bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of radiotherapy in combined modality treatment of locally advanced non-small-cell lung cancer.
Authors: Kubota K , Furuse K , Kawahara M , Kodama N , Yamamoto M , Ogawara M , Negoro S , Masuda N , Takada M , Matsui K
Published: February 2017

PURPOSE

For patients with locally advanced (stage III) non-small-cell lung cancer (NSCLC), radiotherapy (RT) has been used conventionally for many years. Few prospective trials have determined the role of RT. Recently, chemotherapy (CT) has been shown to produce excellent responses in regionally advanced disease. We therefore conducted a randomized trial using cisplatin (P)-based CT regimens with or without thoracic irradiation.

PATIENTS AND METHODS

We randomly assigned 92 patients with locally advanced NSCLC to receive one of three arms of P-based combination chemotherapy: vindesine (V) plus P, mitomycin (M) plus V plus P, or etoposide (E) plus P alternating with V plus M. After two cycles of CT, patients were reevaluated and those with stage III were again randomized to receive RT or not. RT consisted of 50 to 60 Gy in 5 to 6 weeks; 2 Gy was delivered once daily in conventional fractions.

RESULTS

Sixty-three patients were included in the second randomization. The patients in the CT/RT group (n = 32) and CT-alone group (n = 31) were comparable in terms of age, sex, performance status, histologic features, stage of disease, and induction CT regimen. The median durations of survival were similar for the two groups (461 days in CT/RT group and 447 days in CT-alone group). The survival rate in the CT/RT group was 58% at 1 year, 36% at 2 years, and 29% at 3 years, as compared with 66%, 9%, and 3% at 1, 2, and 3 years, respectively, in the CT-alone group. One patient in the CT/RT group died of pneumonitis, but there were no CT-related deaths.

CONCLUSION

In locally advanced NSCLC, P-based combination CT followed by chest irradiation significantly increases the number of long-term survivors as compared with CT alone. RT to bulky disease in the thorax is thus an important part of combined modality therapy, and a necessary part of further studies in locally advanced disease.
Multiinstitutional phase II trial of intensive combination chemoimmunotherapy for metastatic melanoma.
Authors: Atkins M B , O'Boyle K R , Sosman J A , Weiss G R , Margolin K A , Ernest M L , Kappler K , Mier J W , Sparano J A , Fisher R I
Published: February 2017

PURPOSE

To evaluate the activity and toxicity of combined high-dose cisplatin, dacarbazine (DTIC), and tamoxifen chemotherapy and high-dose bolus interleukin-2 (IL-2) in patients with metastatic melanoma.

PATIENTS AND METHODS

Patients with metastatic melanoma, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and normal organ function were enrolled onto this multiinstitutional Cytokine Working Group trial. Patients received intensive chemoimmunotherapy consisting of cisplatin (50 mg/m2) and DTIC (350 mg/m2) intravenously (IV) on days 1 to 3 and 43 to 45, IL-2 600,000 IU/kg IV every 8 hours on days 12 to 16 and 26 to 30 (maximum, 28 doses), and tamoxifen 20 mg orally each day. Patients were evaluated for response at day 63 of each cycle, and responding patients were given a second cycle of therapy beginning on day 71 to 85.

RESULTS

Thirty-eight patients were entered onto this study. Toxicities were as expected for the chemotherapy and immunotherapy components of this regimen. Overlapping toxicity consisted primarily of thrombocytopenia (76% of patients required platelet transfusions), neutropenia, anemia, fatigue, and weight loss. Despite these cytopenias, bleeding and infectious complications were rare. There were no treatment-related deaths. Three patients achieved a complete response (CR; 8%), and 13 achieved a partial response (PR). The overall objective response rate was 42% (95% confidence interval [CI], 26% to 58%). Six additional patients had greater than 50% tumor reduction at day 63, which did not persist until a subsequent evaluation. The median duration of response was 5 months (range, 2 to 20+), and the median survival duration was 11 months.

CONCLUSION

This intensive treatment regimen appears to possess activity in metastatic melanoma comparable, but not superior, to that of other less intensive cisplatin- and IL-2-based chemoimmunotherapy regimens. Although the toxicity and complexity of this regimen make it unsuitable for phase III testing and impractical for more widespread use, the results of this study support a potential favorable interaction between IL-2 and chemotherapy in this disease and highlight the need for appropriately designed phase III trials.
Phase I/II study of iodine 131-labeled monoclonal antibody A33 in patients with advanced colon cancer.
Authors: Welt S , Divgi C R , Kemeny N , Finn R D , Scott A M , Graham M , Germain J S , Richards E C , Larson S M , Oettgen H F
Published: February 2017

PURPOSE

A phase I/II study was designed to determine the maximum-tolerated dose (MTD) of iodine 131-labeled monoclonal antibody (mAb) A33 (131I-mAb A33) administered intravenously, its limiting organ toxicity, and its radioisotope retention in tumors, and to develop preliminary evidence of antitumor activity.

PATIENTS AND METHODS

Patients (N = 23) with colorectal cancer who had failed to respond to conventional chemotherapy but had not received prior radiotherapy were treated with escalating doses of 131I-mAb A33. Three or more patients were entered at each dose level, starting at 30 mCi/m2, with increments of 15 mCi/m2 to a maximal dose of 90 mCi/m2. Radiolabeling was performed to maintain a specific activity of 30 mCi/m2/4 mg mAb A33 (projected maximum, 15 mCi/mg). Patients were under strict isolation precautions until whole-body radiation levels decreased to less than 5 mrem/h at 1 m. Serial radioimmunoscintigrams were performed in some cases for up to 3 weeks after 131I-mAb A33 administration.

