bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical and Psychological Morbidity After Axillary Lymph Node Dissection for Breast Cancer
Authors: Hack Thomas F. , Cohen Lorenzo , Katz Joel , Robson Lynda S. , Goss Paul
Published: February 2017

PURPOSE: Alternatives to axillary lymph node dissection (ALND) are being developed amid controversy surrounding the therapeutic benefit and overall utility of this routine surgical procedure. Although potential negative side effects associated with ALND are known, we set out to examine whether these side effects contribute significantly to patient reports of quality of life and mental health.

PATIENTS AND METHODS: We surveyed 222 women who had received an ALND as part of breast cancer surgery. All women underwent a physical therapy assessment of range of arm/shoulder motion and completed the Modified Post-operative Pain Questionnaire, the Pain Disability Index, the McGill Pain Questionnaire (short form), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, and the Mental Health Inventory.

RESULTS: Seventy-two percent of the women experienced arm/shoulder pain, weakness, or numbness in the week before the interview, and range of motion of the affected arm/shoulder was impaired in 73% of the women. Severity of pain was reported to be low to moderate, and younger patients experienced greater pain than older patients. Pain severity correlated positively with the number of lymph nodes removed and receipt of chemotherapy and was not significantly related to length of time since surgery or receipt of radiation therapy. Generally high levels of cancer-specific quality of life and mental health were reported. Quality of life was significantly predicted by the McGill Pain Questionnaire, and mental health was significantly predicted by the Pain Disability Index and the physical therapy assessment.

CONCLUSION: Surgery-related symptoms after ALND persist for a majority of women with breast cancer and are not significantly related to time since surgery or receipt of radiation therapy. These symptoms and associated disability are significantly predictive of cancer-specific quality of life and mental health.
Prognostic Factors for the Outcome of Chemotherapy in Advanced Soft Tissue Sarcoma: An Analysis of 2,185 Patients Treated With Anthracycline-Containing First-Line Regimens—A European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study
Authors: Van Glabbeke M. , van Oosterom A.T. , Oosterhuis J.W. , Mouridsen H. , Crowther D. , Somers R. , Verweij J. , Santoro A. , Buesa J. , Tursz T.
Published: February 2017

PURPOSE: A total of 2,185 patients with advanced soft tissue sarcomas who had been treated in seven clinical trials investigating the use of doxorubicin- or epirubicin-containing regimens as first-line chemotherapy were studied in this prognostic-factor analysis.

PATIENTS AND METHODS: Overall survival time (median, 51 weeks) and response to chemotherapy (26% complete response or partial response) were the two end points. The cofactors were sex; age; performance status; prior therapies; the presence of locoregional or recurrent disease; lung, liver, and bone metastases at the time of entry onto the trial; long time period between the initial diagnosis of sarcoma and entry onto the study; and histologic type and grade.

RESULTS: Univariate analyses showed (a) a significant, favorable influence of good performance status, young age, and absence of liver metastases on both survival time and response rate, (b) a significant, favorable influence of low histopathologic disease grade on survival time, despite a significantly lower response rate, (c) increased survival time for patients with a long time period between the initial diagnosis of sarcoma and entry onto the study, despite equivalent response rates, and (d) increased survival time with liposarcoma or synovial sarcoma, a decreased survival time with malignant fibrous histiocytoma, a lower response rate with leiomyosarcoma, and a higher response rate with liposarcoma (P < .05 for all log-rank and χ2 tests). The Cox model selected good performance status (P < .0001), absence of liver metastases (P = .0001), low histopathologic grade (P = .0002), long time lapse since initial diagnosis (P = .0004), and young age (P = .0045) as favorable prognostic factors of survival time. The logistic model selected absence of liver metastases (P < .0001), young age (P = .0024), high histopathologic grade (P = .0051), and liposarcoma (P = .0065) as favorable prognostic factors of response rate.

CONCLUSION: This analysis demonstrates that for advanced soft tissue sarcoma, response to chemotherapy is not predicted by the same factors as is overall survival time. This needs to be taken into account in the interpretation of trials assessing the value of new agents for this disease on the basis of response to treatment.
Pretreatment Nomogram for Prostate-Specific Antigen Recurrence After Radical Prostatectomy or External-Beam Radiation Therapy for Clinically Localized Prostate Cancer
Authors: D'Amico Anthony V. , Whittington Richard , Malkowicz S. Bruce , Fondurulia Julie , Chen Ming-Hui , Kaplan Irving , Beard Clair J. , Tomaszewski John E. , Renshaw Andrew A. , Wein Alan , Coleman C. Norman
Published: February 2017

PURPOSE: To present nomograms providing estimates of prostate-specific antigen (PSA) failure–free survival after radical prostatectomy (RP) or external-beam radiation therapy (RT) for men diagnosed during the PSA era with clinically localized disease.

PATIENTS AND METHODS: A Cox regression multivariable analysis was used to determine the prognostic significance of the pretreatment PSA level, 1992 American Joint Committee on Cancer (AJCC) clinical stage, and biopsy Gleason score in predicting the time to posttherapy PSA failure in 1,654 men with T1c,2 prostate cancer managed with either RP or RT.

