bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of estrogen and estrogen-progestin replacement regimens on mammographic breast parenchymal density.
Authors: Persson I , Thurfjell E , Holmberg L
Published: February 2017

PURPOSE

Hormone replacement therapy (HRT) may increase the mammographic density with a possible reduction in the sensitivity or specificity. If so, the benefit of mammographic screening in women using HRT could be compromised. We evaluated the hypothesis that HRT regimens have differential effects on the mammographic density depending on treatment regimens or on age.

PATIENTS AND METHODS

Among 31,498 Swedish women who received mammographic screening, we selected 554 women who started HRT after the first examination and who were current users at the second, and 554 age-matched women who had never received HRT. Mammograms were examined in a blinded review. The changes in density between the two examinations, graded as moderate or weak reduction, no change, or weak, moderate, or substantial increase, were assessed. We studied four HRT regimens-estradiol compounds only, estradiol compounds cyclically or continuously combined with progestins, and weak estrogens-and used descriptive statistics and logistic regression to analyze the association between HRT and density change.

RESULTS

Density increased in 10% and 28% of women who received estradiol compounds with cyclically or continuously combined progestins, respectively, but in only 3% of unexposed women. Logistic regression analyses showed an elevated risk of a density increase (relative risk [RR] = 3.6; 95% confidence interval [CI], 1.6 to 7.7) in women who received cyclically combined regimens or continuously combined regimens (RR = 12.4; 95% CI, 6.3 to 24.4) compared with unexposed women. Women > or = 50 years of age had even stronger associations; RRs in women on estradiol only, the cyclically combined and the continuously combined regimens were 32.2 (95% CI, 3.9 to 267.5), 21.9 (95% CI, 1.9 to 251.5), and 176.9 (95% CI, 22.8 to 1,372.7), respectively.

CONCLUSION

HRT with estradiol-progestin regimens, especially continuously combined, may increase the mammographic density in a substantial proportion of women.
Revertant and potentiating activity of lonidamine in patients with ovarian cancer previously treated with platinum.
Authors: De Lena M , Lorusso V , Bottalico C , Brandi M , De Mitrio A , Catino A , Guida M , Latorre A , Leone B , Vallejo C , Gargano G
Published: February 2017

PURPOSE

Lonidamine (LND) is an energolytic derivative of indazol-carboxylic acid that has been shown to enhance cisplatin (CDDP) activity in both sensitive (A2780) and resistant (A2780/Cp8) ovarian cancer cell lines. The aim of this study was to confirm the potentiating or reverting activity of LND on CDDP activity obtained in experimental models in a phase II study of advanced ovarian cancer patients previously treated with platinum-based regimens.

PATIENTS AND METHODS

Twenty-seven consecutive women with histologically proven and measurable ovarian cancer previously treated with platinum compounds were treated with CDDP plus LND. CDDP was administered at 1 mg/kg intravenously (IV) once weekly for 6 weeks and every 3 weeks thereafter until disease progression or toxicity. LND was administered at 450 mg daily (1 tablet every 8 hours) for the entire period of therapy starting 3 days before the first CDDP administration. In addition, a higher LND dosage was provided on the day of CDDP administration in an attempt to maximize the synergy of this drug with CDDP.

RESULTS

Ten patients achieved a complete response (CR) or partial response (PR) for an overall response rate of 37% (95% confidence interval [CI], 19% to 55%). In particular, responses were observed in five of 18 (28%) refractory or early relapsed patients (one CR and four PRs) and in five of nine patients (55%) in the late-relapsed group (two CRs and three PRs). Grade 3 or 4 anemia, leukopenia, and thrombocytopenia were observed in 19%, 15%, and 11% of patients, respectively, whereas seven of 27 patients (26%) showed LND-related myalgia. Grade 3 renal toxicity was observed in two patients (8%). Neurotoxicity, often concealed by LND-related myalgia, was recorded as grade 1 or 2 in six patients (22%) and as grade 3 in one (4%).

CONCLUSION

The 37% response rate observed in this study (28% in refractory or early-relapsed patients), suggests that the synergism between CDDP and LND observed in vitro against ovarian cancer cell lines can be clinically confirmed. However, larger series and randomized studies are needed to assess definitely the revertant activity of LND on CDDP-refractory patients.
High-titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer.
Authors: Disis M L , Pupa S M , Gralow J R , Dittadi R , Menard S , Cheever M A
Published: February 2017

PURPOSE

To evaluate HER-2/neu-specific antibody immunity in patients with breast cancer, to determine the rate of occurrence of serum antibodies to HER-2/neu in patients with breast cancer, and to relate the presence of specific immunity to overexpression of HER-2/neu protein in primary tumor.

METHODS

The antibody response to HER-2/neu protein was analyzed in 107 newly diagnosed breast cancer patients. Sera was analyzed for the presence of HER-2/neu-specific antibodies with a capture enzyme-linked immunosorbent assay (ELISA) and verified by Western blot. Sera from 200 volunteer blood donors was used as a control population.

RESULTS

The presence of antibodies to HER-2/neu correlated with the presence of breast cancer. HER-2/neu antibodies at titers of > or = 1:100 were detected in 12 of 107 (11%) breast cancer patients versus none of 200 (0%) normal controls (P < .01). The presence of antibodies to HER-2/neu also correlated to overexpression of HER-2/neu protein in the patient's primary tumor. Nine of 44 (20%) patients with HER-2/neu-positive tumors had HER-2/neu-specific antibodies, whereas three of 63 (5%) patients with HER-2/neu-negative tumors had antibodies (P = .03). The antibody responses could be substantial. Titers of greater than 1:5,000 were detected in five of 107 (5%).

