bluuebunny/crossref_metadata_2025 huggingface dataset:
Adjuvant or Palliative Chemotherapy for Colorectal Cancer in Patients 70 Years or Older
Authors: Popescu R. A. , Norman A. , Ross P. J. , Parikh B. , Cunningham D.
Published: February 2017

PURPOSE: The surgical treatment of colorectal cancer (CRC) in elderly patients (age 70 years or older) has improved, but data on adjuvant and palliative chemotherapy tolerability and benefits in this growing population remain scarce. Elderly patients are underrepresented in clinical trials, and results for older patients are seldom reported separately.

PATIENTS AND METHODS: Using a prospective database, we analyzed demographics, chemotherapy toxicity, response rates, failure-free survival (FFS), and overall survival (OS) of CRC patients receiving chemotherapy at the Royal Marsden Hospital. The cutoff age was 70 years.

RESULTS: A total of 844 patients received first-line chemotherapy with various fluorouracil (5-FU)-containing regimens or raltitrexed for advanced disease, and 543 patients were administered adjuvant, protracted venous infusion 5-FU or bolus 5-FU/folinic acid (FA) chemotherapy. Of the 1,387 patients, 310 were 70 years or older. There was no difference in overall or severe (Common Toxicity Criteria III to IV) toxicity between the two age groups, with the exception of more frequent severe mucositis in older patients receiving adjuvant bolus 5-FU/FA. For patients receiving palliative chemotherapy, no difference in response rates (24% v 29%, P = .19) and median FFS (164 v 168 days) were detected when the elderly were compared with younger patients. Median OS was 292 days for the elderly group and 350 days for the younger patients (P = .04), and 1-year survival was 44% and 48%, respectively. The length of inpatient hospital stay was identical.

CONCLUSION: Elderly patients with good performance status tolerated adjuvant and palliative chemotherapy for CRC as well as did younger patients and had similar benefits from palliative chemotherapy.
Eniluracil Treatment Completely Inactivates Dihydropyrimidine Dehydrogenase in Colorectal Tumors
Authors: Ahmed Fareeda Y. , Johnston Stephen J. , Cassidy James , O'Kelly Terry , Binnie Norman , Murray Graeme I. , van Gennip Albert H. , Abeling Nico G.G.M. , Knight Sidonie , McLeod Howard L.
Published: February 2017

PURPOSE: To determine the effect of eniluracil on colorectal tumor dihydropyrimidine dehydrogenase (DPD) activity.

PATIENTS AND METHODS: Patients who were to undergo primary colorectal tumor resection received oral eniluracil 10 mg/m2 twice daily for 3 days before surgery. Mononuclear cells were obtained before the start of eniluracil and on the morning of surgery, to measure DPD activity, protein, and mRNA. Plasma uracil was also measured at these two time points to assess the effect of eniluracil on pyrimidine accumulation. DPD activity, protein, and mRNA were also assessed in colorectal tumors and adjacent normal mucosa of patients who received eniluracil and untreated control patients.

RESULTS: DPD activity in tumors from 10 untreated patients ranged from 30 to 92 pmol/min/mg of protein. In contrast, there was no detectable tumor DPD activity in 10 patients who received eniluracil. A similar pattern was observed in mononuclear cells, where median pretherapy activity was 366.5 pmol/min/mg of protein (range, 265 to 494 pmol/min/mg of protein) and was undetectable immediately before surgery. Plasma uracil changed from a median less than 0.2 μmol/L before therapy to 27.76 μmol/L before surgery. No difference in DPD protein or mRNA was observed between pretherapy and presurgery mononuclear cell samples or between treated and untreated tumor samples.

CONCLUSION: This study provides definitive evidence that eniluracil completely inactivates DPD activity in human solid tumors. The increased plasma uracil and decreased DPD activity are consistent with systemic inactivation of the enzyme. The mechanism of inactivation is at the catalytic level, because no changes in DPD protein or mRNA were observed. Treatment with eniluracil will eliminate DPD activity as a source of pharmacokinetic fluorouracil variability or resistance in human colorectal cancer.
MART-1 Is Expressed Less Frequently on Circulating Melanoma Cells in Patients Who Develop Distant Compared With Locoregional Metastases
Authors: Curry Benjamin J. , Myers Kieda , Hersey Peter
Published: February 2017

PURPOSE: Polymerase chain reaction (PCR) with tyrosinase and with MART-1 permits detection of small numbers of circulating melanoma cells (CMCs) in patients who have undergone surgical resection of localized disease. In a previous study, we showed that PCR with MART-1 had sensitivity and specificity similar to those of PCR with tyrosinase in terms of detection of CMCs but that PCR with MART-1 seemed to identify a different but overlapping subgroup of patients. In the current study, we examined the utility and prognostic significance of PCR with tyrosinase and with MART-1.

PATIENTS AND METHODS: We analyzed the prognostic significance of the patterns of expression of tyrosinase and MART-1 in 186 patients followed sequentially before and after surgical removal of American Joint Committee on Cancer stage I, II, or III melanoma.

RESULTS: PCR with tyrosinase and with MART-1 in the first 3 months after surgery identified 68.5% of 73 patients who developed recurrence in the 2-year period after surgery. Approximately 35% of patients with positive tests remained disease-free at 2-year follow-up. We found that patients with disseminated recurrence had a significantly lower incidence of MART-1–positive CMCs (16%) than of tyrosinase-positive CMCs (63%). Patients with locoregional metastases had CMCs that expressed tyrosinase and MART-1 at similar rates. These differences in expression of the markers in patients with disseminated recurrence were also associated with a much lower disease-free survival, in those who had CMCs that were positive for tyrosinase but negative for MART-1. The reverse applied in those with locoregional disease.

