bluuebunny/crossref_metadata_2025 huggingface dataset:
A prospective evaluation of 5-fluorouracil plus cisplatin in advanced squamous-cell cancer of the head and neck.
Authors: Dasmahapatra K S , Citrin P , Hill G J , Yee R , Mohit-Tabatabai M A , Rush B F
Published: February 2017

Recent studies have shown improved efficacy of chemotherapy in patients with advanced squamous-cell cancer of the head and neck. Our purpose was to evaluate prospectively the activity of cisplatin plus 5-fluorouracil (5FU) in 37 patients with advanced stage IV squamous-cell cancer of the head and neck. There were two groups. Group 1 consisted of 19 previously untreated patients with either T4 or N3 disease. They received 100 mg/m2 cisplatin (days 1 and 28) and 120-hour infusion of 1,000 mg/m2/24 hours 5FU (days 1 to 5 and 28 to 32). They subsequently were offered preoperative radiotherapy (RT) and surgery. Group 2 consisted of 18 previously treated patients. They received 5FU and cisplatin in the same dosage every 28 days for either recurrent or metastatic disease. It was found that in group 1 there was an 84% response rate (five complete responses (CR) and 11 partial responses (PR) ). Three of those with PR achieved a CR after RT. Seven patients have had RT plus surgery and are disease free at 8 to 27 month follow-up. Six patients (one CR, five PR) refused surgery and progressed within 4 months. In group 2 there was an 11% response rate after two cycles (two PR), three patients had a minimal response (MR, less than 50% response) and received a mean of four cycles of treatment. Three patients with stable disease received a mean of four cycles of chemotherapy until progression. Two of 11 patients who had received previous chemotherapy plus RT showed an MR; nine of these patients had shown a response to their previous chemotherapy. Only one of 14 patients who had RT plus chemotherapy had a PR, and three had MR. Of five patients who had previous surgery, only one had a PR. All five had received chemotherapy as well. It was concluded that 5FU plus cisplatin is an effective combination in previously untreated patients. In previously treated patients with recurrent disease, there is a substantially lower response rate.
Treatment of diffuse histiocytic lymphoma (DHL) with COMLA (cyclophosphamide, oncovin, methotrexate, leucovorin, cytosine arabinoside): a 10-year experience in a single institution.
Authors: Gaynor E R , Ultmann J E , Golomb H M , Sweet D L
Published: February 2017

Between March 1974 and December 1983, 83 patients with diffuse histiocytic lymphoma (DHL) were treated with COMLA (cyclophosphamide 1.5 g/m2 day 1; Oncovin (Lilly, Indianapolis) 1.4 mg/m2 days 1, 8, and 15; and cytosine arabinoside 300 mg/m2 and methotrexate 120 mg/m2 days 22, 29, 36, 43, 50, 57, 64, and 71; and leucovorin 25 mg/m2 every six hours X 4, beginning 24 hours after methotrexate). For the purpose of analysis, patients were divided into two groups. Group 1 (n = 54) included patients age 65 or under who had received no prior curative radiotherapy or chemotherapy. Group 2 (n = 29) included all patients over age 65 and patients who had received prior curative radiation therapy or prior minimal chemotherapy. The median time of follow-up for all patients was 28 months. Group 1 included 11 stage II, ten stage III, and 33 stage IV patients. Of 48 evaluable patients in this group, 21 (44%) achieved a complete remission (CR), eight (17%) achieved a partial remission (PR), and 19 (40%) showed no response (NR). Median survival of CR patients was 114+ months, PR patients, 42 months, and NR patients, 13 months. Six CR patients relapsed. The median disease-free survival of CR patients was 108+ months. Group 2 included nine stage II, seven stage III, and 13 stage IV patients. Of 24 patients evaluable for response, eight (33%) achieved a CR, six (25%) achieved a PR, and ten (42%) showed no response. The median survival of CR patients was 114+ months, that of PR patients was 17 months, and that of NR patients, 9 months. Two CR patients relapsed. The median disease-free survival of CR patients had not been reached at 102 months. The regimen was well tolerated in most patients and toxicity was acceptable. We conclude that COMLA is a well tolerated outpatient chemotherapy regimen capable of inducing durable CRs in some patients with DHL. Results achieved with COMLA, however, are inferior to those of more aggressive treatment programs; thus, the use of COMLA as first-line therapy in DHL should be limited to those patients unable to tolerate a more aggressive treatment program.
Mycosis fungoides involving the central nervous system.
Authors: Hallahan D , Griem M , Griem S , Duda E , Baron J
Published: February 2017

The clinical records of nine patients, followed at the University of Chicago, with mycosis fungoides (MF) and neurologic deficits due to direct CNS involvement were reviewed. Lymph node and visceral involvement was present in all patients. Clinical findings included cranial nerve deficits in four patients, altered mental status in eight, gait disturbances in three, and leg weakness in one. Helpful diagnostic studies included lumbar puncture with CSF cytology, computerized tomography (CT) brain scans, brain biopsy, and myelogram. Two patients, who were treated with radiation therapy (RT), survived 14 and 40 weeks, respectively. Survival of less than 4 weeks limited treatment in the other patients. Autopsies were performed on six patients and revealed meningeal infiltration and perivascular infiltration of the brain. In addition, the cerebral parenchyma was infiltrated in one patient and a lymphomatous tumor was found in the brainstem of another. We conclude that the varied clinical and pathologic features of CNS involvement with mycosis fungoides resemble those seen in leukemias and other lymphoproliferative disorders. Better awareness of the clinical features may permit earlier diagnosis and initiation of therapy.
Phase I and pharmacologic study of hexamethylene bisacetamide in patients with advanced cancer.
Authors: Rowinsky E K , Ettinger D S , Grochow L B , Brundrett R B , Cates A E , Donehower R C
Published: February 2017

