bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor after high-dose cyclophosphamide cancer therapy.
Authors: Bregni M , Siena S , Di Nicola M , Dodero A , Peccatori F , Ravagnani F , Danesini G , Laffranchi A , Bonadonna G , Gianni A M
Published: February 2017

PURPOSE

We compared hematologic and clinical effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) after treatment with high-dose cyclophosphamide (HD-CTX, 7 g/m2), given as the first phase of a high-dose sequential chemotherapy program that includes a myeloablative therapy with mobilized progenitor cell autografting.

PATIENTS AND METHODS

Forty-nine consecutive patients with non-Hodgkin's lymphoma, Hodgkin's disease, or poor-prognosis breast cancer received GM-CSF (n = 27) or G-CSF (n = 22) after HD-CTX in two consecutive, nonrandomized studies. Cytokines were administered in continuous intravenous (i.v.) infusion for 14 to 15 days at a median dose of 5.5 and 10 micrograms/kg/d, respectively, starting 24 hours after HD-CTX.

RESULTS

Neutrophil recovery was faster with G-CSF administration (11.5 v 13.2 days; P = .01), whereas platelet counts recovered more rapidly with GM-CSF (13.7 v 16.6 days; P = .01). Prophylactic platelet transfusions were administered more frequently to patients treated with G-CSF than with GM-CSF (66% v 22% of the patients; P = .02). No clinically significant difference was observed between the two groups concerning days of absolute neutropenia or neutropenic fever. Both cytokines reduced the time to eligibility for subsequent chemotherapy administration compared with historical controls not given cytokine (14 to 16 v 20 days). Both cytokines increased circulation of hematopoietic progenitors. Most side effects were World Health Organization (WHO) median grade 1 to 2, were more frequent during GM-CSF than during G-CSF treatment, and were reversible by simple supportive measures and/or by dose reduction or suspension of the cytokine. Permanent suspension of cytokine administration was never required in either group.

CONCLUSION

GM-CSF or G-CSF administration after HD-CTX reduces hematologic toxicity of high-dose chemotherapy and induces circulation of large amounts of hematopoietic progenitors suitable for autografting in cancer patients.
Early lymphopenia after cytotoxic chemotherapy as a risk factor for febrile neutropenia.
Authors: Blay J Y , Chauvin F , Le Cesne A , Anglaret B , Bouhour D , Lasset C , Freyer G , Philip T , Biron P
Published: February 2017

PURPOSE

Febrile grade four (ie, < or = 500/microL) neutropenia (FN) is a frequent life-threatening complication of cancer chemotherapy. Although its incidence correlates to the dose of chemotherapy, FN may occur after almost any cytotoxic regimen. At present, there is no predictive method to identify patients who will experience FN.

PATIENTS AND METHODS

Univariate and multivariate analyses of risk factors for FN were performed on a retrospective cohort of 112 consecutive patients treated with various chemotherapy regimens. Two independent risk factors were identified by the logistic regression and used to create a risk model for FN. The validity of the model was tested in three distinct groups of patients: two prospective groups of patients treated in two institutions (Centre Léon Berard [CLB] and Institut G. Roussy [IGR]) and the group of patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) treated with the doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) regimen between 1988 and 1992 at CLB.

RESULTS

Within the retrospective group, 23 of 47 (49%) patients with lymphocyte counts < or = 700/microL at day 5 after chemotherapy experienced FN compared with seven of 65 (11%) of other patients (P = .00002). The type of chemotherapy (high dose v others) was also significantly correlated to FN (48% v 11%, P = .0003). Age, performance status, the number of previous chemotherapy cycles, or polymorphonuclear leukocyte (PMN) counts, were not significantly correlated to the incidence of FN in univariate analyses. Two independent risk factors were identified in the logistic regression: day 5 lymphocyte counts (beta = 1.97 +/- 0.53) and the type of chemotherapy regimen (beta = 1.91 +/- 0.53). The calculated probability to experience FN in patients with none, one, and both of these risk factors was 4.3%, 24.0%, and 68.8%, respectively. The validity of this model was tested in the three groups of patients used as validation samples. The observed incidences of FN in the above defined risk subgroups were 3%, 19%, and 67%, respectively, within the CLB prospective series and 6%, 19%, and 75% within the IGR prospective series. In the ACVBP group, the incidence of FN was 33% and 72%, respectively, in patients from the intermediate- and high-risk groups. In the two prospective groups and in the ACVBP series, the observed numbers of FN in the different risk groups did not differ significantly from those calculated by the model (P = .89, P = .86, and P = .72 for these three groups, respectively).

