bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer chemoprevention.
Authors: Lippman S M , Benner S E , Hong W K
Published: February 2017

PURPOSE

To review the most important recent advances in clinical trials and biologic studies within the growing field of chemoprevention.

METHODS

The most critical methods issue concerns the definitive end point of phase III trials, which is now cancer incidence. This end point usually needs thousands of subjects monitored for 5 to 10 or more years to determine efficacy. Biologic markers of potential intermediate end points are under intensive study and may one day replace cancer incidence. Validated intermediate end point biomarkers could greatly reduce phase III trial populations, durations, and costs.

RESULTS

Randomized clinical trials over the last 5 years have produced significant activity in reversing oral, skin, colon, and cervical premalignancy; in preventing primary skin and stomach cancer; and in preventing second primary tumors associated with head and neck and lung cancer. These clinical advances have been paralleled at the basic science level by elegant molecular studies of premalignant carcinogenesis and of chemopreventive agents' mechanisms of action. One major laboratory advance is the discovery of nuclear retinoic acid receptors and strong evidence of their roles both in carcinogenic progression and in its response to retinoids.

CONCLUSION

Chemoprevention has matured greatly in recent years with the significant reversal or suppression of premalignancy by chemopreventive agents in several sites. The future of chemoprevention will be determined largely by several ongoing phase III trials, including trials of retinoids, beta-carotene, and alpha-tocopherol in the aerodigestive tract, of tamoxifen and fenretinide in the breast, and of finasteride in the prostate.
Sequential prophylactic oral and empiric once-daily parenteral antibiotics for neutropenia and fever after high-dose chemotherapy and autologous bone marrow support.
Authors: Gilbert C , Meisenberg B , Vredenburgh J , Ross M , Hussein A , Perfect J , Peters W P
Published: February 2017

PURPOSE

We studied the effectiveness of prophylactic oral ciprofloxacin and rifampin on fever prevention in patients undergoing autologous bone marrow transplantation (ABMT) for breast cancer. Furthermore, we evaluated the toxicity and efficacy of empiric once-daily vancomycin and tobramycin for febrile neutropenia.

PATIENTS AND METHODS

Ninety-nine assessable women received prophylactic ciprofloxacin and rifampin after high-dose chemotherapy (HDC) for advanced or high-risk primary breast cancer supported with either bone marrow and peripheral-blood progenitor cells (PBPCs) or bone marrow purged with chemotherapy and monoclonal antibodies. Neutropenic fever was treated with empiric once-daily vancomycin and tobramycin. Patients were compared with historic controls treated with the identical HDC and bone marrow support regimen.

RESULTS

In patients treated with bone marrow and PBPCs, the incidence of fever during neutropenia was reduced by ciprofloxacin and rifampin from 98% to 57%. Documented infections were reduced from 42% to 13% (P < .01) and bacteremia from 18% to 0% (P < .001). In purged bone marrow recipients, the overall infection rate decreased from 74% to 17% (P < .001), and bacteremia from 29% to 7%. (P = .02). No patient developed breakthrough bacteremia or sepsis syndrome while on study. Serum creatinine level greater than 1.8 g/dL was noted in 7% of controls and 10% of study patients. Increased ototoxicity was not encountered with the higher peak concentrations of vancomycin and tobramycin.

CONCLUSION

The therapeutic strategy of ciprofloxacin and rifampin followed by once-daily vancomycin and tobramycin markedly reduced the incidence of infection and virtually eliminated bacteremia in both purged and nonpurged bone marrow recipients. Once-daily vancomycin and tobramycin was safe and effective and, because of the ease of use, facilitates outpatient management of ABMT patients.
Effect of schedule and maintenance on the antiemetic efficacy of ondansetron combined with dexamethasone in acute and delayed nausea and emesis in patients receiving moderately emetogenic chemotherapy: a phase III trial by the National Cancer Institute of Canada Clinical Trials Group.
Authors: Kaizer L , Warr D , Hoskins P , Latreille J , Lofters W , Yau J , Palmer M , Zee B , Levy M , Pater J
Published: February 2017

PURPOSE

This study examines whether the schedule of ondansetron significantly influences its antiemetic efficacy in the first 24 hours after chemotherapy, whether the administration of oral ondansetron after 24 hours is effective in preventing delayed emesis, and whether the efficacy of ondansetron is preserved over multiple courses of moderately emetogenic chemotherapy.

PATIENTS AND METHODS

A multicenter double-blind study randomized 302 cancer patients to one of three treatment arms. Arm A received dexamethasone 10 mg intravenously (i.v.) plus ondansetron (Zofran; Glaxo Canada Inc, Toronto, Canada) 8 mg i.v. prechemotherapy plus ondansetron 8 mg orally every 12 hours postchemotherapy for nine doses. Arm B received dexamethasone 10 mg i.v. plus ondansetron 16 mg i.v. prechemotherapy plus placebo orally postchemotherapy in the same schedule as arm A. Arm C received dexamethasone 10 mg i.v. plus ondansetron 8 mg prechemotherapy plus ondansetron 8 mg orally postchemotherapy for one dose followed by placebo orally every 12 hours for eight more doses. Response was assessed by the number of reported episodes of vomiting and by severity of nausea measured on a visual analog scale (VAS).