Hexamethylene bisacetamide (HMBA, NSC 95580) has been demonstrated to be the most effective of the known and studied polar-planar compounds at inducing differentiation in a wide variety of leukemic and nonleukemic cell lines. Although HMBA demonstrated no antineoplastic activity in preclinical testing, it was selected for clinical development on the basis of its potent differentiating capabilities in vitro. In this phase I study, HMBA was administered as a continuous five-day infusion every 3 weeks to patients with advanced cancer. Twenty-three patients received 35 evaluable courses at doses that ranged from 4.8 to 33.6 g/m2/d. Dose-limiting toxicities included renal insufficiency, a hyperchloremic metabolic acidemia/acidosis, and CNS toxicities manifested by agitation and delirium, which progressed to coma in one patient who developed concomitant renal insufficiency. Moderate myelosuppression, mucositis, nausea, and vomiting were also observed. The pharmacokinetics of HMBA best fit a single compartmental model and disposition is primarily by renal elimination. Renal excretion of HMBA and of the primary metabolite, 6-acetoamidohexanoic acid, together account for the disposition of 66% to 93% (mean, 74%) of the infused drug. Based on this trial, the maximum tolerated and recommended phase II doses for HMBA administered on this schedule are 33.6 and 24 g/m2/d, respectively. However, since steady-state HMBA levels at these doses were in the range of 1 to 2 mmol/L, only approaching the lower limit demonstrated for in vitro differentiating effectiveness, and because of evidence suggesting that the exposure period is an important variable in the induction of differentiation, additional studies examining longer periods of infusion are warranted.
Clinical trial of recombinant leukocyte A interferon as initial therapy for favorable histology non-Hodgkin's lymphomas and chronic lymphocytic leukemia. An Eastern Cooperative Oncology Group pilot study.
Authors: O'Connell M J , Colgan J P , Oken M M , Ritts R E , Kay N E , Itri L M
Published: February 2017

Twenty patients with disseminated favorable histology non-Hodgkin's lymphomas (16 patients) or chronic lymphocytic leukemia (four patients) who had not received previous chemotherapy were treated with recombinant leukocyte A interferon (IFL-rA) (Hoffmann-La Roche, Nutley, NJ). Treatment was administered in a moderate dose (12 X 10(6) U/m2) by intramuscular (IM) injection three times weekly for 8 weeks, followed by weekly maintenance therapy for an additional 16 weeks in patients responding to therapy. Five patients with stable disease at 8 weeks received four additional weeks of three-times-weekly treatment at an escalated dose (25 X 10(6) U/m2). Interferon was tolerated without severe toxicity by most patients, although treatment was discontinued prematurely due to side effects in four patients. Objective tumor responses (one complete response [CR] and six partial responses [PRs]) were seen in seven of 16 patients with lymphoma (44%). One of four patients with chronic lymphocytic leukemia also experienced a PR. Median time-to-progression from initiation of therapy among responding patients was 26 + weeks (range, 7 + to 84 + weeks). This study has demonstrated single agent antitumor activity of IFL-rA given in a tolerable outpatient dosage regimen in patients with advanced favorable histology non-Hodgkin's lymphomas, and serves as a basis for further trials of IFL-rA combined with chemotherapy as initial therapy for such patients in the future.
A phase I trial of spirohydantoin mustard (NSC 172112) in patients with advanced cancer.
Authors: Brown T D , Ettinger D S , Donehower R C
Published: February 2017

Spirohydantoin mustard (spiromustine, NSC 172112) is a classical bifunctional alkylating agent synthesized in an effort to develop antitumor agents effective against CNS tumors. The rationale was to combine the reactive moiety of an active antitumor agent with the hydantoin part of the molecule, which might serve as a carrier to cross the blood brain barrier. Thirty-eight patients with refractory solid tumors received spiromustine as part of a phase I trial at the Johns Hopkins Oncology Center. Three schedules were investigated: intravenously (IV) daily for three consecutive days, IV every other day for 3 days, and IV on a weekly basis for three doses, all cycled every 28 days. Hematologic toxicity was infrequently seen. Mild to moderate nausea and vomiting occurred on all schedules. The dose limiting toxicity was CNS toxicity characterized by mydriasis, xerostomia, lethargy, confusion, and hallucinations. This CNS toxicity was dose related, cumulative, and reversible. IV physostigmine appeared to diminish the neurotoxicity if administered before spiromustine and at frequent intervals following the drug. The maximum tolerated dose of spiromustine (without concomitant physostigmine) on the three times a week schedule is 6 mg/m2. With physostigmine pretreatment, 8 mg/m2 can be administered. The three times daily and every other day for three days schedules are not recommended for further study due to the severity of neurotoxicity. It is recommended that 6 mg/m2 be used as the starting dose for any phase II studies using the three times weekly schedule, and that physostigmine be used as needed to minimize neurotoxicity. Dose escalation above this level can be considered when individual tolerance has been established. Phase II trials to investigate the activity of this agent against primary and metastatic CNS malignancies appear indicated on the basis of three transient radiographic responses in refractory malignancies metastatic to the CNS.
Metastatic Ewing's sarcoma: remission induction and survival.
Authors: Hayes F A , Thompson E I , Parvey L , Rao B , Kun L , Parham D , Hustu H O
Published: February 2017

