bluuebunny/crossref_metadata_2025 huggingface dataset:
Paclitaxel and Carboplatin in the Treatment of Small-Cell Lung Cancer Patients Resistant to Cyclophosphamide, Doxorubicin, and Etoposide: A Non–Cross-Resistant Schedule
Authors: Groen Harry J.M. , Fokkema Eelco , Biesma Bonne , Kwa Bibi , van Putten John W.G. , Postmus Pieter E. , Smit Egbert F.
Published: February 2017

PURPOSE: To evaluate the efficacy of paclitaxel and carboplatin (PC) in small-cell lung cancer (SCLC) patients resistant to cyclophosphamide, doxorubicin, and etoposide (CDE).

PATIENTS AND METHODS: We performed a phase II study with PC in SCLC patients who relapsed within 3 months after first-line treatment with CDE. Paclitaxel administration (175 mg/m2 by a 3-hour intravenous infusion) was followed by a 30-minute infusion of carboplatin (area under the curve 7; Chatelut formula) once every 3 weeks for five cycles. Dexamethasone, clemastine, and ranitidine were standard premedication before every cycle.

RESULTS: Included were 35 patients (median age, 59 years; 16 with limited disease and 19 with extensive disease; Eastern Cooperative Oncology Group performance status of ≤ 1; median time off treatment 6 weeks) who were previously treated with CDE (n = 33), oral etoposide (n = 2), and reinduction CDE (n = 15); only one patient had received three CDE treatments of five cycles. The CDE regimen was followed by local thoracic radiotherapy in seven patients. Hematologic toxicity of grade 3 or 4, for leukopenia was 27% and 6%, for thrombocytopenia 21% and 13%, and for anemia 17% and 0%, respectively, for a total of 132 cycles. Two patients had neutropenic fever; no toxic death occurred. Nonhematologic toxicity was paresthesia CTC grade 3, diarrhea grade 4, and myalgia grade 3 in one patient each. Reversible paresthesia (CTC grade 1 and 2) in toes and fingers was reported in 69% of patients. Thirty-four patients were assessable for response: complete response in two patients, partial response in 23 patients, stable disease in eight patients, and progressive disease in one patient (response rate, 73.5%; 95% confidence interval, 59% to 88%). One patient was found to have atypical carcinoid at pathologic review and was excluded. Median time to progression was 21 weeks (range, 3 to 40 weeks). Median survival was 31 weeks (range, 6 to 112 weeks). One-year survival was 9%.

CONCLUSION: Second-line PC in CDE-resistant SCLC patients yields a high response rate and seems non–cross-resistant to CDE. Toxicity was mild in these poor-prognosis patients.
Phase II Trial of Primary Chemotherapy Followed by Reduced-Dose Radiation for CNS Germ Cell Tumors
Authors: Buckner Jan C. , Peethambaram Prema P. , Smithson William A. , Groover Robert V. , Schomberg Paula J. , Kimmel David W. , Raffel Corey , O'Fallon Judith R. , Neglia Joseph , Shaw Edward G.
Published: February 2017

PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy.

PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination.

RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or beta–human chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment.

CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.
Prospective Randomized Trial of the Treatment of Patients With Metastatic Melanoma Using Chemotherapy With Cisplatin, Dacarbazine, and Tamoxifen Alone or in Combination With Interleukin-2 and Interferon Alfa-2b
Authors: Rosenberg Steven A. , Yang James C. , Schwartzentruber Douglas J. , Hwu Patrick , Marincola Francesco M. , Topalian Suzanne L. , Seipp Claudia A. , Einhorn Jan H. , White Donald E. , Steinberg Seth M.
Published: February 2017

PURPOSE: The combination of chemotherapy with immunotherapeutic agents such as interleukin-2 and interferon alfa-2b has been reported to provide improved treatment results in patients with metastatic melanoma, compared with the use of chemotherapy alone. We have performed a prospective randomized trial in patients with metastatic melanoma, comparing treatment with chemotherapy to treatment with chemoimmunotherapy.

PATIENTS AND METHODS: One hundred two patients with metastatic melanoma were prospectively randomized to receive chemotherapy composed of tamoxifen, cisplatin, and dacarbazine or this same chemotherapy followed by interferon alfa-2b and interleukin-2. Objective responses, survival, and toxicity in the two groups were evaluated at a median potential follow-up of 42 months.

RESULTS: In 52 patients randomized to receive chemotherapy, there were 14 objective responses (27%), including four complete responses. In 50 patients randomized to receive chemoimmunotherapy, there were 22 objective responses (44%) (P2 = .071), including three complete responses. In both treatment groups, the duration of partial responses was often short, and there was a trend toward a survival advantage for patients receiving chemotherapy alone (P2 = .052; median survival of 15.8 months compared with 10.7 months). Treatment-related toxicities were greater in patients receiving chemoimmunotherapy.

CONCLUSION: With the treatment regimens used in this study, the addition of immunotherapy to combination chemotherapy increased toxicity but did not increase survival. The use of combination chemoimmunotherapy regimens is not recommended in the absence of well-designed, prospective, randomized protocols showing the benefit of this treatment strategy.
Which Cases Are Found and Missed by Neuroblastoma Screening at 1 Year? Results From the 1992 to 1995 Study in Three Federal States of Germany
Authors: Berthold F. , Baillot A. , Hero B. , Schurr P. , Nerenz A. , Hunneman D.H. , Sander J.
Published: February 2017

PURPOSE: Neuroblastoma screening during the first half-year of life is associated with a two- to three-fold overdiagnosis. Because regression processes seem to be confined to infancy, we investigated whether screening at 1 year would be associated with fewer overdiagnoses, and we investigated the characteristics of thus-detected and not-detected patients.