RESULTS

The two schedules of ondansetron used in the first 24 hours were no different in their antiemetic efficacy, with similar rates for complete responses (76.7% v 72.0%, P = .472), complete plus major responses (90.2% v 82.0%, P = .135), and severity of nausea (P = .348). Oral ondansetron after 24 hours was more effective than placebo in preventing delayed nausea and emesis, with superior rates of complete responses (59.6% v 42.1%, P = .012 by one-sided test), complete plus major responses (80.9% v 66.3%, P = .018 by one-sided test), and less severe nausea (9.2 mm v 18.6 mm on a 100-mm VAS, P = .002). The efficacy of ondansetron was maintained over subsequent courses of chemotherapy.

CONCLUSION

The schedule of ondansetron in the first 24 hours does not influence its efficacy. The use of oral maintenance ondansetron is effective in preventing delayed maintenance ondansetron is effective in preventing delayed nausea and emesis after moderately emetogenic chemotherapy.
Leukemia risk following Hodgkin's disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage.
Authors: van Leeuwen F E , Chorus A M , van den Belt-Dusebout A W , Hagenbeek A , Noyon R , van Kerkhoff E H , Pinedo H M , Somers R
Published: February 2017

PURPOSE

The development of leukemia is one of the most serious long-term complications of modern treatment for Hodgkin's disease (HD). This study was undertaken to examine the relation between risk of leukemia and various treatment factors (including cumulative dose of cytostatic drugs and interaction with radiotherapy [RT]), while also assessing the effect of treatment-induced bone marrow damage.

PATIENTS AND METHODS

We conducted a case-control study in a cohort of 1,939 patients treated for HD between 1966 and 1986 in the Netherlands. Detailed information from the medical records was obtained for 44 cases of leukemia and 124 matched controls, in whom leukemia had not developed.

RESULTS

The cumulative dose of mechlorethamine was the most important factor in determining leukemia risk. As compared with patients who received RT alone, patients treated with six or fewer cycles of combinations including nitrogen mustard (mechlorethamine) and procarbazine had an eightfold increased risk of developing leukemia (P = .08), while patients who received more than six of such cycles had a greater than 40-fold excess risk (P < .001). Treatment with lomustine or a combination of teniposide and cyclophosphamide also significantly increased the risk of leukemia. Patients who had received chemotherapy (CT) during two or more time periods had a nearly 40-fold increased risk of leukemia as compared with patients treated only once. The extent of RT did not further increase leukemia risk among patients who also received CT. A significantly increased risk of leukemia was found among patients with low platelet counts, both in response to initial therapy and during follow-up. Patients who experienced 2 or more half-year periods with platelet counts less than 75 x 10(6)/mL had an approximately fivefold risk of developing leukemia, and a similar risk increase was found for patients who responded to initial treatment with a > or = 70% decrease of platelet counts (as compared with patients who had a < or = 50% decrease).

CONCLUSION

In addition to mechlorethamine, lomustine and teniposide combinations were also linked to an elevated risk of developing leukemia. Since the number of CT episodes was found to be a strong determinant of leukemia risk, it is important that new therapies for HD continue to yield high initial cure rates. Further studies are warranted to investigate whether patients at high risk for developing leukemia may be identified from the response of their platelets to initial therapy for HD.
Clinical features and treatment outcome for children with CD30+ large-cell non-Hodgkin's lymphoma.
Authors: Sandlund J T , Pui C H , Santana V M , Mahmoud H , Roberts W M , Morris S , Raimondi S , Ribeiro R , Crist W M , Lin J S
Published: February 2017

PURPOSE

To determine the frequency of CD30 expression and its relationship to clinical features, immunophenotype, histotype, and outcome in childhood large-cell non-Hodgkin's lymphoma (NHL).

PATIENTS AND METHODS

We reviewed 45 cases of large-cell NHL in children treated at St Jude Children's Research Hospital from 1975 to 1990 for whom there was sufficient tissue to perform immunophenotypic studies. All 45 were screened with a panel of antibodies to detect the presence of CD30 and T-cell and B-cell antigens. Cases were classified according to the National Cancer Institute (NCI) Working Formulation and the Kiel classification system. Clinical features, immunophenotype, pathologic classification, and treatment outcome were compared for CD30+ and CD30- cases.

RESULTS

CD30 expression was documented in 18 cases (40%). These 13 boys and five girls had a median age of 13 years at diagnosis. Most (n = 14) had advanced-stage (III and IV) disease. Nodal disease was equally common in CD30+ and CD30- cases, whereas skin involvement was significantly more frequent in CD30+ cases (P = .007). There was no significant association of CD30 expression with histologic subtype according to the NCI Working Formulation, but CD30+ cases were more likely to be anaplastic by the Kiel classification (P < .001). All CD30+ cases had either T-cell or null-cell phenotype, while the majority of CD30- cases were B-cell phenotype (P < .001). Among patients with limited-stage disease, the mean +/- SE estimated 5-year event-free survival (EFS) was 75% +/- 22% for CD30+ cases and 92% +/- 9% for CD30- cases (P = .10); estimates for advanced-stage disease were 57% +/- 17% and 29% +/- 17%, respectively (P = .096). For patients with advanced-stage disease, CD30 expression was associated with a significantly better overall 5-year survival probability (84% +/- 12% v 27% +/- 16%, P = .0016).