RESULTS: Pretherapy PSA, AJCC clinical stage, and biopsy Gleason score were independent predictors (P < .0001) of time to posttherapy PSA failure in patients managed with either RP or RT. Two-year PSA failure rates derived from the Cox regression model and bootstrap estimates of the 95% confidence intervals are presented in the format of a nomogram stratified by the pretreatment PSA, AJCC clinical stage, biopsy Gleason score, and local treatment modality.

CONCLUSION: Men at high risk (> 50%) for early (≤ 2 years) PSA failure could be identified on the basis of the type of local therapy received and the clinical information obtained as part of the routine work-up for localized prostate cancer. Selection of these men for trials evaluating adjuvant systemic and improved local therapies may be justified.
Chemotherapy Dose-Intensification for Pediatric Patients With Ewing's Family of Tumors and Desmoplastic Small Round-Cell Tumors: A Feasibility Study at St. Jude Children's Research Hospital
Authors: Marina Neyssa M. , Pappo Alberto S. , Parham David M. , Cain Alvida M. , Rao Bhaskar N. , Poquette Catherine A. , Pratt Charles B. , Greenwald Carol , Meyer William H.
Published: February 2017

PURPOSE: To evaluate the feasibility of dose-intensification for patients with Ewing's family of tumors (EFT) and desmoplastic small round-cell tumors.

PATIENTS AND METHODS: From February 1992 to June 1996, we treated 53 consecutive patients on our Ewing's protocol. Induction comprised three cycles of ifosfamide/etoposide on days 1 to 3 and cyclophosphamide (CTX)/doxorubicin on day 5, followed by granulocyte colony-stimulating factor. Local control using surgery and/or radiotherapy started at week 9 along with vincristine/dactinomycin. Maintenance included four alternating cycles of ifosfamide/ etoposide and doxorubicin/CTX, with randomization to one of two CTX dose levels to determine the feasibility of dose-intensification during maintenance.

RESULTS: Patients had a median age of 13.4 years (range, 4.5 to 24.9 years); 34 patients were male and 43 patients were white. Nineteen patients presented with metastatic disease, 29 had tumors greater than 8 cm in diameter, and 26 had primary bone tumors. These patients received 155 induction cycles, 91% of which resulted in grade 4 neutropenia, 68% in febrile neutropenia, and 68% in grade 3 to 4 thrombocytopenia. During maintenance, grade 4 neutropenia and grade 3 to 4 thrombocytopenia occurred in 81% and 85% of cycles, respectively. Thirty-five patients (66%) completed all therapy, only 13 without significant delays; three developed secondary myeloid malignancies. The toxicity and time to therapy completion were similar in both CTX arms. Estimated 3-year survival and event-free survival were 72% ± 8% and 60% ± 9%, respectively.

CONCLUSION: Although intensifying therapy seems feasible for 25% of patients on this study, toxicity was considerable. Therefore, the noninvestigational use of dose-intensification in patients with EFT should await assessment of its impact on disease-free survival.
Comparison of High-Dose Therapy and Autologous Stem-Cell Transplantation With Conventional Therapy for Hodgkin's Disease Induction Failure: A Case-Control Study
Authors: André Marc , Henry-Amar Michel , Pico José-Luis , Brice Pauline , Blaise Didier , Kuentz Mathieu , Coiffier Bertr , Colombat Philippe , Cahn Jean-Yves , Attal Michel , Fleury Joël , Milpied Noël , Nedellec Gérard , Biron Pierre , Tilly Hervé , Jouet Jean-Paul , Gisselbrecht for the Société Francaise de Greffe de Moelle Christian
Published: February 2017

PURPOSE: To determine the prognostic factors and outcome of first-line induction failure Hodgkin's disease patients who were treated with a salvage regimen of high-dose chemotherapy and autologous stem-cell transplantation, and to compare them with matched, conventionally treated patients.

PATIENTS AND METHODS: We retrospectively analyzed data relating to 86 Hodgkin's disease patients who underwent autologous stem-cell transplantation after failure of the first chemotherapy regimen, either because they did not enter a complete remission and experienced progression of disease less than 3 months after the end of their first-line treatment or because they showed evidence of disease progression during first-line therapy. Graft patients were matched with 258 conventionally treated patients (three controls per case) for age, sex, clinical stage, B symptoms, and time at risk; patient data were obtained from international databases.

RESULTS: Among the 86 graft patients, the median age at diagnosis was 29 years (range, 14 to 57 years). Thirty-nine percent of patients had stage II disease, 23% had stage III disease, and 38% had stage IV disease. Seventy percent of the patients received chemotherapy and 30% received combined modality therapy; 60% of the patients received a seven- or eight-drug regimen. After this first-line treatment, 91% had disease progression and 9% had a brief partial response. Eighty patients received a second-line treatment; pretransplantation status was as follows: 24% of patients had a complete remission, 38% had a partial remission (PR), 14% had stable disease, and disease progression occurred in 24%. With a median follow-up of 22 months (range, 4 to 105 months) from diagnosis, the 5-year event-free survival and overall survival rates from transplantation were 25% and 35% (95% confidence intervals, 15 to 36 and 23 to 49), respectively. In multivariate analysis, the pretransplantation disease status after salvage therapy was the only significant prognostic factor for survival (PR: relative risk = 2.8, P = .017; progressive disease: relative risk (RR) = 5.26, P < .001). From diagnosis, the 6-year overall survival rates of the graft patients and 258 matched conventionally treated patients were 38% and 29%, respectively (P = .058).