CONCLUSION: These findings suggest that PCR with MART-1 and with tyrosinase identifies subgroups of patients who develop disseminated or locally recurrent metastases. We hypothesize that immune responses against MART-1 may reduce the establishment of disseminated metastases.
Outcomes and Prognostic Factors in Recurrent Glioma Patients Enrolled Onto Phase II Clinical Trials
Authors: Wong Eric T. , Hess Kenneth R. , Gleason Mary Jo , Jaeckle Kurt A. , Kyritsis Athanassios P. , Prados Michael D. , Levin Victor A. , Yung W.K. Alfred
Published: February 2017

PURPOSE: To determine aggregate outcomes and prognostic covariates in patients with recurrent glioma enrolled onto phase II chemotherapy trials.

PATIENTS AND METHODS: Patients from eight consecutive phase II trials included 225 with recurrent glioblastoma multiforme (GBM) and 150 with recurrent anaplastic astrocytoma (AA). Their median age was 45 years (range, 15 to 82 years) and their median Karnofsky performance score was 80 (range, 60 to 100). Prognostic covariates were analyzed with respect to tumor response, progression-free survival (PFS), and overall survival (OS) by multivariate logistic and Cox proportional hazards regression analyses.

RESULTS: Overall, 34 (9%) had complete or partial response, whereas 80 (21%) were alive and progression-free at 6 months (APF6). The median PFS was 10 weeks and median OS was 30 weeks. Histology was a robust prognostic factor across all outcomes. GBM patients had significantly poorer outcomes than AA patients. The APF6 proportion was 15% for GBM and 31% for AA, whereas the median PFS was 9 weeks for GBM and 13 weeks for AA. Results were also significantly poorer for patients with more than two prior surgeries or chemotherapy regimens.

CONCLUSION: Histology is a dominant factor in determining outcome in patients with recurrent glioma enrolled onto phase II trials. Future trials should be designed with separate histology strata.
Radiation Therapy for Intracranial Germinoma: Results of the German Cooperative Prospective Trials MAKEI 83/86/89
Authors: Bamberg Michael , Kortmann Rolf-D. , Calaminus Gabriele , Becker Gerd , Meisner Christoph , Harms Dieter , Göbel Ulrich
Published: February 2017

PURPOSE: A multicenter prospective trial was conducted (Maligue Keimzelltümoren [MAKEI] 83/86/89) to assess outcome in intracranial germinoma after treatment with radiotherapy alone at reduced doses.

PATIENTS AND METHODS: Between 1983 and 1993, 60 patients with histologically (n = 58) or cytologically (n = 2) confirmed germinoma were enrolled onto the study. Patients received radiotherapy alone (craniospinal axis/local boost). In the MAKEI 83/86 study (involving 11 patients), the dose to the craniospinal axis was 36 Gy and the dose to the tumor region was 14 Gy. In the MAKEI 89 study (involving 49 patients), doses were 30 and 15 Gy, respectively.

RESULTS: Median patient age was 13 years (range, 6 to 31 years). Complete remission was achieved in all patients. The estimated (Kaplan-Meier) 5-year relapse-free survival rate was 91.0% ± 3.9% at a mean follow-up of 59.5 months (range, 3 to 180 months); the estimated overall survival rate was 93.7% ± 3.6%. Relapse occurred in five patients 10 to 33 months (mean, 18.4 months) after diagnosis (one patient developed a spinal canal metastasis and underwent salvage radiotherapy and chemotherapy; four patients had metastases outside the CNS and underwent salvage chemotherapy alone). Four patients died: one died from disease, two died from therapy-related complications, and one committed suicide. Acute complications with long-lasting sequelae were tumor or surgery related (three cases of blindness, six of reduced vision, two of hemiparesis). Psychosocial development was normal in the majority of patients.

CONCLUSION: Radiotherapy directed toward the craniospinal axis or tumor site alone at decreased dose levels is effective. To reduce the risk of late side effects, further attempts to decrease total doses are justified. In cases of recurrent disease, chemotherapy administered outside the CNS is the treatment of choice.
Outcome and Reproductive Function After Chemotherapy for Ovarian Dysgerminoma
Authors: Brewer Molly , Gershenson David M. , Herzog Cynthia E. , Mitchell Michele Follen , Silva Elvio G. , Wharton J. Taylor
Published: February 2017

PURPOSE: To review the outcome for all patients with ovarian dysgerminoma treated at the M.D. Anderson Cancer Center who received bleomycin, etoposide, and cisplatin (BEP) and to assess the menstrual and reproductive function of those who received conservative treatment.

PATIENTS AND METHODS: Clinical information was abstracted from the medical record. Patients completed a detailed questionnaire about menstrual and reproductive function; those who did not return the questionnaire were interviewed by telephone.

RESULTS: Twenty-six patients were identified as having been treated with BEP chemotherapy for pure ovarian dysgerminoma from January 1984 to January 1998. Their median age was 19.5 years (range, 7 to 32 years). Sixteen patients underwent fertility-sparing surgery in the form of unilateral salpingo-oophorectomy. At a median follow-up time of 89 months, 25 (96%) of the 26 patients remained continuously disease-free. One patient apparently developed a second primary dysgerminoma in her remaining ovary after BEP and was clinically disease-free after further treatment. Of the 16 patients who underwent fertility-sparing surgery, one was lost to follow-up when she was pregnant, and one was still premenarchal. Of the remaining 14 patients, 10 (71%) maintained their normal menstrual function during and after chemotherapy, and 13 (93%) had returned to their prechemotherapy menstrual pattern at the time of the questionnaire. Five pregnancies have occurred thus far, and two patients have had difficulty conceiving.