CONCLUSION

CD30 is frequently expressed in pediatric large-cell NHL and is significantly associated with T-cell or null-cell phenotype, anaplastic morphology, skin involvement, and better overall survival among advanced-stage patients.
Late effects of intensive treatment for acute myeloid leukemia and myelodysplasia in childhood.
Authors: Liesner R J , Leiper A D , Hann I M , Chessells J M
Published: February 2017

PURPOSE

To perform a comprehensive assessment of the late effects of short-term intensive chemotherapy for childhood acute myeloid leukemia (AML) and myelodysplasia, and compare the sequelae of intensive chemotherapy alone with those of total-body irradiation (TBI).

PATIENTS AND METHODS

Of 33 survivors studied, 26 (group A) received intensive chemotherapy including anthracyclines, one also received busulfan, cyclophosphamide (Bu/Cy), and bone marrow transplantation (BMT). Seven patients (group B) received chemotherapy, TBI, and BMT. Hearing, sight, growth, and endocrine, renal, and cardiac function were assessed.

RESULTS

The mean height standard deviation score of 25 nontransplanted group A patients was +0.67 at diagnosis, -0.11 following treatment (P = .016), and +0.34 7 years later (P > .05), indicating no long-term growth impairment. The patients had normal gonadal function and the girls had normal uterine size and ovarian volume. The Bu/Cy patient had primary ovarian failure. Four group B children required growth hormone and four sex steroids for growth or gonadal failure. The girls had reduced uterine size and ovarian volume. Three had thyroid dysfunction and six had cataracts. Abnormalities of renal function were found in both groups and hearing loss in group A only. The mean cardiac shortening fraction was significantly reduced at 29.2% in group A and 28.6% in group B compared with 36% in normal subjects. Two group A patients have developed cardiac failure.

CONCLUSION

Chemotherapy and TBI before BMT for AML has resulted in growth failure, gonadal and thyroid damage, and cataracts in most children, whereas chemotherapy alone caused cardiac, renal, and hearing abnormalities only.
Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma.
Authors: McIntyre J F , Smith-Sorensen B , Friend S H , Kassell J , Borresen A L , Yan Y X , Russo C , Sato J , Barbier N , Miser J
Published: February 2017

PURPOSE

We investigated the possibility that a significant proportion of children with osteosarcoma harbor germline mutations of the p53 tumor suppressor gene and, therefore, this subgroup of pediatric cancer patients should be considered for large-scale predictive testing.

PATIENTS AND METHODS

Genomic DNA extracted from peripheral-blood leukocytes from 235 unselected children with osteosarcoma from 33 institutions were screened for the presence of germline p53 mutations using constant denaturant gel electrophoresis (CDGE). Exons 5 through 8 were evaluated in all patients and exon 2 and exon 9 were analyzed in 59 and 95 patients, respectively. Those samples that showed aberrant migration on CDGE were sequenced or analyzed by restriction enzyme digestion of polymerase chain reaction (PCR) products to confirm the nature of the gene alteration.

RESULTS

In 18 samples, CDGE showed fragments of the p53 gene with altered electrophoretic mobilities compared with wild-type p53. DNA sequencing showed that 11 samples had an identical, previously described polymorphism. The other seven contained heterozygous p53 mutations located in exon 5 (n = 3), exon 6 (n = 1), exon 7 (n = 1), and exon 8 (n = 2). Six alterations were missense mutations and one was a nonsense mutation. Three of these patients had first-degree relatives with cancer. One of these three kindreds had a family history consistent with Li-Fraumeni syndrome (LFS).

CONCLUSION

We identified germline p53 mutations in seven of 235 (3.0%) children with osteosarcoma. Four of these mutations were found in patients who did not have first-degree relatives with cancer. Although genetic transmission of the altered p53 gene could not be tested in this survey because of how it was designed, it is possible that predictive testing for p53 mutations could identify unaffected relatives of gene carriers who also have a high risk for the development of cancer. This study provides evidence for the importance of considering children with osteosarcoma for predictive testing for germline p53 mutations.
Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia.
Authors: Lee J S , Lippman S M , Benner S E , Lee J J , Ro J Y , Lukeman J M , Morice R C , Peters E J , Pang A C , Fritsche H A
Published: February 2017

PURPOSE

Retinoids have proven chemopreventive efficacy in both preclinical and clinical studies. This trial was designed to confirm the finding of an earlier uncontrolled trial that the synthetic retinoid etretinate had major activity in reversing squamous metaplasia found in the bronchial epithelium of chronic smokers.

PATIENTS AND METHODS

We prospectively evaluated 152 smokers with bronchoscopy and obtained biopsies from six sites. Subjects with dysplasia and/or a metaplasia index of greater than 15% were randomly assigned to receive either 1 mg/kg isotretinoin or placebo daily for 6 months. Of 86 subjects randomized (41 isotretinoin, 45 placebo), 69 were reevaluated at the completion of treatment.

RESULTS

In the group as a whole, the metaplasia index decreased over time from a mean +/- SE of 35.8% +/- 2.7% at baseline to 28.1% +/- 3.3% at the completion of treatment (P = .01) by repeated measures analysis of variance [ANOVA]); a reduction in the metaplasia index (> 8%) was noted in both isotretinoin and placebo groups (19 of 35 [54.3%] and 20 of 34 [58.8%], respectively). Complete reversal of squamous metaplasia was noted in nine subjects from each group. However, the magnitudes of the mean metaplasia index changes did not differ significantly in the two treatment groups. In both groups, smoking cessation resulted in significant declines in the extent of squamous metaplasia, whereas no significant change in metaplasia index was found among those who continued to smoke.

