bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I and pharmacokinetic study of etoposide phosphate by protracted venous infusion in patients with advanced cancer.
Authors: Soni N , Meropol N J , Pendyala L , Noel D , Schacter L P , Gunton K E , Creaven P J
Published: February 2017

PURPOSE

Etoposide has schedule-dependent cytotoxic activity, and clinical resistance may be overcome with prolonged low-dose therapy. Oral bioavailability is variable, and protracted intravenous administration is limited by water insolubility, which requires large infusion volumes. Etoposide phosphate (EP) is a water-soluble prodrug that is rapidly converted in vivo to etoposide, and may be administered in concentrated solution. A phase I study was conducted to determine the toxicity, pharmacokinetics, and pharmacodynamics of EP administered as a protracted venous infusion in the ambulatory setting.

METHODS

Twenty-three patients with advanced cancer were treated with a continuous infusion of EP using ambulatory pumps for 6 weeks followed by a 2-week rest. Cohorts were treated with EP at 10, 20, 25, and 30 mg/m2/d. Steady-state plasma etoposide levels (Css) and stability of EP in infusion pumps were measured using high performance liquid chromatography (HPLC).

RESULTS

Myelosuppression, mucositis, and fatigue were dose-limiting. The maximum-tolerated dose (MTD) of EP was 20 mg/m2/d. The mean Css (+/- SD) of etoposide were 0.67 +/- 0.25, 1.14 +/- 0.24, 1.38 +/- 0.64, and 2.19 +/- 0.52 microg/mL at daily EP doses of 10, 20, 25, and 30 mg/m2, respectively. Neutropenia correlated with Css (r = 0.65, P = .008). EP was stable in infusion pumps for at least 7 days. Partial responses were observed in patients with hepatoma and non-small-cell lung cancer (one each).

CONCLUSION

EP may be conveniently and safely administered as a low-volume protracted venous infusion in the ambulatory setting. Cytotoxic plasma concentrations of etoposide are obtained at the MTD. The pharmacodynamic relationships observed suggest the possibility of pharmacologically based dosing of EP.
Adoptive immunotherapy with vaccine-primed lymph node cells secondarily activated with anti-CD3 and interleukin-2.
Authors: Chang A E , Aruga A , Cameron M J , Sondak V K , Normolle D P , Fox B A , Shu S
Published: February 2017

PURPOSE

In preclinical studies, we have reported the ability to induce immune T cells in lymph nodes (LN) primed by in vivo vaccination with tumor cells admixed with a bacterial adjuvant. These LN cells can be activated and expanded ex vivo for the successful immunotherapy of established tumors. We have applied these methods to generate vaccine-primed LN in patients with advanced melanoma and renal cell cancer (RCC) for therapy.

MATERIALS AND METHODS

Irradiated autologous tumor cells admixed with bacille Calmette-Guérin (BCG) were used to vaccinate patients. Seven days later, draining LN were removed for activation with anti-CD3 monoclonal antibody (mAb) followed by expansion in interleukin-2 (IL-2). Activated LN cells were administered intravenously (IV) with the concomitant administration of IL-2.

RESULTS

A total of 23 patients were evaluated (11 melanoma and 12 RCC). Vaccine-primed LN were expanded ex vivo with a mean of 8.4 x 10(10) cells administered per patient. Among 20 patients assessed, 15 demonstrated minimal cytotoxicity of autologous tumor cells by the activated LN cells, with the remaining mediating nonspecific cytotoxicity. By contrast, a majority of the activated LN cells showed highly specific release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN-gamma) to autologous but not allogeneic tumor stimulation. This tumor-specific cytokine release was found to be major histocompatibility complex (MHC) class I-restricted, which indicates the involvement of CD8+ cells. Among 11 melanoma patients, one had a partial tumor response. Among 12 RCC patients, two had complete and two partial responses. A trend (P = .066) between the enhancement of delayed-type hypersensitivity (DTH) reactivity to autologous tumor after therapy and tumor regression was observed.

CONCLUSION

Tumor vaccines can be used to induce immunologically specific T-cell responses against melanoma and RCC in draining LN. Anti-CD3/IL-2 activation of primed LN cells can be reliably performed for clinical therapy and appears to have activity in patients with metastatic RCC.
Comparative study of dose escalation versus interval reduction to obtain dose-intensification of epirubicin and cyclophosphamide with granulocyte colony-stimulating factor in advanced breast cancer.
Authors: Lalisang R I , Wils J A , Nortier H W , Burghouts J T , Hupperets P S , Erdkamp F L , Schouten H C , Blijham G H
Published: February 2017

PURPOSE

A potential application of hematopoietic growth factors is to obtain an increased dose-intensity. This can be achieved by either higher doses of chemotherapy with standard intervals, or by standard doses with shorter intervals. The potential of these approaches has not been investigated systematically.

PATIENTS AND METHODS

In a randomized, multicenter study, 49 advanced breast cancer patients were treated with granulocyte colony-stimulating factor (G-CSF) and either increasing doses of epirubicin and cyclophosphamide with fixed intervals (arm one) or progressively shorter intervals with fixed doses of epirubicin and cyclophosphamide (arm two). A cohort of at least six patients was studied at each interval/dose. A more intensified interval/dose was given if less than 50% of patients encountered a dose-intensity limiting criterium (DILC) in the first three courses.