CONCLUSION

Day 5 lymphocyte counts < or = 700/microL and the type of chemotherapy regimen enable oncologists to define subgroups of patients treated with chemotherapy as those with a high intermediate, and low risk of FN. These criteria could be used to select subjects in whom prophylactic measures for FN, in particular hematopoietic growth factors, should be proposed.
Phase I study of pharmacologically based dosing of carboplatin with filgrastim support in women with epithelial ovarian cancer.
Authors: Lind M J , Ghazal-Aswad S , Gumbrell L , Fishwick K , Craigs D , Millward M J , Bailey N P , Dore-Green F , Chapman F , Simmons D , Proctor M , Oakey A , Robson L , Middleton I , McCann E , Sinha D , Calvert A H
Published: February 2017

PURPOSE

The aim of this study was to increase the dose intensity of carboplatin in women with International Federation of Gynecology and Obstetrics (FIGO) Stage Ic-IV epithelial ovarian cancer with the use of granulocyte colony-stimulating factor (G-CSF; filgrastim; Amgen, Thousand Oaks, CA).

PATIENTS AND METHODS

A phase I study of escalating target area under the curves (AUCs) of carboplatin with G-CSF (filgrastim) ws undertaken. The target AUCs were 5 mg/mL.min every 21 days for four cycles, 5 mg/mL.min every 14 days for four cycles, 7 mg/mL.min every 14 days for four cycles, 9 mg/mL.min every 14 days for four cycles, and 11 mg/mL.min every 14 days for four cycles. G-CSF was given at a dose of 5 microg/kg/d starting 24 hours after carboplatin administration and lasting until 24 hours before the next cycle and until day 14 after the last cycle.

RESULTS

We were able to escalate to an AUC level of 9 mg/mL.min every 14 days for four cycles. At this dose, severe thrombocytopenia, that necessitated dosage delays, and failure to give subsequent cycles of carboplatin were observed. We then reduced the AUC level to 8 mg/mL.min every 14 days for four cycles. However, severe thrombocytopenia was also observed at this level.

CONCLUSION

An AUC of 7 mg/mL.min every 14 days for four cycles is the maximum tolerated AUC level that can be achieved with G-CSF. Further escalations may be possible using either combinations of cytokines or peripheral stem-cell collections.
Evaluation of race as a prognostic factor in multiple myeloma. An ancillary of Southwest Oncology Group Study 8229.
Authors: Modiano M R , Villar-Werstler P , Crowley J , Salmon S E
Published: February 2017

PURPOSE

The objective of this investigation was to assess the impact of race (black v white) on the survival of patients with multiple myeloma treated within the context of a large clinical trial.

PATIENTS AND METHODS

A cohort of patients randomized to receive one of two treatment regimens and monitored for at least 10 years was studied to assess the impact of race as a prognostic factor, after adjusting for other known factors such as stage of disease. Patients were recruited from the referral network of the Southwest Oncology Group (SWOG), a national multiinstitutional consortium that includes both academic and community treatment centers. Patients had a diagnosis of multiple myeloma and had not previously been treated for this disease. They were carefully characterized as to demographic and clinical features, and were randomized to receive one of two treatment regimens, which proved to have virtually identical outcomes. The outcome measure was survival, measured from the date of randomization to the date of last contact. Patients still alive at last contact date were treated as censored observation.

RESULTS

Survival for black myeloma patients was similar to that for white patients, both overall and adjusted for prognostic factors such as stage.

CONCLUSION

Observed differences in mortality between blacks and whites cannot be attributed to differences in survival after diagnosis, given comparable treatment.
Telephone-based nursing intervention improves the effectiveness of the informed consent process in cancer clinical trials.
Authors: Aaronson N K , Visser-Pol E , Leenhouts G H , Muller M J , van der Schot A C , van Dam F S , Keus R B , Koning C C , ten Bokkel Huinink W W , van Dongen J A , Dubbelman R
Published: February 2017

PURPOSE

Here we report the results of a randomized study undertaken to test the efficacy of a supplementary, telephone-based nursing intervention in increasing patients' awareness and understanding of the clinical trials in which they are asked to participate.