Eighteen patients with previously untreated metastatic Ewing's sarcoma (ES) entered a protocol designed to evaluate the response rate to cyclophosphamide and doxorubicin induction therapy delivered before delayed surgery and delayed lower dose, limited-field radiation therapy, (RT), and maintenance chemotherapy. With chemotherapy and delayed surgery, 14 of 18 were rendered free of gross tumor. RT was delivered to the primary site of 11 of these responding patients, plus four of those not free of gross disease. Following RT, two more attained complete clinical remission. Site of primary or metastases did not influence outcome; however, the size of the primary at diagnosis did appear to do so. Ten patients remain disease-free 16 to 82 months (median, 47 months) from diagnosis.
Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.
Authors: Sherman M L , Spriggs D R , Arthur K A , Imamura K , Frei E , Kufe D W
Published: February 2017

Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using a five-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapy were administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills, hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerated dose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transient thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels. Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated with decreases in high-density lipoproteins, as well as increases in triglycerides and very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay (ELISA) test indicated plasma rH-TNF levels less than 0.2 U/mL. The recommended phase II dose of rH-TNF administered as a five-day continuous infusion is 2.4 X 10(5) U/m2/d.
Two cycles of MOPP and radiotherapy for stage III1A and stage III1B Hodgkin's disease.
Authors: Henkelmann G C , Hagemeister F B , Fuller L M
Published: February 2017

One hundred two adult patients with stage III1A (76 patients) and stage III1B (26 patients) Hodgkin's disease were treated with two cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and radiotherapy (XRT) between 1970 and 1984. Sixty-four of the patients were treated between 1970 and 1978 with two cycles of MOPP and XRT to the mantle, upper abdomen, and pelvis. The remaining 38 patients were treated from 1978 to 1984 with a modification of the protocol in which pelvic XRT was omitted and low-dose whole-lung XRT was administered to patients with unfavorable mediastinal disease. The 10-year actuarial freedom-from-progression (FFP) and determinate survival rates at a mean follow-up of 93 months were 84% and 86% for stage III1 disease, 86% and 84% for stage III1A disease, and 78% and 91% for stage III1B disease. Three patients died of treatment-related toxicities without evidence of Hodgkin's disease, two died of complications of myelosuppression and one of acute nonlymphocytic leukemia (ANLL). Neither FFP nor determinate survival rates were significantly influenced by B symptoms, unfavorable mediastinal disease, histologic subtype, extent of abdominal disease, the omission of pelvic XRT, the use of whole-lung XRT, or the number of splenic nodules. Patients 40 years of age or older had a 73% determinate survival rate at 10 years compared with 88% for patients younger than 40 years (P = .01). This survival difference was due to treatment-related toxicity in the older group. This study indicates that two cycles of MOPP and XRT to the mantle and upper abdomen is as effective as more intensive treatment for all patients with stage III1 Hodgkin's disease. This treatment program can preserve fertility and has had only a 1% actuarial incidence of ANLL at 15 years.
Clinical characterization of non-small-cell lung cancer tumors showing neuroendocrine differentiation features.
Authors: Berendsen H H , de Leij L , Poppema S , Postmus P E , Boes A , Sluiter H J , The H
Published: February 2017

In most cases of small-cell lung carcinomas (SCLC) phenotypic features compatible with a neuroendocrine differentiation status can be identified by monoclonal (MOC) antibody-based immunohistological procedures. Similar features can be recognized only in a minority of non-SCLC tumors. During a period of 30 months, all diagnostic non-SCLC biopsies (141 cases) were prospectively analysed for the presence of markers indicative for neuroendocrine differentiation. In 31% of all cases, such a presence could be noticed. Neuroendocrine differentiation (50% to 100% positive-staining tumor cells) was recognized more frequently in adenocarcinoma when compared to large-cell and squamous-cell carcinoma (chi 2 = 9.31, 2 degrees of freedom, P less than 0.01). To investigate whether the clinical behavior of these "neuroendocrine" non-SCLC cases mimics SCLC, a multivariate analysis for prognostic factors was performed. Among other prognostic factors, biopsies containing more than 50% positive-staining tumor cells with the MOC antibody-1 (MOC-1) were recognized as negative prognostic factors.
Recombinant interleukin-2 by continuous infusion and adoptive transfer of recombinant interleukin-2-activated cells in patients with advanced cancer.
Authors: Paciucci P A , Holland J F , Glidewell O , Odchimar R
Published: February 2017