CONCLUSION

The presence of HER-2/neu antibodies in breast cancer patients and the correlation with HER-2/neu-positive cancer implies that immunity to HER-2/neu develops as a result of exposure of patients to HER-2/neu protein expressed by their own cancer. These findings should stimulate further studies to develop the detection of immunity to oncogenic proteins as tumor markers, as well as the development and testing of vaccine strategies to induce and augment immunity to HER-2/neu for the treatment of breast cancer or prevention of recurrent disease.
Salvage chemotherapy with paclitaxel for recurrent oligodendrogliomas.
Authors: Chamberlain M C , Kormanik P A
Published: February 2017

PURPOSE

A prospective phase II study of paclitaxel was performed in adult patients with recurrent hemispheric oligodendrogliomas.

PATIENTS AND METHODS

Twenty adult patients (14 men and six women), ages 18 to 52 years (median, 40.5), with recurrent supratentorial hemispheric oligodendrogliomas were treated. All patients had previously been treated with surgery, involved-field radiotherapy (median dose, 55 Gy; range 54 to 55 Gy) and nitrosourea-based (procarbazine, lomustine [CCNU], and vincristine [PCV-3 regimen]) chemotherapy (median number of cycles, five; range, four to six). Fourteen patients were treated adjuvantly with radiotherapy and nitrosourea-based chemotherapy; six were treated at recurrence following initial gross total resection with reoperation (subtotal resection in all), radiotherapy, and nitrosourea-based chemotherapy. Paclitaxel was administered intravenously at a dose of 175 mg/m2 every 3 to 4 weeks with neurologic and neuroradiographic evaluation every 8 weeks.

RESULTS

A median of three cycles of paclitaxel (range, two to 10) were administered. All patients were assessable. Toxicity included partial alopecia (12 patients), thrombocytopenia (six), neutropenia (three), and anemia (one). One patient developed neutropenic fever without bacteriologic documentation and four required transfusion of blood products (RBCs, n = 2; platelet, n = 2). No treatment-related deaths occurred. Ten patients (50%) demonstrated either a neuroradiographic partial response (n = 3) or stable disease (n = 7), with a median response and stable disease duration of 10 months (range, 5 to 14).

CONCLUSION

Paclitaxel demonstrated modest efficacy with minimal toxicity in this pretreated cohort of adult patients with recurrent hemispheric oligodendrogliomas.
Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer.
Authors: Moore M J , Tannock I F , Ernst D S , Huan S , Murray N
Published: February 2017

PURPOSE

To evaluate the efficacy and toxicity of gemcitabine (2',2'-difluorodeoxycytidine) in previously untreated patients with advanced transitional cell carcinoma.

PATIENTS AND METHODS

Forty-one patients with measurable advanced transitional cell carcinoma who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,200 mg/m2 intravenously over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Prior adjuvant or neoadjuvant therapy for locally advanced disease was allowed if this was completed greater than 1 year prior to study entry. All patients were treated on an outpatient basis.

RESULTS

There were three complete responses and six partial responses seen in 37 assessable patients, for an overall response rate of nine of 37 (24.3%; 95% confidence interval, 12 to 41). Four patients remain in remission at 14, 23, 24, and 31 months. The median survival was 8 months with 17% of patients alive at 2 years. Treatment generally was well-tolerated with three patients having > or = grade 3 nonhematologic toxicity, five having grade 3 neutropenia, two having grade 3 thrombocytopenia, and two episodes of febrile neutropenia. Most patients were able to receive the drug as scheduled with the primary reason for dose reduction or dose delay being neutropenia.

CONCLUSION

Gemcitabine has promising single-agent activity against urothelial cancer with a favorable toxicity profile. Further studies in combination with other active agents are warranted.
Immunotoxin therapy of small-cell lung cancer: a phase I study of N901-blocked ricin.
Authors: Lynch T J , Lambert J M , Coral F , Shefner J , Wen P , Blattler W A , Collinson A R , Ariniello P D , Braman G , Cook S , Esseltine D , Elias A , Skarin A , Ritz J
Published: February 2017

PURPOSE

Immunotoxins could improve outcome in small-cell lung cancer (SCLC) by targeting tumor cells that are resistant to chemotherapy and radiation. N901 is a murine monoclonal antibody that binds to the CD56 (neural cell adhesion molecule [NCAM]) antigen found on cells of neuroendocrine origin, including SCLC. N901-bR is an immunoconjugate of N901 antibody with blocked ricin (bR) as the cytotoxic effector moiety. N901-bR has more than 700-fold greater selectivity in vitro for killing the CD56+ SCLC cell line SW-2 than for an antigen-negative lymphoma cell line. Preclinical studies suggested the potential for clinically significant cardiac and neurologic toxicity. We present a phase I study of N901-bR in relapsed SCLC.

PATIENTS AND METHODS

Twenty-one patients (18 relapsed, three primary refractory) with SCLC were entered onto this study. Successive cohorts of at least three patients were treated at doses from 5 to 40 microg/kg/d for 7 days. The initial three cohorts received the first day's dose (one seventh of planned dose) as a bolus infusion before they began the continuous infusion on the second day to observe acute toxicity and determine bolus pharmacokinetics. Toxicity assessment included nerve-conduction studies (NCS) and radionuclide assessment of left ventricular ejection fraction (LVEF) before and after N901-bR administration to fully assess potential neurologic and cardiac toxicity.