METHODS

During a 12-month period, 180 cancer patients who were approached to participate in a phase II or III clinical trial were randomized to undergo either of the following: (1) standard informed consent procedures based on verbal explanations from the treating physician plus written information (controls); or (2) standard informed consent procedures plus a supplementary, telephone-based contact with an oncology nurse (intervention). For purposes of evaluation, face-to-face interviews were conducted with all patients approximately 1 week after the informed consent process had been completed.

RESULTS

The two groups were comparable with regard to sociodemographic and clinical variables. Both groups had a high level of awareness of the diagnosis and of the nature and objectives of the proposed treatments. The intervention group was significantly (P < .01) better informed about the following: (1) the risks and side effects of treatment; (2) the clinical trial context of the treatment; (3) the objectives of the clinical trial; (4) where relevant, the use of randomization in allocating treatment; (5) the availability of alternative treatments; (6) the voluntary nature of participation; and (7) the right to withdraw from the clinical trial. The intervention did not have any significant effect on patients' anxiety levels or on rates of clinical trial participation. Patients reported high levels of satisfaction with the intervention.

CONCLUSION

The use of a supplementary, telephone-based nursing intervention is a feasible and effective means to increase cancer patients' awareness and understanding of the salient issues that surround the clinical trials in which they are asked to participate.
Expression of a CD44 variant containing exons 8 to 10 is a useful independent factor for the prediction of prognosis in colorectal cancer patients.
Authors: Yamaguchi A , Urano T , Goi T , Saito M , Takeuchi K , Hirose K , Nakagawara G , Shiku H , Furukawa K
Published: February 2017

PURPOSE

To determine the expression of the CD44 variant containing a variant exon 8 to 10 product (CD44v8-10) in colorectal cancer and to evaluate its prognostic value.

MATERIALS AND METHODS

CD44v8-10 was studied in resected tumors and normal mucosae obtained from 215 colorectal cancer patients (118 colon cancer and 97 rectal cancer). The expression of CD44v8-10 was analyzed immunohistochemically using the anti-CD44v8-10 monoclonal antibody (mAb) 44-1V.

RESULTS

One hundred of 215 cancer tissues expressed CD44v8-10. Positive staining was intense mainly on the cell membranes. There was no significant correlation between expression of CD44v8-10 and histologic type, primary tumor, lymphatic invasion, venous invasion, or peritoneal invasion. There were significant correlations between CD44v8-10 immunoreactivity and both lymph node and hematogenous metastasis. Patients with CD44v8-10-positive tumors had a greater relative risk of death compared with those whose tumors were CD44v8-10-negative. Among 169 patients who underwent curative resection, CD44v8-10 expression correlated with a high recurrence rate. The 5- and 10-year survival rates were 90.3% of patients with CD44v8-10-negative tumors, and 72.1% and 58.0% of those with CD44v8-10-positive tumors, respectively; these differences between the two groups of patients were significant (P < .01). In multivariate analysis using the Cox regression model, CD44v8-10 expression emerged as an independent prognostic indicator.

CONCLUSION

The results suggest that CD44v8-10 plays a role in metastasis of colorectal cancer, and tha CD44v8-10 expression may be a biologic marker of prognostic significance.
Improved detection of medullary thyroid cancer with radiolabeled antibodies to carcinoembryonic antigen.
Authors: Juweid M , Sharkey R M , Behr T , Swayne L C , Rubin A D , Herskovic T , Hanley D , Markowitz A , Dunn R , Siegel J , Kamal T , Goldenberg D M
Published: February 2017

PURPOSE

This investigation was undertaken to assess the targeting of established and occult medullary thyroid cancer (MTC) with radiolabeled monoclonal antibodies (MAbs) reactive with carcinoembryonic antigen (CEA).

PATIENTS AND METHODS

Twenty-six assessable patients with known (n = 17) or occult (n = 9) MTC were studied with radiolabeled anti-CEA MAbs. Scintigraphic images were collected to determine targeting of tumor lesions.