CONCLUSION: Autologous stem-cell transplantation represents the best therapeutic option currently available for patients with primary induction failure and is associated with acceptable toxicity. Response to second-line treatment before high-dose chemotherapy is the only prognostic factor that can be correlated with survival.
Treatment of Patients With Low-Grade B-Cell Lymphoma With the Combination of Chimeric Anti-CD20 Monoclonal Antibody and CHOP Chemotherapy
Authors: Czuczman M. S. , Grillo-López A. J. , White C. A. , Saleh M. , Gordon L. , LoBuglio A. F. , Jonas C. , Klippenstein D. , Dallaire B. , Varns C.
Published: February 2017

PURPOSE: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody, Rituxan (Rituximab, IDEC-C2B8; IDEC Pharmaceuticals Corporation, San Diego, CA), and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy.

PATIENTS AND METHODS: Forty patients with low-grade or follicular B-cell non–Hodgkin's lymphoma received six infusions of Rituxan (375 mg/m2 per dose) in combination with six doses of CHOP chemotherapy.

RESULTS: The overall response rate was 95% (38 of 40 patients). Twenty-two patients experienced a complete response (55%), 16 patients had a partial response (40%), and two patients, who received no treatment, were classified as nonresponders. Medians for duration of response and time to progression had not been reached after a median observation time of 29 + months. Twenty-eight of 38 assessable patients (74%) continued in remission during this median follow-up period. The most frequent adverse events attributable to CHOP were alopecia (38 patients), neutropenia (31 patients), and fever (23 patients). The most frequent events attributed to Rituxan were fever and chills, observed primarily with the first infusion. No quantifiable immune response to the chimeric antibody was detected. In a subset of 18 patients, the bcl-2 [t(14;18)] translocation was positive in eight patients; seven of these patients had complete remissions and converted to polymerase chain reaction (PCR) negativity by completion of therapy.

CONCLUSION: This is the first report demonstrating the safety and efficacy of Rituxan anti-CD20 chimeric antibody in combination with standard-dose systemic chemotherapy in the treatment of indolent B-cell lymphoma. The clinical responses suggest an additive therapeutic benefit for the combination with no significant added toxicity. The conversion of bcl-2 from positive to negative by PCR in blood and/or marrow suggests possible clearing of minimal residual disease not previously demonstrated by CHOP chemotherapy alone.
Bromodeoxyuridine Alternating With Radiation for Advanced Uterine Cervix Cancer: A Phase I and Drug Incorporation Study
Authors: Eisbruch Avraham , Robertson John M. , Johnston Carolyn M. , Tworek Joseph , Reynolds Kevin R. , Roberts James A. , Lawrence Theodore S.
Published: February 2017

PURPOSE: Preclinical studies show a significant increase in the ratio of the radiosensitizer bromodeoxyuridine (BUdR) in tumors versus the intestinal mucosa during the drug elimination period, compared with the ratio during drug infusion. We constructed a phase I study in patients with locally advanced cervix cancer, using alternating cycles of BUdR and radiation therapy (RT).

PATIENTS AND METHODS: Eighteen patients with stage IIB to IVA cervix cancer participated. A treatment cycle consisted of a 4-day BUdR infusion followed by a week of pelvic RT, 15 Gy twice daily in 1.5-Gy fractions. After three cycles, additional BUdR was infused, followed by brachytherapy. The fraction of thymidine replaced by BUdR and the fraction of cells incorporating BUdR were determined in rectal mucosa and tumor biopsies at the end of the first BUdR infusion (day 5), at the middle of the first RT week (day 10), and at the time of brachytherapy.

RESULTS: Dose-limiting toxicity was observed in one of 16 patients receiving 1,000 mg/m2/d × 4 days and inboth patients receiving 1,333 mg/m2/d × 4 days each cycle. After a median follow-up of 39 months, 12 patients (66%) were free of pelvic disease and nine (50%) were alive and disease free. The ratio of tumor to rectum BUdR incorporation averaged 1.5 to 1.8 and did not differ significantly between day 5 and day 10. A trend toward reduced ratio was observed at brachytherapy. Drug-containing cells in rectal biopsies migrated from the crypts to the mucosal surface.

CONCLUSION: In this schedule, 1,000 mg/m2/d is the maximum-tolerated dose of BUdR. BUdR incorporation levels in tumors were consistent with clinically significant radiosensitization. The migration of BUdR-containing rectal mucosa cells from the crypts to the surface at the time of RT suggests that this regimen may offer a relative sparing of the mucosa from radiosensitization.
Implementing Guidelines for Cancer Pain Management: Results of a Randomized Controlled Clinical Trial
Authors: Du Pen Stuart L. , Du Pen Anna R. , Polissar Nayak , Hansberry Jennifer , Kraybill Beth Miller , Stillman Mark , Panke Joan , Everly Rebecca , Syrjala Karen
Published: February 2017

PURPOSE: Pain and symptom management is an integral part of the clinical practice of oncology. A number of guidelines have been developed to assist the clinician in optimizing comfort care. We implemented clinical guidelines for cancer pain management in the community setting and evaluated whether these guidelines improved care.

