bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of metastatic renal cell carcinoma by continuous intravenous infusion of recombinant interleukin-2: a single-center phase II study.
Authors: Geertsen P F , Hermann G G , von der Maase H , Steven K
Published: February 2017

PURPOSE

A single-center phase II study was performed to evaluate the efficacy of recombinant interleukin-2 (rIL-2) administered by continuous infusion to patients with metastatic renal cell carcinoma (RCC).

PATIENTS AND METHODS

Thirty-one patients with RCC were entered onto the study. rIL-2 (Proleukin; Eurocetus Corp, Amsterdam, The Netherlands) was administered intravenously in a dose of 18 x 10(6) IU/m2 per 24 hours. A maximum of two induction cycles and four maintenance cycles were given. Each induction cycle consisted of two rIL-2 infusion periods of 120 hours and 108 hours duration, respectively; these were separated by a 6-day rest period. Each maintenance cycle consisted of a 120 hours rIL-2 infusion period.

RESULTS

Six of 30 assessable patients (20%) responded; two (7%) with a complete response (CR) and four (13%) with a partial response (PR). The response duration for patients with CR was 209 and 715+ days, and for those with PR 161, 197, 245, and 353 days. Seven patients had stable disease (SD) with a median duration of 261 days (range, 127 to 381 days). The overall median survival was 261 days (range, 13 to 905+ days). The most frequent toxicities requiring dose reductions of rIL-2 were: hypotension in 87% of patients, dyspnea in 32%, CNS toxicity in 55%, and an increase in serum creatinine levels in 48%. Septicemia occurred in 16% of patients. Toxicities usually reversed on interruption of rIL-2 infusion. One patient (3%) died as a result of the treatment from initial CNS toxicity followed by multiorgan failure.

CONCLUSIONS

The study confirmed the antitumor efficacy of rIL-2 administered by continuous infusion in patients with metastatic RCC. The response rate was similar to that obtained by high-dose bolus injections of rIL-2. Toxicity was substantial but manageable in a specialized oncology ward without routine use of an intensive care unit.
Epirubicin in malignant mesothelioma: a phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.
Authors: Mattson K , Giaccone G , Kirkpatrick A , Evrard D , Tammilehto L , van Breukelen F J , Planteydt H T , van Zandwijk N
Published: February 2017

PURPOSE

The doxorubicin analog, epirubicin (EPI), was tested in patients with malignant mesothelioma.

PATIENTS AND METHODS

Sixty-three patients with malignant mesothelioma were given EPI 110 mg/m2 every 3 weeks. Histology was reviewed and confirmed by a pathology panel. On the basis of unconvincing or wrong histology, insufficient material or cytology only, nine cases were considered ineligible for the study. None of the patients had received prior chemotherapy.

RESULTS

The main side effects were myelosuppression, alopecia, and gastrointestinal toxicity. Tumor response, assessed by computed tomographic (CT) scans, was assessable in 48 patients. Seven patients (15%) achieved a partial response that lasted a median of 37 weeks; 19 patients had stable disease, and 22 patients progressed on treatment. Median survival time was 40 weeks from the start of chemotherapy, and the median survival of responding patients was 87 weeks. One responding patient is still alive and free of relapse 4 years from the start of chemotherapy.

CONCLUSION

We conclude that further testing of EPI in malignant mesothelioma is warranted.
Interleukin-2 and Lymphokine-Activated Killer Cells in 15 Children With Advanced Metastatic Neuroblastoma
Authors: Negrier S. , Michon J. , Floret D. , Bouffet E. , Gentet J.C. , Philip I. , Cochat P. , Stamm D. , Costil J. , Gaspard M. , Andreu G. , Palmer P. , Franks C.R. , Zucker J.M. , Bernard J.L. , Fridman W.H. , Favrot M. , Philip T.
Published: February 2017

The institutional support statement regarding the report "Interleukin-2 and Lymphokine-Activated Killer Cells in 15 Children With Advanced Metastatic Neuroblastoma" (J Clin Oncol 9:1363–1370, 1991) should have read as follows: "Supported by the Association pour la Recherche contre le Cancer grant no 6243, Inserm grant reseau no 486022, and Ligue Nationale Francaise Contre le Cancer Comite de Paris grant no RS-01/88."
Comparison of high-dose and low-dose radiation with and without chemotherapy for children with Hodgkin's disease: an analysis of the experience at the Children's Hospital of Philadelphia and the Hospital of the University of Pennsylvania.
Authors: Maity A , Goldwein J W , Lange B , D'Angio G J
Published: February 2017

PURPOSE

In an effort to minimize complications related to high-dose radiotherapy (RT), children with Hodgkin's disease are often treated with low-dose RT (less than 25 Gy) plus chemotherapy. We performed a retrospective study comparing the results in these children with those from children treated with higher doses of RT (30 to 40 Gy) with or without chemotherapy.

PATIENTS AND METHODS

From 1970 to 1988, 121 patients younger than 18 years of age with newly diagnosed Hodgkin's disease were treated at the Children's Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania (HUP). Before 1977, most children underwent laparotomy and received high-dose RT with or without chemotherapy. Since then, high-dose RT alone has been reserved for pathologic stage IA and IIA postpubertal children without large mediastinal masses. In general, most postpubertal children with stage IIB through IVB disease or large mediastinal masses and all prepubertal children have received low-dose RT plus chemotherapy without laparotomy.