CONCLUSION

Squamous metaplasia was frequently observed in bronchial biopsy samples from chronic smokers. From this study, we conclude that isotretinoin has no effect on squamous metaplasia, a potential intermediate end point of bronchial carcinogenesis. Although determining the exact role of isotretinoin in lung cancer prevention requires further study, the finding that there was a significant decrease in squamous metaplasia in the placebo group emphasizes the critical importance of a placebo-controlled study design in chemoprevention trials using intermediate end points.
Clinical activity of chronic oral etoposide in previously treated metastatic breast cancer.
Authors: Martín M , Lluch A , Casado A , Santabárbara P , Adrover E , Valverde J J , López-Martín J A , Rodriguez-Lescure A , Azagra P , García-Conde J
Published: February 2017

PURPOSE

This study was undertaken to assess the antitumor activity and tolerance of chronic oral etoposide (50 mg/m2/d for 21 days every 4 weeks) in metastatic breast cancer (MBC).

PATIENTS AND METHODS

Forty-three consecutive metastatic breast cancer patients with at least one site of measurable disease entered the study. All patients had received prior chemotherapy (adjuvant, three patients; adjuvant plus chemotherapy for metastases, 21; chemotherapy for metastases, 19). Twenty-two and 21 patients had also received prior hormonal and radiation therapy, respectively.

RESULTS

Thirty-five percent of patients (15 of 43; 95% confidence interval, 21% to 51%) had objective responses, according to an intention-to-treat analysis. Responses were seen in lymph nodes (six of 14), skin and soft tissues (eight of 16), lung (six of 14), lytic lesions of the bone (two of six), liver (four of 23), and peritoneum (one of one). The median duration of response was 7 months (range, 3+ to 12). The main toxic side effects were leukopenia (overall, 65% of patients; World Health Organization [WHO] grade 4, 21%), thrombocytopenia (21%; WHO grade 4, 5%) and anemia (51%; WHO grade 4, 5%). Nine patients (21%) required a 25% dose reduction because of myelosuppression, and one patient abandoned treatment because of gastrointestinal toxicity and severe asthenia. Ninety-one percent of patients developed alopecia, 39.5% had mucositis (WHO grade 3, 9.5%) and 60.5% had some degree of emesis (11.5% nausea, 46.5% transient vomiting, 2.5% intractable vomiting). No toxic deaths occurred.

CONCLUSION

Chronic oral etoposide appears to be an active and well-tolerated regimen in MBC patients previously exposed to chemotherapy. This schedule of etoposide administration warrants further studies, alone or in combination, in MBC.
Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group.
Authors: Loehrer P J , Kim K , Aisner S C , Livingston R , Einhorn L H , Johnson D , Blum R
Published: February 2017

PURPOSE

The purpose of this study was to evaluate the impact of cisplatin, doxorubicin, and cyclophosphamide (PAC) in patients with advanced thymoma with respect to response rate, duration of remission, and overall survival.

PATIENTS AND METHODS

Assessable patients with thymoma (n = 29) or thymic carcinoma (n = 1) with metastatic or locally progressive recurrent disease following radiotherapy were treated with intravenous cisplatin (50 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) with normal saline hydration. Courses were repeated every 3 weeks for a maximum of eight cycles of therapy.

RESULTS

Toxicity, which was primarily hematologic, was mild, with only one patient developing a fever associated with neutropenia. Three complete responses (CRs) and 12 partial responses (PRs) were observed (CR+PR rate, 50%; 95% confidence interval, 31.3% to 68.7%). Ten patients had stable disease. The median duration of response was 11.8 months (range, 0.9 to 70.5+), the time to treatment failure 18.4 months (range, 0.8 to 91.9+), and median survival time 37.7 months (range, 2 to 91.9+).

CONCLUSION

This trial demonstrates that objective response rates and prolonged survival can be achieved in patients with advanced thymoma.
High-dose treatment with carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: a phase I/II study. The German Testicular Cancer Cooperative Study Group.
Authors: Siegert W , Beyer J , Strohscheer I , Baurmann H , Oettle H , Zingsem J , Zimmermann R , Bokemeyer C , Schmoll H J , Huhn D
Published: February 2017

PURPOSE

This trial evaluated the toxicity and efficacy of high-dose carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in patients with refractory or relapsed germ cell cancer.

PATIENTS AND METHODS

Between August 1989 and September 1992, 74 patients with refractory or recurrent germ-cell tumors received one cycle of escalating doses of carboplatin (1,500 to 2,000 mg/m2), etoposide (1,200 to 2,400 mg/m2), and ifosfamide (0 to 10 g/m2). Before high-dose therapy, two cycles of conventional-dose cisplatin, etoposide, and ifosfamide were administered to assess tumor responsiveness. Seventy-four patients were assessable for toxicity and 68 for response.