PATIENTS AND METHODS: Eighty-one cancer patients, aged 37 to 76 years, were enrolled onto a prospective, longitudinal, randomized controlled study from the outpatient clinic settings of 26 western Washington–area medical oncologists. A multilevel treatment algorithm based on the Agency for Health Care Policy and Research Guidelines for Cancer Pain Management was compared with standard-practice (control) pain and symptom management therapies used by community oncologists. The primary outcome of interest was pain (Brief Pain Inventory); secondary outcomes of interest were all other symptoms (Memorial Symptom Assessment Scale) and quality of life (Functional Assessment of Cancer Therapy Scale).

RESULTS: Patients randomized to the pain algorithm group achieved a statistically significant reduction in usual pain intensity, measured as slope scores, when compared with standard community practice (P < .02). Concurrent chemotherapy and patient adherence to treatment were significant mediators of worst pain. There were no significant differences in other symptoms or quality of life between the two treatment groups.

CONCLUSION: This guideline implementation study supports the use of algorithmic decision making in the management of cancer pain. These findings suggest that comprehensive pain assessment and evidence-based analgesic decision-making processes do enhance usual pain outcomes.
Chemotherapy and Bone Marrow Transplantation for Cancer Patients Who Are Also Chronic Hepatitis B Carriers: A Review of the Problem
Authors: Liang Raymond , Lau George K.K. , Kwong Y. L.
Published: February 2017

In places where hepatitis B virus (HBV) infection is endemic, itis often necessary to give chemotherapy to or perform bone marrowtransplantation for cancer patients who are also chronic HBV carriers.When standard chemotherapy was given to lymphoma patients, elevation ofliver transaminases was observed in nearly half of those who werechronic HBV carriers. Ten percent of them became jaundiced, and theoverall liver-related mortality was about 5%. There is currently noreliable way to predict the severity of HBV reactivation afterchemotherapy. The risk is probably higher when the chemotherapy used issignificantly immunosuppressive and the viral load in the liver ishigh. Different strategies have been used in an attempt to reduce therisk of HBV reactivation after chemotherapy, but they have not beenvery successful. Further studies will be required to determine theimpact of newly available antiviral agents that are active against HBV.

Recipients who are carriers of HBV or who receive hepatitis B surfaceantigen (HBsAg)-positive marrow are at increased risk of hepatitisB-related morbidity and mortality after bone marrow transplantation(BMT). There is evidence to suggest that prophylactic use of an activeantiviral agent, such as famciclovir, may result in a significantdecrease in the incidence and severity of HBV reactivation after BMT.Sustained serologic clearance of chronic HBV infection has also beenreported in many HBsAg-positive marrow recipients receiving hepatitis Bsurface antibody-positive marrow from their allogeneic donors. Thereseems to be a transfer of both humoral and cellular immunity againstHBV from donors to recipients.

Further prospective studies are required to define the best approach tomanage HBsAg-positive cancer patients receiving chemotherapy or BMT. Itis recommended that all cancer patients be checked for their hepatitisB status before receiving chemotherapy or a bone marrow transplant,especially if they reside in or come from endemic areas of HBVinfection.
B-Cell Chronic Lymphocytic Leukemia: A Bird of a Different Feather
Authors: Caligaris-Cappio Federico , Hamblin Terry J.
Published: February 2017

PURPOSE: To review the recent major advances in the molecular and cell biology of B-cell chronic lymphocytic leukemia (B-CLL).

METHODS: We analyzed the nature of malignant B-CLL B cells and their interactions with the microenvironment.

RESULTS: B-CLL is a malignancy of a mantle zone-based subpopulation of anergic, self-reactive, activated CD5+B cells devoted to the production of polyreactive natural autoantibodies. It is the quintessential example of a human malignancy that primarily involves defects in the induction of programmed cell death. An abnormal karyotype is observed in about 50% of patients with B-CLL. Patients with 13q14 abnormalities show heavy somatic mutation and have a benign disease. Trisomy 12 is associated with unmutated VH genes, atypical cellular morphology, and progressive disease. Extended cell survival is further shielded by a kinetic refractoriness likely promoted by abnormalities of the B-cell antigen receptor complex and favored by some cytokines that highlight a reciprocal dialog between malignant B and T cells. Because the tumor cells act as the major accessory cells, the accumulating malignant B-cell population per se is a hurdle to the production of normal antibodies and leads to a progressive and severe hypogammaglobulinemia. Conceivably, in the presence of certain immunoglobulin genes and when the T-cell control becomes deficient, activated malignant B cells may become able to present self-antigens and drive residual normal B cells to produce polyclonal autoantibodies restricted to self-antigens expressed only by blood cells and cause autoimmune cytopenias.

