel 60 mg/m2 given every 3 weeks without G-CSF. When used with G-CSF, it is Doxil 30 mg/m2 and docetaxel 75 mg/m2 every 4 weeks.
Late Mortality Experience in Five-Year Survivors of Childhood and Adolescent Cancer: The Childhood Cancer Survivor Study
Authors: Mertens Ann C. , Yasui Yutaka , Neglia Joseph P. , Potter John D. , Nesbit Mark E. , Ruccione Kathy , Smithson W. Anthony , Robison Leslie L.
Published: February 2017

PURPOSE: Survivors of childhood and adolescent cancer are at risk for long-term effects of disease and treatment. The Childhood Cancer Survivor Study assessed overall and cause-specific mortality in a retrospective cohort of 20,227 5-year survivors.

PATIENTS AND METHODS: Eligible subjects were individuals diagnosed with cancer (from 1970 to 1986) before the age of 21 who had survived 5 years from diagnosis. Underlying cause of death was obtained from death certificates and other sources and coded and categorized as recurrent disease, sequelae of cancer treatment, or non–cancer-related. Age and sex standardized mortality ratios (SMRs) were calculated using United States population mortality data.

RESULTS: The cohort, including 208,947 person-years of follow-up, demonstrated a 10.8-fold excess in overall mortality (95% confidence interval, 10.3 to 11.3). Risk of death was statistically significantly higher in females (SMR = 18.2), individuals diagnosed with cancer before the age of 5 years (SMR = 14.0), and those with an initial diagnosis of leukemia (SMR = 15.5) or CNS tumor (SMR = 15.7). Recurrence of the original cancer was the leading cause of death among 5-year survivors, accounting for 67% of deaths. Statistically significant excess mortality rates were seen due to subsequent malignancies (SMR = 19.4), along with cardiac (SMR = 8.2), pulmonary (SMR = 9.2), and other causes (SMR = 3.3). Treatment-related associations were present for subsequent cancer mortality (radiation, alkylating agents, epipodophyllotoxins), cardiac mortality (chest irradiation, bleomycin), and other deaths (radiation, anthracyclines). No excess mortality was observed for external causes (SMR = 0.8).

CONCLUSION: While recurrent disease remains a major contributor to late mortality in 5-year survivors of childhood cancer, significant excesses in mortality risk associated with treatment-related complications exist up to 25 years after the initial cancer diagnosis.
Phase II Study of Sequential Administration of Docetaxel Followed by Doxorubicin and Cyclophosphamide as First-Line Chemotherapy in Metastatic Breast Cancer
Authors: Khayat D. , Chollet P. , Antoine E. C. , Monfardini S. , Ambrosini G. , Benhammouda A. , Mazen M.-F. , Sorio R. , Borg-Olivier O. , Riva A. , Ramazeilles C. , Azli N.
Published: February 2017

PURPOSE: To evaluate the feasibility and efficacy of a sequential administration of four cycles of docetaxel (100 mg/m2 every 3 weeks) followed by four cycles of doxorubicin and cyclophosphamide (AC; 60/600 mg/m2 every 3 weeks), with subsequent consolidation with docetaxel or AC, as first-line chemotherapy in patients with metastatic breast cancer (MBC).

PATIENTS AND METHODS: Forty-eight patients received 443 cycles of chemotherapy (median, 11 cycles/patient; range, 1 to 13 cycles). A total of 267 cycles of docetaxel (60.3%) and 176 of AC (39.7%) were given. Consolidation therapy was given to 33 patients (29 with docetaxel).

RESULTS: Grade 4 neutropenia was the most frequent toxicity (83% of patients). This was not cumulative and was rarely complicated by febrile neutropenia or severe infection. The nonhematologic safety profile was favorable: there were no grade 4 adverse events, and grade 3 episodes were infrequent. Docetaxel-specific toxicities were generally not severe. With a median cumulative doxorubicin dose of 397 mg/m2 (range, 150 to 543 mg/m2), two incidences of unrelated congestive heart failure after further treatment with anthracyclines and two of asymptomatic left ventricular ejection fraction decrease were observed. Among the 42 assessable patients, five (12%) had complete and 25 (60%) had partial responses, for an overall response rate of 71% (95% confidence interval, 55% to 84%). Median duration of response was 53 weeks (range, 12 to 72 weeks), and median time to progression was 46 weeks (range, 3 of 72 weeks). With a median follow-up of 40.4 months, median survival was 32 months (range, 2 to 55 months).