RESULTS

The dose-limiting toxicity (DLT) of N901-bR given by 7-day continuous infusion is capillary leak syndrome, which occurred in two of three patients at the dose of 40 microg/kg (lean body weight [LBW])/d. Detectable serum drug levels equivalent to effective in vitro drug levels were achieved at the 20-, 30-, and 40-microg/kg(LBW)/d dose levels. Specific binding of the immunotoxin to tumor cells in bone marrow, liver, and lung was observed. Cardiac function remained normal in 15 of 16 patients. No patient developed clinically significant neuropathy. However, a trend was noted for amplitude decline in serial NCS of both sensory and motor neurons. One patient with refractory SCLC achieved a partial response.

CONCLUSION

N901-bR is an immunotoxin with potential clinical activity in SCLC. N901-bR is well tolerated when given by 7-day continuous infusion at the dose of 30 microg/kg(LBW)/d. Neurologic and cardiac toxicity were acceptable when given to patients with refractory SCLC. A second study to evaluate this agent after induction chemoradiotherapy in both limited- and extensive-stage disease was started following completion of this study.
High-dose cytarabine dose modification reduces the incidence of neurotoxicity in patients with renal insufficiency.
Authors: Smith G A , Damon L E , Rugo H S , Ries C A , Linker C A
Published: February 2017

PURPOSE

To determine the impact of high-dose cytarabine (ARA-C) (HDAC) dose modification, based on renal function, on the incidence of neurotoxicity (NT).

PATIENTS AND METHODS

We retrospectively analyzed the records of 256 patients treated with HDAC (> or = 2.0 g/m2 per dose) for acute myelogenous leukemia (AML) at the University of California, San Francisco (UCSF). From 1985 to 1994, a total of 358 cycles of HDAC were administered, using either a twice-daily schedule (n = 208) or a once-daily regimen (n = 48). In 1989, a dose-modification algorithm was initiated at our institution, which reduced ARA-C doses in the setting of renal insufficiency (RI). For patients with a serum creatinine (Cr) level of 1.5 to 1.9 mg/dL during treatment, or an increase in Cr during treatment (deltaCr) of 0.5 to 1.2 mg/dL, ARA-C was decreased to 1 g/m2 per dose. For patients with a Cr > or = 2.0 mg/dL or a deltaCr greater 1.2 mg/dL, the dose was reduced to 0.1 g/m2/d.

RESULTS

Overall, the incidence of NT was 16% (34 of 208) for patients treated with twice-daily HDAC and 0% (none of 48) for patients treated with daily HDAC (P = .003). NT occurred more often in patients treated on a twice-daily schedule with 3 g/m2 per dose compared with 2 g/m2 per dose (25% v 8%; P = .009). NT occurred in 55% of the twice-daily-treated patients with RI, compared with 7% of those with normal renal function (P = .00001). In patients with RI, NT occurred in none of 11 dose-modified cycles versus five of 11 (45%) total unmodified cycles (P = .01). None of 14 patients treated with once-daily HDAC given during RI developed NT, compared to 55% of patients (23 of 42) receiving twice-daily HDAC during RI (P = .009). By univariate analysis, NT was not associated with patient age or serum alkaline phosphatase, but NT was significantly increased in patients treated with twice-daily HDAC when the serum bilirubin was > or = 2.0 mg/dL compared with twice-daily HDAC given when the total bilirubin was less than 2.0 mg/dL (33% v 14%; P = .017). Multivariate analysis confirmed that RI was the most significant risk factor associated with the development of NT.

CONCLUSION

HDAC NT is strongly associated with RI. The risk of HDAC NT can be reduced by the following: (1) routinely reducing the ARA-C dose from 3 to 2 g/m2 per dose; (2) modifying the ARA-C dose based on daily Cr values; and (3) administering HDAC on a once-daily rather than twice-daily schedule.
Phase I and pharmacologic study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors.
Authors: Creemers G J , Gerrits C J , Eckardt J R , Schellens J H , Burris H A , Planting A S , Rodriguez G I , Loos W J , Hudson I , Broom C , Verweij J , Von Hoff D D
Published: February 2017

PURPOSE

Topotecan is a specific inhibitor of topoisomerase I. Recently bioavailability of an oral formulation of approximately 30% with limited variability was reported. We conducted a phase I and pharmacokinetic study of the oral formulation of topotecan to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and antitumor effects in patients with refractory malignancies.

PATIENTS AND METHODS

Patients were treated with oral topotecan given twice daily for 21 days, with cycles repeated every 28 days. In subsequent cohorts, the dose was escalated from 0.15 to 0.6 mg/m2 twice daily. Pharmacokinetics were performed on day 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods.

RESULTS

Thirty-one patients entered the study; one patient was not assessable for toxicity and response as therapy was prematurely interrupted on request of the patient who had not experienced toxicity. Thirty patients received a total of 59 courses. The dose-limiting toxicity (DLT) was reached at a dose of 0.6 mg/m2 twice daily and consisted of diarrhea, which started subacutely at a median onset on day 15 (range, 12 to 20) and resolved after a median of 8 days (range, 7 to 16). Other toxicities were mild, including leukocytopenia, thrombocytopenia, nausea, and vomiting. The MTD was 0.5 mg/m2 twice daily. No responses were observed. Pharmacokinetics showed a substantial variation of the area under the plasma concentration-time curve at time point "t" [AUC(t)] of topotecan and ring-opened product hydroxyacid. A significant correlation was observed between the percentage of decrease in WBC count versus the AUC(t) of topotecan (r = .75), which was modeled by a sigmoidal maximal effect concentration (Emax) function.