CONCLUSION: Most patients with metastatic dysgerminoma can expect cure with maintenance of normal reproductive function when treated with conservative surgery and BEP chemotherapy.
Phase III Comparison of Twice-Daily Split-Course Irradiation Versus Once-Daily Irradiation for Patients With Limited Stage Small-Cell Lung Carcinoma
Authors: Bonner James A. , Sloan Jeff A. , Shanahan Thomas G. , Brooks Burke J. , Marks Randolph S. , Krook James E. , Gerstner James B. , Maksymiuk Andrew , Levitt Ralph , Mailliard James A. , Tazelaar Henry D. , Hillman Shauna , Jett James R.
Published: February 2017

PURPOSE: Because small-cell lung cancer is a rapidly proliferating tumor, it was hypothesized that it may be more responsive to thoracic irradiation (TI) given twice-daily than once-daily. This hypothesis was tested in a phase III trial.

PATIENTS AND METHODS: Patients with limited-stage small-cell lung cancer were entered onto a phase III trial, and all patients initially received three cycles of etoposide (130 mg/m2 × 3) and cisplatin (30 mg/m2 × 3). Subsequently, patients who did not have progression to a distant site (other than brain) were randomized to twice-daily thoracic irradiation (TDTI) versus once-daily thoracic irradiation (ODTI) given concomitantly with two additional cycles of etoposide (100 mg/m2 × 3) and cisplatin (30 mg/m2 × 3). The irradiation doses were TDTI, 48 Gy in 32 fractions, with a 2.5-week break after the initial 24 Gy, and ODTI, 50.4 Gy in 28 fractions. After thoracic irradiation, the patients received a sixth cycle of etoposide/cisplatin, followed by prophylactic cranial irradiation (30 Gy/15 fractions) if they had a complete response.

RESULTS: Of 311 assessable patients enrolled in the trial, 262 underwent randomization to TDTI or ODTI. There were no differences between the two treatments with respect to local-only progression rates, overall progression rates, or overall survival. The patients who received TDTI had greater esophagitis (≥ grade 3) than those who received ODTI (12.3% v 5.3%; P = .05). Although patients received thoracic irradiation encompassing the postchemotherapy volumes, only seven of 90 local failures were out of the portal of irradiation.

CONCLUSION: When TI is delayed until the fourth cycle of chemotherapy, TDTI does not result in improvement in local control or survival compared with ODTI.
Phase II Study of Irinotecan Plus Cisplatin in Patients With Advanced Non–Small-Cell Lung Cancer
Authors: DeVore Russell F. , Johnson David H. , Crawford Jeffrey , Garst Jennifer , Dimery Isaiah W. , Eckardt John , Eckhardt S. Gail , Elfring Gary L. , Schaaf Larry J. , Hanover Cristy K. , Miller Langdon L.
Published: February 2017

PURPOSE: To evaluate the antitumor efficacy and safety of a combination of irinotecan (CPT-11) and cisplatin in patients with inoperable non–small-cell lung cancer (NSCLC). A secondary objective was to characterize the pharmacokinetics and pharmacodynamics of CPT-11 and its active metabolite, SN-38.

PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC were treated with repeated 4-week courses comprising CPT-11 (60 mg/m2) administered on days 1, 8, and 15, and a single dose of cisplatin (80 mg/m2) after CPT-11 administration on day 1.

RESULTS: Fifty-two patients were enrolled, including 33 men and 19 women. The median age was 61 years (range, 29 to 79 years). Southwest Oncology Group performance status was 0 in 12 patients, 1 in 32 patients, and 2 in eight patients. Eleven and 41 patients had stage IIIB and IV disease, respectively. Objective responses occurred in 28.8% of patients (15 of 52; 95% confidence interval, 16.5% to 41.2%). The median survival duration was 9.9 months (range, 1.6 to 30.8 months). The 1-year survival rate was 37%. Grade 3/4 adverse events consisted primarily of nausea (32.7% ) or vomiting (13.5%), late-onset diarrhea (17.3%), and neutropenia (46.1%). The study design led to preferential modification of CPT-11 doses, resulting in CPT-11 dose attenuations to ≤ 40 mg/m2 in the majority of patients (31 of 52; 60%), whereas dose reductions of cisplatin were uncommon. CPT-11 pharmacokinetic parameters were comparable to those reported previously in single-agent studies.

CONCLUSION: CPT-11/cisplatin is an active combination regimen with manageable toxicity in the therapy of stage IIIB/IV NSCLC. Future studies should be designed with schedules and dose modification provisions that avoid unnecessary CPT-11 dose reductions to exploit more directly the therapeutic synergy of these agents.
Phase III Multicenter Randomized Trial of the Dartmouth Regimen Versus Dacarbazine in Patients With Metastatic Melanoma
Authors: Chapman Paul B. , Einhorn Lawrence H. , Meyers Michael L. , Saxman Scott , Destro Alicia N. , Panageas Katherine S. , Begg Colin B. , Agarwala Sanjiv S. , Schuchter Lynn M. , Ernstoff Marc S. , Houghton Alan N. , Kirkwood John M.
Published: February 2017

PURPOSE: Several single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients.

PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m2 and cisplatin 25 mg/m2 days 1 to 3, carmustine 150 mg/m2 day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1,000 mg/m2. Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity.