RESULTS

The 10-year actuarial survival for all children was 86%, and the event-free survival (EFS) was 67% (median follow-up, 6.6 years). For 58 children treated with low-dose RT plus chemotherapy, 10-year survival and EFS (median follow-up, 6.8 years) were 88% and 67%, respectively. The corresponding figures for 10-year survival and EFS in 48 children treated with high-dose RT with or without chemotherapy were 88% and 66%, respectively. In children receiving combined modality therapy, the in-field failure rate was 7% for sites given between 17.5 and 22.5 Gy and 2% for sites given more than 32.5 Gy. In children receiving RT alone, the failure rate was 5% for sites given more than 32.5 Gy.

CONCLUSION

We conclude that low-dose RT plus chemotherapy has yielded results comparable to those with higher doses of RT with or without chemotherapy.
Treatment of patients with relapsed and resistant non-Hodgkin's lymphoma using total body irradiation, etoposide, and cyclophosphamide and autologous bone marrow transplantation.
Authors: Gulati S , Yahalom J , Acaba L , Reich L , Motzer R , Crown J , Toia M , Igarashi T , Lemoli R , Hanninen E
Published: February 2017

PURPOSE

Patients with non-Hodgkin's lymphoma (NHL) who do not achieve a complete response (CR) after induction chemotherapy or who relapse after achieving a CR are rarely cured of their disease by the usual salvage therapy. Success of high-dose cytotoxic therapy with an autologous bone marrow transplant (AuBMT) is limited. We describe the results of a prospective single-institution study using a new conditioning regimen for patients with relapsed or resistant NHL who underwent AuBMT.

PATIENTS AND METHODS

Forty-four patients were reinduced with cytotoxic therapy and then evaluated for response. All patients received the conditioning regimen of hyperfractionated total body irradiation (TBI), etoposide (VP-16), and cyclophosphamide (CTX) followed by autologous bone marrow reinfusion.

RESULTS

The disease-free survival (DFS) rate was 57% with a median follow-up of 42+ months. The only variable significantly associated with DFS was the patient's remission status at AuBMT. Patients who underwent AuBMT in CR had a DFS of 80%, whereas patients who underwent AuBMT in partial response (PR) or with progressive disease (PD) had a DFS of 60% and 11%, respectively (P = .002). The major toxicity was hemorrhage at the site of bulky disease, especially in patients with residual mediastinal and/or pulmonary disease.

CONCLUSION

Planned reinduction cytotoxic therapy followed by TBI, VP-16, and CTX with AuBMT is an effective treatment for patients with relapsed and resistant NHL.
Constitutive production of tumor necrosis factor-alpha in hairy cell leukemia: possible role in the pathogenesis of the cytopenia(s) and effect of treatment with interferon-alpha.
Authors: Foa R , Guarini A , Francia di Celle P , Trentin L , Gillio Tos A , Bellone G , Carbone A , Attisano C , Massaia M , Raspadori D
Published: February 2017

PURPOSE

In view of the pleomorphic role cytokines play in human lymphoproliferative disorders, we investigated the possible involvement of tumor necrosis factor-alpha (TNF) in hairy cell leukemia (HCL).

PATIENTS AND METHODS

The levels of TNF were measured in the serum of untreated patients, and in the culture supernatants of unstimulated and stimulated enriched hairy cells (HC). Furthermore, the presence of TNF mRNA transcripts in HC was analyzed. The possibility that HC could inhibit the in vitro growth of normal erythroid progenitors via the release of TNF was also investigated. Finally, in an attempt to correlate the circulating levels of TNF with the course of the disease, these were retested during and after treatment with interferon-alpha (IFN).

RESULTS

Significantly increased levels of TNF were found in the sera of untreated HCL patients compared with normal control sera were seen from patients with other diseases (P less than .001), with values greater than 10 pg/mL in 21 of 42 samples tested. A significant decrease (P less than .01) of TNF levels was recorded following IFN-2a administration in 16 cases with detectable pretreatment serum levels of TNF. In two cases, an increase in TNF values was associated with persistence or progression of disease. The likelihood that the circulating levels of TNF were caused by the pathologic cells is supported by the evidence that purified HC may release TNF spontaneously. The values can be markedly increased following in vitro activation with the phorbol ester 12-0-tetradecanoylphorbol-13 acetate (PMA), with B-cell growth factor (BCGF), and, to a further extent, with the combination of PMA and BCGF. Furthermore, the constitutive mRNA for TNF was found in seven of eight HC samples analyzed. Although supernatants of enriched HC, were capable of reducing the growth of normal bone marrow erythroid progenitors by 50%, duplicate experiments using an anti-TNF antibody produced an almost complete disappearance of the inhibitory effect.

CONCLUSION

The results of this study suggest that TNF plays an important role in the pathogenesis of the cytopenia(s) characteristically associated with HCL.
Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration.
Authors: Kleinerman E S , Jia S F , Griffin J , Seibel N L , Benjamin R S , Jaffe N
Published: February 2017

PURPOSE

A phase II trial that uses liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in patients with relapsed osteosarcoma is underway. To determine if in vivo cytokine induction plays a role in the mechanism of action of L-MTP-PE, we investigated the circulating cytokine levels of 16 patients who were undergoing therapy.

PATIENTS AND METHODS

Patients had histologically proven osteosarcoma and pulmonary metastases that developed either during adjuvant chemotherapy or that were present at diagnosis and persisted despite chemotherapy. Patients were rendered disease-free by surgery. The major goal of the study was to improve the disease-free interval in this high-risk group. L-MTP-PE 2 mg/m2 was infused during a 1-hour period twice a week for 12 weeks, then once a week for 12 weeks. Serial blood samples were collected after L-MTP-PE administration and were assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha] interleukin-1 alpha [IL-1 alpha], IL-1 beta, IL-6, interferon-gamma [IFN-gamma], neopterin, C-reactive protein).