RESULTS

In arm one, epirubicin 140 mg/m2 and cyclophosphamide 800 mg/m2 every 21 days was too toxic. Subsequently, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 was tested with two of 10 patients encountering a DILC. All initial DILCs consisted of febrile neutropenia. In arm two, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely with 14- and 12-day intervals. In the 10-day interval, eight of 12 patients completed the first three cycles without a DILC. In the 8-day interval, seven of eight patients encountered a DILC. Incomplete neutrophil recovery, and to a lesser extent stomatitis, were dose-limiting.

CONCLUSION

In combination with G-CSF, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 every 21 days was feasible (projected dose-intensity, 40 mg/m2/wk and 233 mg/m2/wk, respectively). Epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely every 10 days, allowing a projected dose-intensity of 52.5 mg/m2/wk and 350 mg/m2/wk, respectively.
Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer.
Authors: Livingston R B , Ellis G K , Gralow J R , Williams M A , White R , McGuirt C , Adamkiewicz B B , Long C A
Published: February 2017

PURPOSE

We evaluated weekly single-agent intravenous (IV) vinorelbine as salvage therapy for metastatic breast cancer. After the first five patients, all received elective growth factor support with granulocyte colony-stimulating factor (G-CSF; filgrastim) in an attempt to maximize delivered dose-intensity (DDI). Objective tumor response, DDI, and toxicity were assessed, as well as time to progression (TTP) and survival.

PATIENTS AND METHODS

This single-center nonrandomized trial enrolled 40 patients. Anthracycline exposure and subsequent progression were common to all patients, and 38 of 40 were paclitaxel-refractory. Vinorelbine was given initially at 30 mg/m2/wk, then at 35 mg/m2/wk in a phase I/II design, which involved first intermittent (6 days of 7) and then continuous (daily) administration of G-CSF at 5 micrograms/kg.

RESULTS

The maximum-tolerated starting dose was 35 mg/m2/wk with continuous G-CSF support. The mean DDI was 27.7 mg/m2/wk for all patients. There were two complete responses (CRs) and eight partial responses (PRs) in 40 assessable patients for an overall response rate of 25% (95% confidence interval [CI], 13% to 41%). The median TTP was 13 weeks and median survival time 33 weeks. The dose-limiting toxicity was neutropenia, with dose delay or reduction required in 14 of 27 patients entered at 35 mg/m2. Febrile neutropenia that required hospitalization was unusual (three of 40 patients, 8%). There were no treatment-related deaths. Grade 3/4 thrombocytopenia occurred in nine patients (23%) and 26 patients (65%) required RBC transfusions for anemia. Seven patients (18%) had reversible grade 3/4 nonhematologic complications, primarily related to neurotoxicity. Grade > or = 3 mucositis was absent.

CONCLUSION

Concurrent administration of weekly vinoralbine and daily G-CSF is feasible and permits an increase in DDI for vinorelbine of 43% to 76% over that reported in series without growth factor support. The response rate, TTP, and survival data are encouraging for therapy given to heavily pretreated patients with metastatic breast cancer. Vinorelbine is not cross-resistant with paclitaxel and should be considered for further trials in the dose-intensified mode made possible by G-CSF, alone or combined with other agents.
Weekly paclitaxel and cisplatin with concurrent radiotherapy in locally advanced non-small-cell lung cancer: a phase I study.
Authors: Frasci G , Comella P , Scoppa G , Guida C , Gravina A , Fiore F , Casaretti R , Daponte A , Parziale A , Comella G
Published: February 2017

PURPOSE

Both cisplatin (CDDP) and paclitaxel have shown good antitumor activity in non-small-cell lung cancer (NSCLC) patients and are able to potentiate the antitumor effects of radiation therapy (RT). This study aimed to determine the maximum-tolerated doses (MTDs) of CDDP and paclitaxel (escalated alternately) when given concurrently with RT and to define the nature of the dose-limiting toxicity (DLT).

PATIENTS AND METHODS

Chemotherapy-naive patients with locally advanced NSCLC received six weekly administrations of a CDDP-paclitaxel combination with concurrent local RT. The starting doses of CDDP and paclitaxel were 30 mg/m2/wk and 35 mg/m2/wk, respectively. RT was initially given at the dose of 1.2 Gy twice daily for 5 days per week for 5 weeks (total dose, 60 Gy) and at a single daily dose of 2 Gy for 5 days per week for 6 weeks in the last two cohorts of patients. The drug doses were escalated alternately until DLT occurred in more than one third of the patients in a given cohort.

RESULTS

Overall, 25 patients were recruited through five different cohorts. All were assessable for toxicity. Esophagitis was the main toxicity and occurred in 16 of 25 patients (64%) and was grade 3 or 4 in five of them. At step 3 (CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk), two of five patients had to discontinue treatment because of severe esophagitis and one of these died of complications related to grade 4 esophagitis. However, keeping the same doses of chemotherapy and replacing hyperfractionation with a standard single-day fraction, weekly doses of CDDP and paclitaxel of 35 mg/m2 and 45 mg/m2 could be safely administered. Neutropenia was by far the most relevant hematologic toxicity and occurred in 33 of 141 weekly delivered courses, but it was of grade 4 in only four courses. Substantial pulmonary or neurologic toxicity was not observed in this study. Two complete responses (CRs) and 13 partial responses (PRs) were observed, for a 60% overall response rate (95% confidence interval [CI], 39% to 79%). The median survival time was 16 months, with a 66% 1-year survival probability.