CONCLUSION

The DLT in this phase I study for chronic oral topotecan for 21 days was diarrhea. The recommended dose for phase II studies is 0.5 mg/m2 twice daily.
Mitoguazone therapy in patients with refractory or relapsed AIDS-related lymphoma: results from a multicenter phase II trial.
Authors: Levine A M , Tulpule A , Tessman D , Kaplan L , Giles F , Luskey B D , Scadden D T , Northfelt D W , Silverberg I , Wernz J , Espina B , Von Hoff D
Published: February 2017

PURPOSE

Patients with AIDS-related lymphoma usually have extensive lymphomatous disease, with relatively frequent involvement of the CNS. Approximately half may achieve complete remission after chemotherapy. Mitoguazone, an inhibitor of polyamine biosynthesis, has demonstrated efficacy in patients with de novo recurrent lymphoma. The drug is relatively nonmyelotoxic and may cross the blood-brain barrier. The current study was designed to assess the safety and potential efficacy of mitoguazone in patients with relapsed or refractory AIDS-lymphoma.

PATIENTS AND METHODS

Thirty-five patients were accrued, all of whom had failed one (51%) or multiple (two to six) prior regimens. Mitoguazone (600 mg/m2) was given intravenously on days 1 and 8, and then every 2 weeks, until best response, progression, or toxicity.

RESULTS

The median age was 39 years. High-grade lymphoma was diagnosed in 29 patients (83%). Extranodal disease was present in 30 patients (86%), with multiple extranodal sites (two to seven) in 18 (51%). The median CD4 cell count at study entry was 66/dL (range, zero to 549). Twenty-six patients were assessable for response. The objective response rate was 23% (95% confidence interval [CI], 6.9 to 39.3), with complete remission in three patients (11.5%), and partial remission (PR) in three patients (11.5%). Six patients experienced stable disease. Median survival from study entry was 2.6 months for the group as a whole; 21.5 months (range, 3.8 to 29.1) in complete responders, 5.6 months (range, 3.8 to 34.8) in partial responders. The most common toxicities occurred solely during drug infusion and included vasodilation (63%), paresthesia (86%), and somnolence (17%). Fourteen patients (40%) experienced nausea and 16 (46%) vomiting (grade 3 in one). Ten patients (29%) developed stomatitis, including grade 3 in two and grade 4 in one. Seven patients (20%) developed neutropenia, with grade 4 in one. Thrombocytopenia occurred in nine patients (26%). While on study, three patients developed sepsis, four had pneumonia, and two developed opportunistic infections.

CONCLUSION

Mitoguazone is an effective agent in patients with multiply relapsed or refractory AIDS-related lymphoma, with acceptable toxicity. Further study in patients with newly diagnosed disease is warranted.
Treatment of hairy-cell leukemia with cladribine: response, toxicity, and long-term follow-up.
Authors: Hoffman M A , Janson D , Rose E , Rai K R
Published: February 2017

PURPOSE

To analyze initial and long-term outcomes after treatment of patients with active hairy-cell leukemia (HCL) with a single cycle of cladribine (2-CdA).

PATIENTS AND METHODS

Forty-nine patients with active HCL were treated with 2-CdA by continuous intravenous infusion at 0.1 mg/kg/d for a total of 7 days at the Long Island Jewish Medical Center between September 1990 and August 1992. Here we report on all patients followed-up until April 1996.

RESULTS

At 3 months after treatment, complete response (CR) occurred in 37 patients (76%) and partial response (PR) occurred in 12 patients (24%), for an overall response rate of 100% (95% confidence interval, 94% to 100%). At a median follow-up of 55 months, the relapse-free survival is 80% and overall survival is 95%. Ten patients (20%) have relapsed. Of the 26 patients in whom lymphocyte phenotyping was performed, four were found to have a CD25-negative phenotype. All four of these patients had PRs only and all relapsed. Eight patients have been re-treated with 2-CdA, and all achieved at least a partial remission; two of these have already relapsed with remission durations of less than 1 year. Five second malignancies have occurred in four patients.

CONCLUSION

With a median follow-up of more than 4 years, 39 patients (80%) continue in remission. Only two deaths have occurred. A CD25-negative phenotype may predict for a poorer response to 2-CdA. Patients who relapse may be re-treated with 2-CdA, but subsequent remissions may be of shorter duration. There has not been a markedly increased incidence of second malignancies or late opportunistic infections.
Randomized study of prophylactic platelet transfusion threshold during induction therapy for adult acute leukemia: 10,000/microL versus 20,000/microL.
Authors: Heckman K D , Weiner G J , Davis C S , Strauss R G , Jones M P , Burns C P
Published: February 2017

PURPOSE

We designed and conducted a randomized single-institution trial comparing two common prophylactic platelet transfusion thresholds in patients undergoing induction therapy for acute leukemia.

PATIENTS AND METHODS

Seventy-eight patients undergoing induction therapy for acute leukemia were randomized to receive prophylactic apheresis platelet concentrates when the platelet count was either < or = 10,000/microL or < or = 20,000/microL.

RESULTS

There was no significant difference in the total number of bleeding episodes per patient with a median of four in the < or = 10,000/microL arm and two in the < or = 20,000/microL arm (25th to 75th percentiles of 2, 7 and 1, 5, respectively; P = .12). Patients randomized to the < or = 10,000/microL arm received more platelet transfusions for bleeding [one (0, 2) v zero (0, 0); P = .0003]. In contrast, patients on the < or = 20,000/microL arm received more platelet transfusions for prophylactic indications [10 (5, 14) v six (3, 8); P = 0.001], as would be expected, but less for bleeding. Nevertheless, the total number of platelet transfusions given to patients on the < or = 20,000/microL arm was higher and nearly significant [11 (6, 15) v seven (5, 11); P = .07]. There were no statistically significant differences between the groups with regard to RBC transfusion requirements, febrile days, days hospitalized, days thrombocytopenic, need for HLA-matched platelets, remission rate, or death during induction chemotherapy. No patient in either group died from hemorrhage or underwent major surgery for bleeding complications.