CONCLUSION: The distinctiveness of B-CLL B cells explains why B-CLL is different from other B-cell tumors and accounts for the development of immune deficiency and autoimmunity.
Review of the Comparative Pharmacology and Clinical Activity of Cisplatin and Carboplatin
Authors: Go Ronald S. , Adjei Alex A.
Published: February 2017

PURPOSE: To review the pharmacodynamics, pharmacokinetics, toxicities, and relative clinical activities of cisplatin and carboplatin. Through a search of the MEDLINE database, we identified phase III clinical trials and pharmacologic studies comparing cisplatin and carboplatin published in the English language medical literature from January 1966 to December 1997.

RESULTS: Prospective randomized trials comparing cisplatin to carboplatin were identified for ovarian (n = 12), germ cell (n = 4), non–small-cell lung (n = 1), small-cell lung (n = 3), and head and neck (n = 4) cancers. Carboplatin and cisplatin were equally effective in suboptimally debulked ovarian cancer and extensive-stage small-cell lung cancer. One study each showed a trend toward better survival in favor of cisplatin for patients with optimally debulked ovarian and limited-stage small-cell lung cancers. These results were, however, based on subset analyses. In germ cell tumors, carboplatin was inferior because of lower relapse-free survival rates. Cisplatin produced superior response rates and survival in head and neck cancers. There are no published randomized phase III studies of bladder, cervical, endometrial, and esophageal cancers.

CONCLUSION: Carboplatin does not possess equivalent activity to cisplatin in all platinum-sensitive tumors. Carboplatin can replace cisplatin in chemotherapy regimens for suboptimally debulked ovarian cancer. Two ongoing studies will address the same question in optimally debulked disease. Carboplatin can also be substituted for cisplatin in the treatment of non–small-cell and extensive-stage small-cell lung cancers. Its role in limited-stage small-cell lung cancer needs to be investigated further. Carboplatin is inferior to cisplatin in germ cell, head and neck, and esophageal cancers. Randomized studies are needed to determine whether carboplatin has equivalent efficacy to cisplatin in bladder, cervical, and endometrial cancers.
Positron Emission Tomography for Evaluating Para-aortic Nodal Metastasis in Locally Advanced Cervical Cancer Before Surgical Staging: A Surgicopathologic Study
Authors: Rose Peter G. , Adler Lee P. , Rodriguez Michael , Faulhaber Peter F. , Abdul-Karim Fadi W. , Miraldi Floro
Published: February 2017

PURPOSE: Positron emission tomographic (PET) scanning provides a novel means of imaging malignancies. This prospective study was undertaken to evaluate PET scanning in detecting para-aortic nodal metastasis in patients with locally advanced cervical carcinoma and no evidence of extrapelvic disease before planned surgical staging lymphadenectomy.

MATERIALS AND METHODS: After 20 mCi of 2-[18F]fluoro-2-deoxy-d-glucose (FDG) were administered intravenously, the abdomen and pelvis were scanned. Continuous bladder irrigation was used to reduce artifact. Patients were classified by the presence or absence of FDG uptake in the primary tumor and in pelvic or para-aortic nodes. Para-aortic node metastases were classified as present or absent according to a standardized staging procedure. Pelvic node metastases were similarly classified in a subset of patients who underwent pelvic node resection.

RESULTS: Thirty-two patients with stage IIB (n = 6), IIIB (n = 24), and IVA (n = 2) tumors were studied. Fluorodeoxyglucose was taken up by 91% of the cervical tumors. Six of eight patients with positive para-aortic node metastasis had PET scan evidence of para-aortic nodal metastasis. One of the two false-negatives had only one microscopic focus of metastatic cancer. In the para-aortic nodes, PET scanning had a sensitivity of 75%, a specificity of 92%, a positive predictive value of 75%, and a negative predictive value of 92%. Fluorodeoxyglucose para-aortic nodal uptake conferred a relative risk of 9.0 (95% confidence interval, 2.3 to 36.0) for para-aortic nodal metastasis. All 10 of 17 patients with metastasis were predicted by PET scanning (P < .001); five of these patients had abnormalities on computed tomographic scans.

CONCLUSION: Cervical cancers have a high avidity for FDG. The use of PET-FDG scanning accurately predicts both the presence and absence of pelvic and para-aortic nodal metastatic disease.
First-Line Chemotherapy With Epirubicin, Paclitaxel, and Carboplatin for Advanced Ovarian Cancer: A Phase I/II Study of the Arbeitsgemeinschaft Gynäkologische Onkologie Ovarian Cancer Study Group
Authors: du Bois A. , Lück H. J. , Bauknecht T. , Meier W. , Richter B. , Kuhn W. , Quaas J. , Pfisterer J.
Published: February 2017

PURPOSE: Despite the progress that has been achieved over the years, survival rates in patients with advanced ovarian cancer are still disappointing. New methods to improve the efficiency of first-line chemotherapy are warranted. One method to improve results is to add more non–cross-resistant drugs to platinum-paclitaxel combination regimens. Anthracyclines are among the candidates for incorporation as the “third drug” into first-line regimens for advanced ovarian cancer.

PATIENTS AND METHODS: We performed a phase I/II trial with escalating doses of epirubicin (60, 75, and 90 mg/m2) combined with fixed doses of paclitaxel and carboplatin in 27 previously untreated patients with advanced gynecologic malignancies.