RESULTS

After the infusion of L-MTP-PE, there was rapid induction of circulating TNF alpha and IL-6. TNF alpha levels peaked 1 to 2 hours after infusion in 10 of 16 patients, whereas peak IL-6 levels were detected at 2 to 3 hours in all patients. Induction of circulating TNF alpha and IL-6 was evident only after the first dose of L-MTP-PE. Neither IL-1 alpha nor IL-1 beta was detected in the plasma. Neopterin levels increased at 24 hours postinfusion, which indicated macrophage activation, and were not related to the induction of circulating IFN-gamma. C-reactive protein was elevated in all patients at 24 hours and decreased by 72 hours. Unlike circulating TNF alpha and IL-6, elevations in C-reactive protein and neopterin could be detected throughout the treatment course.

CONCLUSION

It is concluded that L-MTP-PE has specific biologic effects in patients with osteosarcoma that may be important to the drug's immunostimulatory capacity and its effectiveness as an antitumor agent.
Phase I trial of thiotepa in combination with recombinant human granulocyte-macrophage colony-stimulating factor.
Authors: O'Dwyer P J , LaCreta F P , Schilder R , Nash S , McAleer C , Miller L L , Hudes G R , Ozols R F
Published: February 2017

PURPOSE

The ability of growth factors to stimulate marrow recovery suggests their potential for use in dose intensification of cytotoxic drugs. We performed a phase I study of the alkylating agent thiotepa in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), with the goal of dose-escalation of thiotepa. Thiotepa was selected based on its capacity for dose escalation to more than 1 g/m2 in the marrow transplantation setting.

PATIENTS AND METHODS

The starting dose of thiotepa (75 mg/m2) was the highest dose evaluated in our previous phase I trial. Thirteen patients received 22 courses of thiotepa and GM-CSF. The dose of GM-CSF was 10 micrograms/kg subcutaneously daily in six patients and 5 micrograms/kg in seven patients.

RESULTS

Three patients (23%) developed grade 3 to 4 neutropenia on the first course, with a recovery to more than 1000/mm3 in 4.7 days (mean). Recovery was as rapid with the 5 micrograms/kg as it was with the 10 micrograms/kg GM-CSF dose. Thrombocytopenia grade 3 to 4 affected seven of 13 (54%) patients in the first course; counts recovered to more than 50,000/mm3 in a median of 15 days. GM-CSF at either dose did not influence markedly the severity or duration of thrombocytopenia, and did not permit dose escalation of thiotepa. Among the seven patients who received a second cycle of treatment, six of seven experienced grade 3 or 4 thrombocytopenia that lasted a median of 15.5 days. Five had thrombocytopenia that lasted more than 35 days after one to three cycles of treatment. Plasma concentrations of thiotepa and tepa were measured by gas chromatography in eight patients. The plasma elimination of thiotepa fit a two-compartment open model with a harmonic mean terminal half-life of 2.44 hours. The mean total body clearance was 217.9 mL/min/m2, and the mean steady-state volume of distribution (Vdss) was 36.8 L/m2. The half-life of tepa was 7.98 hours, and the ratio of the area under the plasma concentration versus time curve (AUC) of tepa to that of thiotepa was 0.79.

CONCLUSIONS

These data were consistent with our previous observations at this dose, and indicated that the severity of toxicity in these patients was not explained by aberrant pharmacokinetic indices. We conclude that, independent of effects on neutropenia, severe and cumulative platelet toxicity precludes further escalation of thiotepa dose despite the use of GM-CSF.
No benefit of ifosfamide in Ewing's sarcoma: a nonrandomized study of the French Society of Pediatric Oncology.
Authors: Oberlin O , Habrand J L , Zucker J M , Brunat-Mentigny M , Terrier-Lacombe M J , Dubousset J , Gentet J C , Schmitt C , Ponvert D , Carrié C
Published: February 2017

PURPOSE

To undertake a new protocol with the goals of improving the chemotherapeutic treatment of pediatric Ewing's sarcoma by introducing ifosfamide, and to widen the indications for surgical resection of Ewing's tumor to obtain better local control and to reduce radiation doses.

PATIENTS AND METHODS

The French Society of Pediatric Oncology initiated its first cooperative Ewing's sarcoma study in 1978, using a four-drug regimen (cyclophosphamide, dactinomycin, Adriamycin [doxorubicin; Farmitalia Carlo Erba, Rueil-Malmaison, France], and vincristine). Ninety-five patients were included, and, at 5 years, the disease-free survival reached a plateau of 51%. After encouraging responses of recurrent soft tissue or bone sarcomas to ifosfamide, a second study began in 1984 using a new chemotherapy regimen in which cyclophosphamide was replaced by ifosfamide. Sixty-five patients were treated.

RESULTS

By February 1992, the median follow-up was 5.8 years. The estimated 5-year disease-free survival was 52%. We observed unexpected cardiac toxicity. Three patients experienced acute cardiac failure that was lethal in two cases. The acute toxicity of ifosfamide prompted us to stop the protocol. Retrospectively, the lack of efficacy reinforced our decision.

CONCLUSION

We conclude that ifosfamide did not improve the outcome of the patients despite the fact that these two treatment regimens were not randomized.
Expression of P-glycoprotein and glutathione-S-transferase in recurrent lymphomas: the possible role of Epstein-Barr virus, immunophenotypes, and other predisposing factors.
Authors: Cheng A L , Su I J , Chen Y C , Lee T C , Wang C H
Published: February 2017

PURPOSE

We previously have reported the poor prognoses of recurrent peripheral T-cell lymphoma (PTCL) and Epstein-Barr virus (EBV)-associated PTCL (J Clin Oncol 7:725-731, 1989; Blood 77:799-808, 1991). To study the role that drug resistance plays in this scenario, we conducted a retrospective study of 23 adult patients.