CONCLUSION: This docetaxel-based sequential schedule is safe and effective in first-line therapy for MBC, without incurring cumulative toxicity, and provides a feasible chemotherapeutic option in this clinical setting.
Comparison of Breast Magnetic Resonance Imaging, Mammography, and Ultrasound for Surveillance of Women at High Risk for Hereditary Breast Cancer
Authors: Warner E. , Plewes D. B. , Shumak R. S. , Catzavelos G. C. , Di Prospero L. S. , Yaffe M. J. , Goel V. , Ramsay E. , Chart P. L. , Cole D. E.C. , Taylor G. A. , Cutrara M. , Samuels T. H. , Murphy J. P. , Murphy J. M. , Narod S. A.
Published: February 2017

PURPOSE: Recommended surveillance for BRCA1 and BRCA2 mutation carriers includes regular mammography and clinical breast examination, although the effectiveness of these screening techniques in mutation carriers has not been established. The purpose of the present study was to compare breast magnetic resonance imaging (MRI) with ultrasound, mammography, and physical examination in women at high risk for hereditary breast cancer.

PATIENTS AND METHODS: A total of 196 women, aged 26 to 59 years, with proven BRCA1 or BRCA2 mutations or strong family histories of breast or ovarian cancer underwent mammography, ultrasound, MRI, and clinical breast examination on a single day. A biopsy was performed when any of the four investigations was judged to be suspicious for malignancy.

RESULTS: Six invasive breast cancers and one noninvasive breast cancer were detected among the 196 high-risk women. Five of the invasive cancers occurred in mutation carriers, and the sixth occurred in a woman with a previous history of breast cancer. The prevalence of invasive or noninvasive breast cancer in the 96 mutation carriers was 6.2%. All six invasive cancers were detected by MRI, all were 1.0 cm or less in diameter, and all were node-negative. In contrast, only three invasive cancers were detected by ultrasound, two by mammography, and two by physical examination. The addition of MRI to the more commonly available triad of mammography, ultrasound, and breast examination identified two additional invasive breast cancers that would otherwise have been missed.

CONCLUSION: Breast MRI may be superior to mammography and ultrasound for the screening of women at high risk for hereditary breast cancer.
Prognostic Significance of a Novel Hypoxia-Regulated Marker, Carbonic Anhydrase IX, in Invasive Breast Carcinoma
Authors: Chia Stephen K. , Wykoff Charles C. , Watson Peter H. , Han Cheng , Leek Russell D. , Pastorek Jaromir , Gatter Kevin C. , Ratcliffe Peter , Harris Adrian L.
Published: February 2017

PURPOSE: To assess the frequency of expression and the prognostic significance of a hypoxia-regulated marker, carbonic anhydrase IX (CA IX), in a cohort of patients with invasive breast cancer.

PATIENTS AND METHODS: CA IX expression was evaluated by immunohistochemistry with a murine monoclonal antibody, M75, in a series of 103 women treated surgically for invasive breast cancer. The majority of patients were treated with adjuvant hormonal or chemotherapy. The frequency of CA IX expression, its association with recognized prognostic factors, and the relationship with outcome was evaluated by univariate and multivariate statistical analyses.

RESULTS: CA IX expression was present in 49 (48%) of 103 cases. The level of CA IX expression was found to be significantly associated with tumor necrosis (P < .001), higher grade (P = .02), and negative estrogen receptor status (P < .001). Furthermore, CA IX expression was associated with a higher relapse rate (P = .004) and a worse overall survival (P = .001). By multivariate analysis, CA IX was also shown to be an independent predictive factor for overall survival (hazard ratio, 2.61; 95% confidence interval, 1.01 to 6.75, P = .05).