CONCLUSION

CDDP 35 mg/m2/wk and paclitaxel 45 mg/m2/wk can be safely administered with concurrent standard RT. The use of hyperfractionation is associated with a more frequent occurrence of severe esophagitis and requires a reduction of the CDDP dose to 30 mg/m2/ wk. Only future randomized trials will elucidate which of these two approaches (standard or hyperfractionated RT) is the better option to improve the outcome of patients with locally advanced NSCLC.
Phase I and pharmacologic study of the combination paclitaxel and carboplatin as first-line chemotherapy in stage III and IV ovarian cancer.
Authors: Huizing M T , van Warmerdam L J , Rosing H , Schaefers M C , Lai A , Helmerhorst T J , Veenhof C H , Birkhofer M J , Rodenhuis S , Beijnen J H , ten Bokkel Huinink W W
Published: February 2017

PURPOSE

To determine the maximum-tolerated dose for the combination paclitaxel and carboplatin administered every 4 weeks and to gain more insight into the pharmacokinetics and pharmacodynamics of this combination in previously untreated ovarian cancer patients.

PATIENTS AND METHODS

Thirty-five chemotherapy-naive patients with suboptimally debulked stage III (tumor masses > 3 cm) and stage IV ovarian cancer were entered onto this phase I trial in which paclitaxel was administered as a 3-hour intravenous (IV) infusion at dosages of 125 to 225 mg/m2 immediately followed by carboplatin over 30 minutes at dosages of 300 to 600 mg/m2. A total of six courses was planned, followed by a second-look laparoscopy/laparotomy. Patients with a response and/or minimal residual disease at second-look laparoscopy received three additional courses. Twenty-six patients participated in the pharmacokinetic part of the study.

RESULTS

The most important hematologic toxicity encountered was neutropenia. Neutropenia was more pronounced for the higher dose levels (DLs) and was cumulative. Thrombocytopenia was mild in the first eight DLs, but increased during the treatment courses. Nonhematologic toxicities consisted mainly of vomiting, neuropathy, fatigue, rash, pruritus, myalgia, and arthralgia. Dose-limiting toxicities (DLTs) in this trial were neutropenic fever, thrombocytopenia that required platelet transfusions, and cumulative neuropathy. Of 33 patients assessable for response, 26 major responders (78%, 20 complete response [CR] and six partial response [PR]) were documented. The maximal concentration (Cmax) of paclitaxel and the area under the concentration-time curve (AUC) were not different from the historical data for paclitaxel as a single agent. Retrospective analysis using a modified Calvert formula showed that the measured carboplatin AUCs in plasma ultrafiltrate (pUF) were 30% +/- 3.4% less than the calculated carboplatin AUC. Neutropenia was more pronounced than could be expected on the basis of the historical times above a threshold concentration greater than 0.1 mumol/L (T > or = 0.1 mumol/L) or 0.05 mumol/L (T > or = 0.05 mumol/L), and thrombocytopenia was less than could be expected from historical sigmoidal Emax models.

CONCLUSION

The combination of paclitaxel 200 mg/ m2 and carboplatin 550 mg/m2 every 4 weeks is a well-tolerated treatment modality. The paclitaxel-carboplatin combination is highly active in stage III (bulky) and stage IV ovarian cancer. No indications for a pharmacokinetic drug-drug interaction between carboplatin and paclitaxel were found.
Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation--a report from the Société Française de Greffe de Moelle.
Authors: Michel G , Socié G , Gebhard F , Bernaudin F , Thuret I , Vannier J P , Demeocq F , Leverger G , Pico J L , Rubie H , Mechinaud F , Reiffers J , Gratecos N , Troussard X , Jouet J P , Simonin G , Gluckman E , Maraninchi D
Published: February 2017

PURPOSE

To evaluate growth, thyroid function, puberty, cardiac function, and the incidence of cataracts in children who received allogeneic bone marrow transplantation (BMT) for acute myeloblastic leukemia (AML) in first complete remission (CR) after a preparation with or without total-body irradiation (TBI).

PATIENTS AND METHODS

Among 45 children studied, 26 received busulfan-cyclophosphamide (Bu-Cy) in preparation for transplantation and 19 received TBI. TBI was fractionated in nine cases and delivered as a single dose in 10. Four children in the Bu-Cy group and none in the TBI group had received prior cranial radiation. The mean follow-up duration after BMT was 5.9 years for the whole group.

RESULTS

The mean cumulative changes in height SD score (SDS) were -0.86 at 3 years and -1.56 at 5 years in the TBI group, whereas these changes were only -0.05 and -0.17 in the Bu-Cy group (P < .01 at 3 and 5 years). The 6-year probability of hypothyroidism was 9% +/- 8% in the Bu-Cy group and 43% +/- 15% after TBI (P < .02). Pubertal development after Bu-Cy was assessable in two girls and five boys: both girls had primary ovarian failure, whereas Leydig cell function appeared to be preserved in the five boys. One child who had received anthracycline when he was less than 1 year old developed cardiac dysfunction 4 years after Bu-Cy. The 6-year probability of cataracts was 70% +/- 13% in the TBI group and 0% after Bu-Cy.

CONCLUSION

The use of Bu-Cy represents an alternative transplant cytoreductive regimen for children with AML in first CR, which can reduce the risk of posttransplant growth impairment, thyroid dysfunction, Leydig cell damage, and the incidence of cataracts.
Efficacy, toxicity, and applicability of high-dose sequential chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary nodes: five-year results.
Authors: Gianni A M , Siena S , Bregni M , Di Nicola M , Orefice S , Cusumano F , Salvadori B , Luini A , Greco M , Zucali R , Rilke F , Zambetti M , Valagussa P , Bonadonna G
Published: February 2017

PURPOSE

To assess the efficacy, toxicity, and applicability of high-dose therapy administered as adjuvant initial treatment to women with breast cancer with extensive nodal involvement.