RESULTS

The doses of carboplatin 1,500 mg/m2, etoposide 2,400 mg/m2, and ifosfamide 10 g/m2 appeared to be safe. At this dosage, we treated 20 patients and observed World Health Organization (WHO) grade 3 and 4 hematotoxicity (100%), nausea (100%), diarrhea (30%), and hepatotoxicity (10%). All patients developed granulocytopenic fever. At carboplatin doses of 1,500 mg/m2, kidney toxicity was mild, with a median maximum creatinine level of 1.4 mg/dL (range, 1.1 to 3.0 mg/dL). However, at carboplatin doses of 1,750 and 2,000 mg/m2, we observed nonacceptable nephrotoxicity and neurotoxicity. Two (3%) patients died of treatment-related complications. Six patients required hemodialysis, which was temporary in five patients and permanent in one. Objective responses were obtained in 43 of 68 (63%) patients, including 21 (31%) complete remissions (CRs) and 14 (20%) inoperable partial remissions (PRs) with marker normalization. The median observation time of surviving patients was 12 months (range, 2 to 32). The probabilities of overall survival, event-free survival, and the relapse-free survival at 2 years were 44% (SD 8%), 35% (SD 6%), and 67% (SD 9%), respectively. Patients with disease refractory to conventional-dose pretreatment had a poor prognosis, with only one of 23 patients surviving event-free at 7 months after high-dose chemotherapy (HDT). In contrast, 24 of 45 (53.3%) patients with sensitive disease survive event-free with a probability of event-free survival at 2 years of 50% (SD 8%).

CONCLUSION

High-dose carboplatin, etoposide, and ifosfamide plus autologous stem-cell transplantation can be used in refractory and relapsed germ cell cancer with acceptable toxicity, and represents an effective, potentially curative salvage treatment.
Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients.
Authors: Abbruzzese J L , Abbruzzese M C , Hess K R , Raber M N , Lenzi R , Frost P
Published: February 2017

PURPOSE

To evaluate the natural history, validate previous observations, and identify prognostic factors in patients with unknown primary carcinoma (UPC).

PATIENTS AND METHODS

Nine hundred twenty-seven consecutive patients referred to the M.D. Anderson Cancer Center with a preliminary diagnosis of UPC were prospectively identified. A standardized evaluation narrowed the study population to 657 patients with UPC. All data were recorded and computerized for storage, retrieval, and analysis. The primary end point for the study was survival, which was calculated from the first day of patient registration. Survival curves were estimated using the Kaplan-Meier method and compared using the Cox-Mantel log-rank test. To identify important prognostic factors, univariate and multivariate analyses were conducted.

RESULTS

The demographics of the UPC patient population mirrored those of the general population of patients referred to our cancer center except for an excess of men among the UPC patients. Most patients had histologic or cytologic evidence of adenocarcinoma and had more than one organ site metastatically involved. Univariate and multivariate analyses identified numerous important prognostic factors with a significant influence on survival, including sex, number of organ sites involved, specific organ sites involved, and pathologic subtypes.

CONCLUSION

This study validated previously identified important prognostic factors for survival in UPC. Additional variables that had an impact on survival were identified and the complex interaction of the factors was explored. As patient numbers increase, this database will be able to provide further analyses of patient subsets and potentially relate specific clinical features to the evolving molecular and biochemical understanding of these malignancies.
Treatment of hepatocellular carcinoma: too many options?
Authors: Venook A P
Published: February 2017

PURPOSE

This study attempts to review the therapeutic interventions being used to treat patients with hepatocellular carcinoma (HCC).

DESIGN

An English language literature search, including abstracts and original articles, and a review of the bibliographies of such articles, was conducted.

RESULTS

Surgery is possible in few patients and curative in only a small percentage. Conventional chemotherapy is ineffective in HCC. Modifications of chemotherapy, including intraarterial infusion, chemoembolization, lipiodol, styrene-maleic acid-neocarzinostatin (SMANCS), and isolated hepatic perfusion, have led to improved tumor responses, but have not materially affected patient outcome. Radioimmunotherapy and conformal radiotherapy have had no more than a marginal impact on patient outcome. Surgical innovations such as cryosurgery and percutaneous alcohol injection have not yet been shown to offer any advantage, and liver transplantation, while curative in some patients, requires an enormous expenditure of resources to achieve cure in few patients.

CONCLUSION

Prevention is the ideal approach to HCC. Surgical cure is rarely possible, and while numerous therapies may palliate symptoms, patient selection and the lack of randomized studies make their impact on median survival difficult to assess. Patients being treated for HCC should be enrolled on treatment protocols testing multimodality or new strategies.
Applicability of the International Index for aggressive lymphomas to patients with low-grade lymphoma.
Authors: López-Guillermo A , Montserrat E , Bosch F , Terol M J , Campo E , Rozman C
Published: February 2017

PURPOSE

Variables used to build up the International Index for aggressive lymphomas (age, performance status, stage, extranodal involvement, and lactic dehydrogenase [LDH]) are also important in low-grade lymphoma. To assess the prognostic value of this index in low-grade lymphoma, we have applied it to a series of 125 patients.

PATIENTS AND METHODS

One hundred twenty-five patients with low-grade lymphoma who were diagnosed at a single institution over a 20-year period and treated with standard chemotherapy were studied. End points of the study were response to therapy and survival according to the International Index. In addition to the International Index, main initial and evolutive variables were evaluated. Univariate and multivariate methods were used.

RESULTS

After applying the International Index, the patients divided into four risk groups: low (36% of cases), low-intermediate (32%), high-intermediate (20.8%), and high (11.2%), with complete response (CR) rates in the four groups being 60%, 35%, 23%, and 21%, respectively. Ten-year overall survival rates for the risk groups were as follows: low, 73.6%; low-intermediate, 45.2%; high-intermediate, 53.5%; and high, 0% (P < .001). When the International Index was included in a multivariate analysis, along with the main initial variables, International Index (P < .001) and sex (male, worse) (P = .038) were the only parameters related to survival. When response to therapy was also included, achievement of CR (P < .0001) and International Index (P < .001) were the most important factors. In patients who achieved a CR, the International Index was the only parameter related to survival (P = .051). The results were the same when the International Index was applied to the subset of 107 patients with follicular lymphoma.