PATIENTS AND METHODS: Thin-layer chromatography was used for semiquantitative assessment of urine samples dried on filter paper and obtained when patients were 10 to 14 months old (sample 1) and 17 to 19 months old (sample 2). Abnormal results were reanalyzed quantitatively from the same specimen by high-performance liquid chromatography and/or gas chromatography–mass spectrometry.

RESULTS: A total of 200,054 children of the German federal states Lower Saxony, Northern Rhine-Westphalia, and Bremen were screened from May 1992 to April 1995. Of 229,078 investigated samples (100%), 228,245 (99.6%) were first, 657 (0.3%) were second, and 176 (0.08%) were third urine specimens. The compliance rate was 27.8%, but it continued to increase throughout the study period and in the last year it was 43.3%. The second screening offered at 18 months was accepted by only 12.1% (24,259) of the children. Thirty children underwent clinical examination, and nine asymptomatic neuroblastoma cases were detected (stage 1, n = 4; stage 2, n = 2; stage 3, n = 2; stage 4, n = 1; detection rate, 1:22,228). The results of 21 tests were false-positive. Ten children with false-negative test results presented 8 to 35 months later with neuroblastoma (stage 1 tumor, n = 1; stage 2, n = 1; stage 3, n = 1; stage 4, n = 7; five of nine tumors were N-myc–amplified tumors). Three children were nonsecretors at the time of diagnosis. Fifty-two patients were “missed” (not screened), and 37 children developed neuroblastoma before the age of screening (early cases). During the same period, a total of 23.6 cases per million children within the screening area and 24.0 cases per million children outside the screening area were diagnosed as neuroblastoma cases (not significant [NS]). In prescreening times in the area of the later screening states, 20.7 cases per million children were found (NS).

CONCLUSION: Screening at 1 year of age demonstrated a lower detection rate than earlier screening programs and did not produce a “halo effect.” The good prognostic features of early-detected cases and the poor characteristics of not-detected-but-late-presenting cases corresponded to those of the related age groups.
Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas
Authors: Cheson Bruce D. , Horning Sandra J. , Coiffier Bertr , Shipp Margaret A. , Fisher Richard I. , Connors Joseph M. , Lister T. Andrew , Vose Julie , Grillo-López Antonio , Hagenbeek Anton , Cabanillas Fernando , Klippensten Donald , Hiddemann Wolfgang , Castellino Ronald , Harris Nancy L. , Armitage James O. , Carter William , Hoppe Richard , Canellos George P.
Published: February 2017

ABSTRACT: Standardized guidelines for response assessment are needed to ensure comparability among clinical trials in non-Hodgkin's lymphomas (NHL). To achieve this, two meetings were convened among United States and international lymphoma experts representing medical hematology/oncology, radiology, radiation oncology, and pathology to review currently used response definitions and to develop a uniform set of criteria for assessing response in clinical trials. The criteria that were developed include anatomic definitions of response, with normal lymph node size after treatment of 1.5 cm in the longest transverse diameter by computer-assisted tomography scan. A designation of complete response/unconfirmed was adopted to include patients with a greater than 75% reduction in tumor size after therapy but with a residual mass, to include patients—especially those with large-cell NHL—who may not have residual disease. Single-photon emission computed tomography gallium scans are encouraged as a valuable adjunct to assessment of patients with large-cell NHL, but such scans require appropriate expertise. Flow cytometric, cytogenetic, and molecular studies are not currently included in response definitions. Response rates may be the most important objective in phase II trials where the activity of a new agent is important and may provide support for approval by regulatory agencies. However, the goals of most phase III trials are to identify therapies that will prolong the progression-free survival, if not the overall survival, of the treated patients. We hope that these guidelines will serve to improve communication among investigators and comparability among clinical trials until clinically relevant laboratory and imaging studies are identified and become more widely available.
Nongastrointestinal Low-Grade Mucosa-Associated Lymphoid Tissue Lymphoma: Analysis of 75 Patients
Authors: Zinzani Pier Luigi , Magagnoli Massimo , Galieni Piero , Martelli Maurizio , Poletti Venerino , Zaja Francesco , Molica Stefano , Zaccaria Alfonso , Cantonetti Anna Maria , Gentilini Patrizia , Guardigni Luciano , Gherlinzoni Filippo , Ribersani Michela , Bendandi Maurizio , Albertini Patrizia , Tura Sante
Published: February 2017

PURPOSE: Nongastrointestinal locations represent about 30% to 40% of all low-grade mucosa-associated lymphoid tissue (MALT) lymphomas. We report a retrospective analysis of 75 patients with nongastrointestinal low-grade MALT lymphoma, presenting their clinical, therapeutic, and follow-up data with respect to the initial location of the lymphoma.

PATIENTS AND METHODS: From January 1988 to October 1997, 75 patients with untreated nongastrointestinal low-grade MALT lymphoma were subjected to treatments ranging from local radiotherapy and local interferon alfa administration to chemotherapy. The lymphomas were located in the lung (19 patients), orbital soft tissue (16 patients), skin (seven patients), thyroid (seven patients), lachrymal gland (six patients), conjunctiva (six patients), salivary gland (six patients), breast (three patients), eyelid (two patients), larynx (one patient), bone marrow (one patient), and trachea (one patient).

RESULTS: Complete and partial remissions were achieved in 59 (79%) and 16 (21%) of the 75 patients, respectively, with an overall response rate of 100%. All but two of the patients are still alive, with a median follow-up of 47 months; these two patients died from other causes. The estimated time to treatment failure rate is 30% at 5 years. In the thyroid and lachrymal gland sites, no relapses were reported.