RESULTS

All 20 patients with radiologic evidence of disease showed localization of radioisotope to sites of disease. Two patients with elevated carcinoembryonic antigen (CEA) levels and negative radiologic tests did not have positive antibody scans. One patient with a small-bowel cancer also had a negative antibody scan. The major toxicity was hematologic and was more pronounced in patients with compromised bone marrow due to prior chemotherapy. Of five patients who received 78 to 84 mCi/m2 131I-mAb A33, one had grade 3 and one grade 4 toxicity; of six patients treated with 86 to 94 mCi/m2 131I-mAb A33, two had grade 4 and one grade 1 toxicity. The MTD was determined to be 75 mCi/m2 in these heavily pretreated patients. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild (n = 8) or absent. No major responses were observed; however, three patients had evidence of mixed responses, and CEA levels decreased in two patients without clinical or radiologic measurable disease. Immunoreactivity of radiolabeled mAb A33 decreased at the highest dose levels in preparations in which specific activity exceeded 18 mCi/mg.

CONCLUSION

The A33 antigen appears to be a promising target for radioimmunotherapy of colon cancer. The modest antitumor activity of 131I-mAb A33 in heavily pretreated patients is encouraging because of its lack of toxicity in the bowel, the only antigen-positive normal tissue.
Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report.
Authors: Yang J C , Topalian S L , Parkinson D , Schwartzentruber D J , Weber J S , Ettinghausen S E , White D E , Steinberg S M , Cole D J , Kim H I
Published: February 2017

PURPOSE

A randomized prospective study was performed to compare the efficacy and toxicity of high-dose intravenous bolus interleukin-2 (IL-2) and a lower-dose intravenous bolus regimen for the treatment of metastatic renal cell carcinoma (RCC).

PATIENTS AND METHODS

Between March 1991 and April 1993, 125 patients with metastatic RCC were randomized to receive IL-2 by intravenous bolus every 8 hours at either 720,000 IU/kg (high-dose) or 72,000 IU/kg (low-dose) to the maximum-tolerated number of doses (or a maximum of 15 doses). After approximately 7 to 10 days, both treatment groups were re-treated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5 to 6 weeks later went on to receive re-treatment with another course (two cycles) of therapy. Response rates and toxicity were determined for the two treatment arms.

RESULTS

One hundred twenty-five patients received a total of 208 courses of therapy. Sixty patients were randomized to receive low-dose, and 65 to receive high-dose IL-2. There were no treatment-related deaths in either arm. There was a greater incidence of grade III or IV thrombocytopenia, malaise, and hypotension in patients who received high-dose IL-2, while patients who received low-dose IL-2 had significantly more infections. Three percent of treatment courses with low-dose IL-2 required vasopressor support, compared with 52% of courses with high-dose IL-2. Patients who received low-dose IL-2 had a 7% complete response (CR) and an 8% partial response (PR) rate, and patients who received high-dose IL-2 had a 3% CR and a 17% PR rate.

CONCLUSION

Low-dose intravenous bolus IL-2 represents an effective regimen for the treatment of metastatic RCC, with preliminary results comparable to those observed with high-dose IL-2. Low-dose IL-2 can be administered with significantly fewer complications, reduced use of vasopressor support, and fewer admissions to an intensive care unit (ICU).
Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group.
Authors: Spaulding M B , Fischer S G , Wolf G T
Published: February 2017

PURPOSE

In 1984, the Department of Veterans Affairs Cooperative Studies Program began a trial in which patients with resectable squamous cell carcinoma of the larynx were randomized to receive standard surgery followed by radiation therapy or to receive neoadjuvant therapy with cisplatin and fluorouracil (5-FU) followed by radiation therapy for those achieving a greater than 50% tumor response to chemotherapy. This analysis reviews the tumor responses, toxicity, compliance, and long-term survival for those patients randomized to the chemotherapy arm.

PATIENTS AND METHODS

One hundred sixty-six patients were randomized to the chemotherapy arm. Standard tumor response data, chemotherapy toxicity, and survival have been examined using standard statistical methods.

RESULTS

The high response rates and acceptable toxicity to cisplatin and 5-FU of previously untreated patients were confirmed. Long-term disease-free survival was more likely to occur in patients who achieved a complete response to chemotherapy, particularly in those who had a confirmed histologic response to chemotherapy. Pretreatment histologic growth patterns were highly predictive of responses to chemotherapy.

CONCLUSION

Neoadjuvant chemotherapy was well tolerated and did not negatively affect the definitive treatment that followed. The survival of nonresponding patients who underwent prompt salvage surgery was also not impaired. The role of organ preservation should be explored in other head and neck sites.
Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion.
Authors: Wilson W H , Berg S L , Bryant G , Wittes R E , Bates S , Fojo A , Steinberg S M , Goldspiel B R , Herdt J , O'Shaughnessy J
Published: February 2017

PURPOSE

A phase I study of paclitaxel infused over 96-hours was performed to determine toxicity, maximum-tolerated dose (MTD), and pharmacokinetics in patients with incurable lymphomas and solid tumors. A phase II study was performed at the MTD of paclitaxel in patients with doxorubicin/mitoxantrone-refractory metastatic breast cancer.