CONCLUSION

Giving prophylactic platelets at a threshold of < or = 10,000/microL compared with < or = 20,000/microL can decrease the total utilization of platelets with only a small adverse effect on bleeding, and no statistically significant effect on morbidity.
Orbital development in long-term survivors of retinoblastoma.
Authors: Kaste S C , Chen G , Fontanesi J , Crom D B , Pratt C B
Published: February 2017

PURPOSE

To determine the effects of enucleation, irradiation, and age at diagnosis on bony orbital growth in long-term survivors of retinoblastoma using measurements based on computed tomographic (CT) imaging.

PATIENTS AND METHODS

We used CT obtained at a median age of 13 years to measure orbital volume and configuration in 54 patients who had been treated for retinoblastoma a minimum of 5 years previously.

RESULTS

Enucleation and high-dose orbital irradiation (> 35 Gy) both independently adversely affected orbital development (P = .014 and P = .022, respectively). Orbital volume differences for children treated when < or = 1 year old were no greater than those for children treated when older than 1 year of age. In children treated for bilateral retinoblastoma, the impact of enucleation on orbital development was not statistically different from that of irradiation (P = .13). Small implants (12 to 14 mm in diameter) were more commonly associated with smaller orbital volumes. Migration of orbital implants was associated with the smaller orbital sphere size in children < or = 1 year of age (P < .035).

CONCLUSION

Treatment for retinoblastoma compromises orbital development. Resulting orbital asymmetry seems to be at least partially related to the size of the implant. Detailed imaging-based measurements of orbital volume and configuration may aid the planning for cosmetic and reconstructive surgery in those who develop orbital asymmetry.
Phase III controlled evaluation of sucralfate to alleviate stomatitis in patients receiving fluorouracil-based chemotherapy.
Authors: Loprinzi C L , Ghosh C , Camoriano J , Sloan J , Steen P D , Michalak J C , Schaefer P L , Novotny P J , Gerstner J B , White D F , Hatfield A K , Quella S K
Published: February 2017

PURPOSE

Stomatitis is a major dose-limiting toxicity of bolus fluorouracil (5FU)-based chemotherapy regimens, despite the use of oral cryotherapy. Pursuant to preliminary data that suggested a sucralfate oral solution could alleviate chemotherapy-induced oral mucositis, we developed a prospective trial to test this contention.

PATIENTS AND METHODS

A phase III, double-blind, placebo-controlled clinical trial was designed. Patients were entered onto the study at the time of the first cycle of 5FU-based chemotherapy. All patients received oral cryotherapy for 30 minutes with each dose of 5FU. In addition, each patient was randomized to receive either a sucralfate solution or a placebo solution to be used if they developed mouth tenderness or mouth sores. The study solution was to be used four times daily for 7 days starting on the first day of mouth tenderness or mouth sores. Stomatitis scores were determined by health care providers and by patients themselves.

RESULTS

There was a total of 131 assessable patients entered onto this trial, 50 of whom developed mucositis and used the study medication (27 sucralfate and 23 placebo). There was no suggestion of any difference in stomatitis severity or duration on either protocol arm.

CONCLUSION

The resultant data from this clinical trial did not support the prestudy hypothesis that sucralfate would be beneficial for the treatment of 5FU-induced stomatitis.
Decision analysis in locally advanced non-small-cell lung cancer: is it useful?
Authors: Brundage M D , Groome P A , Feldman-Stewart D , Davidson J R , Mackillop W J
Published: February 2017

PURPOSE

The optimal management of locally advanced non-small-cell lung cancer (NSCLC) has not been established. While combined-modality treatments have been shown to increase the survival of patients with this illness, the appropriate balance between the benefit of increased quantity of life and the quality-of-life costs of the more toxic treatment combinations remains unresolved. Decision analysis has been promoted as useful when medical decisions must be made under conditions of uncertainty. We consider the potential of this method to guide therapy in locally advanced NSCLC.

METHODS

We developed two types of decision models that addressed the choice between radiation alone and combined chemotherapy-radiation therapy in locally advanced NSCLC. The models were constructed using the principles of decision analysis.

RESULTS

The models successfully replicated results of relevant clinical trials published in the literature. The analyses of both models showed that the treatment decision was sensitive to patients' values, despite significant increases in survival rates. The models clarified a need for further validation of the three fundamental components: structuring the decision, determining the probabilities of events, and assigning utilities to treatment outcomes.

CONCLUSION

In the setting of NSCLC, the models suggest that quality-of-life considerations are important in the treatment choice. Further research is required to identify the health states critical to the decision, the probabilities for occurrence of these health states, and valid measures of their utility.
Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: a phase I study.
Authors: Safran H , King T P , Choy H , Hesketh P J , Wolf B , Altenhein E , Sikov W , Rosmarin A , Akerley W , Radie-Keane K , Cicchetti G , Lopez F , Bland K , Wanebo H J
Published: February 2017

PURPOSE

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and potential antitumor activity of weekly paclitaxel with concurrent radiation (RT) for locally advanced pancreatic and gastric cancer.