CONCLUSION: Our data regarding the largest reported series of nongastrointestinal MALT lymphomas confirm the good prognosis of this particular clinicopathologic entity and the significant efficacy of different therapeutic approaches to specific sites.
Empirical Comparison of Commonly Used Measures to Evaluate Pain Treatment in Cancer Patients With Chronic Pain
Authors: de Wit Rianne , van Dam Frits , Abu-Saad Huda Huijer , Loonstra Simone , Zandbelt Linda , van Buuren Anneke , van der Heijden Karin , Leenhouts Gerleen
Published: February 2017

PURPOSE: There is limited consensus about the most appropriate measures to evaluate the adequacy of pain treatment in cancer patients. There are no known studies describing commonly used measures to simultaneously evaluate the adequacy of cancer pain treatment. The purpose of this study was to compare measures, which are frequently reported in the literature, to assess the adequacy of pain treatment in cancer patients with chronic pain. This study was part of a randomized controlled trial.

PATIENTS AND METHODS: In total, 313 cancer patients with a pain duration of at least 1 month were evaluated. After a baseline measure in the hospital, patients were followed up at 2, 4, and 8 weeks after discharge at home. Adequacy of cancer pain treatment was evaluated by means of four different types of outcome measures. The four types included three pain intensity markers based on patients' pain intensity, a pain relief scale, a patient satisfaction scale, and three pain management indexes that related patients' pain medication with pain intensity.

RESULTS: The proportion of inadequately treated pain patients varied extremely. Depending on the outcome measure used, the percentage of inadequately treated patients ranged from 16% to 91%. The choice of measure, rather than pain treatment itself, determined the proportion of inadequacy.

CONCLUSION: There is an urgent need for consensus about how to evaluate the effectiveness of pain treatment. Studies that evaluate adequacy of pain treatment should be interpreted with caution. Further research is necessary to elucidate the validity and reliability of outcome measures simultaneously.
p53 and K-ras Gene Mutations Correlate With Tumor Aggressiveness But Are Not of Routine Prognostic Value in Colorectal Cancer
Authors: Tortola Silvia , Marcuello Eugenio , González Isabel , Reyes Germán , Arribas Rosa , Aiza Gemma , Sancho Francesc J. , Peinado Miguel A. , Capella Gabriel
Published: February 2017

PURPOSE: p53 gene and K-ras mutations are among the most common genetic alterations present in colorectal cancer. The prognostic utility of such mutations remains controversial. The purpose of this study was to prospectively evaluate the prognostic significance of p53 and K-ras gene mutations in colorectal cancer.

PATIENTS AND METHODS: One hundred forty patients were analyzed. Tumors belonging to the microsatellite mutator phenotype were excluded (n = 8). Mutations at the K-ras and p53 genes were detected and characterized by restriction fragment length polymorphism, single-strand conformation polymorphism, and sequencing, as appropriate.

RESULTS: p53 mutations were detected in 66 (50%) and K-ras mutations were detected in 54 (41%) of the 132 patients. In 26 cases (20%), ras and p53 mutations coexisted; in 38 cases (29%), neither mutation was found. Multivariate analysis of the whole population analyzed (n = 132) showed that survival was strongly correlated with the presence of p53 mutations alone or in combination with K-ras mutations (P = .002; log-rank test). When only patients undergoing a radical resection were considered (R0; n = 101), p53 mutations were no longer of prognostic significance.

CONCLUSION: p53 mutations alone or in combination with K-ras mutations are correlated with a worse outcome. However, the routine use of these mutations as prognostic markers in the clinical setting is not recommended.
Detection of Human Papillomavirus Types 16 and 18 mRNA in Peripheral Blood of Advanced Cervical Cancer Patients and Its Association With Prognosis
Authors: Tseng Chih-Jen , Pao Chia C. , Lin Jen-Daw , Soong Yung-Kuei , Hong Ji-Hong , Hsueh Swei
Published: February 2017

PURPOSE: To evaluate the feasibility of detecting human papillomavirus E6 (HPVE6) gene mRNA in the peripheral blood of patients with locally advanced cervical cancer, and the relationship of the circulating HPV viral–specific mRNA with clinicopathologic factors and prognosis of locally advanced cervical cancer.

PATIENTS AND METHODS: The presence of types 16 and 18 HPVE6 gene mRNA was determined by reverse transcription followed by nested polymerase chain reaction. Thirty-five patients with locally advanced cervical cancer who were positive for HPV type 16 or 18 DNA were included in the study. All patients received external-beam radiation therapy followed by intracavitary brachytherapy.

RESULTS: Eighteen (51.4%) of 35 HPV DNA–positive cervical cancer patients had HPV-specific mRNA in their peripheral blood cells, compared with none of 17 HPV DNA–negative cervical cancer patients and none of 12 control volunteers. The presence of HPVE6 gene mRNA in peripheral blood was associated with bulky tumor volume (> 4 cm) and pelvic lymph node metastasis (tumor volume, P = .03; lymph node status, P = .03). After a median follow-up of 22 months, patients who were positive for peripheral-blood HPVE6 gene mRNA had a significantly higher risk of recurrence than those who were negative (10 of 18 v three of 17, P = .02; mean recurrent time, 20.7 months v 12.6 months, P = .02). There was also a statistically significant association of peripheral-blood HPVE6 gene mRNA positivity with distant metastasis (eight of 18 v one of 17; P = .01).