PATIENTS AND METHODS

In the phase I study, paclitaxel dose levels ranged from 120 to 160 mg/m2, administered on a 21-day cycle. Patients with metastatic breast cancer who had either no response or a partial response (PR) to doxorubicin or mitoxantrone and had measurable disease were eligible for the phase I and II studies. Expression of the multidrug resistance (mdr-1) gene was determined in tumor biopsies by mRNA quantitative polymerase chain reaction.

RESULTS

Twelve patients received a total of 73 cycles of paclitaxel on the phase I study. Dose-limiting mucositis and/or grade IV granulocytopenia was reached at 160 mg/m2, and 140 mg/m2 was selected as the phase II dose. Thirty-six consecutive patients with metastatic breast cancer were treated, of whom three were not assessable. The median age was 49 years, with disease in the liver and/or lung in 76%. Patients received a median of two prior regimens for metastatic disease, and 73% had no response to prior doxorubicin or mitoxantrone. Of 33 patients treated with paclitaxel, 16 patients (48%) achieved a PR and five (15%) achieved a minor response (MR). With a median potential follow-up duration of 60 weeks, the median progression-free and overall survival durations were 27 and 43 weeks, respectively. No correlation was found between extent of prior treatment or prior response to doxorubicin/mitoxantrone, and response to paclitaxel. Paclitaxel pharmacokinetics showed a correlation between both granulocyte and mucosal toxicity, and serum steady-state concentrations (Css) more than 0.07 mumol/L. Patients with liver metastases had significantly decreased paclitaxel clearance and higher paclitaxel Css. Levels of mdr-1 were uniformly low in all tumor biopsies studied.

CONCLUSION

The recommended phase II dose of paclitaxel is 140 mg/m2 in patients without liver metastases and 105 mg/m2 in patients with liver metastases. Ninety-six-hour infusions of paclitaxel were effective and well tolerated in patients with doxorubicin/mitoxantrone-refractory breast cancer. Prolonged infusion schedules may be more effective than shorter schedules and deserve further study.
Salvage therapies in women who fail to respond to first-line treatment with fluorouracil, epirubicin, and cyclophosphamide for advanced breast cancer.
Authors: Porkka K , Blomqvist C , Rissanen P , Elomaa I , Pyrhönen S
Published: February 2017

PURPOSE

We studied all salvage therapies given until death or the end of follow-up evaluation in women who failed to respond to the same first-line cytotoxic therapy for metastatic breast cancer.

PATIENTS AND METHODS

The study cohort consisted of 140 women who had received the fluorouracil, epirubicin, and cyclophosphamide (FEC) regimen for metastatic breast cancer. Eight patients were excluded. No exclusions with respect to disease site, performance status, or biochemical abnormalities were made. The median follow-up time was 29 months for surviving patients.

RESULTS

Most patients (88%) died during the follow-up period. Patients received a median of three salvage therapies (range, zero to eight) during the course of disease. Most courses (52%) were not assessable for response. Fifty-percent of courses consisted of chemotherapy: 35% of hormonal and 15% of combination of cytotoxic and hormonal therapies. The median duration of therapy (DT) ranged from 4 to 1 months, and decreased with advancing stages of therapy. Similarly, median time to treatment failure (TTF) ranged from 3 to 0.5 months. For unknown causes, patients who received second-line hormonal therapy fared better than those who received other forms of therapy. Of 366 analyzed courses, only one complete response (CR) and 18 partial responses (PRs) were observed (response rate, 11% for assessable and 5% for all courses). Stable disease for at least 3 months was found in 20% to 25% of courses. Most responses (n = 10) occurred during first salvage therapy, and no responses were observed after third salvage therapy.

CONCLUSIONS

Response rates for salvage therapies were low, and median treatment times short. The value of offering more than two salvage chemotherapy regimens to an unselected group of patients is questionable.
Patient characteristics associated with high-risk methotrexate concentrations and toxicity.
Authors: Relling M V , Fairclough D , Ayers D , Crom W R , Rodman J H , Pui C H , Evans W E
Published: February 2017

PURPOSE

Following high-dose methotrexate (HD-MTX) treatment, delayed MTX elimination is an important problem because it necessitates increased leucovorin rescue and additional hospitalization for hydration and urinary alkalinization. Our purpose was to identify factors associated with high-risk MTX plasma concentrations (defined by plasma concentration > or = 1.0 mumol/L at 42 hours from the start of MTX) and with toxicity.

PATIENTS AND METHODS

Variables associated with MTX concentrations and toxicity were assessed in 134 children treated with one to five courses of HD-MTX (900 to 3,700 mg/m2 intravenously [i.v.] over 24 hours for a total of 481 courses) for acute lymphoblastic leukemia (ALL).

RESULTS

High-risk MTX concentrations, toxicity (usually mild mucositis), and delay in resuming continuation chemotherapy occurred in 106 (22%), 123 (26%), and 66 (14%) of 481 courses, respectively. Using a mixed effects model for repeated measures, high-risk MTX concentrations were significantly associated with a higher MTX area-under-the-concentration-time curve (AUC), low urine pH, emesis, low MTX clearance, low urine output relative to intake, use of antiemetics during the MTX infusion, and concurrent intrathecal therapy (all p values < .01). Clinical toxicities and delay in resumption of continuation chemotherapy due to myelosuppression were more common in those with high 42-hour MTX concentrations, despite increased leucovorin rescue for all patients with high-risk MTX concentrations. However, with individualized rescue, no patient developed life-threatening toxicity. A more aggressive hydration and alkalinization regimen for subsequent courses reduced the frequency of high-risk MTX concentrations to 7% of courses (13 of 183) (P = .0001), and the frequency of toxicity decreased to 11% of courses (P = .0074).