Twenty-five patients with disseminated cancer (nine with renal cell carcinoma, five with melanoma, three with Hodgkin's lymphoma and chronic myelocytic leukemia [CML], two with soft tissue sarcoma, one each with large-cell lymphoma, breast cancer, and colon cancer), 13 males and 12 females, aged 25 to 68, were treated with recombinant human interleukin-2 (rIL2) by continuous infusion and adoptive transfer of autologous lymphocytes activated in vitro with IL2. Patients underwent leukapheresis on days 1, 8, 15, and 22 of the treatment. Cells, bulk activated for 20 hours in serum-free culture medium with 1,000 U IL2/mL in transfusion transfer packs as culture vessels, were transfused the following day. The infusion of IL2 by continuous infusion for six days started immediately after each adoptive transfer for 4 weekly courses. The dose of IL2 was escalated weekly in each patient; starting doses of IL2 were also escalated in subsequent cohorts of patients until maximally tolerated doses were reached. Nine patients had objective tumor regressions (three with renal cell cancer, two with Hodgkin's lymphoma, and one each with melanoma, sarcoma, breast, and colon cancer). Six responses were partial, two were minor, and one was mixed. Responding patients were maintained with IL2 by continuous infusion for six days every 6 to 8 weeks, without adoptive cell transfer. The median duration of responses was 16 weeks (3 to 60 + weeks). Tumor regression was related to the dose of IL2 (greater than or equal to 3.4 x 10(6) U/m2/d for six days) and to the in vivo lymphoproliferative effects of the lymphokine, but not to the total number of cells adoptively transferred. Side effects of treatment were transient and quickly reversible. Renal, hepatic dysfunction, and dyspnea were directly related to the dose of IL2 and to lymphocytosis. Other toxicities were mild hypotension with mild fluid retention, oral mucositis, anemia, thrombocytopenia, fever, and fatigue.
Combined versus sequential chemo-endocrine therapy in advanced prostate cancer: final results of a randomized Southwest Oncology Group study.
Authors: Osborne C K , Blumenstein B , Crawford E D , Coltman C A , Smith A Y , Lambuth B W , Chapman R A
Published: February 2017

Cytotoxic chemotherapy has not provided survival benefit in metastatic prostate cancer, although it has been used most frequently in patients with far-advanced, refractory disease. To evaluate the effects of chemotherapy given earlier in the course of the disease, the Southwest Oncology Group (SWOG) performed a randomized trial between September 1982 and October 1986 comparing endocrine therapy (diethylstilbestrol [DES] or orchiectomy) alone followed by cyclophosphamide-Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) chemotherapy at progression versus initial combined chemo-endocrine therapy. One hundred forty-three patients were registered, and only six were declared ineligible. Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate (63%) compared with endocrine therapy alone (48%). A log-linear model of tumor response and treatment arm adjusted for the stratification factors favored the combination arm (P = .059). Only three of 27 patients on the endocrine therapy alone arm had an objective partial response when crossed over to chemotherapy, while two others had stable disease. Despite the difference in initial response rate, time to treatment failure and survival were identical in the two treatment arms. Seventy-seven percent of patients on the initial endocrine therapy alone arm have died (median survival, 25.6 months) compared with 78% on the chemo-endocrine therapy arm (median survival, 22.0 months). No significant effect of treatment on survival was observed even after adjustment for the stratification variables in a Cox regression model. Exploratory survival analyses with patients on both arms combined did show a marginally significant time to treatment failure and survival advantage for patients treated with DES rather than orchiectomy as initial endocrine therapy. Eighty-six percent of patients treated by orchiectomy have died compared with only 65% of those treated with DES. These data do not support the addition of cytotoxic chemotherapy to initial endocrine therapy in patients with metastatic prostate cancer.
Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation.
Authors: Wahl R L , Zasadny K , Helvie M , Hutchins G D , Weber B , Cody R
Published: February 2017

PURPOSE

We assessed the feasibility of noninvasive metabolic monitoring of cancer chemohormonotherapy using sequential quantitative positron emission tomographic (PET) scans of tumor glucose metabolism with the glucose analog 2-[18F]-fluoro-2-deoxy-D-glucose (FDG).

PATIENTS AND METHODS

Eleven women with newly diagnosed primary breast cancers larger than 3 cm in diameter beginning a chemohormonotherapy program underwent a baseline and four follow-up quantitative PET scans during the first three cycles of treatment (days 0 to 63). Tumor response was sequentially determined clinically, radiographically, and then pathologically after nine treatment cycles.

RESULTS

Eight patients had partial or complete pathologic responses. Their maximal tumor uptake of FDG assessed by PET decreased promptly with treatment to the following: day 8, 78 +/- 9.2% (P < .03); day 21, 68.1 +/- 7.5% (P < .025); day 42, 60 +/- 5.1% (P < .001); day 63, 52.4 +/- 4.4% (P < .0001) of the basal values. Tumor diameter did not decrease significantly during this period through 63 days. Prompt decreases in the FDG influx rate (K) from basal levels (from .019 to .014 mL/cm3/min) after 8 days of treatment (P < .02) and in the estimated rate of FDG phosphorylation to FDG-6-phosphate (k3) from .055 to .038 min-1 after 8 days of treatment (P < .02) to .029 +/- .004 min-1 at 21 days) (P < .02) were observed. Three nonresponding patients had no significant decrease in tumor uptake of FDG (81 +/- 18% of basal value), influx rate (.015 to .012 mL/cm3/min), or tumor size (81 +/- 12% of basal diameter) comparing basal versus 63-day posttreatment values.

CONCLUSION

Quantitative FDG PET scans of primary breast cancers showed a rapid and significant decrease in tumor glucose metabolism after effective treatment was initiated, with the reduction in metabolism antedating any decrement in tumor size. No significant decrease in FDG uptake (SUV) after three cycles of treatment was observed in the nonresponding patients. FDG PET scanning has substantial promise as an early noninvasive metabolic marker of the efficacy of cancer treatment.
Early evaluation of combined fluorouracil and leucovorin as a radiation enhancer for locally unresectable, residual, or recurrent gastrointestinal carcinoma. The North Central Cancer Treatment Group.
Authors: Moertel C G , Gunderson L L , Mailliard J A , McKenna P J , Martenson J A , Burch P A , Cha S S
Published: February 2017

PURPOSE

To develop a tolerable regimen of fluorouracil (5-FU), low-dose leucovorin, and radiation, and to obtain an early estimate of therapeutic effectiveness.