CONCLUSION

In this study, the International Index has been found to be an important prognostic tool in low-grade lymphomas. Such an index could be used to predict prognosis not only in aggressive, but also in low-grade lymphomas.
Primary small-intestinal lymphomas in Taiwan: immunoproliferative small-intestinal disease and nonimmunoproliferative small-intestinal disease.
Authors: Shih L Y , Liaw S J , Dunn P , Kuo T T
Published: February 2017

PURPOSE

The clinicopathologic findings in 45 adult Chinese patients with primary small-intestinal lymphoma (PSIL) are described and compared with those in Western countries and in underdeveloped nations. The efficacy of combination chemotherapy is also assessed.

PATIENTS AND METHOD

Six patients had immunoproliferative small-intestinal disease (IPSID) indicated by the presence of alpha-heavy chain protein (alpha-CP) in body fluids or tumor tissues. Thirty-nine patients had non-IPSID, including one with postrenal transplant lymphoma. Thirty-three non-IPSID patients received a minimum of four cycles of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP).

RESULTS

All IPSID patients presented with the clinical and laboratory features of severe intestinal malabsorption, and all had diffuse lymphoplasmacytic infiltration in the mucosa of the small bowel. Lymphomas were localized mainly in the jejunum and mesenteric nodes. The histologic subtypes were diffuse large cell in two, immunoblastic in three, and diffuse mixed in one. All patients responded poorly to chemotherapy, with a median survival duration of 10.5 months. The common presenting symptoms of the 39 non-IPSID patients included abdominal pain (90%), weight loss (31%), abdominal mass (26%), obstruction (26%), and perforation (23%). Diffuse large-cell and immunoblastic lymphomas constituted 82% of cases. Four patients had stage IE, 19 stage II 1E, and 16 stage 112E disease according to the Musshoff's criteria; 22 had bulky tumors and 19 had multiple tumors. The tumors were completely resected in 14 patients. Of 33 patients treated with combination chemotherapy, 73% achieved a complete remission. With a median follow-up duration of 90 months, there have been four relapses, with only one at the primary tumor site. The overall 5-year survival and disease-free survival rates for non-IPSID patients who were treated with chemotherapy were 59% and 54%, respectively.

CONCLUSION

Intensive chemotherapy produces long-term disease-free survival in locally advanced non-IPSID PSIL.
Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: the Indiana University experience.
Authors: Saxman S B , Nichols C R , Einhorn L H
Published: February 2017

PURPOSE

Patients with relapsed extragonadal germ cell tumors (EGCT) are usually treated in an identical fashion as patients with recurrent testicular cancer. However, little is known about the long-term outcome in these patients and whether they have comparable results to patients with a testicular primary tumor. The purpose of this study was to evaluate the effect of salvage chemotherapy on long-term survival in patients with EGCT.

MATERIALS AND METHODS

We conducted a retrospective review of 73 patients with relapsed extragonadal nonseminomatous germ cell tumors (GCTs) treated at Indiana University between 1976 and 1993. All patients received cisplatin-containing regimens as primary chemotherapy.

RESULTS

Only five of 73 patients (7%) were long-term disease-free survivors after salvage chemotherapy. The remaining 68 patients are either dead of disease or toxicity (n = 63), or alive with progressive disease (PD) (n = 5). Twenty-eight patients received high-dose chemotherapy with autologous bone marrow transplant (ABMT) at some point during their disease, and none of these patients are continuously disease-free.

CONCLUSION

Although similar salvage chemotherapy strategies will cure approximately 30% of patients with recurrent testicular cancer, new approaches are needed for EGCT.
A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: A Gynecologic Oncology Group study.
Authors: Thigpen J T , Blessing J A , DiSaia P J , Yordan E , Carson L F , Evers C
Published: February 2017

PURPOSE

From 1979 to 1984, 356 eligible patients with advanced or recurrent endometrial carcinoma no longer amenable to therapy with surgery, radiotherapy, or progestins were treated with doxorubicin alone or doxorubicin in combination with cyclophosphamide.

PATIENTS AND METHODS

Patients were randomized to receive doxorubicin 60 mg/m2 intravenously (i.v.) with or without cyclophosphamide 500 mg/m2 i.v. every 3 weeks for eight drug courses. All patients had received prior therapy with progestins with subsequent progression of disease. No patients had received prior therapy with cytotoxic drugs. Of 356 patients, 300 had measurable disease.

RESULTS

Among 132 patients treated with doxorubicin alone, there were seven complete responses (5%), 22 partial responses (17%), 73 with stable disease (55%), and 30 with increasing disease within 2 months of study entry (23%). For the 144 patients who received the combination, there were 18 complete responses (13%), 25 partial responses (17%), 75 with stable disease (52%), and 26 with increasing disease (18%). The median progression-free interval for those patients who received doxorubicin alone was 3.2 months, while it was 3.9 months for those who received the combination. The median survival duration for doxorubicin patients was 6.7 months, while it was 7.3 months for the combination patients. None of the unadjusted estimates of treatment differences are statistically significant. Prognostic features that had an impact on outcome included one factor associated with an increased likelihood of response (presence of measurable lung metastases) and four features associated with a poorer survival (poor performance status [PS] of 2 or 3, high pathologic grade, and presence of liver metastases or other intraabdominal disease). If these features are taken into account in multivariate analyses, there is no statistically significant evidence for differences in response rates (relative odds of response, 1.58; P = .06, one-tailed test), and survival duration is slightly longer in the combination regimen (17% reduction in death rate; P = .048).