CONCLUSION: Results of this study seem to suggest that the presence of HPVE6 gene mRNA in peripheral blood may provide an early marker that identifies patients who are at risk for metastasis.
Prospective Randomized Trial of Docetaxel Versus Mitomycin Plus Vinblastine in Patients With Metastatic Breast Cancer Progressing Despite Previous Anthracycline-Containing Chemotherapy
Authors: Nabholtz J.-M. , Senn H. J. , Bezwoda W. R. , Melnychuk D. , Deschênes L. , Douma J. , Vandenberg T. A. , Rapoport B. , Rosso R. , Trillet-Lenoir V. , Drbal J. , Molino A. , Nortier J.W.R. , Richel D. J. , Nagykalnai T. , Siedlecki P. , Wilking N. , Genot J. Y. , Hupperets P.S.G.J. , Pannuti F. , Skarlos D. , Tomiak E. M. , Murawsky M. , Alakl M. , Riva A. , Aapro M.
Published: February 2017

PURPOSE: This phase III study compared docetaxel with mitomycin plus vinblastine (MV) in patients with metastatic breast cancer (MBC) progressing despite previous anthracycline-containing chemotherapy.

PATIENTS AND METHODS: Patients (n = 392) were randomized to receive either docetaxel 100 mg/m2 intravenously (IV) every 3 weeks (n = 203) or mitomycin 12 mg/m2 IV every 6 weeks plus vinblastine 6 mg/m2 IV every 3 weeks (n = 189), for a maximum of 10 3-week cycles.

RESULTS: In an intention-to-treat analysis, docetaxel produced significantly higher response rates than MV overall (30.0% v 11.6%; P < .0001), as well as in patients with visceral involvement (30% v 11%), liver metastases (33% v 7%), or resistance to previous anthracycline agents (30% v 7%). Median time to progression (TTP) and overall survival were significantly longer with docetaxel than MV (19 v 11 weeks, P = .001, and 11.4 v 8.7 months, P = .0097, respectively). Neutropenia grade 3/4 was more frequent with docetaxel (93.1% v 62.5%; P < .05); thrombocytopenia grade 3/4 was more frequent with MV (12.0% v 4.1%; P < .05). Severe acute or chronic nonhematologic adverse events were infrequent in both groups. Withdrawal rates because of adverse events (MV, 10.1%; docetaxel, 13.8%) or toxic death (MV, 1.6%; docetaxel, 2.0%) were similar in both groups. Quality-of-life analysis was limited by a number of factors, but results were similar in both groups.

CONCLUSION: Docetaxel is significantly superior to MV in terms of response, TTP, and survival. The safety profiles of both therapies are manageable and tolerable. Docetaxel represents a clear treatment option for patients with MBC progressing despite previous anthracycline-containing chemotherapy.
Breast-Conserving Therapy: Proteases as Risk Factors in Relation to Survival After Local Relapse
Authors: Meijer-van Gelder Marion E. , Look Maxime P. , Vries Joan Bolt-de , Peters Harry A. , Klijn Jan G.M. , Foekens John A.
Published: February 2017

PURPOSE: To evaluate whether cathepsin D, urokinase-type plasminogen activator (uPA), its inhibitor, plasminogen activator inhibitor-1 (PAI-1), or clinical factors can predict which patients are at risk for developing distant metastases after local recurrence (LR).

PATIENTS AND METHODS: Of 1,630 patients treated with breast-conserving surgery and radiotherapy of the breast between 1980 and 1992, LR developed in 171 as a first event. From the available primary tumor tissues, we determined the cytosolic levels of cathepsin D, uPA and PAI-1.

RESULTS: In patients with LR, a short (≤ 2 years) disease-free interval (DFI) and skin involvement of LR were associated with poor postrelapse distant metastasis-free survival (PR-DMFS, P = .001, both) and postrelapse overall survival (PR-OS; P < .0001 and P < .0002, respectively). The primary tumor levels of uPA and PAI-1 were elevated for patients with a short DFI (P < .01), but such a relation was not observed for patients with skin involvement. In univariate analyses, high levels of uPA and PAI-1 in the primary tumor were associated with poor PR-OS (P = .038 and P = .040, respectively) but not PR-DMFS. In Cox multivariate analyses for PR-DMFS and PR-OS, only a short DFI and skin involvement of the LR were independently associated with a poor clinical outcome.

CONCLUSION: In patients treated with breast-conserving therapy who had LR as a first event, a short DFI and skin involvement were strong indicators for poor PR-DMFS and PR-OS. The proteases studied did not contribute significantly to the final multivariate model.
Cerebrospinal Fluid Asparagine Concentrations After Escherichia coli Asparaginase in Children With Acute Lymphoblastic Leukemia
Authors: Woo Michael H. , Hak Lawrence J. , Storm Michael C. , Gajjar Amar J. , Sandlund John T. , Harrison Patricia L. , Wang Bo , Pui Ching-Hon , Relling Mary V.
Published: February 2017

PURPOSE: The CNS is an important sanctuary site in childhood acute lymphoblastic leukemia (ALL). CSF asparagine concentration reflects asparaginase systemic pharmacodynamics. We evaluated the time course of CSF asparagine depletion in children with ALL during and after a course of Escherichia coli asparaginase.

PATIENTS AND METHODS: Thirty-one children (24 newly diagnosed and seven at relapse) received E coli asparaginase 10,000 IU/m2 intramuscularly three times weekly for six and nine doses, respectively, as part of multiagent induction chemotherapy. CSF asparagine levels were measured before, during, and after asparaginase dosing.