CONCLUSION: CA IX expression was associated with worse relapse-free survival and overall survival in an unselected cohort of patients with invasive breast carcinoma. The potential role of CA IX as a marker of hypoxia within breast carcinomas was also indicated by a significant association with necrosis. Further work assessing its prognostic significance in breast cancer is warranted, particularly interactions with radiotherapy and chemotherapy resistance.
Prognostic Significance of Pathologic Features in Localized Prostate Cancer Treated With Radical Prostatectomy: Implications for Staging Systems and Predictive Models
Authors: Quinn David I. , Henshall Susan M. , Haynes Anne-Maree , Brenner Phillip C. , Kooner Raji , Golovsky David , Mathews Jayne , O’Neill Gordon F. , Turner Jennifer J. , Delprado Warick , Finlayson John F. , Sutherland Robert L. , Grygiel John J. , Stricker Phillip D.
Published: February 2017

PURPOSE: Although predicting outcome for men with clinically localized prostate cancer (PC) has improved, the staging system and nomograms used to do this are based on results from the North American health system. To be internationally applicable, these models require testing in cohorts from a variety of different health systems based on the predominant PC case identification methods used.

PATIENTS AND METHODS: We studied 732 men with localized PC treated with radical prostatectomy and no preoperative therapy between 1986 and 1999 at one Australian institution to determine the effect of clinicopathologic features on disease-free survival.

RESULTS: Preoperative serum prostate-specific antigen (PSA) concentration, Gleason score, pathologic stage, and year of surgery were independent predictors of outcome. Although margin status demonstrated only a trend toward significance in multivariate modeling overall, it proved to be independent in subgroups based on later year of surgery (1986 to 1994 v 1995 to 1998), preoperative PSA of less than 10 ng/mL, and Gleason score ≥ 7. Adjuvant radiation therapy improved disease-free survival rates in patients with multiple surgical margin involvement.

CONCLUSION: This work confirms the prognostic significance of pathologic stage, Gleason score, and preoperative serum PSA. In the context of a contemporaneous screening effect in Australia, these findings may have implications for methods that predict outcome following surgery as screening becomes more prevalent in a population. The independent prognostic effect of margin status may alter with an increase in the proportion of screening-identified PCs. Staging systems and nomograms that predict outcome following surgery require validation in cohorts with different health practices before being universally applied.
Risk of Death From Intercurrent Disease Is Not Excessively Increased by Modern Postoperative Radiotherapy for High-Risk Resected Non–Small-Cell Lung Carcinoma
Authors: Machtay Mitchell , Lee Jason H. , Shrager Joseph B. , Kaiser Larry R. , Glatstein Eli
Published: February 2017

PURPOSE: Some studies report a high risk of death from intercurrent disease (DID) after postoperative radiotherapy (XRT) for non–small-cell lung cancer (NSCLC). This study determines the risk of DID after modern-technique postoperative XRT.

PATIENTS AND METHODS: A total of 202 patients were treated with surgery and postoperative XRT for NSCLC. Most patients (97%) had pathologic stage II or III disease. Many patients (41%) had positive/close/uncertain resection margins. The median XRT dose was 55 Gy with fraction size of 1.8 to 2 Gy. The risk of DID was calculated actuarially and included patients who died of unknown/uncertain causes. Median follow-up was 24 months for all patients and 62 months for survivors.

RESULTS: A total of 25 patients (12.5%) died from intercurrent disease, 16 from confirmed noncancer causes and nine from unknown causes. The 4-year actuarial rate of DID was 13.5%. This is minimally increased compared with the expected rate for a matched population (approximately 10% at 4 years). On multivariate analysis, age and radiotherapy dose were borderline significant factors associated with a higher risk of DID (P = .06). The crude risk of DID for patients receiving less than 54 Gy was 2% (4-year actuarial risk 0%) versus 17% for XRT dose ≥ 54 Gy. The 4-year actuarial overall survival was 34%; local control was 84%; and freedom from distant metastases was 37%.

CONCLUSION: Modern postoperative XRT for NSCLC does not excessively increase the risk of intercurrent deaths. Further study of postoperative XRT, particularly when using more sophisticated treatment planning and reasonable total doses, for carefully selected high-risk resected NSCLC is warranted.
Ectopic Expression of Guanylyl Cyclase C in CD34+ Progenitor Cells in Peripheral Blood
Authors: Fava Tracy A. , Desnoyers Rodwige , Schulz Stephanie , Park Jason , Weinberg David , Mitchell Edith , Waldman Scott A.
Published: February 2017

PURPOSE: To examine the utility of guanylyl cyclase C (GC-C)–specific nested reverse transcriptase polymerase chain reaction (RT-PCR) to detect circulating tumor cells in patients with colorectal cancer.