RESULTS: Median survival time from randomization was 7 months; 25% of the patients survived ≥ 1 year.There was no difference in survival time between the two treatment arms when analyzed on an intent-to-treat basis or when only the 231 patients who were both eligible and had received treatment were considered. Tumor response was assessable in 226 patients. The response rate to dacarbazine was 10.2% compared with 18.5% for the Dartmouth regimen (P = .09). Bone marrow suppression, nausea/vomiting, and fatigue were significantly more common in the Dartmouth arm.

CONCLUSION: There was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma.
Contribution of Single-Photon Emission Computed Tomography in the Diagnosis and Follow-Up of CNS Toxicity of a Cytarabine-Containing Regimen in Pediatric Leukemia
Authors: Véra Pierre , Rohrlich Pierre , Stiévenart Jean Louis , Elmaleh Monique , Duval Michel , Bonnin François , Bok Bernard , Vilmer Etienne
Published: February 2017

PURPOSE: Cytarabine (ara-C) is one of the most effective chemotherapeutic agents in patients with acute leukemia (AL), with a clear dose effect. Use of high-dose ara-C is hampered, however, by a noticeable toxicity, particularly to the CNS. We investigated the usefulness of CNS perfusion imaging with technetium-99m (99mTc)-hexamethyl-propylene-amine oxime (HMPAO) single-photon emission computed tomography (SPECT) concurrent to magnetic resonance imaging (MRI) to specifically assess the effects of standard- and high-dose ara-C in children with AL.

PATIENTS AND METHODS: Twenty-six perfusion studies using 99mTc-HMPAO SPECT were performed in 12 children (age range, 4 to 15 years) with AL after induction therapy, which consisted of a standard-dose ara-C, immediately after consolidation with high-dose ara-C, and later during follow-up (range, 6 to 44 months). The chemotherapy-related adverse events were monitored and correlated to SPECT and MRI.

RESULTS: After the induction phase, all children were neurologically normal on MRI. On SPECT imaging, four children displayed a slightly heterogeneous perfusion. After high-dose ara-C (4 to 36 g/m2), five children had regressive neurologic signs of potential toxic origin. Of these five children, only one had an abnormal MRI scan, whereas all patients showed evidence of diffuse cerebral and/or cerebellar heterogeneous perfusion on SPECT. The seven other patients without any neurologic symptoms had normal MRI scans; SPECT was normal for three patients and abnormal for four patients. On follow-up, for four children who had presented with clinical neurologic toxicity, SPECT improved in three patients and remained unchanged in one patients. In two of these four children, delayed abnormalities (T2 white matter hypersignal and cerebellar atrophy) appeared on MRI scans.

CONCLUSION: In our series, diffuse heterogeneous brain hypoperfusion is often the sole early objective imaging feature identified by SPECT of high-dose ara-C neurotoxicity, where MRI still demonstrates normal pictures.
Parallel Phase I Studies of Daunorubicin Given With Cytarabine and Etoposide With or Without the Multidrug Resistance Modulator PSC-833 in Previously Untreated Patients 60 Years of Age or Older With Acute Myeloid Leukemia: Results of Cancer and Leukemia Group B Study 9420
Authors: Lee Edward J. , George Stephen L. , Caligiuri Michael , Szatrowski Ted P. , Powell Bayard L. , Lemke Sheila , Dodge Richard K. , Smith Ruth , Baer Maria , Schiffer Charles A.
Published: February 2017

PURPOSE: The Cancer and Leukemia Group B conducted parallel phase I trials of cytarabine, daunorubicin, and etoposide (ADE) with or without PSC-833 (P), a modulator of p-glycoprotein–mediated multidrug resistance.

PATIENTS AND METHODS: One hundred ten newly diagnosed patients ≥ 60 years of age with de novo acute myeloid leukemia (AML) were treated. All patients received cytarabine by continuous infusion for 7 days at 100 mg/m2/d. The starting dose of daunorubicin was 30 mg/m2/d for 3 days. Etoposide was administered at a dose of 100 mg/m2/d for 3 days, except in the last cohort administered ADEP, who received 60 mg/m2. PSC-833 was given intravenously with a loading dose of 1.5 mg/kg over 2 hours and a simultaneous continuous infusion of 10 mg/kg/d continued until 24 hours after the last dose of daunorubicin or etoposide.

RESULTS: There was no toxicity attributed to the PSC-833. Dose-limiting toxicity was primarily gastrointestinal (diarrhea, mucositis in the ADEP group). The estimated maximum-tolerated doses, calculated using a logistic regression model, were daunorubicin 40 mg/m2/d for 3 days with etoposide 60 mg/m2 for 3 days in the ADEP group and daunorubicin 60 mg/m2/d for 3 days and etoposide 100 mg/m2/d for 3 days in the ADE group. Twenty-one (48%) of 44 patients achieved complete remission with ADE, compared with 29 (44%) of 66 patients treated with ADEP.

CONCLUSION: It is necessary to decrease the doses of daunorubicin and etoposide when they are administered with PSC-833, presumably because of the effect of the modulator on the pharmacokinetics of these agents. A phase III trial comparing the regimens derived from this phase I trial has recently begun.
Prospective Randomized Trial of Interferon Alfa-2a Plus Vinblastine Versus Vinblastine Alone in Patients With Advanced Renal Cell Cancer
Authors: Pyrhönen Seppo , Salminen Eeva , Ruutu Mirja , Lehtonen Timo , Nurmi Martti , Tammela Teuvo , Juusela Harri , Rintala Erkki , Hietanen Päivi , Kellokumpu-Lehtinen Pirko-Liisa
Published: February 2017

PURPOSE: The combination of interferon alfa-2a (IFNα2a) plus vinblastine (VLB) induces objective tumor responses in patients with advanced renal cell cancer. However, no prospective randomized trial has shown that this treatment prolongs overall survival. We compared overall survival after treatment with IFNα2a plus VLB versus VLB alone in patients with advanced renal cell cancer.