PATIENTS AND METHODS

Forty patients with locally unresectable or recurrent gastrointestinal carcinoma were studied (pancreas, n = 22; rectum and sigmoid, n = 10; gastric, n = 6; other, n = 2). Irradiation therapy was administered in 1.8-Gy fractions 5 days per week, with total doses ranging from 45 to 54 Gy. 5-FU 400 mg/m2/d plus leucovorin 20 mg/m2/d, both by rapid intravenous injection, were administered for 3 or 4 days during the first and fifth weeks of radiation. 5-FU 425 mg/m2/d plus leucovorin 20 mg/m2/d were administered for 4 days at 4 weeks following radiation and for 5 days at 9 weeks.

RESULTS

Major toxicities with upper abdominal treatment were nausea, vomiting, weight loss, and leukopenia. A tolerable dosage regimen was radiation at 45 Gy with 4 days of 5-FU plus leucovorin during the first week and 3 days during the last week with postradiation chemotherapy. Major toxicities with pelvic radiation were diarrhea and leukopenia. A tolerable regimen was 54 Gy with 4 days of 5-FU plus leucovorin during the first and fifth week followed by the postradiation chemotherapy. Median survival durations for pancreatic and rectal/sigmoid carcinomas are 13 months and 31 months, respectively. Five patients have no evidence of disease from 38 to 50 months after the onset of therapy (rectal, n = 2; stomach, n = 2; pancreas, n = 1).

CONCLUSION

We have developed patient-tolerable regimens for combined 5-FU plus leucovorin followed by radiation to the abdomen and to the pelvis. The favorable results observed in locally unresectable disease allow cautious optimism for possible effectiveness in the surgical adjuvant setting, a possibility currently being tested in national trials of rectal and gastric carcinoma.
Prospective evaluation of internal adenopathy in a cohort of 43 patients with hairy cell leukemia.
Authors: Hakimian D , Tallman M S , Hogan D K , Rademaker A W , Rose E , Nemcek A A
Published: February 2017

PURPOSE

To determine the role of computed tomography (CT) in patients with hairy cell leukemia (HCL), we report a series of 43 patients prospectively evaluated for internal adenopathy by CT before and after treatment with 2-chlorodeoxyadenosine (2-CdA).

PATIENTS AND METHODS

CT was performed on 43 consecutive patients with HCL before and 3 months after a single cycle of 2-CdA. Twenty-four patients were previously diagnosed and 19 were newly diagnosed. Adenopathy was considered bulky if the greatest dimension of any confluent mass was between 5 and 10 cm and massive if greater than 10 cm.

RESULTS

Internal adenopathy was present in six of 43 patients (14%). Three of the six patients had massive abdominal adenopathy and one had bulky abdominal adenopathy. All six patients with adenopathy were previously diagnosed, while none of the 19 newly diagnosed patients had internal adenopathy. In those patients previously diagnosed, the six with adenopathy had a median disease duration of 68 months, while the 18 patients without adenopathy had a median disease duration of 24 months (P = .01). Adenopathy was more common in splenectomized patients. In previously diagnosed patients, adenopathy occurred in five of 10 (50%) splenectomized patients and one of 14 (7%) nonsplenectomized patients (P = .05). However, the 10 splenectomized patients had a median disease duration of 56 months, while the 14 nonsplenectomized patients had a median disease duration of 16 months (P = .004). All six patients had significant reduction in adenopathy 3 months after 2-CdA and were without residual HCL in the bone marrow.

CONCLUSION

Significant internal adenopathy in patients with HCL is more frequent than previously recognized. Adenopathy is rare at diagnosis and appears to be related to disease duration. As patients treated with 2-CdA have long disease-free survival durations, detection of significant adenopathy by CT scan may be important; however, routine CT scans are not recommended at the time of diagnosis.
Steady-state levels and bone marrow toxicity of etoposide in children and infants: does etoposide require age-dependent dose calculation?
Authors: Boos J , Krümpelmann S , Schulze-Westhoff P , Euting T , Berthold F , Jürgens H
Published: February 2017

PURPOSE

Most pediatric treatment protocols specify dose calculations for cytostatic drugs based on body-surface area (BSA). However, for children less than 1 year of age, calculation guidelines vary. Normally, reduced dosages are recommended with calculations based on body weight (BW). However, the optimal dose for infants should take age-dependent and drug-specific pharmacokinetic parameters into account.

PATIENTS AND METHODS

The current investigation focused on the effects of different dose-reduction rules on the steady-state levels (Css) of etoposide and related bone marrow toxicity. One hundred seventy three treatment courses in 78 children on a 96-hour continuous infusion schedule were monitored for Css (determined by high-performance liquid chromatography [HPLC]), and 100 courses were documented in detail with regard to dose calculation (125 mg/m2, 4.17/kg, or 2/3 x 4.17/kg) and toxicity.

RESULTS

Dose calculation on the basis of BSA led to Css of 4.9 +/- 1.2 micrograms/mL, which on the basis of BW was 3.5 +/- 1.1 micrograms/mL and 1.95 +/- 0.6 micrograms/mL (2/3.kg-dose), respectively. However, conversion of the latter levels to those expected with the regular square-meter-dose, resulted in values of 4.7 +/- 1.4 micrograms/mL and 4.2 +/- 1.2 micrograms/mL (/125 mg/m2). Lower etoposide Css levels resulted in less pronounced thrombocyte and WBC nadirs in the respective groups. The dose-calculation rules for infants, therefore, decreased both dose-intensity and related toxicity. Etoposide clearance rates related to BW (0.8 +/- 0.3 mL/min/kg) or BW (19 +/- 6 mL/min/m2) did not show any differences between children and infants, even in the age range of 3 to 12 months.