PATIENTS AND METHODS

Thirty-four patients with locally advanced adenocarcinoma of the pancreas or stomach were studied. The initial dose of paclitaxel was 30 mg/m2 by 3-hour intravenous (I.V.) infusion repeated every week for 6 weeks with 50 Gy RT. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients until dose-limiting toxicity was observed.

RESULTS

The dose-limiting toxicities at 60 mg/m2/wk were abdominal pain within the RT field, nausea, and anorexia. Of 23 patients with assessable disease, 11 (seven with gastric, four with pancreatic cancer) had objective responses for an overall response rate of 48%.

CONCLUSION

Concurrent paclitaxel with upper abdominal RT is well tolerated at dosages that have substantial activity. A phase II trial of neoadjuvant paclitaxel and RT at the MTD of 50 mg/m2/wk is underway.
Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study.
Authors: Scheithauer W , Kornek G , Marczell A , Salem G , Karner J , Kovats E , Burger D , Greiner R , Pidlich J , Schneeweiss B , Raderer M , Rosen H , Depisch D
Published: February 2017

PURPOSE

To compare the efficacy and toxicity of fluorouracil (FU) and racemic leucovorin (d,l-LV) versus FU combined with the l-isomer of leucovorin (l-LV) in the treatment of advanced colorectal cancer.

PATIENTS AND METHODS

A total of 248 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either FU (400 mg/m2/d by intravenous [I.V.] infusion for 2 hours) and racemic LV (100 mg/m2/d by I.V. bolus injection) given for 5 consecutive days, or the combination of FU and the pure l-isomer of LV using the same dose schedule. In both treatment arms, courses were administered every 28 days if toxicity allowed for a total of 6 months, unless evidence of tumor progression was documented earlier.

RESULTS

There were no significant differences between the FU/racemic LV and the FU/l-LV arm in the overall response rate (25% v 32%), duration of response (7.2 v 8.0 months), median time to progression or death (6.25 v 8.0 months), or median overall survival time (14.5 v 15.0 months). Except for minor myeloid toxic effects associated with FU/l-LV, there was also no significant difference in terms of adverse reactions. Gastrointestinal symptoms, specifically mucasitis and diarrhea, were less frequent and less severe in both treatment arms compared with other trials with FU/racemic LV reported in the literature, which might be because of the prolonged administration of FU used in both arms.

CONCLUSION

The combination of FU/l-LV produced response rates, response durations, and survival times similar to those with FU/d,l-LV. Biochemical modulation of FU by either pure l-LV or racemic LV thus appears to result in equivalent clinical efficacy.
Liver resection for colorectal metastases.
Authors: Fong Y , Cohen A M , Fortner J G , Enker W E , Turnbull A D , Coit D G , Marrero A M , Prasad M , Blumgart L H , Brennan M F
Published: February 2017

PURPOSE

More than 50,000 patients in the United States will present each year with liver metastases from colorectal cancers. The current study was performed to determine if liver resection for colorectal metastases is safe and effective and to evaluate predictors of outcome.

MATERIALS AND METHODS

Data for 456 consecutive resections performed between July 1985 and December 1991 in a tertiary referral center were analyzed.

RESULTS

The perioperative mortality rate was 2.8%, with a mortality rate of 4.6% for resections that involved a lobectomy or more. The median hospital stay was 12 days and only 9% of patients were admitted to the intensive care unit. The 5-year survival rate is 38%, with a median survival duration of 46 months. By univariate analysis, nodal status of the primary lesion, short disease-free interval before detection of liver metastases, carcinoembryonic antigen (CEA) level greater than 200 ng/mL, multiple liver tumors, extrahepatic disease, large tumors, or positive resection margin was predictive of poorer outcome. Sex, age greater than 70 years, site of primary tumor, or perioperative transfusion was not predictive of outcome. By multivariate analysis, positive margin, size greater than 10 cm, disease-free interval less than 12 months, multiple tumors, and extrahepatic disease were independent predictors of poorer outcome. Short disease-free interval or multiple tumors were nevertheless associated with a 5-year survival rate greater than 24%.

CONCLUSION

Liver resection for colorectal metastases is safe and effective therapy and currently represents the only potentially curative therapy for metastatic colorectal cancer. The only absolute contraindication to resection is extrahepatic disease. A randomized trial to examine efficacy of surgical resection cannot ethically be performed. Liver resection should be considered standard therapy for all fit patients with colorectal metastases isolated to the liver.
High-dose chemotherapy with hematopoietic rescue in patients with stage III to IV ovarian cancer: long-term results.
Authors: Legros M , Dauplat J , Fleury J , Cure H , Suzanne F , Chassagne J , Bay J O , Sol C , Canis M , Condat P , Choufi B , Tavernier F , Glenat C , Chollet P , Plagne R
Published: February 2017

PURPOSE

A series of 53 patients with poor-prognosis epithelial ovarian cancer treated with high-dose chemotherapy (HDC) followed by hematopoietic rescue was retrospectively studied from the day of diagnosis for toxicity and long-term survival analysis.

PATIENTS AND METHODS

Patients were treated with surgery followed by cisplatin combination chemotherapy. After second-look operation (SLO), HDC was administered: 23 patients received melphalan (140 mg/m2 on day 1) and 30 patients received a combination of carboplatin (400 mg/m2 on days 1 to 4) and cyclophosphamide (1.6 g/m2 on days 1 to 4). After HDC, autologous stem-cell transplantation was performed for hematologic support.