PATIENTS AND METHODS: We prospectively randomized 160 patients with locally advanced or metastatic renal cell cancer to receive either VLB alone or IFNα2a plus VLB for 12 months or until progression of disease. In both groups, VLB was administered intravenously at 0.1 mg/kg every 3 weeks, and in the combination group IFNα2a was administered subcutaneously at 3 million units three times a week for 1 week, and 18 million units three times a week thereafter for the second and subsequent weeks. For patients unable totolerate IFNα2a at 18 million units per injection, the dose was reduced to 9 million units.

RESULTS: Median survival was 67.6 weeks for the 79 patients receiving IFNα2a plus VLB and 37.8 weeks for the 81 patients treated with VLB (P = .0049). Overall response rates were 16.5% for patients treated with IFNα2a plus VLB and 2.5% for patients treated with VLB alone (P = .0025). Treatment with the combination was associated with constitutional symptoms and abnormalities in laboratory parameters, but no toxic deaths were reported.

CONCLUSION: The combination of IFNα2a plus VLB is superior to VLB alone in the treatment of patients with locally advanced or metastatic renal cell carcinoma. This is the first study to demonstrate that survival can be prolonged by using IFNα2a for these patients.
Definitive Chemoradiotherapy for T4 and/or M1 Lymph Node Squamous Cell Carcinoma of the Esophagus
Authors: Ohtsu Atsushi , Boku Narikazu , Muro Kei , Chin Keisho , Muto Manabu , Yoshida Shigeaki , Satake Mitsuo , Ishikura Satoshi , Ogino Takashi , Miyata Yoshinori , Seki Shigeki , Kaneko Kazuhiro , Nakamura Akira
Published: February 2017

PURPOSE: To investigate the efficacy and feasibility of concurrent chemoradiotherapy for locally advanced carcinoma of the esophagus.

PATIENTS AND METHODS: Fifty-four patients with clinically T4 and/or M1 lymph node (LYM) squamous cell carcinoma of the esophagus were enrolled. Patients received protracted infusion of fluorouracil 400 mg/m2/24 hours on days 1 to 5 and 8 to 12, 2-hour infusion of cisplatin 40 mg/m2 on days 1 and 8, and concurrent radiation therapy at a dose of 30 Gy in 15 fractions over 3 weeks. Filgrastim was prophylactically administered to 35 patients. This schedule was repeated twice every 5 weeks, for a total radiation dose of 60 Gy, followed by two courses of fluorouracil (800 mg/m2/24 hours for 5 days) and cisplatin (80 mg/m2 on day 1).

RESULTS: There were 21 patients with T4M0 disease, one with T2M1 LYM, 17 with T3M1 LYM, and 15 withT4M1 LYM. Forty-nine patients (91%) completed at least the chemoradiotherapy segment. The 18 patients (33%) who achieved a complete response included nine (25%) of the 36 with T4 disease and nine (50%) of the 18 with non-T4 disease. Major toxicities were leukocytopenia and esophagitis; there were four (7%) treatment-related deaths. Prophylactic filgrastim reduced the incidence of grade 3 or worse leukopenia without improving dose-intensity or response. With a median follow-up duration of 43 months, median survival time was 9 months. The 3-year survival rate was 23%.

CONCLUSION: Despite its significant toxicity, this combined modality seemed to have curative potential even in cases of locally advanced carcinoma of the esophagus.
Dysregulation of Apoptosis in Cancer
Authors: Reed John C.
Published: February 2017

ABSTRACT: Each day, approximately 50 to 70 billion cells perish in the average adult because of programmed cell death (PCD). Cell death in self-renewing tissues, such as the skin, gut, and bone marrow, is necessary to make room for the billions of new cells produced daily. So massive is the flux of cells through our bodies that, in a typical year, each of us will produce and, in parallel, eradicate a mass of cells equal to almost our entire body weight. The morphologic ritual cells go through when experiencing PCD has been termed apoptosis and is executed by a family of intracellular proteases, called caspases. Unlike accidental cell deaths caused by infarction and trauma, these physiologic deaths culminate in fragmentation of cells into membrane-encased bodies which are cleared through phagocytosis by neighboring cells without inciting inflammatory reactions or tissue scarring. Defects in the processes controlling PCD can extend cell life span, contributing to neoplastic cell expansion independently of cell division. Moreover, failures in normal apoptosis pathways contribute to carcinogenesis by creating a permissive environment for genetic instability and accumulation of gene mutations, promoting resistance to immune-based destruction, allowing disobeyance of cell cycle checkpoints that would normally induce apoptosis, facilitating growth factor/hormone–independent cell survival, supporting anchorage-independent survival during metastasis, reducing dependence on oxygen and nutrients, and conferring resistance to cytotoxic anticancer drugs and radiation. Elucidation of the genes that constitute the core machinery of the cell death pathway has provided new insights into tumor biology, revealing novel strategies for combating cancer.
Myelofibrosis With Myeloid Metaplasia: Diagnostic Definition and Prognostic Classification for Clinical Studies and Treatment Guidelines
Authors: Barosi Giovanni
Published: February 2017

PURPOSE: Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and extramedullary hematopoiesis. Recent studies provide definite diagnostic criteria and prognostic classifications of the disease, and allogeneic stem-cell transplantation (SCT) now offers a chance of curing the disease. In order to put diagnostic criteria and prognostic classifications of the disease into the perspective of developing guidelines for treatment strategies, all studies published in the English literature over the last 30 years were reviewed.