CONCLUSION

In the case of etoposide, special dose-calculation guidelines for infants are not substantiated by age-dependent pharmacokinetics or tolerance.
Predictive factors for peripheral-blood progenitor-cell collections using a single large-volume leukapheresis after cyclophosphamide and granulocyte-macrophage colony-stimulating factor mobilization.
Authors: Passos-Coelho J L , Braine H G , Davis J M , Huelskamp A M , Schepers K G , Ohly K , Clarke B , Wright S K , Noga S J , Davidson N E
Published: February 2017

PURPOSE

(1) To study the ability of mobilized peripheral-blood progenitor cells (PBPC) collected in a single large-volume leukapheresis performed on a predetermined date to accelerate engraftment after high-dose cyclophosphamide and thiotepa; (2) to establish the minimum dose of PBPC associated with early engraftment; and (3) to identify parameters predictive of collection of large numbers of PBPC.

PATIENTS AND METHODS

Twenty-three patients with breast cancer received cyclophosphamide (4 g/m2) and granulocyte-macrophage colony-stimulating factor ([GM-CSF] 5 micrograms/kg/d x 15 days) for PBPC mobilization. A single leukapheresis was performed 15 days after cyclophosphamide administration. Then, patients received high-dose cyclophosphamide and thiotepa followed by reinfusion of PBPC and 4-hydroperoxycyclophosphamide (4HC)-purged bone marrow. PBPC concentration was measured in serial peripheral-blood samples and in the leukapheresis product. Correlation analysis between PBPC dose and engraftment and between leukapheresis yield and patient characteristics was attempted.

RESULTS

A single leukapheresis processed a median 36 L (range, 24 to 46) blood and collected 5 x 10(6) CD34+ cells/kg (< 0.3 to 24) and 6.2 x 10(5) colony-forming units granulocyte-macrophage (CFU-GM)/kg (< 0.001 to 29). All sixteen patients (70%) reinfused with > or = 2.9 x 10(6) CD34+ cells/kg reached a level of greater than 1,000 leukocytes/microL by day 13 and greater than 50,000 platelets/microL by day 15. All of these patients had a percentage of peripheral-blood CD34+ cells > or = 0.5%, and all but one, a level of greater than 100,000 platelets/microL, on the day of leukapheresis. The bone marrow CD34+ cell percentage at study entry predicted the number of CD34+ cells collected after PBPC mobilization (R2 = .42, P = .002). All patients with > or = 2.5% bone marrow CD34+ cells experienced early engraftment.

CONCLUSION

Reinfusion of PBPC collected in a single leukapheresis accelerates engraftment in the majority of patients. Pretreatment bone marrow CD34+ cell content determines PBPC mobilization capacity and may help select hematopoietic rescue strategies.
Phase II study of continuous infusion fluorouracil and interferon alfa-2b in the palliation of malignant neuroendocrine tumors.
Authors: Andreyev H J , Scott-Mackie P , Cunningham D , Nicolson V , Norman A R , Badve S S , Iveson A , Nicolson M C
Published: February 2017

PURPOSE AND METHODS

Twenty-four patients with rapidly progressive neuroendocrine tumors were treated with a new regimen of continuous infusion fluorouracil for 20 weeks (200 mg/m2/d) together with interferon alfa-2b (5 MU three times per week). Maintenance interferon alfa at the same dose was continued after the initial 20-week period.

RESULTS

Of 15 patients with carcinoid tumors, seven (47%) had an objective response, with a median duration of 20.5 months (range, 8.5 to 41), and five (33%) had stabilization of disease for between 3.5 and 42 months. Improvement in symptoms was reported by 10 patients (67%). Three early deaths occurred, all in patients with advanced disease. Of nine patients with neuroendocrine tumors other than carcinoid, three (33%) had an objective response that lasted 2.5 to 24.5 months, and five had disease stabilization for between 2.5 and 16 months.

CONCLUSION

These data, particularly in respect to carcinoid tumors, are encouraging, especially since serious complications from treatment were limited. This regimen is not generally toxic, is well tolerated, and offers useful palliation and symptom control in patients with disease that does not respond to simple pharmacologic manipulations.
Peripheral-blood stem-cell collections after paclitaxel, cyclophosphamide, and recombinant human granulocyte colony-stimulating factor in patients with breast and ovarian cancer.
Authors: Demirer T , Rowley S , Buckner C D , Appelbaum F R , Lilleby K , Storb R , Schiffman K , Bensinger W I
Published: February 2017

PURPOSE

Here we evaluate Taxol (paclitaxel; Bristol-Myers Squibb, Princeton, NJ) and cyclophosphamide (CY) with recombinant human granulocyte colony-stimulating factor (rhG-CSF) for mobilization of peripheral-blood stem cells (PBSCs) for autologous stem-cell transplantation in patients with breast and ovarian cancer.

PATIENTS AND METHODS

PBSCs were collected from 17 patients with breast (n = 11), ovarian (n = 5), and gastric (n = 1) cancer after administration of Taxol (170 mg/m2 x 1) and CY (4 g/m2 x 1) followed by rhG-CSF (10 micrograms/kg/d). PBSC collections after Taxol and CY were compared with PBSC collections from nine patients with stage IV breast (n = 8) or stage III ovarian (n = 1) cancer who had received CY (4 g/m2 x 1) followed by rhG-CSF (16 micrograms/kg/d) for mobilization.