PATIENTS AND METHODS

Sixty-seven patients with stage II to III breast cancer involving > or = 10 axillary nodes received a novel high-dose sequential (HDS) regimen, including the high-dose administration of three non-cross-resistant drugs (cyclophosphamide, methotrexate, and melphalan) given within the shortest interval of time as possible with hematologic and nonhematologic toxicity.

RESULTS

Sixty-three patients completed the program as planned, one patient died of acute toxicity, and three patients were switched to standard-dose adjuvant therapy. After a median follow-up duration of 48.5 months and a lead follow-up of 78 months, actuarial relapse-free survival for all 67 registered patients is 57% and overall survival is 70%, respectively. Comparison with a historical control group of 58 consecutive patients showed a significantly superior rate of freedom from relapse for the HDS-treated group (57% v 41%, respectively), in particular when two subgroups of patients, more homogeneous for their number of involved nodes, were compared (65% v 42%). Overall, treatment was of short duration (median, 70 days), required a median of 32 days of hospital stay, and was associated with only a few severe side effects (the most distressing being oral mucositis after melphalan therapy).

CONCLUSION

HDS therapy emerges as an effective and applicable regimen, whose major toxicity was occasional. Final assessment of its value in a randomized, multicenter trial is presently underway.
Growth of newly diagnosed, untreated metastatic gastrinomas and predictors of growth patterns.
Authors: Sutliff V E , Doppman J L , Gibril F , Venzon D J , Yu F , Serrano J , Jensen R T
Published: February 2017

PURPOSE

The growth pattern of untreated metastatic neuroendocrine tumors is unknown. This uncertainty contributes to the disagreement regarding timing and could effect evaluation of the efficacy of antitumor treatment. The purpose of this study was to determine the growth rate of untreated hepatic metastatic gastrinoma and to identify its predictors.

PATIENTS AND METHODS

Nineteen patients with histologically proven metastatic gastrinoma in the liver with Zollinger-Ellison syndrome were studied. Conventional imaging studies were performed initially and at 4- to 6-month intervals before any treatment. Metastases growth rates were calculated and correlated with laboratory and clinical parameters, as well as tumor extent on initial tumor assessment.

RESULTS

Twenty-six percent of patients (five of 19) demonstrated no growth over a mean follow-up time of 29 months, 32% (six of 19) had slow growth (1% to 50% increase in volume per month) over a 19-month period, and 42% (eight of 19) had rapid growth (> 50% volume increase per month) over an 11-month period. In patients with rapid growth, 62% died; 0% of the no-growth or slow-growth group died. No clinical or laboratory parameter correlated with growth rate, except the rate increase in fasting serum gastrin and the presence of bilobar liver or bone metastases. The growth rate was highly predictive of death from tumor.

CONCLUSION

The growth rate of metastatic gastrinoma varies markedly in different patients and 26% demonstrate no growth. The growth rate needs to considered in the determination of when and in whom antitumor therapy is initiated, as well as in the assessment of response to tumoricidal therapies.
Megestrol acetate and aminoglutethimide/hydrocortisone in sequence or in combination as second-line endocrine therapy of estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group phase III trial.
Authors: Russell C A , Green S J , O'Sullivan J , Hynes H E , Budd G T , Congdon J E , Martino S , Osborne C K
Published: February 2017

PURPOSE

A phase III randomized trial was performed to determine whether combination hormonal therapy with aminoglutethimide (AG) and hydrocortisone (HC) plus megestrol acetate (MA) improved response rates, response duration, or increased survival over the sequential use of each hormone in women with estrogen receptor-positive metastatic breast cancer (MBC) who had maintained stable disease for at least 6 months or responded to tamoxifen.

PATIENTS AND METHODS

Two hundred eighty-eight postmenopausal women with progressive estrogen receptor-positive MBC were randomly selected to receive MA 40 mg four times daily (arm I), AG 250 mg four times daily with HC 40 mg daily in divided doses (arm II), versus the combination of MA plus AG given at the same dosages (arm III). Patients on arms I and II who progressed after an adequate trial were crossed over to the other treatment arm.

RESULTS

Two hundred thirty-five eligible patients were evaluated for response, time to treatment failure, and survival. Response was only reported for patients with measurable disease and was not statistically different among the three arms. There were two partial responses (PRs) on MA (6%), four complete responses (CRs) and six PRs on AG (24%), and eight PRs and three CRs on MA plus AG (23%) in 32, 42, and 48 measurable patients, respectively. Median times to treatment failure were also similar at 5, 4, and 7 months. Survival was also not statistically different among the three arms at 26, 27, and 26 months for arms I, II, and III, respectively. Toxicity was greater in the two AG arms with respect to fatigue, nausea and vomiting, and rash.

CONCLUSION

With the exception of toxicity, there is no response, time to treatment failure, or survival benefit for any one group when comparing MA, AG, or the combination at their stated doses in women with estrogen receptor-positive MBC who had previously responded to or stabilized with tamoxifen.
Overview of randomized perioperative polychemotherapy trials in women with early-stage breast cancer.
Authors: Clahsen P C , van de Velde C J , Goldhirsch A , Rossbach J , Sertoli M R , Bijnens L , Sylvester R J
Published: February 2017

PURPOSE

To determine whether perioperative polychemotherapy (PeCT) can significantly prolong the overall survival of women with early-stage breast cancer.