PATIENTS AND METHODS: Peripheral-blood mononuclear cells from 24 patients with Dukes’ stage D colorectal cancer were analyzed by GC-C-specific nested RT-PCR using 1 μg of total RNA. Peripheral-blood mononuclear cells from 20 healthy volunteers served as controls. Additionally, peripheral-blood CD34+ progenitor cells were assayed for the expression of both GC-C and other epithelial cell–specific markers.

RESULTS: GC-C mRNA was detected in blood mononuclear cells from all 24 patients with colorectal cancer and all healthy volunteers. These unexpected positive results reflected low-level ectopic transcription of GC-C in CD34+ progenitor cells. Moreover, CD34+ progenitor cells expressed other epithelial cell–specific markers, including prostate-specific antigen, prostate-specific membrane antigen, carcinoembryonic antigen, CK-19, CK-20, mucin 1, and GA733.2. Limiting the quantity of mononuclear cell total RNA analyzed to ≤ 0.8 μg eliminated detection of GC-C and other tissue-specific transcripts in blood of healthy volunteers. However, under the same conditions, GC-C mRNA was detected in mononuclear cells from all 24 patients with metastatic colorectal cancer. Using 0.5 μg of total RNA and GC-C–specific primers, nested RT-PCR detected a single human colon carcinoma cell (approximately 20 to 200 GC-C transcripts/cell) in 106 to 107 mononuclear blood cells.

CONCLUSION: These data suggest that GC-C may be useful for detecting circulating colorectal cancer cells. They also demonstrate that CD34+ cells are a source of ectopically expressed epithelial cell–specific markers and that CD34+ cells may contribute to the high false-positive rate generally observed when those markers are used to detect rare circulating metastatic cancer cells by RT-PCR.
Clinical Value of Routine Serum Squamous Cell Carcinoma Antigen in Follow-Up of Patients With Early-Stage Cervical Cancer
Authors: Esajas Martha D. , Duk Jitze M. , de Bruijn Henk W.A. , Aalders Jan G. , Willemse Pax H.B. , Sluiter Wim , Pras Betty , ten Hoor Klaske , Hollema Harry , van der Zee Ate G.J.
Published: February 2017

PURPOSE: To investigate the contribution to recurrence detection and survival of serum squamous cell carcinoma antigen (SCC-ag) analysis in the follow-up of early-stage cervical cancer patients.

PATIENTS AND METHODS: Follow-up data were evaluated in patients with early-stage squamous cell cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy with or without radiotherapy. Routine serum SCC-ag determination was performed at each follow-up visit.

RESULTS: Recurrent disease occurred in 35 (16%) of 225 patients and was preceded or accompanied by serum SCC-ag elevation 26 times (sensitivity, 74%). In five (14%) of these 35 patients, elevated serum SCC-ag was the first measured clinical indicator. Desite salvage therapy, all five patients died of disease. In the other 31 patients (21 with serum SCC-ag elevation), either symptoms and/or positive signs led to recurrence detection. Median survival time after recurrence was worse (9 months; range, 2 to 112+) for patients with an elevated serum SCC-ag value at recurrence in comparison with patients with normal serum SCC-ag values (20 months; range, 4 to 96; P < .01). In 23 of the 190 patients without recurrences, serum SCC-ag values became falsely elevated. In 16 of these 23 patients, the repeat sample after 6 weeks showed a normal SCC-ag, and in seven patients benign (especially skin) disorders were found.

CONCLUSION: Serum SCC-ag analysis results in earlier recurrence detection in a small proportion (14%) of patients but did not contribute to better survival. As long as treatment possibilities for recurrent cervical cancer patients are not improved, serum SCC-ag analysis should not be carried out in routine follow-up.
Phase II Trial of Intratumoral Administration of ONYX-015, a Replication-Selective Adenovirus, in Patients With Refractory Head and Neck Cancer
Authors: Nemunaitis J. , Khuri F. , Ganly I. , Arseneau J. , Posner M. , Vokes E. , Kuhn J. , McCarty T. , Landers S. , Blackburn A. , Romel L. , Randlev B. , Kaye S. , Kirn D.
Published: February 2017

PURPOSE: To determine the safety, humoral immune response replication, and activity of multiple intratumoral injections of ONYX-015 (replication selective adenovirus) in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN).