RESULTS

Mean WBC and platelet counts on the first day of apheresis were 6.3 x 10(9)/L (range, 1.9 to 22.1) and 35 x 10(9)/L (range, 19 to 77), respectively. The median numbers of CD34+ cells, peripheral-blood mononuclear cells (PBMNC), and peripheral-blood total nucleated cells (PBTNC) collected were 13.02 x 10(6)/kg (range, 5.4 to 57.8; mean, 16.02), 6.86 x 10(8)/kg (range, 1.9 to 51.2), and 17.41 x 10(8)/kg (range, 2.4 to 106.6), respectively. In the comparison group, the median yield of CD34+ cells was 6.39 x 10(6)/kg (range, 0.2 to 28; mean, 10.01; P = .01). The mean daily yield of CD34+ cells/kg/collection was 3.5 (range, 0.8 to 28.9) after Taxol and CY, as compared with 1.3 (range, 0.1 to 7.0) for patients who received CY alone (P = .01). All patients who received CY and Taxol reached a target level of 5 x 10(6) CD34+ cells/kg, as compared with five of nine patients (55.5%) who received CY alone (P = .03).

CONCLUSION

These data suggest that Taxol and CY followed by rhG-CSF mobilizes PBSCs in patients with advanced breast and ovarian cancer more effectively than this regimen without Taxol.
Radiation oncologist density and pancreatic cancer mortality.
Authors: Aneja S. , Yu J. B.
Published: February 2017

350

Background: Though the role of radiation oncologists (RO) in the curative treatment of pancreatic cancer (PC) is not well defined, RO are important for the multidisciplinary care of cancer patients. The impact of this variation on PC outcomes remains unexplored. The goal of this study was to determine the effect of RO density on PC mortality.

Methods: Using county-level data from the 2008 Area Resource File, National Program for Cancer Registries, and U.S. Centers for Disease Control, a multivariate regression model was constructed for PC mortality, controlling for county-level categorized RO density, demographics, socioeconomic status, and existing health care facilities.

Results: There was a statistically significant reduction in PC mortality (reduction ranging from 27% to 51% p<.001) associated with counties that possessed at least one RO. Also there existed a statistically significant improvement in mortality in counties with a density of at least two RO per 100,000 people compared to counties with one radiation oncologist per 100,000 people.

Conclusions: The presence of a RO is associated with lowered morality for PC within that county. In contrast to our other density analyses investigating the association between radiation oncology density and colorectal cancer and esophageal cancer mortality, the association between additional RO and PC mortality was equivocal. This may reflect the varying use of radiation oncology in different counties for the curative treatment of PC. Our study suggests that RO play an important role in the treatment of PC.

[Table: see text]

No significant financial relationships to disclose.
Updated survival results of the randomized phase II study comparing cisplatin/capecitabine (CX) with epirubicin plus CX (ECX) in advanced gastric cancer (AGC).
Authors: Lim T. , Yun J. , Lee J. , Park S. , Park J. , Park Y. , Lim H. , Kang W.
Published: February 2017

46

Background: We previously reported results of a randomized study showing that CX is equally active to ECX in terms of progression-free survival (PFS) (Yun et al. Eur J Cancer. 2010). Here we report updated overall survival (OS) results with an additional 12 months' follow-up.

Methods: Ninety-one chemotherapy-naïve patients with histologically-confirmed, measurable AGC were randomized to receive CX (cisplatin 75 mg/m2 iv on day 1 and capecitabine 1,000 mg/m2 bid po on days 1-14, n=45) or ECX (epirubicin 50 mg/m2 plus CX, n=44) every 3 weeks. After CX or ECX had failed, second-line chemotherapy (SLC) was recommended for all patients if their performance status was preserved.

Results: Treatment duration was similar for both arms (4.4 for CX v 4.2 months for ECX). There was no relevant difference in the occurrence of overall grade 3 or 4 toxicities between the CX and ECX arms (80% v 78%, respectively; p=0.516). However, none in the CX and 12% in the ECX arm discontinued treatment because of toxicity. There were no significant differences in therapeutic efficacy between CX and ECX with respect to the response rate (38% v 37%, respectively), PFS (6.4 v 6.5 months), as well as OS (12.7 v 13.8 months; p=0.51). After failure, 60% of patients (26 CX and 28 ECX patients) received SLC. However, OS was not differed whether a patient was treated with SLC or not (13.1 v 11.2 months; p=0.94).

Conclusions: The present analysis confirms previous findings that both CX and ECX appear to be comparatively active as first-line chemotherapy for AGC. Furthermore, the role of SLC in AGC warrants further evaluation.

No significant financial relationships to disclose.
Conatumumab (CON) plus FOLFIRI (F) or ganitumab (GAN) plus F for second-line treatment of mutant (MT) KRAS metastatic colorectal cancer (mCRC).
Authors: Cohn Allen Lee , Tabernero Josep , Maurel Juan , Nowara Elzbieta , Dubey Sarita , Baker Nigel , Hei Yong Jiang , Galimi Francesco , Choo SuPin
Published: February 2017

534

Background: EGFR inhibitors are not an option for patients (pts) with MT KRAS mCRC; therefore, there is an unmet medical need for novel agents to treat this pt population. CON (agonist) and GAN (antagonist) are investigational, fully human monoclonal antibodies to death receptor 5 and type 1 insulin-like growth factor receptor, respectively. In colorectal xenografts, CON enhanced the activity of 5FU, and both agents enhanced the activity of irinotecan. A 3-arm, placebo (pbo)-controlled, double-blind, double dummy, randomized phase 2 study evaluated both agents in MT KRAS mCRC.