RESULTS: The percentage of patients with undetectable (< 0.04 μmol/L) CSF asparagine was 3.2% (one of 31 patients) at baseline, 73.9% (17 of 23) during asparaginase therapy, and 56.3% (nine of 16) 1 to 5 days, 43.8% (seven of 16) 6 to 10 days, 20.0% (two of 10) 11 to 30 days and 0% (zero of 21) more than 30 days after asparaginase therapy. The proportion of patients with depleted CSF asparagine was higher during asparaginase therapy than at baseline (P < .001), 11 to 30 days (P = .003), and more than 30 days after asparaginase therapy (P < .001). Median CSF asparagine concentrations were 4.42 μmol/L before, less than 0.04 μmol/L during, and less than 0.04 μmol/L at 1 to 5 days, 1.63 μmol/L at 6 to 10 days, 1.70 μmol/L at 11 to 30 days, and 5.70 μmol/L at more than 30 days after asparaginase therapy, respectively. CSF depletion was more common in patients with low baseline CSF asparagine concentrations (P = .003).

CONCLUSION: CSF asparagine concentrations are depleted by conventional doses of E coli asparaginase in the majority of patients, but they rebound once asparaginase therapy is completed.
Impact of Therapeutic Research on Informed Consent and the Ethics of Clinical Trials: A Medical Oncology Perspective
Authors: Daugherty Christopher K.
Published: February 2017

PURPOSE: To create a more meaningful understanding of the informed consent process as it has come to be practiced and regulated in clinical trials, this discussion uses the experience gained from the conduct of therapeutic research that involves cancer patients.

DESIGN: After an introduction of the ethical tenets of the consent process in clinical research that involves potentially vulnerable patients as research subjects, background that details the use of written consent documents and of the term “informed consent” is provided. Studies from the cancer setting that examine the inadequacies of written consent documents, and the outcome of the consent process itself, are reviewed. Two ethically challenging areas of cancer clinical research, the phase I trial and the randomized controlled trial, are discussed briefly as a means of highlighting many dilemmas present in clinical trials. Before concluding, areas for future research are discussed.

RESULTS: Through an exclusive cancer research perspective, many current deficiencies in the informed consent process for therapeutic clinical trials can be critically examined. Also, new directions for improvements and areas of further research can be outlined and discussed objectively. The goals of such improvements and research should be prevention of further misguided or ineffective efforts to regulate the informed consent process.

CONCLUSION: To ignore this rich and interesting perspective potentially contributes to continued misunderstanding and apathy toward fulfilling the regulatory and ethically obligatory requirements involved in an essential communication process between a clinician-investigator and a potentially vulnerable patient who is considering clinical trial participation.
Role of FHIT in Human Cancer
Authors: Croce Carlo M. , Sozzi Gabriella , Huebner Kay
Published: February 2017

ABSTRACT: Through investigation of hemizygous and homozygous deletions in common human cancers, including lung cancer, we have cloned and characterized a gene at chromosome region 3p14.2, FHIT, that is inactivated in epithelial tumors, particularly in tumors resulting from exposure to environmental carcinogens. In some tumors, particularly those associated with environmental carcinogens, alterations in the FHIT gene occur quite early in the development of cancer. In other cancers, Fhit inactivation seems to be a later event, possibly associated with progression to more aggressive neoplasias. Thus, detection of Fhit expression by immunohistochemistry in premalignant and malignant tissues may provide important diagnostic and prognostic information.
Mastectomy or Lumpectomy? Helping Women Make Informed Choices
Authors: Whelan Timothy , Levine Mark , Gafni Amiram , Sanders Kenneth , Willan Andrew , Mirsky Douglas , Schnider Denise , McCready David , Reid Susan , Kobylecky Anna , Reed Kenneth
Published: February 2017

PURPOSE: To develop an instrument to help clinicians inform their patients about surgical treatment options for the treatment of breast cancer and to evaluate the impact of the instrument on the clinical encounter.

METHODS: We developed an instrument, called the Decision Board, to present information regarding the benefits and risks of breast-conserving therapy (lumpectomy plus radiation therapy) and mastectomy to women with early-stage breast cancer to enable them to express a preference for the type of surgery. Seven surgeons from different communities in Ontario administered the instrument to women with newly diagnosed clinical stage I or II breast cancer over an 18-month period. Patients and surgeons were interviewed regarding acceptability of the instrument. The rates of breast-conserving surgery performed by surgeons before and after the introduction of the instrument were compared.

RESULTS: The Decision Board was administered to 175 patients; 98% reported that the Decision Board was easy to understand, and 81% indicated that it helped them make a decision. The average score on a true/false test of comprehension was 11.8 of 14 (84%) (range, 6 to 14). Surgeons found the Decision Board to be helpful in presenting information to patients in 91% of consultations. The rate of breast-conserving surgery decreased when the Decision Board was introduced (88% v 73%, P = .001)

CONCLUSION: The Decision Board is a simple method to improve communication and facilitate shared decision making. It was well accepted by patients and surgeons and easily applied in the community.
S100-Beta, Melanoma-Inhibiting Activity, and Lactate Dehydrogenase Discriminate Progressive From Nonprogressive American Joint Committee on Cancer Stage IV Melanoma
Authors: Deichmann Martin , Benner Axel , Bock Michael , Jäckel Andreas , Uhl Karen , Waldmann Volker , Näher Helmut
Published: February 2017

PURPOSE: Monitoring advanced malignant melanoma, serum levels of S100-beta (S100β) and melanoma-inhibiting activity (MIA) were assessed for the ability to discriminate progressive from nonprogressive disease. S100β and MIA were supposed to be superior to conventional variables, such as lactate dehydrogenase (LDH) level.