MATERIALS AND METHODS:  Studies were identified through a MEDLINE search (1966 to present) and from the bibliographies of relevant articles.

RESULTS: The Italian Consensus Conference on diagnostic criteria is a structured enterprise aimed at formulating a definition of MMM that will be used for enrolling patients onto clinical studies. It relies on the obligatory presence of myelofibrosis and on the exclusion of the BCR-ABL rearrangement or Philadelphia chromosome, in association with combinations of traditional features. Prognostic scores allow us to identify classes of patients on the basis of hemoglobin, age, WBC count, and chromosomal abnormalities. Several nonrandomized studies have indicated that allogeneic SCT for patients under the age of 55 is effective in prolonging survival in more than 50% of cases and in possibly curing the disease. Patients with the most severe prognosis are candidates.

CONCLUSION: “Consensus” methodology offers a definition of MMM useful for conducting and reporting clinical studies. A detailed knowledge of prognostic factors can help to delineate guidelines for addressing patients with allogeneic SCT.
Chemoreduction and Local Ophthalmic Therapy for Intraocular Retinoblastoma
Authors: Friedman Debra L. , Himelstein Bruce , Shields Carol L. , Shields Jerry A. , Needle Michael , Miller David , Bunin Greta R. , Meadows Anna T.
Published: February 2017

PURPOSE: To study the effectiveness of combined systemic chemotherapy and local ophthalmic therapy for retinoblastoma with the goal of avoiding enucleation and external-beam radiation therapy (EBRT).

PATIENTS AND METHODS: This was a prospective, nonrandomized, single-arm clinical trial. Seventy-five eyes were followed in 47 children. Patients were treated with a six-cycle protocol of vincristine, etoposide, and carboplatin. Most (83%) also received ophthalmic treatment (cryotherapy, laser photocoagulation, thermotherapy, or plaque radiation therapy) during and/or after the chemotherapy.

RESULTS: With a median follow-up of 13 months, event-free survival was 74%, with an event defined as enucleation and/or EBRT. Six children required EBRT in seven eyes (9%); five required enucleation of one eye (7%); five required a combination of EBRT and enucleation in six eyes (8%). Reese-Ellsworth groups 1, 2, and 3 eyes had excellent results, with avoidance of EBRT or enucleation in all 39. Treatment of groups 4 and 5 was less successful, with 33% of six eyes and 53% of 30 eyes, respectively, requiring EBRT and/or enucleation. Toxicities from chemotherapy were mild and included cytopenias (89%), fever and neutropenia (28%), infection (9%), and gastrointestinal symptoms, dehydration, and vincristine neurotoxicity (40%). No patients developed a second malignancy, metastatic disease, renal disease, or ototoxicity.

CONCLUSION: In retinoblastoma patients with Reese-Ellsworth eye groups 1, 2, or 3, systemic chemotherapy used with local ophthalmic therapies can eliminate the need for enucleation or EBRT without significant systemic toxicity. More effective therapy is required for Reese-Ellsworth eye groups 4 and 5.
Phase III Trial of Gemcitabine Plus Cisplatin Versus Cisplatin Alone in Patients With Locally Advanced or Metastatic Non–Small-Cell Lung Cancer
Authors: Sandler A.B. , Nemunaitis J. , Denham C. , von Pawel J. , Cormier Y. , Gatzemeier U. , Mattson K. , Manegold Ch. , Palmer M.C. , Gregor A. , Nguyen B. , Niyikiza C. , Einhorn L.H.
Published: February 2017

PURPOSE: The Hoosier Oncology Group has previously reported the results of its phase II trial of the combination of cisplatin plus gemcitabine. In that study of 27 assessable patients with advanced or metastatic non–small-cell lung cancer (NSCLC), the response rate was 33%, with a median survival of 8.4 months. Based on such favorable results, the Hoosier Oncology Group designed this randomized phase III study of gemcitabine plus cisplatin compared with cisplatin alone in chemotherapy-naive patients with advanced NSCLC.

PATIENTS AND METHODS: Patients were randomized to receive either cisplatin (100 mg/m2 intravenously on day 1 of a 28-day cycle) or the combination of cisplatin (100 mg/m2 intravenously on day 1) plus gemcitabine (1,000 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle).

RESULTS: From August 1995 to February 1997, 522 assessable chemotherapy-naive patients were randomized. Toxicity was predominantly hematologic and was more pronounced in the combination arm, with grade 4 neutropenia occurring in 35.3% of patients compared with 1.2% of patients on the cisplatin monotherapy arm. The incidence of neutropenic fevers was less than 5% in both arms. Grade 4 thrombocytopenia occurred in 25.4% of patients on the combination arm compared with 0.8% of patients on the cisplatin monotherapy arm. No serious hemorrhagic events related to thrombocytopenia were reported for either arm. The combination of gemcitabine plus cisplatin demonstrated a significant improvement over single-agent cisplatin with regard to response rate (30.4% compared with 11.1%, respectively; P < .0001), median time to progressive disease (5.6 months compared with 3.7 months, respectively; P = .0013), and overall survival (9.1 months compared with 7.6 months, respectively; P = .004).