PATIENTS AND METHODS

All patients had recurrent lymphoma tissue available for immunophenotyping and screening for the existence of EBV DNA in tumor cells by Southern blot analysis and in situ hybridization. Expression of a multidrug resistance P-glycoprotein ([P-gp]mdr-1) and a glutathione redox cycle-related glutathione-S-transferase pi (GST-pi) was determined by an immunohistochemistry method.

RESULTS

Expression of mdr-1 or GST-pi was found in 11 (48%) and 12 (52%) cases, respectively. Most (11 of 12) of the GST-pi expression occurred simultaneously with mdr-1. Prechemotherapy tumor tissues were available in 11 cases; only two (18.2%) of these cases expressed mdr-1. Four (36%) of 11 cases that expressed mdr-1 (mdr-1(+)) and nine (90%) of 10 cases that did not express mdr-1 (mdr-1(-)) responded to second-line chemotherapy (P < .05). The survival-after-recurrence (SAR) curves significantly favored mdr-1(-) recurrent lymphoma (P < .05). The mdr-1 expression was further correlated with the immunophenotype and EBV association. All six cases of EBV-associated lymphoma (PTCL, five cases; Hodgkin's disease, one case) had significant simultaneous expression of mdr-1 and GST-pi in their recurrent tumor tissues.

CONCLUSION

(1) mdr-1 expression is a significant prognostic factor in recurrent lymphomas; (2) high expression of mdr-1 is observed in recurrent EBV-associated PTCL; and (3) GST-pi usually expresses simultaneously with mdr-1 in recurrent lymphomas. The role of EBV in the development of mdr-1 and the biologic significance of the simultaneous expression of mdr-1 and GST-pi in recurrent lymphomas are well worth further exploration.
Treatment outcomes in patients less than 2 years of age with small, stage I, favorable-histology Wilms' tumors: a report from the National Wilms' Tumor Study.
Authors: Green D M , Breslow N E , Beckwith J B , Takashima J , Kelalis P , D'Angio G J
Published: February 2017

PURPOSE

Retrospective analyses were performed to determine the effect of tumor weight and therapy modifications on outcome in patients less than 2 years of age with stage I favorable-histology Wilms' tumors.

PATIENTS AND METHODS

The 4-year relapse-free and overall survival percentages for patients randomized to different treatment regimens in National Wilms' Tumor Studies (NWTS)-1, -2, and -3 were calculated and compared.

RESULTS

The 4-year relapse-free survival percentages of patients whose specimen weight was less than 550 g were found to be 89.1% on NWTS-1, 96.0% on NWTS-2, and 93.2% on NWTS-3. There was no evidence that the relapse-free survival of these patients had improved over time (P value for trend = .99). The 4-year relapse-free survival percentage for similar age and stage patients whose specimen weight was 550 g or greater was significantly poorer than that of patients with smaller tumors (P = .02).

CONCLUSION

Changes in the NWTS treatment regimens over a period of more than 20 years have not improved on the excellent prognosis of patients who are less than 2 years of age at diagnosis and who have a stage I, favorable-histology Wilms' tumor with specimen weight less than 550 g. These data could be used as the basis for a future trial in which a subgroup of such patients is treated with nephrectomy only.
Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study.
Authors: Douglass E C , Reynolds M , Finegold M , Cantor A B , Glicksman A
Published: February 2017

PURPOSE

To estimate the disease-free survival rate in children with grossly resected hepatoblastoma treated with cisplatin, vincristine, and fluorouracil (CDDP/VCR/FU) and to assess the disease-response rate and disease-free survival (DFS) rate in children with unresectable or metastatic tumors treated with this combination.

PATIENTS AND METHODS

Sixty assessable patients with hepatoblastoma received therapy with five (stage I and II) to seven (stage III and IV) courses of CDDP (90 mg/m2), day 1, and VCR (1.5 mg/m2), and FU (600 mg/m2), day 3.

RESULTS

Nineteen of 21 patients with stage I or II disease survive free of disease (actuarial survival, 90% at 5 years). Twenty-four of 31 patients with stage III disease achieved a complete remission (CR) after chemotherapy and surgical excision; actuarial DFS at 4 years is 67%. Only one of eight patients with stage IV disease achieved a remission and survives.

CONCLUSION

Relatively brief exposure to chemotherapy with CDDP/VCR/FU provided excellent disease control to patients with grossly resected tumors. In patients with initially unresectable disease, this therapy provides a response rate and DFS rate comparable to regimens that contain doxorubicin (DOX).
Tumor-cell DNA content predicts outcome in children and adolescents with clinical group III embryonal rhabdomyosarcoma. The Intergroup Rhabdomyosarcoma Study Committee of the Children's Cancer Group and the Pediatric Oncology Group.
Authors: Pappo A S , Crist W M , Kuttesch J , Rowe S , Ashmun R A , Maurer H M , Newton W A , Asmar L , Luo X , Shapiro D N
Published: February 2017

PURPOSE

The prognostic value of tumor-cell DNA content (ploidy) was evaluated in children with unresectable, nonmetastic rhabdomyosarcoma of embryonal histology.