PATIENTS AND METHODS: This phase II trial enrolled patients with SCCHN who had recurrence/relapse after prior conventional treatment. Patients received ONYX-015 at a dose of 2 × 1011particles via intratumoral injection for either 5 consecutive days (standard) or twice daily for 2 consecutive weeks (hyperfractionated) during a 21-day cycle. Patients were monitored for tumor response, toxicity, and antibody formation.

RESULTS: Forty patients (30 standard and 10 hyperfractionated) received 533 injections of ONYX-015. Standard treatment resulted in 14% partial to complete regression, 41% stable disease, and 45% progressive disease rates. Hyperfractionated treatment resulted in 10% complete response, 62% stable disease, and 29% progressive disease rates. Treatment-related toxicity included mild to moderate fever (67% overall) and injection site pain (47% on the standard regimen, 80% on the hyperfractionated regimen). Detectable circulating ONYX-015 genome suggestive of intratumoral replication was identified in 41% of tested patients on days 5 and 6 of cycle 1; 9% of patients had evidence of viral replication 10 days after injection during cycle 1, and no patients had evidence of replication ≥ 22 days after injection.

CONCLUSION: ONYX-015 can be safely administered via intratumoral injection to patients with recurrent/refractory SCCHN. ONYX-015 viremia is transient. Evidence of modest antitumoral activity is suggested.
Phase I Clinical Trial of Oral COL-3, a Matrix Metalloproteinase Inhibitor, in Patients With Refractory Metastatic Cancer
Authors: Rudek Michelle A. , Figg William D. , Dyer Valerie , Dahut William , Turner Maria L. , Steinberg Seth M. , Liewehr David J. , Kohler David R. , Pluda James M. , Reed Eddie
Published: February 2017

PURPOSE: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors.

PATIENTS AND METHODS: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug.

RESULTS: Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042).

CONCLUSION: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.
Intensification of Adjuvant Chemotherapy: 5-Year Results of a Randomized Trial Comparing Conventional Doxorubicin and Cyclophosphamide With High-Dose Mitoxantrone and Cyclophosphamide With Filgrastim in Operable Breast Cancer With 10 or More Involved Axillary Nodes
Authors: Fumoleau Pierre , Chauvin Franck , Namer Moïse , Bugat Roland , Tubiana-Hulin Michèle , Guastalla Jean Paul , Delozier Thierry , Kerbrat Pierre , Devaux Yves , Bonneterre Jacques , Filleul Annie , Clavel Michel
Published: February 2017

PURPOSE: To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes.

PATIENTS AND METHODS: Patients (n = 150) were randomized to receive either four cycles of standard doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m2 plus cyclophosphamide 600 mg/m2, with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates.

RESULTS: There were no significant differences in DFS (P = .44), DDFS (P = .67), or OS (P = .99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P = .01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P < .001).

CONCLUSION: This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m2 with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.
Treatment of Advanced Breast Cancer with Vinorelbine and Docetaxel With or Without Human Granulocyte Colony-Stimulating Factor
Authors: Kornek Gabriela V. , Ulrich-Pur Herbert , Penz Melitta , Haider Karin , Kwasny Werner , Depisch Dieter , Kovats Erwin , Lang Fritz , Schneeweiss Bruno , Scheithauer Werner
Published: February 2017

PURPOSE: A multicenter phase II trial was performed to investigate the efficacy and tolerance of docetaxel, vinorelbine with or without recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer.

PATIENTS AND METHODS: Between February 1998 and March 1999, 57 patients participated in this trial. Forty-two patients received this combination as first-line and 15 patients as second-line chemotherapy, including 10 patients who had failed anthracyclines. Therapy consisted of vinorelbine 30 mg/m2 on days 1 and 15 and docetaxel 30 mg/m2 on days 1, 8, and 15 every 4 weeks. Depending on the absolute neutrophil counts on the day of scheduled chemotherapeutic drug administration, a 5-day course of G-CSF 5 μg/kg/d was given.