CONCLUSIONS: For the first-line treatment of NSCLC, the regimen of gemcitabine plus cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival.
Phase I and Pharmacologic Study of PN401 and Fluorouracil in Patients With Advanced Solid Malignancies
Authors: Hidalgo Manuel , Villalona-Calero Miguel A. , Eckhardt S. Gail , Drengler Ronald L. , Rodriguez Gladys , Hammond Lisa A. , Diab Sami G. , Weiss Geoffrey , Garner Allison M. , Campbell Elizabeth , Davidson Karen , Louie Arthur , O’Neil James D. , von Borstel Reid , Von Hoff Daniel D. , Rowinsky Eric K.
Published: February 2017

PURPOSE: To assess the feasibility of administering PN401, an oral uridine prodrug, as a rescue agent for the toxic effects of fluorouracil (5-FU), and to determine the maximum-tolerated dose of 5-FU when given with PN401, with an 8-hour treatment interval between these agents.

PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of 5-FU, given as a rapid intravenous infusion weekly for 3 consecutive weeks every 4 weeks. PN401 was administered orally 8 hours after 5-FU administration, to achieve sustained plasma uridine concentrations of at least 50 μmol/L. Initially, patients received 6 g of PN401 orally every 8 hours for eight doses (schedule 1). When dose-limiting toxicity (DLT) was consistently noted, patients then received 6 g of PN401 every 2 hours for three doses and every 6 hours thereafter for 15 doses (schedule 2).

RESULTS: Twenty-three patients received 50 courses of 5-FU and PN401. Among patients on schedule 1, DLT (grade 4 neutropenia complicated by fever and diarrhea) occurred in those receiving 5-FU 1,250 mg/m2/wk. Among patients on schedule 2, 5-FU 1,250 mg/m2/wk was well tolerated, but grade 4, protracted (> 5 days) neutropenia was consistently noted in those treated with higher doses of the drugs. Nonhematologic effects were uncommon and rarely severe. The pharmacokinetics of 5-FU, assessed in 12 patients on schedule 2, were nonlinear, with the mean area under the time-versus-concentration curve (AUC) increasing from 298 ± 44 to 962 ± 23 μmol/L and mean clearance decreasing from 34 ± 4 to 15.6 ± 0.38 L/h/m2 as the dose of 5-FU was increased from 1,250 to 1,950 mg/m2/wk. 5-FU AUCs achieved with 5-FU 1,250 mg/m2/wk for 6 weeks along with the intensified PN401 dose schedule were approximately five-fold higher than those achieved with 5-FU alone. Plasma uridine concentrations increased with each of the three PN401 doses given every 2 hours, and uridine steady-state concentrations were greater than 50 μmol/L.

CONCLUSION: Treatment with oral PN401 beginning 8 hours after 5-FU administration is well tolerated and results in sustained plasma uridine concentrations above therapeutic-relevant levels. The recommended 5-FU dosage for phase II evaluations is 1,250 mg/m2/wk for 3 weeks every 4 weeks with the intensified PN401 dose schedule (schedule 2). At this dose, systemic exposure to 5-FU as measured by AUC was five-fold higher than that observed after administration of a conventional 5-FU bolus.
Biologic Variables in the Outcome of Stages I and II Neuroblastoma Treated With Surgery as Primary Therapy: A Children’s Cancer Group Study
Authors: Perez Carlos A. , Matthay Katherine K. , Atkinson James B. , Seeger Robert C. , Shimada Hiroyuki , Haase Gerald M. , Stram Daniel O. , Gerbing Robert B. , Lukens John N.
Published: February 2017

PURPOSE: To determine prospectively whether surgery alone is sufficient therapy for Evans stages I and II neuroblastoma and to define biologic and clinical features having prognostic potential for this group.

PATIENTS AND METHODS: Between June 1989 and August 1995, 374 eligible children (age range, 0 to 18 years) with newly diagnosed stage I (n = 141) and stage II (n = 233) neuroblastoma were registered onto Children’s Cancer Group trial 3881. Surgical resection was the only primary therapy except in cases with spinal cord compression, where radiation therapy was allowed. Event-free survival (EFS) and overall survival (OS) were analyzed by life-table methods according to clinical and biologic features.

RESULTS: EFS and OS (mean ± SE) for all stage I patients were 93% ± 3.0% and 99% ± 1.0%, respectively, compared with 81% ± 4.0% and 98% ± 2.0%, respectively, for stage II patients. The significantly higher recurrence rate among stage II patients was managed successfully in 38 of 43 children with either surgery or multimodality treatment. There was one death among stage I patients and six among stage II. For stage II patients tumor MYCN gene amplication, unfavorable histopathology, an age greater than 2 years, and positive lymph nodes predicted a lower OS (P < .05).

CONCLUSION: Children with stages I and II neuroblastoma have 98% survival with surgery alone as primary therapy. Supplemental treatment was necessary in only 10% of stage I patients and 20% of stage II patients. In children with localized neuroblastoma, a subset of patients that are at higher risk for death can be defined as those with stage II disease who have tumor MYCN amplification or who are ≥ 2 years of age with either unfavorable histopathology or positive lymph nodes.
Phase I Study of 3-Week Schedule of Irinotecan Combined With Cisplatin in Patients With Advanced Solid Tumors
Authors: de Jonge Maja J. A. , Sparreboom Alex , Planting André S. T. , van der Burg Maria E. L. , de Boer-Dennert Maureen M. , Steeg Judith ter , Jacques Christian , Verweij Jaap
Published: February 2017

PURPOSE: To assess the feasibility, pharmacokinetic interaction, and possible sequence-dependent effects of the irinotecan/cisplatin combination given every 3 weeks, and to assess the influence of additional granulocyte colony-stimulating factor (G-CSF) on the hematologic toxicity.