PATIENTS AND METHODS

Flow-cytometric techniques were used to estimate the ploidy of tumor specimens from 34 patients with embryonal rhabdomyosarcoma who were enrolled in the intergroup rhabdomyosarcoma study III (IRS III) from 1985 to 1991. Tumors were classified as diploid or hyperdiploid (DNA content, 1.1 to 1.8 times that of normal diploid cells). The influence of ploidy on clinical outcome was assessed by the Kaplan-Meier technique and Cox regression analysis with stepwise selection.

RESULTS

Twelve of the tumor specimens were diploid and 22 were hyperdiploid. The patient groups defined by diploid or hyperdiploid tumors had similar presenting characteristics (eg, age, tumor size, and anatomic site). Significantly more children with hyperdiploid tumors achieved a complete response than did children with diploid tumors (85% v 42%; P = .01). The probability of progression-free survival at 5 years (+/- SE) was 91% +/- 6% for the hyperdiploid group, compared with 17% +/- 11% for the diploid group (P < .001). Hyperdiploidy was also associated with a significantly higher overall survival rate at 5 years: 96% +/- 4% versus 50% +/- 14% (P = .004). Ploidy retained its prognostic significance after adjustment for tumor site in the Cox regression model.

CONCLUSION

Tumor-cell ploidy strongly correlates with outcome in children with nonmetastic, unresectable embryonal rhabdomyosarcoma. The two biologically distinct groups identified by this measure would benefit from further refinements in risk-directed therapy.
Paclitaxel and recombinant human granulocyte colony-stimulating factor as initial chemotherapy for metastatic breast cancer.
Authors: Reichman B S , Seidman A D , Crown J P , Heelan R , Hakes T B , Lebwohl D E , Gilewski T A , Surbone A , Currie V , Hudis C A
Published: February 2017

PURPOSE

A phase II study of Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ) as initial chemotherapy for metastatic breast cancer was conducted. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was used to ameliorate myelosuppression, the anticipated dose-limiting toxicity.

PATIENTS AND METHODS

Twenty-eight patients with bidimensionally measurable breast cancer who had not received prior chemotherapy for metastatic disease were treated. Taxol was administered at 250 mg/m2 as a continuous 24-hour intravenous (i.v.) infusion every 21 days. rhG-CSF was administered at 5 micrograms/kg/d subcutaneously on days 3 through 10.

RESULTS

Objective responses were observed in 16 of 26 assessable patients (62%; 95% confidence interval, 41% to 80%). There were three (12%) complete responses (CRs) and 13 (50%) partial responses (PRs). Ten of 16 patients (63%) who had received prior adjuvant chemotherapy responded, which included one CR and four PRs among eight patients who had received prior doxorubicin-containing therapy. Responses were observed in all sites of metastatic disease. The median time to first objective response was 5 weeks (range, 1 to 14). Administration of rhG-CSF was associated with a short duration of neutropenia (median, 2 days with absolute neutrophil count < 500 cells/microL). Eight of 26 patients (31%) who received more than one course received subsequent therapy without dose reduction. One hundred seventy-eight cycles of treatment were administered, with a median of six cycles per patient (range, one to 19). Eight courses (4.5%) were associated with admissions for neutropenic fever. Twenty-two patients (79%) did not require admission for neutropenic fever. Treatment was well tolerated. Adverse effects included generalized alopecia in all patients. Myalgias, arthralgias, and peripheral neuropathy were mild. No hypersensitivity reactions and no cardiac toxicity were observed.

CONCLUSION

Taxol is highly active as initial chemotherapy for metastatic breast cancer. Administration of rhG-CSF reduced the incidence, depth, and duration of neutropenia, compared with published prior experience. Further studies of Taxol in breast cancer, including combinations with other active agents, are clearly warranted.
Adult acute lymphoblastic leukemia: a multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Acute Lymphoblastic Leukemia.
Authors: Fière D , Lepage E , Sebban C , Boucheix C , Gisselbrecht C , Vernant J P , Varet B , Broustet A , Cahn J Y , Rigal-Huguet F
Published: February 2017

PURPOSE

In a prospective multicenter study, we analyzed the benefits of allogeneic bone marrow transplantation (BMT) in a nonselected group of adult patients with acute lymphoblastic leukemia (ALL) and, by a randomized trial, evaluated the effectiveness of autologous BMT over chemotherapy as postremission therapy in patients younger than 50 years who were not candidates for allogeneic BMT.

PATIENTS AND METHODS

After induction therapy that randomized patients to receive one of two anthracycline-containing regimens, either daunorubicin (DNR) or zorubicin (ZRB), patients were assigned to postremission treatment according to age and results of HLA typing. Patients younger than 40 years with an HLA-identical sibling (group 1) were scheduled to receive cyclophosphamide 60 mg/kg on days 1 and 2, total-body irradiation (TBI), and allogeneic BMT. Patients older than 50 years (group 2) received the chemotherapy arm composed of three monthly consolidation courses (DNR or ZRB, cytarabine, and asparaginase) followed by maintenance chemotherapy (modified L10 regimen). The remaining population (group 3) was randomly assigned to receive, after the three 1-month consolidation courses, either the chemotherapy arm or autologous BMT following a conditioning regimen similar to that of group 1.

RESULTS

Of the 572 assessable patients, 436 achieved complete remission (78% +/- 2% for DNR v 74% +/- 3% for ZRB; P = .3). The estimated 3-year disease-free survival (DFS) rate for the 116 patients included in group 1 was 43% +/- 5%. Both autologous BMT (95 patients) and chemotherapy (96 patients) produced comparable 3-year DFS rates (39% +/- 5% v 32% +/- 5%) and survival durations (49% +/- 5% v 42% +/- 5%). However, late relapses after 36 months were mainly observed in the chemotherapy arm.