Methods: Planned sample size = 150. Eligibility: MT KRAS mCRC; disease progression on 1 prior oxaliplatin and fluoropyrimidine therapy. Randomization was 1:1:1 to Arm 1: CON 10 mg/kg + GAN pbo + F Q2W; Arm 2: CON pbo + GAN 12 mg/kg + F Q2W; Arm 3: CON pbo + GAN pbo + F Q2W. Randomization was stratified by PS (0 vs 1) and prior anti-VEGF therapy (yes vs no). Pts received CON, GAN, or pbo IV day (D)1 and 15; irinotecan 180 mg/m2 D1; leucovorin 400 mg/m2 over 2 h D1; 5FU bolus 400 mg/m2 over 2-4 min D1 then 5FU 2400 mg/m2 over 46-48 h. Primary endpoint: PFS by investigator assessment.

Results: 155 pts (Arms 1/2/3: 51/52/52 pts) were randomized between 3/09 and 2/11; 50/50/52 received ≥ 1 dose of study drug. Median age, 59/58/59 years; women, 47/54/56%; colon cancer, 75/65/83%; PS 1, 37/42/40%; prior anti-VEGF therapy, 43/40/42%. See table for efficacy. % pts with grade 3-5 adverse events (Arms 1/2/3) included: neutropenia 30/25/18%; diarrhea 18/2/10%; intestinal obstruction 4/6/8%. There was 1 treatment-related death of unknown cause on Arm 1.

Conclusions: CON + F and GAN + F were tolerable in this pt population. CON + F, but not GAN + F, improved PFS. ORR was increased vs pbo. OS data are immature. Further study of CON may be warranted in mCRC.

[Table: see text]
A phase III randomized, open-label multicenter trial to evaluate the benefit of leuprorelin acetate for 24 months after radical prostatectomy in patients with high risk of recurrence (AFU-GETUG 20/0310).
Authors: Rozet Francois , Habibian Muriel , Berille Jocelyne , Roca Lise , Salomon Laurent , Soulie Michel , Culine Stephane
Published: February 2017

252

Background: Post radical prostatectomy patients (RP) with extra prostatic extension or high Gleason grade are considered to have a high risk of treatment failure. Actual role of LH-RH agonists after RP in patients with high risk of recurrence remains unclear, except for the patients with positive lymph nodes. No randomized prospective study has been published with LH-RH agonists in the PSA era. Recent SWOG 9921 study shows a favorable disease-free and 5-year overall survival of 96% for high-risk patients treated with 24 months of ADT after surgery. However, this study does not define the optimal protocol of adjuvant ADT, and does not demonstrate the superiority of immediate vs delayed treatment. The Objective of the AFU-GETUG 20 study is to evaluate the benefit of leuprorelin acetate for 24 months after RP in patients with high risk of recurrence.

Methods: Academic Phase III randomised, open-label, multicenter trial starting in late 2011. Inclusion criteria : R0, N0-Nx M0 patients after RP in the 3 months preceding inclusion and with postoperative Gleason score > 7, or ≥ 7 with the presence of 5 grade Gleason patterns or, or pT3b tumor, and with postoperative PSA < 0.1 ng/mL. Exclusion criteria : previous/current therapy for PCa. Primary endpoint is the evaluation of metastatic progression free survival. Secondary endpoints include overall survival, disease-specific survival, PSA evolution, evaluation of testosterone level, and quality of life.

Results: A total of 700 patients (350 in each arm) and 250 events are required to have 80% ability to detect a difference with a bilateral Logrank test with α= 0.05 and β= 0.20. Decision rules will be determined by the O’ Brien-Fleming sequential boundaries at the time of the analysis. Interim analysis is planned at the 125th event (50% of events) for 6.5 years after the start of the trial. Final analysis is planned for 12 years after the inclusion of the first patient.

Conclusions: The AFU-GETUG 20 study is a pioneering French multicenter trial aiming to evaluate the actual role and place of ADT after RP for patients with high-risk prostate cancer.
Use of Palliative Cisplatinum for Advanced Cervical Cancer in a Resource-Poor Setting: A Case Series From Kenya
Authors: Orang’o Elkanah , Itsura Peter , Tonui Philip , Muliro Hellen , Rosen Barry , van Lonkhuijzen Luc
Published: February 2017

Purpose

To evaluate the effectiveness and feasibility of cisplatinum for palliative treatment of advanced cervical cancer in a resource-poor setting.

Methods

An observational case series is reported from a university teaching hospital in Kenya. All women presenting with advanced cervical cancer and planned for palliative cisplatinum therapy from 2010 to 2014 were included. Women were treated with cisplatinum 50 mg/m2every 4 weeks in an outpatient setting. Data on tumor stage and symptoms control were prospectively collected in an electronic database. The main outcome measure was control of symptoms such as bleeding, discharge, and pain.

Results

Of the women who originally presented with bleeding, 62% reported improvement in this symptom, 31.3% reported the bleeding completely stopped, 58% had improvement of their vaginal discharge, and 20.5% reported complete resolution. Of the women who presented with pain, 54% reported improvement; 30.9% reported pain had completely resolved. After each treatment cycle, approximately 30% of patients did not return for their next treatment.

Conclusion

Cisplatinum as palliative treatment of advanced cervical cancer is feasible in a resource-poor setting and leads to effective symptom control. However, unknown barriers may inhibit women from returning for regular treatment.