METHODS

A meta-analysis that used updated individual patient data from all available randomized trials of PeCT, both published and unpublished, was conducted. Data on 6,093 patients (1,124 deaths and 1,912 recurrences) from five clinical trials were available (median follow-up duration, 5.3 years; maximum, 11.3 years).

RESULTS

No significant effect of PeCT on overall survival was observed. However, patients who received PeCT had a significantly longer disease-free survival (hazards ratio [HR], 0.89; 95% confidence interval [CI], 0.82 to 0.98; P = .02). Time to local recurrence was significantly prolonged in the PeCT arm (HR, 0.68; 95% CI, 0.58 to 0.80; P < .0001). Likewise, there was a borderline significant difference in favor of PeCT in terms of time to distant metastases (HR, 0.90; 95% CI, 0.81 to 1.00; P = .05). Subgroup analyses suggest that node-negative women benefited the most from treatment.

CONCLUSION

At present, there is no evidence that PeCT is able to prolong overall survival in patients with early-stage breast cancer; however, further follow-up evaluation is required. PeCT significantly prolongs disease-free survival, especially in node-negative women, which emphasizes once more the need for clinical trials in this subgroup.
Access to bone marrow transplantation for leukemia and lymphoma: the role of sociodemographic factors.
Authors: Mitchell J M , Meehan K R , Kong J , Schulman K A
Published: February 2017

PURPOSE

Use of bone marrow transplantation (BMT), a complex, costly treatment for many forms of cancers, has increased significantly in recent years. The increasingly competitive health care marketplace raises concerns about patient access to costly medical procedures such as BMT. We attempted to evaluate patient access to BMT for the treatment of leukemias and lymphomas.

METHODS

We analyzed inpatient hospital discharge data from four states (California, Maryland, Massachusetts, and New York) for 2 years (1988 and 1991) to examine whether the use of BMT for patients with either leukemia or lymphoma varies by sociodemographic characteristics and insurance coverage. We developed a sorting algorithm to collapse the discharge data into patient level records. We used logistic regression to analyze the odds of receiving a BMT stratified by disease type (leukemia or lymphoma).

RESULTS

After controlling for other factors, black patients with leukemia are 51% to 53% as likely as whites, while black patients with lymphoma are 34% to 45% as likely as white patients to undergo a BMT (P < .05). Medicaid, self-pay patients, and Health Maintenance Organization (HMO) enrollees with either leukemia or lymphoma are significantly less likely to undergo a BMT compared with patients with private insurance. Younger patients are significantly more predisposed to undergo a BMT than older patients. The odds of receiving a BMT have increased over time, but the rates of increase vary by state. Consistent with clinical expectations, the relative odds of BMT vary significantly by type of leukemia or lymphoma.

CONCLUSION

Substantial variation exists in access to BMT for patients with either leukemia or lymphoma. Black patients, those enrolled in HMOs, those covered by Medicaid, and self-pay patients were less likely to receive a BMT when admitted for either leukemia or lymphoma. These findings raise concerns about access to cancer treatments for patients in the current health care system.
Cost-effectiveness of interferon alfa in chronic myelogenous leukemia.
Authors: Liberato N L , Quaglini S , Barosi G
Published: February 2017

PURPOSE

To evaluate the cost-effectiveness of interferon alfa (IFN alpha) treatment of patients with chronic myelogenous leukemia relative to conventional chemotherapy.

MATERIALS AND METHODS

A decision-analysis model that involved a multistate Markov process was designed to estimate the expected cost and quality-adjusted life expectancies for two cohorts of patients to be administered conventional chemotherapy or IFN alpha. Two IFN alpha strategies were modeled: prolonged treatment for patients who achieved a hematologic response (scenario A) or only for patients who achieved a cytogenetic remission in a 2-year period (scenario B). Data on response and transition probabilities between health states were obtained from the literature by a MEDLINE search and pooled with a meta-analytic method. Costs were based on local charges. Expected survival was adjusted for quality of life on the basis of an expert panel judgment.

RESULTS

Baseline analysis showed IFN alpha treatment to increase the quality-adjusted life expectancy by 15.5 and 12.5 months relative to conventional chemotherapy, in scenarios A and B, respectively. Marginal cost-effectiveness was $89,500 and $63,500 per quality-adjusted life-year (QALY) gained. Sensitivity analysis confirmed IFN alpha as the most effective approach. Cost-effectiveness results were sensitive to the cost of IFN alpha therapy and to the assumptions about the rate of cytogenetic remission. Reducing the drug dose, as suggested by a recent report, would decrease the marginal cost-effectiveness to less than $20,000.

CONCLUSION

IFN alpha is substantially superior to conventional chemotherapy in terms of quality-adjusted survival, but, at the current doses, marginal cost-effectiveness ranges from $50,000 to $100,000 per QALY gained under most of our assumptions.
Factors that influence the collection and engraftment of allogeneic peripheral-blood stem cells in patients with hematologic malignancies.
Authors: Brown R A , Adkins D , Goodnough L T , Haug J S , Todd G , Wehde M , Hendricks D , Ehlenbeck C , Laub L , DiPersio J
Published: February 2017

PURPOSE

To determine the number of CD34+ cells associated with a high probability of rapid engraftment after allogeneic peripheral-blood stem-cell (PBSC) transplant, and to examine the relationship between certain donor characteristics and the effectiveness of PBSC mobilization.