CONCLUSION

This first interim analysis did not demonstrate a benefit of this autologous BMT procedure over classical maintenance chemotherapy in patients with ALL who received consolidation chemotherapy.
Carboplatin in the treatment of advanced breast cancer: a phase II study using a pharmacokinetically guided dose schedule.
Authors: O'Brien M E , Talbot D C , Smith I E
Published: February 2017

PURPOSE

We performed a phase II study of single-agent carboplatin against metastatic/locally advanced breast cancer using a pharmacokinetically guided dose schedule, to define further the potential role for this agent in combination and high-dose therapy.

PATIENTS AND METHODS

Forty patients with metastatic/locally advanced breast cancer were treated with carboplatin based on glomerular filtration rate (GFR) to achieve an area under the concentration-versus-time curve (AUC) of 7 mg/mL.min, with each course repeated at 4-week intervals. The median age was 57 years (range, 37 to 71).

RESULTS

Ten patients achieved a partial response (PR), for an overall response rate of 25% (95% confidence interval, 13% to 41%). One of 13 (8%) previously treated patients responded compared with nine of 27 (33%) patients who had not received previous chemotherapy. Median response duration was 18 weeks (range, 10 to 68). World Health Organization (WHO) grade 2 or greater toxicity was as follows: anemia, 42%; leukopenia, 20%; thrombocytopenia, 35%; nausea/vomiting, 39%; and infection, 9%.

CONCLUSION

This study confirms other reports indicating that carboplatin has moderate activity in previously untreated patients, but not in previously treated patients. In our view, carboplatin is a more appropriate agent than cisplatin for inclusion in high-dose chemotherapy schedules with autologous bone marrow rescue, and our results support the concept of calculating dose escalation on the basis of the area under the dose-response curve using the Calvert formula, rather than on surface area.
A new peripherally implanted subcutaneous permanent central venous access device for patients requiring chemotherapy.
Authors: Salem R R , Ward B A , Ravikumar T S
Published: February 2017

PURPOSE

A peripherally implanted central venous access device (P.A.S. Port; Pharmacia Deltec Inc, St Paul, MN) was evaluated for ease of insertion, functionality, acceptance, and complications in patients who required long-term venous access. A hand-held tracking system (Cath-Finder; Pharmacia Deltec Inc) used to determine catheter tip location was also evaluated.

PATIENTS AND METHODS

A P.A.S. Port was placed in 47 patients who required long-term intravenous access. The median follow-up duration has been 32 weeks (range, 2 to 112). Total usage has been 2,028 catheter-weeks. The Cath-Finder was used to determine catheter tip location during insertion. Nursing staff and patient satisfaction were polled and functionality and complications were recorded.

RESULTS

The device was found to be simple to insert, the procedure well tolerated, and, with one exception, the Cath-Finder accurately predicted catheter tip location. There was a 6.4% incidence of transient phlebitis and a 6.4% incidence of symptomatic axillary or subclavian vein thrombosis. There were no infectious complications. Access was simple in all but two obese patients. The device functioned well in all patients, except three in whom blood aspiration was difficult and two in whom fluid administration was slow. The device was well tolerated by all patients and nursing staff satisfaction was high.

CONCLUSION

This device provides a highly acceptable, additional method of implantable, permanent central venous access for chemotherapy patients with a low complication rate. The successful use of the Cath-Finder and minor extent of the procedure may allow this device to be inserted in a clinic procedure room without sedation and fluoroscopy.
In search of an optimal regimen for elderly patients with advanced-stage diffuse large-cell lymphoma: results of a phase II study of P/DOCE chemotherapy.
Authors: O'Reilly S E , Connors J M , Howdle S , Hoskins P , Klasa R , Klimo P , Stuart D S
Published: February 2017

PURPOSE

The results of a prospective, phase II trial of an 8-week treatment program consisting of epirubicin or doxorubicin, vincristine, cyclophosphamide, etoposide, and prednisone (P/DOCE) for elderly patients with advanced large-cell lymphoma are reported and compared with previous phase II studies conducted in similar patients at the same institution.

PATIENTS AND METHODS

Between March 1988 and September 1991, 63 previously untreated patients aged 65 to 85 years (median, 75) with advanced-stage diffuse large-cell lymphoma, defined as Ann Arbor stage III or IV or stage I or II with B symptoms or bulky disease, were enrolled on a brief, 8-week protocol consisting of five outpatient chemotherapy treatments.

RESULTS

The complete response (CR) rate was 62%. The treatment-related mortality rate was 8%, the actuarial 4-year failure-free survival (FFS) rate was 41%, and the overall survival (OS) rate was 45%. These results were compared with two earlier, 12-week protocols, low-dose doxorubicin, cyclophosphamide, vincristine, bleomycin, and prednisone (LD-ACOB-B) and etoposide, doxorubicin, bleomycin, and prednisone (VABE), performed at the same center. There was no difference in outcome among the three regimens. If all 133 patients treated on any one of these three specially designed regimen for elderly patients are combined, the projected 5-year OS rate is 38%.

CONCLUSION

The 8-week P/DOCE chemotherapy regimen is equal in efficacy and similar in toxicity to 3 months of chemotherapy administered on a weekly schedule and similar to the results reported in the literature for longer, anthracycline-based chemotherapy treatments. There does not appear to be any improvement in outcome from more protracted treatment programs compared with the 8-week P/DOCE protocol.
Primary mediastinal B-cell lymphoma with sclerosis: an aggressive tumor with distinctive clinical and pathologic features.
Authors: Lazzarino M , Orlandi E , Paulli M , Boveri E , Morra E , Brusamolino E , Kindl S , Rosso R , Astori C , Buonanno M C
Published: February 2017

PURPOSE

To evaluate the clinical features of presentation, the morphologic and immunohistochemical pattern, the modality of spread, and the response to current treatments of patients with primary mediastinal B-cell lymphoma, a recently documented subtype of non-Hodgkin's lymphoma (NHL).