RESULTS: Dose-limiting toxicity occurred at dose level 2 (75 mg/m2 epirubicin) and consisted of myelosuppression (neutropenia, thrombocytopenia). No dose-limiting, nonhematologic toxicities were observed. The maximum tolerable dose was epirubicin 60 mg/m2 (E) combined with a 3-hour infusion of paclitaxel 175 mg/m2 (T) and carboplatin AUC 5 (Carbo). Preliminary analysis indicated promising activity against ovarian cancer.

CONCLUSION: The three-drug combination ET-Carbo, given according to the outlined dose and schedule, should be considered for further phase III evaluation. A randomized German-French intergroup trial comparing ET-Carbo with carboplatin-paclitaxel has already been initiated.
Randomized Phase II Study of High-Dose Paclitaxel With or Without Amifostine in Patients With Metastatic Breast Cancer
Authors: Gelmon K. , Eisenhauer E. , Bryce C. , Tolcher A. , Mayer L. , Tomlinson E. , Zee B. , Blackstein M. , Tomiak E. , Yau J. , Batist G. , Fisher B. , Iglesias J.
Published: February 2017

PURPOSE: To determine whether the neurotoxicity of paclitaxel 250 mg/m2 given over 3 hours every 3 weeks could be reduced by pretreatment with amifostine 910 mg/m2. Secondary objectives included comparing myelosuppression, myalgias, and response rates of the two groups.

PATIENTS AND METHODS: Forty womenwith metastatic breast cancer were randomized to receive either paclitaxel alone (arm 1) or paclitaxel preceded by amifostine (arm 2). All were assessable for toxicity, and 37 were assessable for response. At baseline and after each cycle, all patients completed questionnaires for neurologic symptoms and had standardized neurologic examinations, including objective assessments of power and vibration sense. In addition, standard follow-up assessments for other toxicities and tumor response were undertaken. Changes from baseline after courses 1, 2, and 3 were assessed. The sample size was sufficient to detect a 50% improvement in the expected determination in sensory change.

RESULTS: There were no differences observed in any of the measures of neurotoxicity. Other toxicity was similar in arms 1 and 2, including hair loss (95% v 90%), neurosensory changes (100% v 100%), fatigue/lethargy (85% v 90%), myalgia (95% v 90%), and grade 4 neutropenia (47% v 60%). Nausea, vomiting, dizziness, hypotension, and sneezing were more common in the amifostine arm. Response rates (22.2% v 36.8%) and paclitaxel pharmacokinetics were not significantly different.

CONCLUSION: There was no protection from paclitaxel-related neurotoxicity or hematologic toxicity in this study. These results suggest that the mechanism of action of paclitaxel-related toxic effects is not amenable to the cytoprotective action of amifostine.
Telomerase Activity and Prognosis in Primary Breast Cancers
Authors: Carey Lisa A. , Kim Nam W. , Goodman Steven , Marks Jeffrey , Henderson Gregory , Umbricht Christopher B. , Dome Jeffrey S. , Dooley William , Amshey Stefan R. , Sukumar Saraswati
Published: February 2017

PURPOSE: Recent studies associate telomerase activity with prognostic factors and survival. We compared quantitative telomerase activity in primary tumors with traditional prognostic factors and outcome in a group of invasive but nonmetastatic breast cancers.

PATIENTS AND METHODS: Telomerase activity was measured in 203 invasive breast cancers by the quantitative telomeric repeat amplification protocol method. Telomerase expression was compared with 28S rRNA level, tumor content, and clinical variables, including outcome. For clinical correlations, telomerase activity was standardized by two methods: (1) a correction for cellularity using 28S rRNA levels, and (2) a correction for the histologically determined invasive proportion of the specimen.

RESULTS: Telomerase activity was found in 82% of breast cancers with measurable 28S rRNA levels. Telomerase activity was associated with the proliferative index (P < .01) of the tumor but not with any other prognostic variable. Neither uncorrected nor corrected telomerase activity was associated with relapse-free or overall survival in this study.

CONCLUSION: Telomerase activity level was associated with the proliferative index of invasive breast cancers, but its measurement in samples from this group of nonmetastatic breast cancer patients did not predict survival.
Effect of Radiotherapy and Chemotherapy on Pulmonary Function After Treatment for Breast Cancer and Lymphoma: A Follow-Up Study
Authors: Theuws Jacqueline C.M. , Muller Sara H. , Seppenwoolde Yvette , Kwa Stefan L.S. , Boersma Liesbeth J. , Hart Guus A.M. , Baas Paul , Lebesque Joos V.
Published: February 2017

PURPOSE: To determine the changes in pulmonary function tests (PFTs) 0 to 48 months after treatment for breast cancer and lymphoma.

PATIENTS AND METHODS: The alveolar volume (VA), vital capacity, forced expiratory volume in 1 second, and corrected transfer factor of carbon monoxide (TL,COc) were measured in 69 breast cancer and 41 lymphoma patients before treatment and 3, 18, and 48 months after treatment with radiotherapy alone or radiotherapy in combination with chemotherapy (mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine; cyclophosphamide, epidoxorubicin, fluorouracil; cyclophosphamide, thiotepa, carboplatin; cyclophosphamide, methotrexate, fluorouracil). The three-dimensional dose distribution in the lung of each patient was converted to the mean lung dose. Statistical analysis was used to evaluate the changes in PFT values over time in relation to age, sex, smoking, chemotherapy, and the mean lung dose.