CONCLUSION

This study identified several clinical variables that influence MTX disposition that, when modified, can reduce the frequency of high-risk MTX concentrations and toxicity.
Transient acantholytic dermatosis in oncology patients.
Authors: Guana A L , Cohen P R
Published: February 2017

PURPOSE

To evaluate the characteristics of patients with cancer who have a previous history, concurrent episode, or subsequent appearance of transient acantholytic dermatosis (TAD).

METHODS

We report four oncology patients who developed TAD and review the 22 reports that have previously been published of individuals in whom TAD appeared either before, concomitant with, or after the diagnosis of their malignancy.

RESULTS

TAD was associated more frequently in patients with hematologic malignancies, especially acute and chronic myelogenous leukemia. It also appeared in patients with solid tumors, primarily those of the genitourinary organs. In almost all the cases, the onset of TAD was either concurrent or followed the discovery of malignancy. The TAD resolved completely, with or without treatment, in at least 20 patients in a median of 3 weeks.

CONCLUSION

TAD is a benign and temporary condition that may occur in patients with an internal malignancy. When the diagnosis of TAD is being considered, a lesional skin biopsy readily establishes histologic confirmation in a febrile patient with cancer who develops a new rash. TAD has been observed most frequently in oncology patients who have either myelogenous leukemia or carcinoma of the genitourinary organs. The appearance of TAD coincided with either the detection or the recurrence of malignancy in three individuals (12%). In the other 23 oncology patients, TAD was most likely secondary to either antineoplastic agents, excessive perspiration, fever, occlusive immobility, and/or ionizing or UV radiation.
Effect of a National Cancer Institute Clinical Alert on breast cancer practice patterns.
Authors: Johnson T P , Ford L , Warnecke R B , Nayfield S G , Kaluzny A , Cutter G , Gillings D , Sondik E , Ozer H
Published: February 2017

PURPOSE

This study evaluates the effect of the 1988 National Cancer Institute Clinical Alert regarding treatment of early-stage breast cancer on the patterns of treatment provided to patients.

PATIENTS AND METHODS

Data analyzed were collected from the hospital and outpatient records of 12,534 female patients with a primary diagnosis of breast cancer (stages I and II) initially diagnosed during the years 1983 through 1989.

RESULTS

Analyses revealed that the proportions of patients with a negative lymph node status diagnosed after the May 1988 Clinical Alert who received adjuvant treatment (tamoxifen and/or multidrug chemotherapy) were significantly greater than predicted from treatment trends established before the Alert's release. Proportions of patients with positive lymph node status receiving adjuvant therapy subsequent to the Alert's release, in contrast, did not fall outside the projected confidence intervals for that group. Additional analyses showed a significant effect of the Clinical Alert among several subgroups of node-negative patients.

CONCLUSION

Findings suggest that the Clinical Alert mechanism, followed by publication in the peer-reviewed scientific literature, is an effective way to communicate important research findings to practitioners in the community. However, the Alert mechanism is controversial and should be used judiciously to ensure its credibility.
Immunohistochemical assessment of individual tumor cells in lymph nodes of patients with non-small-cell lung cancer.
Authors: Passlick B , Izbicki J R , Kubuschok B , Nathrath W , Thetter O , Pichlmeier U , Schweiberer L , Riethmüller G , Pantel K
Published: February 2017

PURPOSE

This prospective study was designed to evaluate the prognostic relevance and biologic characteristics of a minimal lymphatic tumor load in non-small-cell lung cancer (NSCLC).

METHODS

Frozen-tissue sections from 391 regional lymph nodes of 72 patients with completely resected NSCLCs, who were staged as free of metastases (pT1-3, pN0,M0,R0) by clinical tumor staging procedures and histopathologic examinations, were studied. For tumor-cell detection, we applied the alkaline phosphatase-antialkaline phosphatase (APAAP) immunostaining technique with monoclonal antibody Ber-Ep4 against two glycoproteins of 34 and 49 kd present of the surface and cytoplasm of epithelial cells.

RESULTS

Individual Ber-Ep4-positive cells were detected in 11 of 72 (15.2%) cancer patients, while positive staining was consistently absent in all sections from control nodes of 24 noncarcinoma patients. No correlation between a positive lymph node finding and either the size or differentiation grade of the primary tumor or the presence of micrometastatic tumor cells in bone marrow assessed by immunocytochemistry with antikeratin monoclonal antibody CK2 was observed. Following a median observation time of 26.0 months (range, 15 to 39), patients with lymph node micrometastases showed a significantly shorter disease-free survival duration than node-negative patients (log-rank test, P = .005). The independence of this prognostic significance was demonstrated by a multivariate analysis (Cox regression model, P = .005).

CONCLUSION

Our results provide evidence that the presence of single lung carcinoma cells in lymph nodes is an independent indicator of the disseminatory capacity of an individual primary tumor. Immunohistochemical assessment of micrometastases in lymph nodes is recommended for current tumor staging in NSCLC, as it might lead to better stratification of patients for adjuvant therapy.
Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. Childrens Cancer Group.
Authors: Finlay J L , Boyett J M , Yates A J , Wisoff J H , Milstein J M , Geyer J R , Bertolone S J , McGuire P , Cherlow J M , Tefft M
Published: February 2017

PURPOSE

In a previous randomized trial, the addition of adjuvant chemotherapy to postoperative radiotherapy proved beneficial in the treatment of childhood high-grade astrocytomas. The present study tests the hypothesis that an eight-drug adjuvant chemotherapy regimen would improve survival in such children compared with the three-drug regimen of the prior study.