PATIENTS AND METHODS: Seventy-one patients with stage IV malignant melanoma according to the criteria of the American Joint Committee on Cancer (AJCC) were included in the study. Results of restaging examinations were used as an independent reference standard for diagnosing progressive disease, and S100β, MIA, LDH level, and erythrocyte sedimentation rate (ESR) were determined in venous blood just before restaging. Sensitivities and specificities of the parameters were calculated by logistic regression analysis. Discrimination ability was assessed by Somers' Dxy rank correlation and the area under the receiver-operating characteristic curve (ROC-AUC).

RESULTS: All tested serum parameters were significantly elevated in patients with progressive disease. The highest sensitivities according to the established thresholds were found for S100β and MIA (91% and 88%, respectively). LDH had the highest specificity (92%). ESR was dropped from the analysis because of low specificity. In calculating Somers' Dxy and ROC-AUC values, S100β, MIA, and LDH showed high discrimination ability. By multiple logistic regression, LDH was identified to be the only statistically significant marker for progressive disease. S100β and MIA did not provide additional significant information because of their high correlation with LDH with respect to clinical outcome.

CONCLUSION: Elevated serum levels of S100β, MIA, and LDH indicate current disease progression in AJCC stage IV melanoma. LDH was the most relevant overall parameter.
Maximized Reduction of Primary Breast Tumor Size Using Preoperative Chemotherapy With Doxorubicin and Docetaxel
Authors: von Minckwitz Gunter , Costa Serban Dan , Eiermann Wolfgang , Blohmer Jens-Uwe , Tulusan Augustinos Harjanto , Jackisch Christian , Kaufmann Manfred
Published: February 2017

PURPOSE: To assess the toxicity and efficacy of preoperative chemotherapy with doxorubicin and docetaxel in patients with primary operable breast cancer.

PATIENTS AND METHODS: Forty-two patients with histologically confirmed primary breast cancer tumors of at least 2 cm in diameter received doxorubicin (50 mg/m2 intravenously [IV] over 15 minutes) and docetaxel (75 mg/m2 IV over 1 hour) every 14 (24 patients) or 21 (18 patients) days for four cycles.

RESULTS: The median size of the primary tumor decreased significantly, from 4 cm (range, 2 to 10 cm) to 2 cm (range, 0 to 5 cm) on physical examination and from 3.4 cm (range, 1 to 8 cm) to 1.8 cm (range, 0 to 4 cm) on sonography (P < .001). The overall response rate as assessed by physical examination was 93%, and complete remission of the primary tumor occurred in 33% of patients. The remission rate as assessed by sonographic measurement was 67%. Two patients (5%) had histologically confirmed complete responses. Sonography was more reliable than palpation in predicting histologically determined response. No grade 4 toxicity was noted, and grade 3 toxicity was reported with alopecia (95%), lethargy (17%), loss of appetite (10%), stomatitis (7%), leukopenia (5%), skin desquamation (5%), infection (5%), motor neuropathy (2%), and nausea (2%). The 3-week schedule was associated with less toxicity than the 2-week schedule.

CONCLUSION: Preoperative combination chemotherapy with doxorubicin and docetaxel is highly effective and feasible in primary operable breast cancer.
Telomerase Is a Highly Sensitive and Specific Molecular Marker in Fine-Needle Aspirates of Breast Lesions
Authors: Poremba Christopher , Shroyer Kenneth R. , Frost Michael , Diallo Raihanatou , Fogt Franz , Schäfer Karl-Ludwig , Bürger Horst , Shroyer A. Laurie , Dockhorn-Dworniczak Barbara , Boecker Werner
Published: February 2017

PURPOSE: Telomerase has been detected in a majority of human malignant tumors, making telomerase activity (TA) one key difference between mortal and immortal cells. In this study, we evaluated in blind-trial fashion the association of TA with cytologic and final clinical/pathologic diagnosis in fine-needle aspirates (FNAs) of breast lesions.

MATERIALS AND METHODS: In 172 FNAs, including 80 samples that were cytologically malignant, 18 that were atypical but not diagnostic for malignancy, and 74 that were cytologically benign, TA was determined by a modified nonradioactive telomeric repeat amplification protocol (TRAP) assay. Final diagnosis was made by pathologic examination of follow-up surgical material available for all the cytologically malignant samples, a majority of the cytologically atypical samples, and a portion of the cytologically benign samples.

RESULTS: TA was detected in 85 of 172 samples. Comparison of the cytologic and histologic diagnoseswith TA showed that 80 of 87 samples from patients with breast cancer were telomerase-positive, resulting in a sensitivity of 92%. TA was found in four of five FNAs from carcinomas that were considered cytologically atypical but not diagnostic for malignancy. Eighty of 85 samples from patients with benign breast lesions were telomerase-negative, revealing a specificity of 94%. The five positive cases in this group were all fibroadenomas with low TA. Among the 18 cases with a cytologic diagnosis of atypia, there was a strong positive relationship between TRAP findings and histologic diagnosis.

CONCLUSION: The detection of TA in FNAs of breast lesions is a highly sensitive and specific marker of malignancy and may be used as an adjunct in cases with an equivocal cytologic diagnosis.
Investigation of Endometrial Abnormalities in Asymptomatic Women Treated With Tamoxifen and an Evaluation of the Role of Endometrial Screening
Authors: Love C.D.B. , Muir B. B. , Scrimgeour J. B. , Leonard R. C.F. , Dillon P. , Dixon J. M.
Published: February 2017

PURPOSE: Tamoxifen is the most commonly prescribed adjuvant therapy for women with breast cancer. It has agonist activity on the endometrium and is associated with an increased risk of endometrial cancer. The aim of this study was to evaluate whether screening with transvaginal ultrasound (TV USS) with or without hysteroscopy is worthwhile.