RESULTS

The targeting results of technetium 99m (99mTc)-,iodine 123 (123I)-, and iodine 131 (131I)-labeled anti-CEA antibodies (all directed against the same epitope of CEA) indicated that all these reagents were capable of detecting established and occult MTC. The sensitivity for detection of known sites of disease ranged from 76% to 100% for the various anti-CEA MAbs used, when compared with computed tomography (CT), magnetic resonance imaging (MRI), bone scan, or other imaging modalities. Moreover, the antibody scan was positive in seven of nine patients with occult disease (patients with negative conventional imaging studies, but who had elevated calcitonin and/or CEA levels). Three of seven patients underwent surgery and the disease was confirmed by histopathology in all three.

CONCLUSION

Anti-CEA MAbs are excellent agents for imaging recurrent, residual, or metastatic MTC. The high lesion sensitivity in patients with known lesions, combined with the ability to detect disease, may make these agents ideal for staging patients, monitoring disease pretherapy or posttherapy, and especially for evaluating patients with recurrent or persistent hypercalcitonemia or CEA elevations after primary surgery. Analogous to radioiodine in the evaluation of patients with differentiated thyroid cancer, radiolabeled anti-CEA MAbs may achieve a similar role in diagnosing and monitoring patients with MTC.
Phase I trial of dose escalation with growth factor support in patients with previously untreated diffuse aggressive lymphomas: determination of the maximum-tolerated dose of ProMACE-CytaBOM.
Authors: Gordon L I , Anderson J , Habermann T M , Winter J N , Glick J , Schilder R J , Cassileth P
Published: February 2017

PURPOSE

The aim of this study was to determine the maximum-tolerated dose (MTD) of cyclophosphamide, doxorubicin, etoposide, prednisone, bleomycin, cytarabine, methotrexate, and leucovorin (ProMACE-CytaBOM) when the myelotoxic drugs cyclophosphamide, doxorubicin, etoposide, and cytarabine are escalated.

PATIENTS AND METHODS

Thirty-eight eligible patients with diffuse aggressive non-Hodgkin's lymphoma were treated on a phase I trial of dose escalation using the ProMACE-CytaBOM regimen and granulocyte-macrophage colony-stimulating factor (GM-CSF; Schering, Kenilworth, NJ). Patients were treated with recombinant (r)GM-CSF 10 microg/kg/d subcutaneously from day 9 to 19. Twenty-seven patients had stage IV disease, four had stage III, and seven had bulky stage II. Half of the patients had bone marrow involvement. The median age was 45 years.

RESULTS

We found that the MTD was 200% for the escalated drugs in this regimen (although we never escalated above the MTD or defined by dose-limiting toxicity) and that the normalized dose-intensity (NDI; defined as the ratio of the received dose-intensity to the 100% dose-intensity of ProcMACE-CytaBOM) decreased with each cycle and was lower for the day-8 drug (cytarabine) than for the day-1 drugs. The complete response (CR) rate was 66%, and 92% of patients who achieved CR are alive without disease with a median follow-up time for survival of 3.6 years.

CONCLUSION

The MTD of cyclophosphamide, doxorubicin, etoposide, and cytarabine in the ProMACE-CytaBOM regimen given with growth factor support is 200%, and this dose should be tested in larger phase II trials.
Alternating versus hybrid MOPP and ABVD combinations in advanced Hodgkin's disease: ten-year results.
Authors: Viviani S , Bonadonna G , Santoro A , Bonfante V , Zanini M , Devizzi L , Soncini F , Valagussa P
Published: February 2017

PURPOSE

To compare, in a prospective randomized trial, the efficacy of two different sequences of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy in untreated advanced Hodgkin's disease.

PATIENTS AND METHODS

From June 1982 to September 1990, 427 consecutive previously untreated patients with pathologic stage IB, IIA bulky, IIB, III (A and B), and IV (A and B) disease were prospectively randomized to receive two different sequences of MOPP and ABVD for a minimum of six cycles followed by radiotherapy (median dose, 30 Gy) to the nodal site(s) of pretreatment bulky disease. Of 415 assessable patients, 211 received one cycle of MOPP monthly, alternated with one cycle of ABVD (alternating regimen), and 204 patients received one-half cycle of MOPP alternated with one-half cycle of ABVD within a 1-month period (hybrid regimen).