PATIENTS AND METHODS

Thirty consecutive patients (14 males, 16 females; median age, 26 years) with primary mediastinal B-cell lymphoma with sclerosis were studied.

RESULTS

The clinical aspects were largely homogeneous: 93% presented with chest symptoms of a rapidly enlarging mass of the anterior mediastinum; the tumor was bulky in 73%, and superior vena cava syndrome (SVCS) was present in 57%. Also, patients without SVCS symptoms showed subclinical venacaval compression at computed tomographic (CT) scan, for a total incidence of caval obstruction of 80%. Intrathoracic extension to adjacent organs was seen in 47% of patients. Despite its invasive behavior, only four patients showed extrathoracic spread at diagnosis. In 23 cases, the tumor presented with morphologic features that resembled follicular center-cell lymphomas. In seven, the neoplastic population was composed mainly of centrocyte-like cells with abundant clear cytoplasm not referable to any known B-cell lymphoma subtype. All cases showed huge sclerosis. Of 29 patients assessable for response, 16 (55%) achieved a complete response (CR): five of 14 (36%) treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), and 11 of 15 (73%) treated with methotrexate plus leucovarin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) or etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) (P = .047). We could identify no clinical, biologic, or histopathologic features significantly correlated with response. After chemotherapy, 14 of 16 remitters received consolidation radiotherapy to the mediastinum. At 3 years, the actuarial survival rate is 38% for all cases and 72% for remitters. None of the 13 patients who did not achieve CR responded to salvage treatments.

CONCLUSION

This study shows that primary mediastinal B-cell lymphoma with sclerosis is a distinctive subtype of NHL with unique clinicopathologic aspects and aggressive behavior. Prompt recognition and aggressive treatment may provide long survival in a good proportion of cases. However, a subset of patients is extremely refractory to first- and second-line treatment. Conventional prognostic factors seem inadequate to identify these very-poor-risk cases.
One hundred autotransplants for relapsed or refractory Hodgkin's disease and lymphoma: value of pretransplant disease status for predicting outcome.
Authors: Rapoport A P , Rowe J M , Kouides P A , Duerst R A , Abboud C N , Liesveld J L , Packman C H , Eberly S , Sherman M , Tanner M A
Published: February 2017

PURPOSE

One hundred autotransplants for Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL) were examined prospectively to identify variables with prognostic significance.

PATIENTS AND METHODS

Ninety-six patients with relapsed or refractory HD or NHL underwent 100 autotransplants. Patients received high-dose carmustine (BCNU), etoposide, cytarabine, and cyclophosphamide (BEAC) followed by unpurged autologous stem-cell rescue.

RESULTS

The 3-year actuarial event-free survival (EFS) rate for the 47 HD patients is 49%, with a median followup duration of 2 years. For the 53 NHL patients, the 3-year actuarial EFS rate is 40%, with a median follow-up duration of 19 months. By multivariate analysis, minimal disease on admission (all areas < or = 2 cm) is associated with improved EFS (HD, P = .003, NHL, P = .03). The projected EFS rate for HD patients entering with minimal disease is 70% versus 15% for patients with bulky disease (P = .0001). The projected EFS rate for NHL patients with minimal disease is 48% versus 25% for patients with bulky disease (P = .04). Posttransplant involved-field radiotherapy, administered to 26 of the last 61 patients, was associated with an improved EFS rate for NHL patients (P = .015). The BEAC regimen was well tolerated by patients who entered the study with minimal disease (mortality rate, < 5%), but caused significant toxicity in patients with bulky disease (mortality rate, 25%).

CONCLUSION

Disease burden before autotransplantation is an important predictor of regimen-related toxicity and EFS. Posttransplant involved-field radiotherapy may improve outcomes in select patients with NHL. The BEAC regimen is safe and effective, particularly for patients with minimal disease.
Second malignancies after treatment of Hodgkin's disease: the influence of treatment, follow-up time, and age.
Authors: Abrahamsen J F , Andersen A , Hannisdal E , Nome O , Abrahamsen A F , Kvaløy S , Høst H
Published: February 2017

PURPOSE

In the period 1968 through 1988, The Norwegian Radium Hospital (NRH) treated an unselected population of 1,152 patients with Hodgkin's disease (HD) that comprised more older patients (mean age, 43 years) than most other institutions. We considered it important to evaluate these patients for development of second cancers (SCs).

PATIENTS AND METHODS

The Norwegian Cancer Registry identified previously untreated patients with HD treated at NRH who had developed a SC more than 1 year after diagnosis of HD. The relative risk ratio (RR) (observed/expected cases) and the cumulative risk were calculated.

RESULTS

Sixty-eight patients had developed a SC, including nine acute nonlymphocytic leukemias (ANLLs), eight non-Hodgkin's lymphomas (NHLs), and 51 solid tumors, including 11 lung cancers. The RR of SC and leukemia was 1.86 (95% confidence interval [CI], 1.4 to 2.4) and 24.3 (95% CI, 11.1 to 46.2), respectively. The RR of SC was highest in younger patients (< 41 years, RR = 3.8). No significant association between splenectomy and development of ANLL was found. The influence of treatment and follow-up time on the development of SC agrees with data from other large cancer institutions.