RESULTS

One patient died of cardiac failure after HDC, but the acute toxicity was acceptable for the other patients. With a median follow-up of 81.5 months, the 5-year overall survival rate for the 53 patients was 59.9% and the disease-free survival (DFS) rate at 5 years was 23.6%. Twenty-four patients (45.3%) were alive, 12 with no evidence of disease and 12 with recurrent disease. The best results were achieved in 19 patients with pathologic complete response at SLO (74.2% 5-year overall survival; 32.8% 5-year DFS).

CONCLUSION

HDC followed by autologous stem-cell support is a well-tolerated therapeutic approach for patients with poor-prognosis ovarian carcinoma. In this report, the 59.9% survival of 53 patients at 5 years must be compared to the 20% to 30% 5-year survival observed after conventional therapy. These results should be confirmed by an ongoing prospective randomized trial.
Treatment of brain metastases in patients with testicular cancer.
Authors: Bokemeyer C , Nowak P , Haupt A , Metzner B , Köhne H , Hartmann J T , Kanz L , Schmoll H J
Published: February 2017

PURPOSE

Despite improved cure rates for patients with metastatic testicular cancer with cisplatin-based combination chemotherapy, patients who develop brain metastases are generally considered to possess a poor prognosis. This report summarizes the long-term results in 44 patients with brain metastases from testicular cancer treated between 1978 and 1995 at Hannover University Medical School.

PATIENTS AND METHODS

Histologically, 42 patients (95%) had a nonseminomatous germ cell cancer and two patients (5%) a seminoma. Thirty-nine patients (89%) had lung metastases and 37 (84%) fulfilled the criteria for advanced disease according to the Indiana University classification even without considering the brain metastases. Eighteen patients (41%) presented with brain metastases at primary diagnosis (group 1), four (9%) developed brain metastases at relapse after a previous favorable response to combination chemotherapy (group 2), and 22 (50%) developed brain metastases during or directly after cisplatin-based chemotherapy. Chemotherapy consisted of cisplatin-based combination treatment and radiotherapy was given as whole-brain irradiation of 30 to 40 Gy and in single cases combined with a boost of 10 Gy to single lesions.

RESULTS

Overall, 10 patients achieved long-term survival (23%; 95% confidence interval [CI], 10.1% to 35.4%). The prognosis was significantly better for patients in groups 1 and 2, with six of 18 (33%) and three of four (75%) patients alive, compared with only one of 22 (5%) in group 3 (P < .01). Patients treated with either chemotherapy or radiotherapy alone did not achieve long-term survival, while nine of 28 (32%) who received treatment with both modalities with or without surgery achieved sustained long-term survival. During univariate analysis, patients with the diagnosis of brain metastases at first presentation (P < .01), patients with a single brain lesion (P < .02), and patients who received combined chemotherapy and radiotherapy (P < .03) had a significantly improved outcome.

CONCLUSIONS

Long-term survival can be achieved in approximately 25% of patients with brain metastases from testicular cancer by combined treatment with brain irradiation and aggressive cisplatin-based chemotherapy. Patients who develop brain metastases during systemic treatment should receive only palliative radiation therapy, since sustained survival will not be reached.
Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients.
Authors: Gupta E , Mick R , Ramirez J , Wang X , Lestingi T M , Vokes E E , Ratain M J
Published: February 2017

PURPOSE

We conducted a pharmacokinetic and pharmacodynamic evaluation of irinotecan (CPT-11) and determined the effect of race and sex on disposition and toxicity of CPT-11. We tested the efficacy of acetaminophen (AAP) to phenotype SN-38 glucuronidation.

PATIENTS AND METHODS

Forty patients received a dose of 145 mg/m2 of CPT-11 as a 90-minute infusion. Total CPT-11, SN-38, and SN-38G were quantitated in plasma and urine samples. Following administration of 1 g AAP, urinary concentrations of AAP and AAP-glucuronide (AAP-G) were assessed.

RESULTS

CPT-11 exhibited a mean elimination half-life (t1/2) of 8.8 hours, an average clearance (CL) of 14.6 L/h/m2, and a mean volume of distribution at steady-state (Vdss) of 136 L/m2. SN-38 and SN-38G had low plasma availabilities (3% and 10% relative to CPT-11), with mean t1/2 values of 11.6 and 10.5 hours, respectively. Urinary recovery accounted for 15% of the dose. Race and sex had no effect on the plasma availability of CPT-11, SN-38, and SN-38G. The applicability of biliary index (BI) in predicting dose-limiting intestinal toxicity was validated. Patients who developed grade 3 or 4 toxicity had significantly higher index values compared with patients with grade 0 to 2 toxicity (P = .001). There was no difference in the incidence and severity of toxicity based on race and sex. AAP was a poor predictor of SN-38 glucuronidation.

CONCLUSION

The high degree of interpatient variability in parameter estimates suggests pharmacogenetic variation or differential induction or inhibition of the sequential metabolic pathway of CPT-11, as well as variability in transport systems. The low urinary recovery indicates substantial biliary excretion and supports the significant correlation between intestinal toxicity and BI. Black patients are not at increased risk of toxicity. An assessment of individual differences in SN-38 conjugation remains to be established.
High-dose therapy with iodine-131-labeled monoclonal antibody CC49 in patients with gastrointestinal cancers: a phase I trial.
Authors: Tempero M , Leichner P , Dalrymple G , Harrison K , Augustine S , Schlam J , Anderson J , Wisecarver J , Colcher D
Published: February 2017

PURPOSE

A phase I trial that evaluated for extrahematopoietic toxicity was conducted with iodine-131 (131I) labeled monoclonal antibody (MAb) CC49. Correlative studies included pharmacokinetic and biodistribution analyses, estimates of absorbed radiation dose, and measurement of human antimonoclonal antibodies (HAMA).