RESULTS: After an initial reduction in PFT values at 3 months, significant recovery was seen at 18 months for all patients. Thereafter, no further improvement could be demonstrated. Reductions in spirometry values and VAwere related to the mean lung dose only (0.9% per Gy at 3 months and 0.4% per Gy mean dose at 18 months). TL,COcdecreased 1.1% per Gy mean dose and additionally decreased 6% when chemotherapy was given after radiotherapy. Chemotherapy administered before radiotherapy reduced baseline TL,COcvalues by 8% to 21%. All patients showed an improvement of 5% at 18 months.

CONCLUSION: On the basis of the mean lung dose and the chemotherapy regimen, the changes in PFT values can be estimated before treatment within 10% of the values actually observed in 72% to 85% of our patients with healthy lungs.
High-Dose Therapy and Autologous Stem-Cell Transplantation for Adult Patients With Hodgkin's Disease Who Do Not Enter Remission After Induction Chemotherapy: Results in 175 Patients Reported to the European Group for Blood and Marrow Transplantation
Authors: Sweetenham John W. , Carella Angelo M. , Taghipour Golnaz , Cunningham David , Marcus Robert , Volpe Aldo Della , Linch David C. , Schmitz Norbert , Goldstone Anthony H.
Published: February 2017

PURPOSE: To investigate the results of high-dose therapy and autologous stem-cell transplantation (ASCT) in adults with Hodgkin's disease who do not enter remission after induction therapy, to determine overall survival (OS) and progression free survival (PFS), and to identify prognostic factors.

PATIENTS AND METHODS: A retrospective analysis of 175 patients reported to the European Group for Blood and Marrow Transplantation between November 1979 and October 1995. One hundred were male and 75 were female, with a median age of 26.5 years. Responses to first-line therapy were defined as progressive disease (PD) in 88 and stable/minimally responsive disease (SD/MR) in 87. Seventy-five patients received ASCT after failure of one induction regimen. Second-line therapy was given to the remaining 100 patients. Response to second-line therapy was PD in 34 and SD/MR in 66. OS and PFS rates were determined, and prognostic factors were investigated using univariate and multivariate analyses.

RESULTS: Responses to high-dose therapy and ASCT were complete response (30%), partial response (28%), no response (14%), PD (14%), and toxic death (14%). Actuarial 5-year OS and PFS rates were 36% and 32%, respectively. In univariate analysis for PFS and OS, adverse factors were use of a second-line chemotherapy regimen and interval of more than 18 months between diagnosis and ASCT. In multivariate analysis, the interval between diagnosis and ASCT maintained prognostic significance for OS. Response to the chemotherapy regimen given immediately before ASCT had no predictive value.

CONCLUSION: High-dose therapy and ASCT is an effective treatment strategy for patients with Hodgkin's disease for whom induction chemotherapy fails. Outcome was equivalent for those with obvious PD or SD/MR in response to the regimen given immediately before high-dose therapy. Prospective randomized studies are required to compare this approach with conventional-dose salvage therapy.
Increased Incidence of Hodgkin's Disease After Allogeneic Bone Marrow Transplantation
Authors: Rowlings Philip A. , Curtis Rochelle E. , Passweg Jakob R. , Deeg H. Joachim , Socié Gérard , Travis Lois B. , Kingma Douglas W. , Jaffe Elaine S. , Sobocinski Kathleen A. , Horowitz Mary M.
Published: February 2017

PURPOSE: Immune dysregulation associated with allogeneic bone marrow transplantation (BMT) is linked to an increased risk of posttransplant lymphoproliferative disorders (PTLD); however, reports of Hodgkin's disease (HD) after transplantation are rare.

PATIENTS AND METHODS: We evaluated the risk of HD among 18,531 persons receiving allogeneic BMT between 1964 and 1992 at 235 centers. The number of HD cases was compared with that expected in the general population. Risk factors were identified using Poisson regression and a nested case-control study.

RESULTS: Risk of HD was increased in the postBMT population compared with the general population with an observed-to-expected incidence ratio (O/E) of 6.2 (observed cases, n = 8; 95% confidence interval [CI], 2.7 to 12). A significantly increased risk of HD remained after excluding two human immunodeficiency virus–positive patients (observed cases, n = 6; O/E = 4.7, 95% CI, 1.7 to 10.3). Mixed cellularity subtype predominated (five of eight cases, 63%). Five of six assessable cases contained Epstein-Barr virus (EBV) genome. Posttransplant HD differed from PTLD by later onset (> 2.5 years) and lack of association with established risk factors (such as T-cell depletion and HLA disparity). Patients with HD were more likely than matched controls to have had grade 2 to 4 acute graft-versus-host disease (GVHD), required therapy for chronic GVHD, or both (P = .002), although analysis included small numbers of patients.