PATIENTS AND METHODS: A total of 487 women with breast cancer, 357 treated with tamoxifen and 130 controls, were screened with TV USS, and endometrial thickness was measured. Women with thickened endometrium underwent outpatient hysteroscopy.

RESULTS: Length of time on tamoxifen ranged from 5 to 191 months (mean, 66 months), and endometrial thickness ranged from 1 to 38 mm (mean, 7.3 mm). Women treated with tamoxifen had significantly thicker endometrium than did controls (P < .0001). There was a statistically significant (P < .0001) positive correlation between length of time on tamoxifen and endometrial thickness. One hundred forty-five women had endometrium greater than 5 mm on USS, and 134 underwent successful outpatient hysteroscopy, 61 of whom had atrophic endometrium, resulting in a 46% false-positive scan rate. The remaining women all had benign features to explain the USS findings.

CONCLUSION: TV USS detects a high incidence (41%) of apparent endometrial thickening in women treated with tamoxifen, although 46% had atrophic endometrium on further assessment, and none of the remaining asymptomatic women had significant lesions. Length of time on tamoxifen relates to endometrial thickening as measured by TV USS. TV USS is a poor screening tool because of the high false-positive rate. The low frequency of significant findings suggests that endometrial screening in asymptomatic women is not worthwhile.
Gemcitabine as Second-Line Treatment for Advanced Non–Small-Cell Lung Cancer: A Phase II Trial
Authors: Crinò Lucio , Mosconi Anna Maria , Scagliotti Giorgio , Selvaggi Giovanni , Novello Silvia , Rinaldi Massimo , Della Giulia Marina , Gridelli Cesare , Rossi Antonio , Calandri Cesare , De Marinis Filippo , Noseda Mariantonietta , Tonato Maurizio
Published: February 2017

PURPOSE: To investigate the activity and toxicity of gemcitabine as a single agent in patients with advanced non–small-cell lung cancer (NSCLC) after recurrence or failure of previous treatment with a platinum-containing regimen.

PATIENTS AND METHODS: From November 1995 to October 1997, 83 patients with stage IIIB or IV NSCLC received gemcitabine 1,000 mg/m2 once a week for 3 weeks every 28 days. Responses were assessed every two treatment courses. The median age of the patients was 63 years; Eastern Cooperative Oncology Group performance status was 0 to 1 in 62 patients and 2 in 21 patients. The predominant histology was squamous (39 patients); 49 patients had stage IV disease and 34 patients had stage III disease (33 stage IIIB and one stage IIIA).

RESULTS: Sixteen patients (19%) achieved a partial response to treatment; the median duration of response was 29 weeks (range, 6 to 50 weeks). Treatment was well tolerated: grade 2 to 3 (World Health Organization standardized response criteria) leukopenia and thrombocytopenia occurred in 23% and 20% of patients, respectively. Mild asthenia was observed in 16% of patients, and peripheral edema in 5% of patients. Nausea and vomiting were present in 16% of patients.

CONCLUSION: In this experience, gemcitabine showed significant activity without relevant toxicity, mainly in patients who were previously responsive to chemotherapy. This suggests a possible role for gemcitabine as a second-line treatment in patients who had a previous response or achieved stable disease with a platinum-containing regimen.
Smoking Before Surgery Predicts Poor Long-Term Survival in Patients With Stage I Non–Small-Cell Lung Carcinomas
Authors: Fujisawa Takehiko , Iizasa Toshihiko , Saitoh Yukio , Sekine Yasuo , Motohashi Shin-ichiro , Yasukawa Tomohisa , Shibuya Kiyoshi , Hiroshima Kenzo , Ohwada Hidemi
Published: February 2017

PURPOSE: The majority of lung carcinoma patients requiring resection have smoking habits prior to surgical treatment, and the correlation of smoking with postoperative complications is well known. However, few studies have investigated the correlation between long-term survival and cigarette smoking in patients with primary, resected lung carcinoma. We analyzed the relationship between clinical factors, including cigarette smoking before surgery, and 10-year survival in stage I non–small-cell lung carcinoma (NSCLC).

PATIENTS AND METHODS: Cigarette smoking habit and other factors influencing either the overall survival or the disease-specific survival rates of patients with stage I primary, resected NSCLC were evaluated according to the Cox proportional hazards model using a total of 369 patients with stage I–NSCLC.

RESULTS: Comparison of the cause of death in patients with 30 or more pack-years and patients with less than 30 pack-years showed significant differences in the prevalence of recurrent disease and onset of nonmalignant disease. Multivariate analysis demonstrated significant correlations between overall survival and age and pack-years. Disease-specific survival showed significant correlations with age, tumor classification, and visceral pleural invasion.

CONCLUSION: Smoking pack-years is an important clinical prognostic factor in evaluating overall long-term survival in patients with stage I primary, resected NSCLC.
Role of Radiation Therapy in the Combined-Modality Treatment of Patients With Extensive Disease Small-Cell Lung Cancer: A Randomized Study
Authors: Jeremic Branislav , Shibamoto Yuta , Nikolic Nebojsa , Milicic Biljana , Milisavljevic Slobodan , Dagovic Aleksandar , Aleksandrovic Jasna , Radosavljevic-Asic Gordana
Published: February 2017

PURPOSE: To investigate the efficacy and toxicity of cisplatin/etoposide (PE) chemotherapy (CHT) with or without accelerated hyperfractionated radiation therapy (ACC HFX RT) and concurrent daily carboplatin/etoposide (CE) in patients with extensive-disease small-cell lung cancer.