PATIENTS AND METHODS

Between April 1985 and May 1990, patients between the ages of 18 months and 21 years with newly diagnosed high-grade astrocytomas were eligible for this study, as determined by the treating institution's histopathologic diagnosis. Treatment consisted of postoperative local-field radiotherapy and adjuvant chemotherapy, either lomustine (CCNU), vincristine, and prednisone (control regimen) or eight-drugs-in-1-day chemotherapy (experimental regimen). Two cycles of postoperative preirradiation chemotherapy were administered in the experimental regimen. Patients were evaluated radiographically every 3 months after irradiation.

RESULTS

Eighty-five eligible patients were randomized to the control regimen and 87 to the experimental regimen. The progression-free survival (PFS) and overall survival (OS) at 5 years were 33% (SE = 5%) and 36% (SE = 6%), respectively. There was no statistical difference in outcome between the two chemotherapy regimens. In patients with confirmed diagnoses of anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM), anaplastic astrocytoma, greater than 90% resection, and nonmidline tumor location were characteristics predictive of an improved PFS. There was a difference in toxicity between the two chemotherapeutic regimens, with greater myelosuppression and hearing loss in the experimental regimen. Tumor recurrence occurred primarily within the primary tumor site.

CONCLUSIONS

There is no benefit to the treatment of high-grade astrocytomas in children with eight-drugs-in-1-day chemotherapy compared with CCNU, vincristine, and prednisone. Extent of tumor resection and histopathologic diagnosis are significant prognostic variables. The overall outcome for children with high-grade astrocytomas remains poor.
Results of the United Kingdom Children's Cancer Study Group first Wilms' Tumor Study.
Authors: Pritchard J , Imeson J , Barnes J , Cotterill S , Gough D , Marsden H B , Morris-Jones P , Pearson D
Published: February 2017

PURPOSE

The first United Kingdom Children's Cancer Study Group (UKCCSG) Wilms' Tumor Trial (UKW1) applied treatment regimens stratified by stage and histology in accordance with National Wilms' Tumor Study (NWTS) criteria, seeking to reduce treatment of low-stage, favorable-histology (FH) tumors without impairing survival and to improve prognosis of stage III and IV (FH) and unfavorable-histology (UH) tumors with more intensive chemotherapy.

PATIENTS AND METHODS

Three hundred eighty-four consecutively diagnosed patients with Wilms' tumor were recruited from the 20 UKCCSG centers and Oslo, Norway, between January 1980 and June 1986. The regimen for stage I patients was vincristine (Vcr) only, while stage II patients received Vcr and dactinomycin (Act-D). Stage III patients received three-drug therapy and stage IV and UH patients four-drug regimens. Act-D was given as pulsed doses of 1.5 mg/m2 every 3 or every 6 weeks. No lung irradiation was used in stage IV patients. No randomized comparisons were attempted. End points were survival and event-free survival (EFS).

RESULTS

Survival at 6 years in FH patients was 96% for stage I, 93% for stage II, 83% for stage III, 65% for stage IV, and 50% for UH patients of all stages.

CONCLUSION

Vcr alone is as effective for stage I FH tumors as the two-drug regimen used in the NWTS and International Society of Pediatric Oncology (SIOP) studies. Fractionation of Act-D is unnecessary. The poorer results for stage IV FH and UH patients compared with the NWTS may be due to treatment differences, such as the use of lung irradiation for stage IV FH patients in NWTS3, and/or to case selection bias.
Effectiveness of interferon alfa-2a combined with phototherapy for mycosis fungoides and the Sézary syndrome.
Authors: Kuzel T M , Roenigk H H , Samuelson E , Herrmann J J , Hurria A , Rademaker A W , Rosen S T
Published: February 2017

PURPOSE

To investigate the efficacy of combined topical therapy and systemic interferon alfa-2a in patients with mycosis fungoides (MF) and the Sézary syndrome (SS).

PATIENTS AND METHODS

Between December 1987 and April 1993, 39 patients with all stages of MF and SS were treated with combined phototherapy and systemic interferon alfa-2a as part of two institutional studies. The initial phase I study of 15 patients established the maximum-tolerated dose of interferon and has been previously reported. Subsequently, 24 patients have been entered onto a phase II trial. Long-term follow-up data are provided for both studies.

RESULTS

The median follow-up duration for the entire cohort is 28 months. Patients with all stages of disease were enrolled (stage IB, n = 14; IIA, n = 5; IIB, n = 6; III, n = 8; IVA, n = 5; IVB, n = 1). Thirty-four patients had received previous therapy. Overall, 36 of 39 patients achieved a complete response (CR; 62%) or partial response (28%) to therapy. The median response duration is 28 months (range, 1 to 64). Twenty-nine of 39 patients are alive, with a median survival duration of 62 months (range, 1 to 66).