CONCLUSION: The increased incidence of HD among BMT recipients adds support to current theories which link overstimulation of cell-mediated immunity and exposure to EBV with various subtypes of HD. The long latency of HD after transplant and lack of association with risk factors for PTLD is noteworthy and should be explored further for possible insights into pathogenesis.
Vinblastine Versus Vinblastine Plus Oral Estramustine Phosphate for Patients With Hormone-Refractory Prostate Cancer: A Hoosier Oncology Group and Fox Chase Network Phase III Trial
Authors: Hudes Gary , Einhorn Lawrence , Ross Eric , Balsham Andrew , Loehrer Patrick , Ramsey Harry , Sprandio John , Entmacher Michael , Dugan William , Ansari Rafat , Monaco Frank , Hanna Mark , Roth Bruce
Published: February 2017

PURPOSE: To compare vinblastine versus the combination of vinblastine plus estramustine as treatment for patients with hormone-refractory prostate cancer (HRPC).

PATIENTS AND METHODS: A total of 201 patients with metastatic prostate cancer, progressive after hormonal therapy and antiandrogen withdrawal (if prior antiandrogen treatment), were randomized to receive vinblastine (V) 4 mg/m2 by intravenous bolus weekly for 6 weeks followed by 2 weeks off, either alone or together with estramustine phosphate (EM-V) 600 mg/m2 PO days 1 through 42, repeated every 8 weeks. Of 193 eligible patients, 98 received V, and 95 received EM-V.

RESULTS: Overall survival trended in favor of EM-V but was not significantly different as determined by Kaplan-Meier analysis (P = .08). Median survival was 11.9 months for EM-V and 9.2 months for V. EM-V was superior to V for secondary end points of time to progression (P < .001, stratified log rank test; median 3.7 v 2.2 months, respectively) and for proportion of patients with ≥ 50% prostate-specific antigen (PSA) decline sustained for at least 3 monthly measurements (25.2% v 3.2%, respectively; P < .0001). Granulocytopenia was significantly less for EM-V compared with V (grade 2, 3, and 4 = 7%, 7%, and 1% v 27%, 18% and 9%, respectively; P < .0001); however, grade 2 or worse nausea (26% v 7%, respectively; P = .0002) and extremity edema (22% v 8%, respectively; P = .005) were more frequent for EM-V.

CONCLUSION: Although overall survival was not significantly greater for the combination, EM-V was superior to V for time to progression and PSA improvement. These results encourage further study of estramustine-based antimicrotubule drug combinations in HRPC.
Further Evaluation of Intensified and Increased Total Dose of Cyclophosphamide for the Treatment of Primary Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-25
Authors: Fisher Bernard , Anderson Stewart , DeCillis Arthur , Dimitrov Nikolay , Atkins James N. , Fehrenbacher Louis , Henry Patrick H. , Romond Edward H. , Lanier Keith S. , Davila Enrique , Kardinal Carl G. , Laufman Leslie , Pierce H. Irving , Abramson Neil , Keller Alan M. , Hamm John T. , Wickerham D.L. , Begovic Mirsada , Tan-Chiu Elizabeth , Tian Wei , Wolmark Norman
Published: February 2017

PURPOSE: In 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results.

PATIENTS AND METHODS: Patients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival.

RESULTS: No significant difference was observed in DFS (P = .20), distant DFS (P = .31), or survival (P = .76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P = .29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P = .71) and 3 (78% v 79%, respectively; P = .86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups.

CONCLUSION: Because intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting.
Micrometastases of Bone Marrow in Localized Prostate Cancer: Correlation With Established Risk Factors
Authors: Weckermann Dorothea , Müller Peter , Wawroschek Friedhelm , Krawczak Gunnar , Riethmüller Gert , Schlimok Günter
Published: February 2017

PURPOSE: The presence of cytokeratin 18–positive cells in bone marrow correlates with conventional risk factors in many tumors. We examined whether this was also valid for localized or lymphatically spread prostate cancer.

PATIENTS AND METHODS: Immediately before radical prostatectomy, bone marrow aspirates from both sides of the iliac crest were taken from 287 patients. The presence of cells containing cytokeratin 18 was interpreted as micrometastasis.

RESULTS: In patients with negative lymph nodes (n = 219), conventional risk factors (Gleason score, pathologic stage, ploidy, and preoperative prostate-specific antigen) did not correlate with the preoperative detection of cells containing cytokeratin 18. There was also no correlation with lymph node metastases. Furthermore, there was no interdependency between the preoperatively detected number of cells and the established risk factors.

CONCLUSION: We assume the presence of epithelial cells in bone marrow to be an independent parameter, the clinical importance of which must be substantiated by further studies.
Eligibility and Response Guidelines for Phase II Clinical Trials in Androgen-Independent Prostate Cancer: Recommendations From the Prostate-Specific Antigen Working Group
Authors: Bubley Glenn J. , Carducci Michael , Dahut William , Dawson Nancy , Daliani Danai , Eisenberger Mario , Figg William D. , Freidlin Boris , Halabi Susan , Hudes Gary , Hussain Maha , Kaplan Richard , Myers Charles , Oh William , Petrylak Daniel P. , Reed Eddie , Roth Bruce , Sartor Oliver , Scher Howard , Simons Jonathan , Sinibaldi Vickie , Small Eric J. , Smith Matthew R. , Trump Donald L. , Vollmer Robin , Wilding George
Published: February 2017

PURPOSE: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters.

RESULT: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point.

CONCLUSION: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.