CONCLUSION

(1) The low RR of developing a SC in this study is probably due to the number of older patients included, who have a lower RR of developing a SC due to less aggressive treatment, shorter follow-up time, and higher incidence of cancer in the expected background population. (2) The low RR and cumulative risk of developing ANLL may be due to the limited use of extensive chemotherapy (CT) in our hospital in the earlier years.
A randomized trial comparing single-agent carboplatin with carboplatin followed by radiotherapy for advanced ovarian cancer: a North Thames Ovary Group study.
Authors: Lambert H E , Rustin G J , Gregory W M , Nelstrop A E
Published: February 2017

PURPOSE

To determine in a randomized trial of advanced ovarian carcinoma whether consolidation therapy with whole-abdominal radiotherapy (RT) after chemotherapy improves survival and disease-free survival compared with the continued chemotherapy.

PATIENTS AND METHODS

Two hundred fifty-four patients with advanced epithelial ovarian cancer (stages IIB to IV) were entered onto a study of five monthly courses of 400 mg/m2 of carboplatin. One hundred seventeen patients with residual disease of 2 cm or less at second-look laparotomy or laparoscopy were then randomized to receive consolidation therapy, either five further courses of carboplatin at the same dosage or whole-abdominal RT (24 Gy). There was no control arm.

RESULTS

Chemotherapy was well tolerated and was usually administered on an outpatient basis. Myelosuppression that was sufficient to delay chemotherapy occurred in only 3% of 1,418 courses analyzed. The main toxicity of carboplatin was nausea and vomiting, but this was easier to control than that with cisplatin. Although RT was well tolerated in the majority of the 58 patients, one patient who had been found to have multiple adhesions at second-look surgery developed fecal fistulae post-RT that resulted in the patient's death from peritonitis. Median survival for the whole group from date of surgery was 25 months. No statistical difference was found in either survival or disease-free survival between those patients who received consolidation chemotherapy and those who were treated with abdominal RT. Prognostic factors used to assess survival were stage, histology, amount of residual disease after primary surgery, and presence of tumor at second-look surgery.

CONCLUSION

There seems to be no significant advantage for consolidation whole-abdominal RT compared with the continuation of the same chemotherapy in the management of advanced epithelial carcinoma of the ovary, even when no macroscopic residual disease is apparent at second-look surgery.
Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies.
Authors: Weber J , Yang J C , Topalian S L , Parkinson D R , Schwartzentruber D S , Ettinghausen S E , Gunn H , Mixon A , Kim H , Cole D
Published: February 2017

PURPOSE

Based on preclinical evidence in murine models that interleukin-6 (IL-6) mediates regression of metastatic tumors, we performed a phase I study of recombinant human IL-6 in patients with refractory advanced malignancies to determine its pharmacokinetics, toxicities, and possible immunologic and antitumor effects.

PATIENTS AND METHODS

Recombinant IL-6 was administered as a single subcutaneous dose daily for 7 days, with 7 days off therapy followed by another 7 days of IL-6. Doses were escalated in cohorts of three patients starting at 3 micrograms/kg/d, provided that toxicity at the preceding dose level was not dose-limiting. Dose-limiting toxicity was defined as grade III or IV major organ toxicity that did not resolve to grade II or less in 24 hours after stopping IL-6, using the National Cancer Institute Common Toxicity Criteria. Patients were treated with 3, 10, and 30 micrograms/kg/d IL-6 subcutaneously.

RESULTS

Three patients each were treated at the 3- and 10-micrograms dose levels. Two of five patients treated with 30 micrograms/kg/d IL-6 subcutaneously had grade III major organ toxicity that required IL-6 therapy to be discontinued. All patients experienced fever, chills, and minor fatigue. Significant increases in C-reactive protein (CRP), fibrinogen, platelet counts, and lymphocyte IL-2 receptor levels were seen in patients at the 10- and 30-micrograms/kg dose levels. Decreases in albumin and hemoglobin were observed, particularly at the 30-micrograms/kg dose level. The half-life (T1/2 beta) was 4.2 hours, with a peak IL-6 level at 5 hours. No antitumor responses were seen.

CONCLUSION

A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.
Yttrium 90-labeled antiferritin followed by high-dose chemotherapy and autologous bone marrow transplantation for poor-prognosis Hodgkin's disease.
Authors: Bierman P J , Vose J M , Leichner P K , Quadri S M , Armitage J O , Klein J L , Abrams R A , Dicke K A , Vriesendorp H M
Published: February 2017

PURPOSE

This study was undertaken to examine the feasibility of combining radiolabeled antibody therapy with high-dose chemotherapy followed by autologous bone marrow transplantation in patients with poor-prognosis Hodgkin's disease.

PATIENTS AND METHODS

Patients were entered onto this protocol if they had chemotherapy-resistant disease, bulky disease, or extensive prior therapy. Patients received yttrium-labeled antiferritin on day -13, -12, or -11, followed by high-dose cyclophosphamide, carmustine, and etoposide (CBV) on days -6 to -3, and then bone marrow infusion on day 0.

RESULTS

Twelve patients received both radiolabeled antibody and high-dose chemotherapy followed by autologous transplantation. Two additional patients started the study, but were unable to complete all therapy. Four of 12 patients experienced early transplant-related mortality. Four patients are alive more than 2 years following transplantation and three are free from disease progression at 24+, 25+, and 28+ months following transplantation. The progression-free survival rate at 1 year is estimated to be 21%. Considering the poor prognostic characteristics of these patients, toxicity on this protocol was not necessarily greater than that observed with high-dose chemotherapy alone.

CONCLUSION

This report demonstrates the feasibility of combining radiolabeled antibody therapy with high-dose chemotherapy and autologous bone marrow transplantation.