RESULTS

The complete remission (CR) rate was 91% with the alternating regimen and 89% with the hybrid regimen. At 10 years, the freedom-from-progression (FFP) rate was 67% versus 69% and the overall survival (OS) rate was 74% versus 72%, respectively. After attainment of CR, 85 patients relapsed in nodal (n = 60) versus extranodal with or without nodal (n = 25) sites. In patients given consolidative radiation because of bulky lymphoma, the true recurrence rate was 13%. A total of 23 second malignancies (6%) were documented, including 11 cases of acute nonlymphocytic leukemia. No cases of congestive heart failure attributable to doxorubicin or pulmonary toxicity related to bleomycin were documented.

CONCLUSION

By delivering MOPP and ABVD, it is possible to cure approximately 70% of patients with advanced Hodgkin's disease. The two different drug sequences yielded superimposable results.
Psychologic and neuropsychologic impact of autologous bone marrow transplantation.
Authors: Ahles T A , Tope D M , Furstenberg C , Hann D , Mills L
Published: February 2017

PURPOSE

The major purpose of the current study was to evaluate the psychologic and neuropsychologic functioning of patients undergoing treatment with autologous bone marrow transplantation (ABMT).

PATIENTS AND METHODS

Fifty-four patients with hematologic disorders or breast cancer completed a battery of psychologic and neuropsychologic tests before ABMT, at mid-treatment (1 to 3 days following bone marrow reinfusion), and predischarge (within 1 to 2 days before discharge from the hospital).

RESULTS

Analysis of pretransplant data showed significantly higher scores on the State-Trait Anxiety Inventory (STAI) and Profile of Mood States (POMS) for patients with hematologic disorders as compared with patients with breast cancer. However, no baseline differences on neuropsychologic measures were found when patients were divided into groups based on prior exposure to cranial radiation and/or intrathecal chemotherapy. Serial evaluations at pretransplant, following return of bone marrow, and at predischarge were available for 34 patients. For the psychologic data, patients with hematologic disorders tended to be more distressed than breast cancer patients at baseline, but became less distressed over time. By contrast, breast cancer patients were relatively less distressed at baseline, demonstrated a significant increase in distress midtreatment, and returned to baseline levels at predischarge assessment. Scores on neuropsychologic measures that assessed higher order cognitive functioning generally worsened over time.

CONCLUSION

The results suggest a differential response on psychologic measures when comparing patients with hematologic disorders with those with breast cancer. However, both groups demonstrated a general decline in performance on neuropsychologic measures over the course of treatment.
Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia.
Authors: Furman W L , Baker S D , Pratt C B , Rivera G K , Evans W E , Stewart C F
Published: February 2017

PURPOSE

To determine the maximum-tolerated systemic exposure (MTSE) and exposure-limiting toxicity of continuous infusion topotecan in children with recurrent acute leukemia.

PATIENTS AND METHODS

Patients received escalating levels of topotecan systemic exposure as measured by steady-state topotecan lactone concentration (Css). Samples obtained within the first 24 hours were measured by high-pressure liquid chromatography (HPLC) for topotecan. A two-compartment model was fit to the data using a Bayesian algorithm. Css was calculated for each patient; if it differed by more than 20% of target, a new dosage was begun within 6 hours. Follow-up concentrations were obtained as well as serial plasma samples postinfusion. Toxicity and evidence of activity were assessed after each course.

RESULTS

Thirteen boys and five girls received 23 courses of topotecan. Target Css ranged from 1.0 to 5.3 ng/mL (topotecan doses, 0.5 to 3.3 mg/m2/d). Nineteen of 23 courses were within +/- 20% of target after adjustment (range, 77% to 139%). The MTSE was 4.0 ng/mL, and mucositis was exposure-limiting at 5.3 ng/mL. A significant relation between topotecan lactone Css and the severity of mucositis was observed. Myelosuppression was experienced but was not considered exposure-limiting. One complete response and one partial response were noted.