CONCLUSION

The combination of doxorubicin plus cyclophosphamide thus appears to offer a small advantage over doxorubicin alone in the management of endometrial carcinoma at the expense of more frequent and severe myelosuppression and gastrointestinal toxicity.
Methotrexate pharmacokinetics and prognosis in osteosarcoma.
Authors: Graf N , Winkler K , Betlemovic M , Fuchs N , Bode U
Published: February 2017

PURPOSE

The influence of methotrexate (MTX) pharmacokinetic parameters on the efficacy of high-dose MTX (HDMTX) in osteosarcoma was analyzed.

PATIENTS AND METHODS

MTX serum peak values from 198 patients in 1,703 treatment courses and more detailed pharmacokinetic data from 185 patients in 1,045 treatment courses from the Cooperative Osteosarcoma Study Group (COSS) studies COSS-80, COSS-82, and COSS-86 were investigated.

RESULTS

A mean threshold peak level of > or = 1,000 mumol/L for the repeated MTX courses of individual patients was found to correlate significantly to prognosis in study COSS-80 (18% v 64% actuarial 10-year disease-free survival [DFS], P = .0001). Six courses of HDMTX per patient who achieved peak values > or = 1,000 mumol/L were found to be sufficient for a full effect to be seen in DFS in COSS-80. The MTX peak level was found to correlate closely to the area under the curve (AUC). However, AUC was a less powerful determinator of prognosis than the mean threshold MTX peak value. In patients who received cisplatin (DDP) as one of the additional drugs to MTX, the peak values and AUC were significantly increased (1,396 v 1,276 mumol/L, P = .011; 6,684 v 5,820 h.mumol/L, P < or = .002) and only a few patients (6%) did not achieve mean threshold MTX peak values. In addition, following restriction of hydration fluid after the MTX infusion from 4.5 to 3.0 L/m2 per 24 hours, the early MTX half-life (t1/2) and the AUC, but not the MTX peak value, were significantly increased (3.4 v 3.05 hours, and 6,760 v 5,998 h.mumol/L, respectively, P < or = .002).

CONCLUSION

MTX pharmacokinetics significantly influence the efficacy of MTX in osteosarcoma. Individual adaptation of the MTX dose to ensure a threshold peak serum level > or = 1,000 mumol/L does not seem necessary at a fixed dose of 12 g MTX/m2, restriction of hydration fluid to 3 L/m2 per 24 hours, and concomitant use of DDP within the drug regimen.
Phase I study of docetaxel administered as a 1-hour intravenous infusion on a weekly basis.
Authors: Tomiak E , Piccart M J , Kerger J , Lips S , Awada A , de Valeriola D , Ravoet C , Lossignol D , Sculier J P , Auzannet V
Published: February 2017

PURPOSE

This phase I study of Taxotere (RP 56976, NSC 628503; docetaxel, Rhône-Poulenc Rorer, Antony, France) was undertaken to determine the maximum-tolerated dose (MTD), toxic effects, and basic pharmacokinetics of a day-1 and -8 schedule of this novel semisynthetic product related to Taxol (paclitaxel; Bristol-Myers Squibb, Wallingford, CT).

PATIENTS AND METHODS

Thirty-two eligible patients with refractory solid malignancies have been treated with a 1-hour infusion of Taxotere on a day-1 and -8 schedule every 3 weeks as long as patients maintained a polymorphonucleotide count > or = 1,500/microL and a platelet count > or = 100,000/microL. Dose levels tested have ranged between 20 and 110 mg/m2 per course.

RESULTS

Considering 128 assessable courses, the main toxicities have been neutropenia (which was dose-limiting), asthenia, alopecia, hypersensitivity reactions, skin toxicity, and edema. No significant cardiac or platelet toxicity has been observed. Seven patients have had aggravation of preexisting paresthesias or new onset of sensory symptoms during Taxotere treatment. The MTD at this schedule appears to be 110 mg/m2 per course, with six of 10 patients at this level experiencing severe toxicity. Five partial remissions have been observed in four heavily pretreated patients with breast cancer and in one patient with adenocarcinoma of unknown origin. Two patients with ovarian cancer have had meaningful decreases in CA125 levels.

CONCLUSION

Like Taxol, this novel chemotherapeutic agent appears to possess promising activity in patients with refractory breast and ovarian neoplasms, with tolerable toxicities. Using this schedule, 100 mg/m2 per course is the recommended dose for future phase II trials.
Pharmacokinetics of undiluted or diluted high-dose etoposide with or without busulfan administered to patients with hematologic malignancies.
Authors: Mross K , Bewermeier P , Krüger W , Stockschläder M , Zander A , Hossfeld D K
Published: February 2017

PURPOSE

We used two different methods to administer high-dose etoposide (VP-16) during a myeloablative conditioning chemotherapy regimen before bone marrow transplantation (BMT). VP-16 was administered either diluted (0.5 mg/mL) or undiluted (20 mg/mL), with or without busulfan.