PATIENTS AND METHODS: Patients who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of a 90-minute irinotecan infusion followed by a 3-hour cisplatin infusion on day 1, with cycles repeated once every 3 weeks. After the maximum-tolerated dose was determined, the sequence of administration was reversed. In a separate cohort of six patients, we assessed the effect of G-CSF on the experienced hematologic toxicity and dose-intensity. Irinotecan doses ranged from 175 to 300 mg/m2 and cisplatin doses ranged from 60 to 80 mg/m2.

RESULTS: Fifty-two patients entered the study; one was not eligible, and two were not assessable for response. Twenty-five patients were pretreated, and 26 were not. Fifty-one patients received a total of 223 courses. The dose-limiting toxicity was a combination of neutropenic fever, diarrhea, and fatigue at a dose level combining irinotecan 300 mg/m2 with cisplatin 80 mg/m2. Neutropenia was common (grades 3 to 4, 68%). Irinotecan pharmacokinetics were linear over the dose range studied. No sequence-dependent side effects were observed. Tumor responses included three complete responses and eight partial responses.

CONCLUSION: For phase II studies, we recommend irinotecan 260 mg/m2 combined with cisplatin 80 mg/m2 once every 3 weeks for chemotherapy-naive patients in good physical condition, and irinotecan 200 mg/m2 combined with cisplatin 80 mg/m2 for other patients.
Randomized Phase II Study of Docetaxel Versus Doxorubicin in First- and Second-Line Chemotherapy for Locally Advanced or Metastatic Soft Tissue Sarcomas in Adults: A Study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group
Authors: Verweij Jaap , Lee Siow Ming , Ruka Wlodzimir , Buesa Jose , Coleman Robert , van Hoessel Rene , Seynaeve Caroline , di Paola Eugenio Donato , van Glabbeke Martine , Tonelli D. , Judson Ian R.
Published: February 2017

PURPOSE: To assess antitumor response and time to progression (TTP) with docetaxel compared with doxorubicin in first-line treatment of advanced and/or metastatic soft tissue sarcoma.

PATIENTS AND METHODS: Patients with measurable soft tissue sarcoma lesions and adequate bone marrow, liver, and renal function were entered onto the study. They were randomized to either docetaxel 100 mg/m2 given as a 1-hour intravenous infusion every 3 weeks or doxorubicin 75 mg/m2 given as a bolus injection every 3 weeks. A maximum of seven cycles of treatment were scheduled. The study was designed as a randomized phase III study evaluating TTP by log-rank model. There was a clause for premature closure of the trial if fewer than five responses were observed among the first 25 assessable patients in the docetaxel treatment arm.

RESULTS: Eighty-six patients were entered onto the study; 85 were assessable for toxicity and 83 for response. The rate of severe granulocytopenia was not significantly different between the two arms. Nausea (P = .001), vomiting (P < .001), and stomatitis (P = .005) were more common with doxorubicin therapy, whereas neurotoxicity was more frequent with docetaxel treatment. The response rate to doxorubicin therapy was 30% (95% confidence interval, 17% to 46%), whereas no responses to docetaxel therapy were seen (P < .001). In view of this, the trial was closed prematurely and the phase III study part was not conducted.

CONCLUSION: Docetaxel is inactive in soft tissue sarcomas and cannot be recommended for further use in treatment of this disease.
Synovial Sarcoma: A Multivariate Analysis of Prognostic Factors in 112 Patients With Primary Localized Tumors of the Extremity
Authors: Lewis Jonathan J. , Antonescu Cristina R. , Leung Denis H. Y. , Blumberg David , Healey John H. , Woodruff James M. , Brennan Murray F.
Published: February 2017

PURPOSE: Synovial sarcoma is a high-grade tumor that is associated with poor prognosis. Previous studies analyzing prognostic factors are limited because of inclusion of heterogeneous cohorts of patients with nonextremity and recurrent tumors. The objective of this study was to determine independent prognostic factors of primary synovial sarcoma localized to the extremity.

PATIENTS AND METHODS: Between July 1, 1982, and June 30, 1996, 112 patients underwent surgical resection for cure at our institution and then were followed-up prospectively. Clinical and pathologic factors examined for prognostic value included age, sex, tumor site and location, depth, size, microscopic status of surgical margins, invasion of bone or neurovascular structures, and monophasic or biphasic histology. The end points analyzed were the time to first local recurrence that was not preceded by a distant recurrence, time to any distant recurrence, and time to disease-related mortality. These end points were modeled using the method of Kaplan and Meier and analyzed by the log-rank test and Cox regression.

RESULTS: The median duration of follow-up among survivors in this cohort of 112 patients was 72 months. The 5-year local-recurrence, distant-recurrence, and mortality rates were 12%, 39%, and 25%, respectively. Tumor size ≥ 5 cm (P = .001; relative risk [RR] = 2.7; 95% confidence interval [CI], 1.5 to 5.2) and the presence of bone or neurovascular invasion (P = .04; RR = 2.3; 95% CI, 1.0 to 5.3) were independent adverse predictors of distant recurrence. Tumor size ≥ 5 cm (P = .003; RR = 2.3; 95% CI, 1.4 to 6.3) and the presence of bone or neurovascular invasion (P = .03; RR = 2.7; 95% CI, 1.0 to 6.5) were also independent adverse predictors of mortality.

CONCLUSION: The natural history of primary synovial sarcoma of the extremity is related to tumor size and invasion of bone and neurovascular structures.