CONCLUSION

The MTSE for continuous infusion topotecan was 4.0 ng/mL. Responses were noted at Css comparable to those producing responses in a severe combined immunodeficiency (SCID) mouse model. Further studies of topotecan are warranted.
Intensive outpatient adjuvant therapy for breast cancer: results of dose escalation and quality of life.
Authors: Swain S M , Rowland J , Weinfurt K , Berg C , Lippman M E , Walton L , Egan E , King D , Spertus I , Honig S F
Published: February 2017

PURPOSE

A dose-escalation study was conducted to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cyclophosphamide (CY) in combination with granulocyte colony-stimulating factor (G-CSF0 and doxorubicin (DOX) given every 2 weeks for eight cycles as outpatient adjuvant therapy for node-positive breast cancer. A pilot study to assess quality of life (QOL) was performed.

PATIENTS AND METHODS

From March 1991 to April 1993, 19 patients were entered. Patients received escalating doses of CY intravenously (i.v.) (1,000 mg/m2, 1,500 mg/m2, 2,000 mg/m2, or 2,500 mg/m2) with DOX 40 mg/m2, G-CSF 10 micrograms/kg/d on days 2 to 12, and mesna, every 2 weeks for eight cycles. QOL was measured by the Profile of Mood States (POMS), the Psychosocial Adjustment to Illness Scale-Self Report (PAIS-SR), and a 27-item QOL scale.

RESULTS

The CY dose of 2,500 mg/m2 every 2 weeks elicited toxicities that required dose reductions secondary to a combination of thrombocytopenia, hematuria, and anemia that required transfusion. The dose of 2,000 mg/m2 resulted in an acceptable toxicity profile. Ninety-two percent of cycles at the 2,000-mg/m2 dose were delivered on schedule and 77% without hospitalization. QOL assessments indicated high levels of distress measured by POMS in 47%, poor overall quality of life in 40%, and significant problems with physical symptoms in less than 27% of all patients for any given cycle.

CONCLUSION

A dose of CY at 2,000 mg/m2 can be administered every 2 weeks with DOX and G-CSF for eight cycles in the outpatient setting with manageable toxicity. The majority of women described levels of physical symptoms and emotional distress as tolerable during treatment.
Neoadjuvant therapy of high-risk gastric cancer: a phase II trial of preoperative FAMTX and postoperative intraperitoneal fluorouracil-cisplatin plus intravenous fluorouracil.
Authors: Kelsen D , Karpeh M , Schwartz G , Gerdes H , Lightdale C , Botet J , Lauers G , Klimstra D , Huang Y , Saltz L , Quan V , Brennan M
Published: February 2017

PURPOSE AND METHODS

We identified patients with gastric cancer at high risk for recurrence before therapy using endoscopic ultrasonography (EUS). Neoadjuvant therapy using the fluorouracil, doxorubicin, and metrotrexate (FAMTX) regimen was given for three courses before planned laparotomy with the intention to perform curative resection. Postoperatively, intraperitoneal (IP) cisplatin and fluorouracil (FU) and intravenous (i.v.) FU were administered to patients undergoing resection.

RESULTS

Fifty-six assessable patients were treated. Preoperative FAMTX therapy was tolerable, with the major toxicity being neutropenic fever. One treatment-related death was seen. Eighty-nine percent of patients underwent surgical exploration and 61% had potentially curative resections. There were two postoperative deaths. Comparison of pathologic tumor (pT) stage with EUS-predicted tumor stage showed apparent downstaging in 51% of patients. Postoperative IP chemotherapy was delivered to 75% of eligible patients. Toxicity was acceptable. There was no increase in operative morbidity or mortality compared with concurrent nonstudy patients undergoing a similar operative procedure and not receiving preoperative therapy. With a median follow-up time of 29 months, the median survival duration was 15.3 months. For patients who underwent potentially curative resections, the median survival duration was 31 months. Peritoneal failure was seen in 16% of patients.

CONCLUSION

Chemotherapy with the FAMTX regimen is tolerable in patients with locally advanced gastric cancer, without an increase in operative morbidity or mortality. IP therapy can be successfully delivered to most resected patients. The intraabdominal failure pattern appears to be decreased compared with expected. This approach is an appropriate investigational arm to pursue in future studies.
Mediastinal tumor size and response to chemotherapy are the only prognostic factors in supradiaphragmatic Hodgkin's disease treated by ABVD plus radiotherapy: ten-year results of the Paris-Ouest-France 81/12 trial, including 262 patients.
Authors: Colonna P , Jais J P , Desablens B , Harousseau J L , Brière J , Boasson M , Lemevel A , Casassus P , Le Prisé P Y , Guilhot F , Ghandour C , Lejeune F , Andrieu J M
Published: February 2017

PURPOSE

To identify prognostic factors in 262 patients with supradiaphragmatic Hodgkin's disease (HD), clinical stages (CS) I and II, prospectively treated between 1981 and 1988 according to the Paris-Ouest-France (POF) 81/12 protocol by three 1-month cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus methylprednisone (ABVD-MP) followed by subtotal nodal irradiation (RT).