RESULTS: The overall response rate was 64.3% (95% confidence interval, 48.1% to 78.4%) in patients receiving docetaxel plus vinorelbine as first-line chemotherapy, including eight complete (19%) and 19 partial remissions (45.3%); 11 patients (26.2%) had disease stabilization, and only four (9.5%) progressed. Second-line treatment with this regimen resulted in eight (53.3%) of 15 objective responses, four had stable disease, and three had progressive disease. The median time to progression was 12 months in the first-line and 9.8 months in the second-line setting, respectively. After a median follow-up time of 18 months, 38 patients (65%) were still alive with metastatic disease. Myelosuppression was commonly observed; World Health Organization grade 3 or 4 neutropenia both occurred in 18 patients (32%) and was complicated by septicemia in four cases; grade 3 or 4 thrombocytopenia was seen in two patients (4%), and grade 3 anemia was seen in only one patient (2%). Severe (grade 3) nonhematologic toxicity, except for alopecia, was rarely observed and included nausea/vomiting in two patients (4%), and stomatitis, peripheral neuropathy, and skin toxicity each in one patient.

CONCLUSION: Our data suggest that docetaxel and vinorelbine with or without G-CSF is an effective and fairly well tolerated regimen for the treatment of advanced breast cancer. It might be particularly useful in patients previously exposed to adjuvant or palliative anthracyclines and/or alkylating agents.
Aromatase Inhibitors in the Treatment and Prevention of Breast Cancer
Authors: Goss Paul E. , Strasser Kathrin
Published: February 2017

PURPOSE: The purpose of this article is to provide an overview of the current clinical status and possible future applications of aromatase inhibitors in breast cancer.

METHODS: A review of the literature on the third-generation aromatase inhibitors was conducted. Some data that have been presented but not published are included. In addition, the designs of ongoing trials with aromatase inhibitors are outlined and the implications of possible results discussed.

RESULTS: All of the third-generation oral aromatase inhibitors—letrozole, anastrozole, and vorozole (nonsteroidal, type II) and exemestane (steroidal, type I)—have now been tested in phase III trials as second-line treatment of postmenopausal hormone-dependent breast cancer. They have shown clear superiority compared with the conventional therapies and are therefore considered established second-line hormonal agents. Currently, they are being tested as first-line therapy in the metastatic, adjuvant, and neoadjuvant settings. Preliminary results suggest that the inhibitors might displace tamoxifen as first-line treatment, but further studies are needed to determine this.

CONCLUSION: The role of aromatase inhibitors in premenopausal breast cancer and in combination with chemotherapy and other anticancer treatments are areas of future exploration. The ongoing adjuvant trials will provide important data on the long-term safety of aromatase inhibitors, which will help to determine their suitability for use as chemopreventives in healthy women at risk of developing breast cancer.
Influences on Oncologists’ Adoption of New Agents in Adjuvant Chemotherapy of Breast Cancer
Authors: Buban Gina M. , Link Brian K. , Doucette William R.
Published: February 2017

PURPOSE: Little is known about how oncologists’ adopt new treatments for breast cancer. This study investigated influences on oncologists’ adoption of paclitaxel as adjuvant chemotherapy for early-stage breast cancer, 9 months after presentation of phase III data suggesting improved disease-free and overall survival when paclitaxel was added to doxorubicin and cyclophosphamide for such patients.

METHODS: Self-reported data were collected with a mail survey of a random sample of 1,200 oncologists practicing in the United States. Using Rogers’ model, we measured four types of influences on adoption of innovation: (1) communication channels, (2) innovation characteristics, (3) a practitioner’s social system, and (4) physician characteristics. Multiple regression analysis assessed the associations between oncologist adoption of paclitaxel for early-stage breast cancer patients and variables representing the modeled influences on adoption.

RESULTS: On average, respondents (n = 181) reported having adopted paclitaxel for 37% of their early-stage breast cancer patients. The overall model was significant, with seven variables associated (P ≤ .05) with adoption of paclitaxel. Significant influences on adoption included use of symposia as a therapy information source, physician experience with paclitaxel to treat late-stage breast cancer, and perceived advantage in efficacy of paclitaxel.