PATIENTS AND METHODS

After collection and cryopreservation of hematopoietic stem cells, 15 patients with gastrointestinal cancers were administered a tracer dose of 131I-MAb CC49. Within 5 to 6 days, 14 patients (two to three per activity level) underwent a single treatment with 131I-MAb CC49 (50, 100, 150, 200, 250, and 300 mCi/m2). Biodistribution was determined using planar and single photon emission computer tomographic (SPECT) imaging. Pharmacokinetic studies were performed by measuring radioactivity in serial blood samples. In some patients, biopsies of metastases and related normal tissues were obtained for radioactivity measurements. Radiation dosimetry estimates were calculated using available biodistribution, pharmacokinetic, and tissue biopsy data. Toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria.

RESULTS

No dose-limiting extrahematopoietic toxicity was identified. Twelve patients experienced grade IV myelosuppression and met criteria for infusion of hematopoietic stem cells. Radioimmunolocalization was excellent. The T1/2 for 131I-MAb CC49 after diagnostic and therapeutic administration was 39.7 +/- 10.4 and 46.1 +/- 10.6 hours, respectively. The percent injected dose per killigram of tumor ranged from 0.2 to 2.1. Absorbed radiation dose in metastatic tumor sites ranged from 630 to 3300 cGy.

CONCLUSION

Although extrahematopoietic dose-limiting toxicity was neither observed or predicted, suboptimal absorbed dose estimates suggested that further escalation of 131I-MAb CC49 would not be useful. Future studies should focus on the use of radionuclides with high energy beta emissions, such as yttrium 90, and on strategies to optimize access of antibody to target antigens.
Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities.
Authors: Picci P , Böhling T , Bacci G , Ferrari S , Sangiorgi L , Mercuri M , Ruggieri P , Manfrini M , Ferraro A , Casadei R , Benassi M S , Mancini A F , Rosito P , Cazzola A , Barbieri E , Tienghi A , Brach del Prever A , Comandone A , Bacchini P , Bertoni F
Published: February 2017

PURPOSE

This study was performed to assess the prognostic value of the proposed histopathologic method to evaluate the response of the primary tumor to preoperative chemotherapy in Ewing's sarcoma.

PATIENTS AND METHODS

The response to chemotherapy was evaluated from the specimens of 118 Ewing's sarcoma patients, who were preoperatively treated by chemotherapy alone. Responses were graded I to III (macroscopic viable tumor, microscopic viable tumor, and no viable tumor cells, respectively). Follow-up data were available for all patients, with a mean follow-up duration of 86 months (range, 30 to 158).

RESULTS

A statistically highly significant difference was observed in outcome among the three groups of patients. For patients with total necrosis (grade III response), the estimated 5-year disease-free survival rate was 95%, in contrast to 68% for grade II responders and 34% for grade III responders (P < .0001). This difference was also confirmed when any single group was compared with the other groups. Among the parameters tested, patient age and the size of tumor had some prognostic value.

CONCLUSION

The proposed histopathologic grading, to evaluate the effect of chemotherapy on the primary tumor, had the strongest correlation to clinical outcome. This method could therefore be used to identify patients with a high risk of recurrent disease. These patients could be randomized to receive alternative postoperative treatments to investigate whether more aggressive therapies will improve outcome.
Granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein versus granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for non-Hodgkin's lymphoma: results of a randomized double-blind trial.
Authors: Vose J M , Pandite A N , Beveridge R A , Geller R B , Schuster M W , Anderson J E , LeMaistre C F , Ahmed T , Granena A , Keating A , Fernandez Ranada J M , Stiff P J , Tabbara I , Longo W , Copelan E A , Nichols C , Smith A , Topolsky D L , Bierman P J , Lebsack M E , Lange M , Garrison L
Published: February 2017

PURPOSE

A phase III trial to compare PIXY321 with granulocyte-macrophage colony-stimulating factor (GM-CSF) following high-dose therapy and autologous bone marrow transplant (ABMT) was conducted to evaluate the time to hematopoietic recovery.

PATIENTS AND METHODS

One hundred seventy-seven patients with non-Hodgkin's lymphoma (NHL) receiving ABMT were randomized to receive either PIXY321 750 micrograms/m2/d divided into two subcutaneous (SC) doses or GM-CSF 250 micrograms/m2/d as a 2-hour intravenous (IV) infusion starting on day 0 post-ABMT for a maximum of 28 days.

RESULTS

The median time to reach an absolute neutrophil count (ANC) > or = 500/microL in the PIXY321 group was 17 days versus 19 days in the GM-CSF group (P = .07) and the median time to reach platelet transfusion independence in the PIXY321 group was 25 days versus 23 days in the GM-CSF group (P = .30). The toxicity profiles of the two agents appeared to be equivalent with the exception of more patients in the PIXY321 group with a rash (64%) compared with the GM-CSF group (48%) (P = .028). A logistic regression model identified the use of a non-total-body irradiation (TBI) regimen and/or receipt of unpurged marrow and a body-surface area greater than 2.0 m2 as predictive of faster neutrophil engraftment, and those three factors, as well as the receipt of < or = two prior chemotherapy regimens as predictive for rapid platelet engraftment.

CONCLUSION

There was a trend toward a slight improvement in neutrophil engraftment post-ABMT with the PIXY321 administered by an SC route compared with GM-CSF administered by an IV route. However, no differences could be identified between the two agents with respect to the time to platelet transfusion independence. Patient, regimen, and graft characteristics were most predictive of the engraftment tempo.