PATIENTS AND METHODS: A total of 210 patients were treated with three cycles of standard PE. Patients with a complete response (CR) at both the local and distant levels (CR/CR) or a partial response (PR) at the local level and CR at the distant level (PR/CR) received either thoracic ACC HFX RT with 54 Gy in 36 fractions over 18 treatment days in combination with CE followed by two cycles of PE (group 1, n = 55) or an additional four cycles of PE (group 2, n = 54). Patients who experienced less response were treated nonrandomly (groups 3, 4, and 5). All patients with a CR at the distant level received prophylactic cranial irradiation.

RESULTS: For 206 assessable patients, the median survival time (MST) was 9 months and the 5-year survival rate was 3.4%. Patients in group 1 had significantly better survival rates than those in group 2 (MST, 17 v 11 months; 5-year survival rate, 9.1% v 3.7%, respectively; P = .041). Local control was also better in group 1, but the difference was only marginally not significant (P = .062). There was no difference in distant metastasis-free survival between groups 1 and 2. Acute high-grade toxicity was higher in group 2 than in group 1.

CONCLUSION: The addition of ACC HFX RT to the treatment of the most favorable subset of patients led to improved survival over that obtained with CHT alone.
Treatment of Children With Medulloblastomas With Reduced-Dose Craniospinal Radiation Therapy and Adjuvant Chemotherapy: A Children's Cancer Group Study
Authors: Packer Roger J. , Goldwein Joel , Nicholson H. Stacy , Vezina L. Gilbert , Allen Jeffrey C. , Ris M. Douglas , Muraszko Karin , Rorke Lucy B. , Wara William M. , Cohen Bruce H. , Boyett James M.
Published: February 2017

PURPOSE: Medulloblastoma is the most common malignant brain tumor of childhood. After treatment with surgery and radiation therapy, approximately 60% of children with medulloblastoma are alive and free of progressive disease 5 years after diagnosis, but many have significant neurocognitive sequelae. This study was undertaken to determine the feasibility and efficacy of treating children with nondisseminated medulloblastoma with reduced-dose craniospinal radiotherapy plus adjuvant chemotherapy.

PATIENTS AND METHODS: Over a 3-year period, 65 children between 3 and 10 years of age with nondisseminated medulloblastoma were treated with postoperative, reduced-dose craniospinal radiation therapy (23.4 Gy) and 55.8 Gy of local radiation therapy. Adjuvant vincristine chemotherapy was administered during radiotherapy, and lomustine, vincristine, and cisplatin chemotherapy was administered during and after radiation.

RESULTS: Progression-free survival was 86% ± 4% at 3 years and 79% ± 7% at 5 years. Sites of relapse for the14 patients who developed progressive disease included the local tumor site alone in two patients, local tumor site and disseminated disease in nine, and nonprimary sites in three. Brainstem involvement did not adversely affect outcome. Therapy was relatively well tolerated; however, the dose of cisplatin had to be modified in more than 50% of patients before the completion of treatment. One child died of pneumonitis and sepsis during treatment.

CONCLUSION: These overall survival rates compare favorably to those obtained in studies using full-dose radiation therapy alone or radiation therapy plus chemotherapy. The results suggest that reduced-dose craniospinal radiation therapy and adjuvant chemotherapy during and after radiation is a feasible approach for children with nondisseminated medulloblastoma.
High-Dose Melphalan With Autotransplantation for Refractory Multiple Myeloma: Results of a Southwest Oncology Group Phase II Trial
Authors: Vesole David H. , Crowley John J. , Catchatourian Rose , Stiff Patrick J. , Johnson David B. , Cromer Jeana , Salmon Sydney E. , Barlogie Bart
Published: February 2017

PURPOSE: To evaluate high-dose melphalan followed by autologous stem-cell transplantation in patients with refractory multiple myeloma.

PATIENTS AND METHODS: Multiple myeloma patients with alkylating agent or vincristine/doxorubicin/dexamethasone–refractory disease were eligible for the phase II multi-institutional Southwest Oncology Group trial S8993. Patients up to age 70 years were enrolled between April 15, 1991, and May 1, 1996. Patients without prior stem-cell collection were primed with high-dose cyclophosphamide (HD-CTX; 6 g/m2) and granulocyte-macrophage colony-stimulating factor. After stem-cell procurement, patients received melphalan 200 mg/m2 with autologous transplantation. Upon recovery from melphalan, patients were to receive interferon alfa-2b until relapse.

RESULTS: Seventy-two patients were enrolled onto S8993; five were ineligible and one received no therapy. Of the 66 assessable patients, 56 patients underwent the transplant procedure; 54 were assessable for response and 56 for toxicity. The response to HD-CTX (n = 37) included three complete remissions (CRs; 8%) and five partial remissions (PR; 14%); response to melphalan (n = 54) included 16 CRs (30%) and 19 PRs (35%), for an overall CR and ≥ PR (n = 66; intent-to-treat) of 27% and 58%, respectively. Toxicities included six treatment-related deaths: two during HD-CTX and four during transplantation. The median progression-free survival (PFS) and overall survival (OS) durations on an intent-to-treat basis from transplant registration was 11 months and 19 months (95% confidence interval, 14 to 29 months), respectively. The 3-year actuarial PFS and OS rates were 25% and 31%, respectively.

CONCLUSION: High-dose therapy with melphalan 200 mg/m2 is feasible with high response rates (58% overall) and an OS of 19 months in patients with refractory multiple myeloma.