CONCLUSION: As new modalities become available to treat cancer, it is vital to understand what factors influence oncologists and patients when choosing to use them. Those parties interested in fostering the adoption of new breast cancer treatments should address features of communication channels (eg, use of symposia), characteristics of new treatments (eg, perceived advantage in efficacy), physicians’ social systems (eg, patient requests), and characteristics of potential adopters (eg, previous experience with the treatment).
Estimation of Risk of Inherited Medullary Thyroid Carcinoma in Apparent Sporadic Patients
Authors: Wiench M. , Wygoda Z. , Gubala E. , Wloch J. , Lisowska K. , Krassowski J. , Scieglinska D. , Fiszer-Kierzkowska A. , Lange D. , Kula D. , Zeman M. , Roskosz J. , Kukulska A. , Krawczyk Z. , Jarzab B.
Published: February 2017

PURPOSE: The study was undertaken to evaluate the frequency of inherited medullary thyroid carcinoma (MTC) among patients with apparent sporadic disease. A stepwise algorithm was used depending on clinical indices and the age of patient at MTC diagnosis.

PATIENTS AND METHODS: One hundred sixteen patients with MTC verified by postoperative pathologic examination were subjected to genetic analysis of RET exons 10, 11, 13, 14, and 16 by means of polymerase chain reaction, restriction endonuclease digestion, and DNA sequencing.

RESULTS: Among 116 apparent sporadic MTC patients, we identified eleven (9.5%) RET germline mutation carriers. Seven of these (6.0%) were found by routine analysis (exons 10 and 11). The frequency of inherited disease among patients younger than 45 years at diagnosis was 10.2% by analysis of typical mutations in exons 10 and 11. Extended genetic analysis (sequencing of exons 11, 13, 14, and 16) yielded 6.1% additional diagnoses, giving a risk of 16.3% in this age group. One previously unreported mutation in exon 11 affected codon 649 (TCG>TTG, Ser>Leu). In the true sporadic MTC patients younger than 30 years at diagnosis, frequencies of 36% and 4.5% in polymorphic variants L769L and S836S, respectively, were observed. The frequency for L769L was higher than in older patients (P < .05).

CONCLUSION: The frequency of inherited disease among apparent sporadic medullary thyroid carcinoma patients is close to 10% in the Polish population of MTC patients. The extended analysis of all known RET proto-oncogene mutation sites is obligatory in patients younger than 45 years at diagnosis, but we also see the need to analyze the impact of rarer mutations in older patients.
Health-Related Quality-of-Life Effects of Radical Prostatectomy and Primary Radiotherapy for Screen-Detected or Clinically Diagnosed Localized Prostate Cancer
Authors: Madalinska Joanna B. , Essink-Bot Marie-Louise , de Koning Harry J. , Kirkels Wim J. , van der Maas Paul J. , Schröder Fritz H.
Published: February 2017

PURPOSE: The current study was undertaken within the framework of a screening trial to compare the health-related quality-of-life (HRQOL) outcomes of two primary treatment modalities for localized prostate cancer: radical prostatectomy and external-beam radiotherapy.

PATIENTS AND METHODS: We conducted a prospective longitudinal cohort study among 278 patients with early screen-detected (59%) or clinically diagnosed (41%) prostate cancer using both generic and disease-specific HRQOL measures (SF-36, UCLA Prostate Cancer Index [urinary and bowel modules] and items relating to sexual functioning) at three points in time: t1 (baseline), t2 (6 months later), and t3 (12 months after t1).

RESULTS: Questionnaires were completed by 88% to 93% of all initially enrolled patients. Patients referred for primary radiotherapy were significantly older than prostatectomy patients (63 v 68 years, P < .01). Analyses (adjusted for age and pretreatment level of functioning) revealed poorer levels of generic HRQOL after radiotherapy. Prostatectomy patients reported significantly higher (P < .01) posttreatment incidences of urinary incontinence (39% to 49%) and erectile dysfunction (80% to 91%) than radiotherapy patients (respectively, 6% to 7% and 41% to 55%). Bowel problems (urgency) affected 30% to 35% of the radiotherapy group versus 6% to 7% of the prostatectomy group (P < .01). Patients with screen-detected and clinically diagnosed cancer reported similar posttreatment HRQOL.