PATIENTS AND METHODS

Blood samples were drawn from 17 patients during the infusion (6 hours) and thereafter daily until 2 days after BMT. VP-16 concentrations were measured in all plasma samples by high-performance liquid chromatography (HPLC) and electrochemical detection, and the results were analyzed with a pharmacokinetic data analysis system.

RESULTS

All calculated pharmacokinetic parameters in the two patient groups (VP-16 administered diluted or undiluted) were similar. There were no statistically significant differences in half-lives, mean residence time (MRT), volume of distribution, total clearance, or area under the curve (AUC). VP-16 was found in blood samples from eight of 17 patients at the time of BMT. Significant differences in systemic drug exposure and systemic clearance were found when patients were grouped according to treatment with busulfan or with total-body irradiation (TBI).

CONCLUSION

The two administration modes for VP-16, either diluted or undiluted, are bioequivalent in pharmacokinetic terms. The terminal half-lives were longer than expected and resulted in significant VP-16 plasma levels at the time of BMT. The biologic significance remains unclear. Busulfan and/or concomitant medication with phenytoin influence plasma clearance (clp) and systemic drug exposure significantly.
Prognostic factors and outcome of incompletely resected invasive thymoma following radiation therapy.
Authors: Ciernik I F , Meier U , Lütolf U M
Published: February 2017

BACKGROUND

Stage III and stage IV thymomas with significant macroscopic infiltration to the neighboring structures are rarely completely resectable. It therefore remains unclear to what extent tumors must be surgically debulked to improve prognosis.

PATIENTS AND METHODS

We reviewed the cases of 31 patients with incompletely resected invasive thymoma and residual macroscopic disease who were referred to postoperative irradiation. Survival and local tumor control were analyzed. All patients were treated between 1958 and 1990 with megavoltage irradiation at doses ranging from 42 to 66 Gy. The shortest follow-up time for living patients was more than 5 years.

RESULTS

The overall median 5-year survival rate was 45%. Eighteen stage III patients had a 5-year survival rate of 61% and a 10-year survival rate of 57%. Thirteen patients had stage IV disease and 5- and 10-year survival rates of 23% and 8%, respectively. Univariate and multivariate analyses confirmed a worse prognosis for stage IV disease. Epithelial or spindle-cell thymoma was associated with stage IV disease. Twenty-two percent of patients with stage III disease had epithelial or spindle-cell thymoma, versus 69% of patients with stage IV disease (P = .02 for univariate and P = .05 for multivariate analysis). Initial tumor diameter greater than 10 cm correlated with poor prognosis in the univariate analysis (P = .05). However, more importantly, debulking of tumor did not significantly improve outcome when compared with patients who received biopsy only. The median survival rate of patients with stage IVa disease did not differ from that of those with stage IVb disease. Mediastinal control was achieved in 23 patients (74%). Stage IV disease did not correlate with an increase in local treatment failure after irradiation, although epithelial or spindle-cell thymoma predisposed for local treatment failure (46% v 11%; P = .04 in univariate and P = .055 in multivariate analysis).

CONCLUSION

Tumor debulking leaving macroscopic residual thymoma, as opposed to biopsy alone, does not improve prognosis when followed by radiation. Radiation therapy for local tumor control is most effective in nonepithelial-predominant thymomas.
Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: a phase II study.
Authors: Abratt R P , Bezwoda W R , Falkson G , Goedhals L , Hacking D , Rugg T A
Published: February 2017

PURPOSE

The aim of this study was to evaluate the efficacy and toxicity of gemcitabine at higher doses than had been used previously in patients with non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS

Eighty-four patients (65 men, 19 women; age range, 35 to 75 years; mean age, 59 years) with locally advanced or metastatic pathologically documented NSCLC were enrolled. Patients had bidimensionally measurable disease, as defined by computed tomographic (CT) scan or chest x-ray. A total of 28.6% had previously been surgically treated, while 9.5% had received radiotherapy. Fifty-three patients commenced at a dose of 1,000 mg/m2, and 31 at a dose of 1,250 mg/m2. Patients were to receive two dose escalations of 25%, provided that overall toxicity was no worse than World Health Organization (WHO) grade 1 or WHO grade 0 for platelets. Responding patients were reviewed and validated by a blinded oncology review board (ORB) of experts not involved with the study. Of the original 84 patients enrolled, 76 were assessable.

RESULTS

The overall response rate was 20% (95% confidence interval [CI], 11.6% to 30.8%). There were two complete responses (3%) and 13 partial responses (17%). Hematologic toxicity was negligible. WHO grade 3 WBC toxicity occurred in 0.9% of doses and WHO grade 4 in 0.1%. WHO grade 3 and 4 thrombocytopenia occurred in 0.1% and 0.1% of all doses, respectively. Nonhematologic toxicity was minor and easily controlled. Common side effects included peripheral edema, asthenia, and transient malaise.

CONCLUSION

The single-agent efficacy of gemcitabine is equivalent to other agents commonly used to treat NSCLC. Gemcitabine has an unusually mild side effect profile for such an active agent. The nausea and vomiting experienced with gemcitabine are mild and generally well controlled with standard antiemetics; 5-HT3 receptor antagonists are typically not required. The use of gemcitabine does not cause significant alopecia, and hematologic toxicity is modest and unlikely to require hospitalization. Gemcitabine may have a role as monotherapy in patients with inoperable NSCLC.