PATIENTS AND METHODS

Between December 1994 and July 1996, we treated 47 patients who had resistant hematologic neoplasms with myeloablative therapy followed by transplantation of allogeneic PBSC collected from histocompatible siblings after mobilization with granulocyte colony-stimulating factor (G-CSF). Expression of CD34 was determined by flow cytometry.

RESULTS

Engraftment was rapid and similar to that observed following autologous PBSC transplant, with an absolute neutrophil count (ANC) greater than 500/microL and platelet count greater than 20,000/microL on median days +9 and +11, respectively. The pace of hematologic recovery correlated with the number of hematopoietic progenitors transplanted, so that patients who received greater than 5 x 10(6) CD34+ cells/kg recipient weight had a 95% likelihood of neutrophil and platelet recovery by day +15. Baseline (precytokine) CD34+ cells per milliliter of donor peripheral blood and total G-CSF dose (donor weight x 10 micrograms/kg) correlated with the number of CD34+ cells collected (R2 = .24 and P = .0009, and R2 = .24 and P < .0001, respectively). Donor age and sex did not effect mobilization.

CONCLUSION

Following allogeneic PBSC transplant, patients who received greater than 5 x 10(6) CD34+ cells/ kg recipient weight had a high probability of rapid engraftment. Donors with low baseline levels of circulating progenitors (< 2,000 CD34+ cells/mL blood) and those who received lower total doses of G-CSF were less likely to be effectively mobilized. For donors with low baseline CD34+ counts, higher doses of G-CSF might improve mobilization. Baseline CD34+ counts and total G-CSF dose accounted for less than half of the variation in CD34+ cells collected, which indicates that other, as yet unidentified, factors play an important role in determining the effectiveness of mobilization.
Phase I study of docetaxel with concomitant thoracic radiation therapy.
Authors: Mauer A M , Masters G A , Haraf D J , Hoffman P C , Watson S M , Golomb H M , Vokes E E
Published: February 2017

PURPOSE

The taxanes have demonstrated activity as radiation sensitizers in preclinical studies. This study was designed to determine the maximum-tolerated dose (MTD), optimal schedule, and toxicities of docetaxel in combination with concomitant standard chest radiotherapy.

PATIENTS AND METHODS

Twenty-nine patients with advanced non-small-cell lung or esophageal cancer enrolled in this phase I study to evaluate escalating docetaxel doses at three schedules. Docetaxel was administered as two 21-day cycles at doses of 40, 60, and 75 mg/m2 per cycle. Docetaxel administration schedules were as follows: schedule A, once every 3 weeks; schedule B, 2 of 3 weeks; or schedule C, weekly. Six weeks of concomitant standard chest radiotherapy in 1.8- to 2.0-Gy daily fractions was delivered to 60 Gy total.

RESULTS

Dose-limiting esophagitis and neutropenia were encountered with schedules A and B at docetaxel doses of 60 mg/m2 per cycle. The docetaxel MTD for schedules A and B was 40 mg/m2 per cycle. Dose-limiting esophagitis was also observed with schedule C; however, there was no neutropenia. For schedule C, we identified the MTD as 60 mg/m2 per cycle (20 mg/m2/wk). Other toxicities encountered included thrombocytopenia, hypersensitivity reaction, and pulmonary infiltrates (fatal in two patients). Late toxicity of esophageal stricture occurred in five patients.

CONCLUSION

Esophagitis and neutropenia are the dose-limiting toxicities of docetaxel administered with concomitant chest radiotherapy. Weekly administration of docetaxel allows for the highest total docetaxel dose during chest radiotherapy. We identified the recommended phase II docetaxel dose as 20 mg/m2 administered weekly with concomitant chest radiotherapy for 6 weeks.
Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: an active and tolerable outpatient regimen.
Authors: Vaughn D J , Malkowicz S B , Zoltick B , Mick R , Ramchandani P , Holroyde C , Armstead B , Fox K , Wein A
Published: February 2017

PURPOSE

To determine the toxicity and efficacy of an outpatient regimen of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium.

PATIENTS AND METHODS

Patients received paclitaxel 150 to 225 mg/m2 over 3 hours followed by carboplatin (targeted area under the concentration-time curve [AUC], 6 mg/mL x min) every 3 weeks. During phase I accrual, 16 patients were treated; 17 additional patients were enrolled at the phase II dose. The median age was 70 years (range, 47 to 82). The median serum creatinine concentration was 1.1 mg/dL (range, 0.7 to 2.7) and the median estimated creatinine clearance was 52 mL/min (range, 24 to 110).

RESULTS

During phase I accrual, the maximum-tolerated dose (MTD) of the regimen was not defined. Phase II accrual occurred at the paclitaxel 225 mg/m2 dose level. A total of 156 cycles were administered. The median number of cycles received was five (range, one to eight). Sensorimotor neuropathy was the principal nonhematologic toxicity. Significant granulocytopenia was common, but significant thrombocytopenia was not. Objective responses were demonstrated at all dose levels. At the phase II dose (paclitaxel 225 mg/m2 followed by carboplatin at AUC 6 mg/mL x min), the objective response rate was 50% (95% confidence interval [CI], 28% to 72%).