CONCLUSION: Prostatectomy and radiotherapy differed in the type of HRQOL impairment. Because the HRQOL effects may be valued differently at the individual level, patients should be made fully aware of the potential benefits and adverse consequences of therapies for early prostate cancer. Differences in posttreatment HRQOL were not related to the method of cancer detection.
Twenty-Two Years of Phase III Trials for Patients With Advanced Non–Small-Cell Lung Cancer: Sobering Results
Authors: Breathnach Oscar S. , Freidlin Boris , Conley Barbara , Green Mark R. , Johnson David H. , Gandara David R. , O’Connell Michael , Shepherd Frances A. , Johnson Bruce E.
Published: February 2017

PURPOSE: To determine the changes in clinical trials and outcomes of patients with advanced-stage non–small-cell lung cancer (NSCLC) treated on phase III randomized trials initiated in North America from 1973 to 1994.

PATIENTS AND METHODS: Phase III trials for patients with advanced-stage NSCLC were identified through a search of the National Cancer Institute’s Cancer Therapy Evaluation Program database from 1973 to 1994, contact with Cooperative Groups, and by literature search of MEDLINE. Patients with advanced NSCLC treated during a similar time interval were also examined in the SEER database. Trends were tested in the number of trials, in the number and sex of patients entered on the trials, and in survival over time.

RESULTS: Thirty-three phase III trials were initiated between 1973 and 1994. Twenty-four trials (73%) were initiated within the first half of this period (1973 to 1983) and accounted for 5,359 (64%) of the 8,434 eligible patients. The median number of patients treated per arm of the trials rose from 77 (1973 to 1983) to 121 (1984 to 1994) (P < .001). Five trials (15%) showed a statistically significant difference in survival between treatment arms, with a median prolongation of the median survival of 2 months (range, 0.7 to 2.7 months).

CONCLUSION: Analysis of past trials in North America shows that the prolongation in median survival between two arms of a randomized study was rarely in excess of 2 months. Techniques for improved use of patient resources and appropriate trial design for phase III randomized therapeutic trials with patients with advanced NSCLC need to be developed.
Localized Ewing Tumor of Bone: Final Results of the Cooperative Ewing’s Sarcoma Study CESS 86
Authors: Paulussen M. , Ahrens S. , Dunst J. , Winkelmann W. , Exner G.U. , Kotz R. , Amann G. , Dockhorn-Dworniczak B. , Harms D. , Müller-Weihrich S. , Welte K. , Kornhuber B. , Janka-Schaub G. , Göbel U. , Treuner J. , Voûte P.A. , Zoubek A. , Gadner H. , Jürgens H.
Published: February 2017

PURPOSE: Cooperative Ewing’s Sarcoma Study (CESS) 86 aimed at improving event-free survival (EFS) in patients with high-risk localized Ewing tumor of bone.

PATIENTS AND METHODS: We analyzed 301 patients recruited from January 1986 to July 1991 (60% male; median age 15 years). Tumors of volume >100 mL and/or at central-axis sites qualified patients for “high risk” (HR, n = 241), and small extremity lesions for “standard risk” (SR, n = 52). Standard-risk patients received 12 courses of vincristine, cyclophosphamide, and doxorubicin alternating with actinomycin D (VACA); HR patients received ifosfamide instead of cyclophosphamide (VAIA). Tumor sites were pelvis (27%), other central axis (28%), femur (19%), or other extremity (26%). The initial tumor volume was <100 mL in 33% of cases and ≥100 mL in 67%. Local therapy was surgery (23%), surgery plus radiotherapy (49%), or radiotherapy alone (28%). Event-free survival rates were estimated by Kaplan-Meier analyses, comparisons were done by log-rank test, and risk factors were analyzed by Cox models.

RESULTS: On May 1, 1999 (median time under study, 133 months), the 10-year EFS was 0.52. Event-free survival did not differ between SR-VACA (0.52) and HR-VAIA (0.51, P = .92). Tumor volume of >200 mL (EFS, 0.36 v 0.63 for smaller tumors; P = .0001) and poor histologic response (EFS, 0.38 v 0.64 for good responders; P = .0007) had negative impacts on EFS. In multivariate analyses, small tumor volumes of <200 mL, good histologic response, and VAIA chemotherapy augured for fair outcome. Six of 301 patients (2%) died under treatment, and four patients (1.3%) developed second malignancies.

CONCLUSION: Fifty-two percent of CESS 86 patients survived after risk-adapted therapy. High-risk patients seem to have benefited from intensified treatment that incorporated ifosfamide.