CONCLUSION

Interferon alfa-2a combined with phototherapy is an effective, safe, durable therapy for MF and SS.
Cytokine levels and systemic toxicity in patients undergoing isolated limb perfusion with high-dose tumor necrosis factor, interferon gamma, and melphalan.
Authors: Thom A K , Alexander H R , Andrich M P , Barker W C , Rosenberg S A , Fraker D L
Published: February 2017

PURPOSE

Isolated limb perfusion (ILP) with tumor necrosis factor (TNF), interferon gamma, and melphalan (M) has been reported to result in high response rates for extremity melanoma and sarcoma. We have evaluated the relationship of systemic TNF exposure to induction of several secondary mediators and incidence of systemic toxicity.

PATIENTS AND METHODS

Nineteen patients with extremity melanoma (n = 16) or sarcoma (n = 3), underwent 90-minute ILP with TNF-alpha, interferon gamma (0.2 mg), and M (10 to 13 mg/L of limb volume) (TNF/IFN/M) (n = 12), or M alone (n = 7). Continuous intraoperative monitoring (CIM) for systemic leak from the perfusion circuit was performed using radioactive iodine-131 albumin. Cytokine levels in the perfusate and systemic circulation during and after ILP were measured by enzyme-linked immunosorbent assay.

RESULTS

Systemic leaks > or = 1% from the perfusion circuit occurred in six patients who received TNF/IFN/M and in four who received M alone. Hypotension that required vasopressor support occurred in six of six patients with evidence of a leak (> or = 1%) and zero of six patients without a leak (< 1%). These six patients had significantly higher peak systemic TNF levels during and after perfusion than patients without a leak (2.8 and 8.2 ng/mL v 0.7 and 2.0 ng/mL, respectively; P < .05). All patients who received TNF/IFN/M had significantly greater increases in systemic interleukin-6 (IL-6) levels than in patients with M alone (12,395 +/- 10,374 pg/mL v 79.4 +/- 7.2 pg/mL, respectively; P < .001). Intracellular adhesion molecule (ICAM), IL-8, and TNF-R levels were also increased after ILP with TNF/IFN/M.

CONCLUSION

ILP with TNF/IFN/M can be safely performed, as I131 albumin provides a sensitive measure of systemic leakage from the perfusion circuit. Patients with a measured leak of > or = 1% develop mild and transient postoperative hypotension with significantly higher systemic TNF levels and lower perfusate TNF levels than in patients without leaks.
Value of P-glycoprotein, glutathione S-transferase pi, c-erbB-2, and p53 as prognostic factors in ovarian carcinomas.
Authors: van der Zee A G , Hollema H , Suurmeijer A J , Krans M , Sluiter W J , Willemse P H , Aalders J G , de Vries E G
Published: February 2017

PURPOSE

To determine the prognostic value of immunostaining of P-glycoprotein (P-gp), glutathione S-transferase (GST) pi, c-erbB-2, and p53 in patients with advanced-stage ovarian carcinoma.

PATIENTS AND METHODS

Immunostaining of P-gp, GST pi, c-erbB-2, and p53 was performed on 89 primary tumors and 38 residual tumors after chemotherapy (P-gp and GST pi) in patients with advanced ovarian carcinoma treated with platinum- and doxorubicin-containing chemotherapy. The results of immunostaining were related to clinicopathologic prognostic factors, response to chemotherapy, and progression-free survival (PFS) and overall survival.

RESULTS

P-gp and GST pi immunoreactivity were present in 13 (15%) and 79 cases (89%), respectively, and were not associated with any other prognostic factor or PFS or overall survival. C-erbB-2 immunoreactivity was present in 18 cases (20%) and was associated with undifferentiated histiotype (P < .05), but not with PFS or overall survival. p53 immunoreactivity was present in the nuclei of 31 cases (35%) and cytoplasm of nine cases (10%). Nuclear p53 staining was associated with grade III tumors, presence of more than 1-L ascites, and residual tumor after first laparotomy more than 2 cm. Nuclear p53 staining was associated with shorter PFS (relative risk [RR], 3.3; 95% confidence interval [CI], 2.0 to 5.6) and overall survival (RR, 2.6; 95% CI, 1.7 to 3.8). After adjustment for presence of more than 1-L ascites or age more than 50 years, nuclear p53 staining did not retain independent prognostic significance in stage III/IV tumors. The frequency of P-gp staining in residual tumors after chemotherapy (18 of 38 cases) was higher in comparison to untreated tumors (13 of 89 cases) (P < .001). No combination of prognostic parameters was able to predict response to chemotherapy adequately.

CONCLUSION

Nuclear immunoreactivity of p53 in ovarian carcinomas is associated with shorter PFS and overall survival and determinants of more aggressive tumor growth. The higher frequency of P-gp immunoreactivity in residual tumors after chemotherapy points to induction of P-gp in ovarian carcinomas by doxorubicin-containing combination chemotherapy. The determination of P-gp, GST pi, c-erbB-2, and p53 does not permit more adequate prediction of response to chemotherapy.
All-trans retinoic acid pharmacokinetics and bioavailability in acute promyelocytic leukemia: intracellular concentrations and biologic response relationship.
Authors: Agadir A , Cornic M , Lefebvre P , Gourmel B , Jérôme M , Degos L , Fenaux P , Chomienne C
Published: February 2017

PURPOSE

This study investigated the in vitro pharmacologic behavior and disposition kinetics of all-trans retinoic acid (ATRA) in acute myeloid leukemic (AML) cells, their sensitivity to its differentiating effect, and the in vivo response of acute promyelocytic leukemia (APL) patients after therapy.