CONCLUSION

Paclitaxel plus carboplatin is an active and tolerable outpatient treatment for patients with advanced carcinoma of the urothelium. The ability to administer this combination over multiple cycles even to patients with advanced age and abnormal renal function makes it well suited for this patient population. Confirmatory trials of this regimen are ongoing.
Influence of surgery on metachronous distant metastases and survival in rectal cancer.
Authors: Köckerling F , Reymond M A , Altendorf-Hofmann A , Dworak O , Hohenberger W
Published: February 2017

PURPOSE

Total mesorectal excision (TME) and other technical surgical factors reduce local recurrence rate in rectal cancer. Scientific evidence of the positive effect of optimal surgery on survival is locking. Whether a reduction in the incidence of distant metastases can be achieved with optimal surgery is uncertain. We examine the effects of the quality of surgery, as reflected by local recurrence rate, on survival and the incidence of initial distant metastases.

PATIENTS AND METHODS

Between 1974 and 1991, 1,581 consecutive patients who underwent curative resection (RO) for rectal carcinoma were monitored for recurrence and survival. TME was introduced in 1985. No patient received adjuvant radiotherapy or chemotherapy. The median follow-up time was greater than 13 years.

RESULTS

The local recurrence rate decreased from 39.4% to 9.8% during the study period (P < .0001). The observed 5-year survival rate improved from 50% to 71% (P < .0001). Three hundred six patients with local recurrence had a significantly lower observed 5-year survival rate (P < .0001). A total of 1,285 patients had no local recurrence, but 275 of them developed distant metastases (International Union Against Cancer [UICC] stage I, 8%; stage II, 16%; stage III, 40%). Better-quality surgery had no effect on the incidence of initial distant metastases, which remained constant (P = .44).

CONCLUSION

Quality of surgery is an independent prognostic factor for survival in rectal cancer, but has no influence on initial occurrence of distant metastases. Local recurrence cannot be considered an outcome criterion of adjuvant treatment without consideration of the surgeon as a risk factor.
Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma: value of augmented preparative regimens--a Southwest Oncology Group trial.
Authors: Stiff P J , Dahlberg S , Forman S J , McCall A R , Horning S J , Nademanee A P , Blume K G , LeBlanc M , Fisher R I
Published: February 2017

PURPOSE

To determine the toxicity and prognosis of patients with relapsed and refractory diffuse aggressive non-Hodgkin's lymphoma (NHL) who underwent an autologous bone marrow transplant (ABMT) using augmented preparative regimens, treated in a major cooperative group setting, and to examine prognostic factors for outcome.

PATIENTS AND METHODS

Ninety-four patients with either chemosensitive (50 patients) or chemoresistant (44 patients) relapse, including 22 who failed induction chemotherapy, were treated with high-dose cyclophosphamide and etoposide with total-body irradiation (TBI) (67 patients) or an augmented carmustine (BCNU), cyclophosphamide, and etoposide (BCV) preparative regimen (27 patients) and an ABMT at 16 Southwest Oncology Group (SWOG) transplant centers. All relapsing patients were required to undergo a minimum of two courses of salvage therapy to determine chemosensitivity before transplant. Overall (OS) and progression-free survival (PFS) were determined and a Cox regression model was used to assess potential prognostic variables.

RESULTS

Of the 94 eligible patients, there were 10 (10.6%) deaths before day 50 posttransplant because of infection (six deaths), hemorrhagic alveolitis (three deaths), or bleeding (one death). The median 3-year PFS and OS for the entire group was 33% and 44%. For those with chemosensitive disease the PFS and OS were 42% and 55%, whereas for those with chemoresistant disease the PFS and OS were 22% and 29%. The PFS and OS for those failing induction chemotherapy were 27% and 32%. The relapse rates within the first 3 years for the chemosensitive relapse, chemoresistant, and induction failure groups were 61%, 40%, and 59%, respectively. For both PFS and OS, only disease status at transplant was a significant factor in the multivariate Cox model.

CONCLUSION

These results single institutional pilot trials exploring augmented preparative regimens. Patients undergoing transplantation for resistant disease, particularly those failing induction chemotherapy, appear to have an improved prognosis as compared with reports using standard preparative regimens. Therapies other than manipulation of standard preparative regimens appear to be required to decrease relapses following autotransplantation.
Capillary protein leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment.
Authors: Semb K A , Aamdal S , Oian P
Published: February 2017

PURPOSE

The aim of our study was to elucidate whether the fluid retention syndrome induced by docetaxel is caused by capillary protein leakage or by other mechanisms.

PATIENTS AND METHODS

Twenty-four patients with advanced or metastatic non-small-cell lung cancer (NSCLC; 23 patients) or metastatic head and neck cancer (one patient) were included on this prospective, nonrandomized trial. Docetaxel 100 mg/m2 was administered every 3 weeks with 5 days of dexamethasone prophylaxis to avoid hypersensitivity reactions and edema formation. Transcapillary forces, ie, colloid osmotic pressure of plasma (COPpl) and interstitial fluid (COPint) and interstitial hydrostatic pressure (Pint), were measured before the start of treatment and after total docetaxel doses of 200 and 500 mg/m2 by means of the well-documented wick and wick-in-needle methods. Body weight, degree of edema, blood pressure, and heart rate and hemoglobin, hematocrit, albumin, and total protein values were registered in parallel.

RESULTS

After a total docetaxel dose of 200 mg/m2, COPpl, COPint, and hemoglobin, hematocrit, albumin, and total protein values had decreased significantly; Pint and body weight were unchanged; and only mild edema was observed. These findings suggest a plasma volume increase followed by enhanced fluid filtration to the interstitium. After a cumulative docetaxel dose of 500 mg/m2, the COPpl continued to decrease significantly, but COPint remained unchanged despite a significant increase in mean body weight and edema formation. These observations support the theory of a capillary protein leakage.

CONCLUSION

Docetaxel appears to induce an initial enhancement of fluid filtration followed by a capillary protein leakage that leads to edema formation.
Effect of duration of treatment on treatment outcome and cost of treatment for Wilms' tumor: a report from the National Wilms' Tumor Study Group.
Authors: Green D M , Breslow N E , Beckwith J B , Finklestein J Z , Grundy P , Thomas P R , Kim T , Shochat S , Haase G , Ritchey M , Kelalis P , D'Angio G J
Published: February 2017

PURPOSE

National Wilms' Tumor Study (NWTS)-4 was designed to evaluate the efficacy, toxicity, and cost of the administration of different regimens for the treatment of Wilms' tumor (WT).

PATIENTS AND METHODS

Between August 6, 1986 and September 1, 1994, 905 previously untreated children aged younger than 16 years with stage II favorable histology (FH) WT (low-risk [LR]), stages III to IV FH WT, or stages I to IV clear-cell sarcoma of the kidney (high-risk[HR]) were randomized after the completion of 6 months of chemotherapy to discontinue (short) or continue for 9 additional months (long) treatment with chemotherapy regimens that included vincristine and either divided-dose (standard [STD]) courses (5 days) or single-dose (pulse-intensive [PI]) treatment with dactinomycin. HR patients also received either divided-dose (STD) courses (3 days) or single-dose (PI) treatment with doxorubicin.

RESULTS

The 4-year relapse-free survival (RFS) rates after the second randomization for LR patients were 83.7% for the 190 patients treated with short and 88.2% for the 187 patients treated with long chemotherapy (P = .11). The 4-year RFS rates after the second randomization for HR FH patients were 89.7% for the 256 patients treated with short and 88.8% for the 246 patients treated with long chemotherapy (P = .87). The charge for treatment with the short PI treatment regimens for all children with stages I through IV FH WT was approximately one half of that with the long STD treatment regimens.

CONCLUSION

The short administration schedule for the treatment of children with WT is no less effective than the long administration schedule and can be administered at a substantially lower total treatment cost.
Economic issues in lung cancer: a review.
Authors: Goodwin P J , Shepherd F A
Published: February 2017

PURPOSE

Lung cancer is a major source of morbidity, mortality, and health care costs in the developed and developing world. It is estimated that lung cancer is responsible for 20% of all cancer care costs. Concerns exist that this expenditure is associated with questionable benefits.

DESIGN

The economic literature that relates to smoking was reviewed, followed by a summary of the economics of the diagnosis, treatment, and palliation of lung cancer. Methodologic considerations are also discussed in this section.

RESULTS

Published studies suggest that the increased lifetime health care costs from smoking-related illnesses in smokers are partially or fully offset by the higher medical costs that result from increased longevity in nonsmokers. However, lost productivity costs, which result from morbidity and early mortality among smokers, result in an overall net cost of smoking to society. Discounting rates of 3% to 5% do not substantively alter these results. The per-patient cost to treat lung cancer is substantial. The major cost center is hospitalization; palliative or terminal treatment is associated with significant costs. Savings can be obtained through the judicious use of diagnostic and staging procedures. Furthermore, combined modality treatment approaches and the palliative use of combination chemotherapy appear to be associated with acceptable cost-effectiveness compared with commonly used therapies for other diseases.

CONCLUSION

Although the increased medical care costs of treating smoking-related diseases are somewhat offset by the higher medical care costs due to increased longevity in nonsmokers, the lost productivity that results from smoking results in a net cost to society. Standard approaches to the management of lung cancer are associated with cost-effectiveness similar to that of other commonly used medical interventions.
Phase I clinical and pharmacokinetic trial of penclomedine using a novel, two-stage trial design for patients with advanced malignancy.
Authors: Berlin J , Stewart J A , Storer B , Tutsch K D , Arzoomanian R Z , Alberti D , Feierabend C , Simon K , Wilding G
Published: February 2017

PURPOSE

A novel phase I trial design was used to determine the maximum-tolerated dose (MTD) and pharmacokinetics for penclomedine when administered as an intravenous (i.v.) infusion over 1 hour daily for 5 days, repeated every 28 days. This study also tests the feasibility of a novel two-stage design for phase I trials.

PATIENTS AND METHODS

Twenty-eight patients with advanced malignancy who met standard eligibility criteria were treated with i.v. penclomedine. The initial daily dose was 50 mg/m2. Dose escalations were planned using a modified Fibonacci sequence. One patient was enrolled on each dose level during the first stage of this trial. In the second stage, patients were enrolled in cohorts of three, proceeding in an up-and-down manner based on toxicities observed. MTD was determined by logistic regression analysis. Pharmacokinetic assessment was performed during the first cycle of treatment.

RESULTS

Dose-limiting toxicities (DLT) observed during this trial were principally neurologic and were self-limited. Although hematologic toxicity was rare, the few patients with significant hematologic changes experienced late nadirs with prolonged time to recovery. The MTD was estimated as 381 mg/m2 (80% CI, 343 to 415 mg/m2). Although there was a long elimination half-life, accumulation of penclomedine over the 5 days of administration was negligible.

CONCLUSION

The novel trial design used in this study was safe and appeared effective in limiting the numbers of patients treated at lower-dose levels. Reversible neurotoxicity was dose-limiting. Although the estimated MTD was 381 mg/m2, any dose within the CI would be reasonable for phase II study.