PATIENTS AND METHODS

Fresh leukemic cells from 14 AML patients (nine APL and five non-APL), were incubated in suspension culture in the absence or presence of 10(-6) mol/L ATRA. Intracellular ATRA concentration and ATRA metabolism was determined by high-performance liquid chromatography (HPLC).

RESULTS

Immediate uptake is observed with maximal intracellular levels (Cmax) achieved after 24 hours of incubation. At this time, ATRA levels were variable, ranging from 20 to 230 pmol/10(6) cells (median, 100 pmol/10(6) cells). Comparison of ATRA intracellular levels with the in vitro response of patients' cell samples as measured by the percentage of nitro blue tetrazolium (NBT)-positive cells after a 3-day incubation period allowed us to discriminate a group of APL patients (n = 6) with high Cmax (group A; median, 200 pmol/10(6) cells) and maximal differentiation at day 3 (median, 80%), and a group of patients (n = 8, three APL and five non-APL) with low Cmax (group B; median, 35 pmol/10(6) cells) and poor in vitro response (median, 40%; APL cases only). Interestingly, all APL patients, except one included in group A (rapid in vitro ATRA uptakers), achieved a complete remission.

CONCLUSION

These findings suggest that intracellular ATRA concentrations are determinant for ATRA response and should be taken into account when monitoring the efficacy of ATRA differentiation therapeutic trials in malignant disorders.
Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin's lymphoma using CHOP versus CNOP chemotherapy.
Authors: Sonneveld P , de Ridder M , van der Lelie H , Nieuwenhuis K , Schouten H , Mulder A , van Reijswoud I , Hop W , Lowenberg B
Published: February 2017

PURPOSE AND METHODS

A prospective, randomized, multicenter phase III trial was performed to investigate the feasibility of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in elderly patients ( > or = 60 years) with advanced non-Hodgkin's lymphoma (NHL) of intermediate- and high-grade malignancy, and to compare the tolerance and efficacy of doxorubicin versus mitoxantrone (CHOP v CNOP).

RESULTS

Of 157 enrolled patients, 148 were eligible and 145 were assessable for response. Thirty-one percent of CNOP and 45% of CHOP patients completed six cycles without dose reduction. The cumulative normalized dose-intensity (NDI) was 92% with CHOP and 90% with CNOP after six cycles. The overall complete response (CR) rates were 49% and 31% in CHOP- and CNOP-treated patients, respectively (P = .03). Survival with CNOP was significantly worse as compared with CHOP (P = .03). Lymphoma-specific survival was significantly better in CHOP-treated patients (P = .034) At 3 years, 42% of CHOP and 26% of CNOP patients were alive. Additional unfavorable prognostic factors at diagnosis were high serum lactate dehydrogenase (LDH) level, bulky mass, and low performance status, but not age. The median disease-free intervals of complete responders were 27 (CHOP) and 15 (CNOP) months, respectively. Considering the complete group of patients, at 3 years 17% of CHOP and 13% of CNOP patients were alive and disease-free (P = .12). Common toxicity criteria (CTC) grade > or = 2 with CNOP and CHOP was not different.

CONCLUSION

CHOP is well tolerated in elderly patients with advanced intermediate- or high-grade NHL and its NDI is not seriously impaired. Treatment with CHOP (doxorubicin) results in better CR and survival rates than CNOP (mitoxantrone). CHOP should be recommended for elderly patients with high-risk NHL.
Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer.
Authors: Jones S , Winer E , Vogel C , Laufman L , Hutchins L , O'Rourke M , Lembersky B , Budman D , Bigley J , Hohneker J
Published: February 2017

PURPOSE

This prospective multicenter randomized trial was performed to compare the effectiveness and safety of intravenous (i.v.) vinorelbine tartrate (Navelbine [NVB]; Burroughs Wellcome Co, Research Triangle Park, NC) with i.v. melphalan (Alkeran [ALK]; Burroughs Wellcome Co) in a heavily pretreated population of patients with anthracycline-refractory advanced breast cancer (ABC). Efficacy end points included time to disease progression (TDP), time to treatment failure (TTF), survival, tumor response rates, and quality of life (QL) and relief of cancer-related symptoms.

PATIENTS AND METHODS

Between August 24, 1990, and December 1, 1992, 183 patients were randomized (2:1) to treatment with NVB (30 mg/m2 weekly) or ALK (25 mg/m2 every 4 weeks) i.v. Patients were stratified by measurable or nonmeasurable-assessable disease and by treatment center.

RESULTS

Time to disease progression was significantly longer with NVB than with ALK, with a median 12 weeks versus 8 weeks, respectively (P < .001). NVB patients also had significantly longer time to treatment failure than ALK patients, with a median 12 weeks versus 8 weeks, respectively (P < .001). The effect of NVB on survival was also statistically significant (P = .034): 1-year survival rates were 35.7% with NVB and 21.7% with ALK and the median survival rate was 35 weeks and 31 weeks, respectively. In total, 46.5% of NVB patients and 28.2% of ALK patients achieved an objective response or stabilization of disease (P = .06). No intergroup differences were noted in patient-assessed QL and cancer-related symptoms. The most common toxicities were hematologic, including granulocytopenia with NVB and thrombocytopenia and granulocytopenia with ALK. Both drugs were generally well tolerated, and no septic deaths were reported.

CONCLUSION

This randomized trial demonstrates a survival benefit in anthracycline-refractory ABC. NVB was well tolerated and demonstrated activity superior to ALK in anthracycline-refractory ABC, without compromising QL. Based on activity of single-agent NVB in this difficult-to-treat patient population, investigations of NVB in combination with other anticancer drugs are warranted.
Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis in head and neck cancer patients after cisplatin, fluorouracil, and leucovorin chemotherapy.
Authors: Chi K H , Chen C H , Chan W K , Chow K C , Chen S Y , Yen S H , Chao J Y , Chang C Y , Chen K Y
Published: February 2017

PURPOSE

To evaluate prospectively the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the reduction of chemotherapy-induced oral mucositis.

PATIENTS AND METHODS

Twenty patients with stage IV squamous cell carcinoma of head and neck were studied. Two-cycles (periods) of identical doses of cisplatin, fluorouracil (5-FU), and leucovorin (PFL) chemotherapy with cisplatin 20 mg/m2/d, 5-FU 800 mg/m2/d, leucovorin 90 mg/m2/d by 96-hour continuous intravenous infusion every 3 weeks were given to each patient. After PFL chemotherapy, GM-CSF 4 micrograms/kg subcutaneously from days 5 to 14 or no therapy was given by a randomized self-controlled crossover study design. Oral mucositis was graded with modified Radiation Therapy Oncology Group criteria.

RESULTS

In the first cycle of PFL chemotherapy, GM-CSF significantly reduced the incidence, mean duration, and mean area under the curve (AUC) of severe oral gross mucositis (grade > or = 3) compared with no therapy. These beneficial effects continued into the second cycle of PFL chemotherapy after crossover to no GM-CSF. The incidence of severe mucositis was reduced when GM-CSF was given in the second cycle of PFL. Analysis of variance indicated significant direct GM-CSF treatment effects on the mean AUC of gross/functional scores and duration of moderate gross mucositis (grade > or = 2) over both periods. There was a significant period effect in favor of giving GM-CSF in the first cycle of chemotherapy.

CONCLUSION

GM-CSF can significantly reduce the severity and duration of chemotherapy-induced oral mucositis after PFL chemotherapy.
Nonsteroidal antiinflammatory drugs for cancer pain: comparison between misoprostol and ranitidine in prevention of upper gastrointestinal damage.
Authors: Valentini M , Cannizzaro R , Poletti M , Bortolussi R , Fracasso A , Testa V , Sozzi M , Fornasarig M , Bortoluzzi F , Grazioli I
Published: February 2017

PURPOSE

The prophylactic strategy of nonsteroidal antiinflammatory drug (NSAID)-induced upper gastrointestinal (UGI) damage has largely been studied in arthritic patients, but not in cancer patients. The efficacy of misoprostol and ranitidine in the prevention of gastroduodenal damage in patients taking diclofenac for their cancer pain has been compared in this study.

PATIENTS AND METHODS

Patients who needed high-dose (200 to 300 mg/d) diclofenac for cancer pain and without mucosal lesions at baseline gastroduodenal endoscopy were randomized to receive misoprostol (200 micrograms twice daily; M group) or ranitidine (150 mg twice daily; R group). UGI endoscopy was repeated after 4 weeks.

RESULTS

Twenty-three patients treated with misoprostol and 26 treated with ranitidine concluded the study. The M group showed a significantly (P < .02) lower incidence of gastroduodenal lesions (two patients; 8.7%) than the R group (10 patients; 38.5%). Gastric ulcers occurred in one (4%) misoprostol-treated patient and in six (23%) ranitidine-treated patients. Six of seven patients with ulcers were asymptomatic. Seventy-one percent and 86% of ulcers occurred in patients older than 60 years and in those who received greater than 3.1 mg/kg of diclofenac, respectively.

CONCLUSION

Misoprostol was significantly more effective than ranitidine in the prevention of gastroduodenal lesions in cancer patients receiving diclofenac.
p53 Status predicts survival in breast cancer patients treated with or without postoperative radiotherapy: a novel hypothesis based on clinical findings.
Authors: Jansson T , Inganäs M , Sjögren S , Norberg T , Lindgren A , Holmberg L , Bergh J
Published: February 2017

PURPOSE AND METHODS

Primary breast cancer tumors without axillary metastases from 206 consecutive patients in a population-based cohort were investigated with regard to the presence of an intact p53 gene using a cDNA-based sequencing method. Clinical follow-up data and outcome of node-negative patients without any adjuvant systemic therapy (n = 168) were related to locoregional radiotherapy and p53 status.

RESULTS

Mutations in p53 occurred in 31 node-negative breast cancer patients who did not receive any systemic adjuvant treatment, but were treated with postoperative locoregional radiotherapy or nothing. Node-negative breast cancer patients with p53 mutations had significantly improved relapse-free survival (P = .0007), breast cancer-corrected survival (P = .01), and overall survival (P = .02) rates when treated with locoregional radiotherapy. In node-negative breast cancer patients with wild-type p53, there was no statistically significant difference in outcome between patients who received locoregional radiotherapy and those who did not. Cox proportional hazards models indicate that mutant p53 is associated with worse prognosis independent of response to radiotherapy and that response to radiotherapy is qualitatively different in tumors with p53 mutations compared with those with wild-type p53.

CONCLUSION

Our clinical findings define a group of breast cancer patients in whom locoregional radiotherapy improves relapse-free, breast cancer-corrected, and overall survival. The outcome for irradiated node-negative breast cancer patients with p53 alterations indicates that irradiation can induce cell death even in the presence of p53 mutations.