PATIENTS AND METHODS

The size of mediastinal tumor (MT) was measured in all patients: 66 did not have MT (NoMT); 105 had a small-size MT (SSMT), ie, mediastinal mass ratio (MMR) less than 0.33; 58 had a medium-size MT (MSMT), ie, MMR > or = 0.33 and less than 0.45; and 33 had a bulky MT (BuMT), ie, MMR > or = 0.45. All patients received three cycles (CS IA, one cycle only) of ABVD-MP; patients in partial remission (PR) or complete remission (CR) after chemotherapy (CT) received supradiaphragmatic RT (involved fields, 40 Gy; adjacent fields, 30 Gy) plus lumboaortic and splenic RT (30 Gy); patients not in CR or PR after CT received salvage CT.

RESULTS

Two hundred seventeen patients (82.8%) entered CR after CT and 258 (98.5%) after RT. Ten-year freedom-from-progression (FFP) and survival rateswere 88.6% and 89.4%, respectively. According to univariate analysis, MT size and post-CT status were the only factors to influence both FFP and survival. For patients with NoMT or SSMT, those with MSMT, and those with BuMT, FFP rates were 94.1%, 87.0%, and 63.0% (P < .001), respectively, while corresponding survival rates were 92.6%, 87.2%, and 78.2% (P < .05). FFP rates were significantly different between the patients who achieved CR and those who did not achieve CR after CT: 94.6% versus 65.3% (P < .001); corresponding survival rates were 89.9% and 73.7% (P < .01). Multivariate analysis confirmed that MT size and post-CT status were the only two prognostic factors for FFP; for survival, the same two characteristics, as well as age (< 40 v > or = 40 years), significantly affected prognosis. We were thus able to identify three groups. The 33 patients (12.6%) with a BuMT had 10-year FFP and survival rates of 63.0% and 78.2%, respectively. Of 229 patients without BuMT, the 195 who attained CR after CT had an optimal prognosis (FFP, 96.6%; survival, 93.6%), while those who failed to achieve CR after CT had an intermediate prognosis (FFP, 68.8%; survival, 77.6%).

CONCLUSION

These results demonstrate the independent impact on HD prognosis of tumor burden and post-CT status.
Limited-sampling models for irinotecan pharmacokinetics-pharmacodynamics: prediction of biliary index and intestinal toxicity.
Authors: Mick R , Gupta E , Vokes E E , Ratain M J
Published: February 2017

PURPOSE

To construct limited-sampling models (LSMs) for irinotecan (CPT-11) pharmacokinetic (PK) measures.

MATERIALS AND METHODS

The recommended phase II dose of weekly CPT-11 administered as a 90-minute infusion is 145 mg/m2 with granulocyte colony-stimulating factor (G-CSF) and maximal antidiarrheal support. Diarrhea is the dose-limiting toxicity. Previously, we demonstrated a highly significant correlation between severity of diarrhea and biliary index (BI), the estimated biliary exposure of SN-38. BI was the product of total CPT-11 area under the concentration-time curve (AUC) and the relative area ratio of SN-38 to SN-38 glucuronide (SN-38G). At 145 mg/m2, PK data were available for 40 patients; 36 were also assessable for intestinal toxicity. Total plasma concentrations of CPT-11, SN-38, and SN-38G from 1.0 to 11.5 hours from the start of the infusion were evaluated. CPT-11 concentration at each time point, t, is denoted by CPT-11t. LSMs were constructed by stepwise linear regression, on a training set (n = 25), and were validated on a test set (n = 15).

RESULTS

LSMs for CPT-11, SN-38, and SN-38G AUCs displayed excellent fit to the training set (R2 = .87, 0.75, and .98, respectively). AUCCPT-11 = 5.25 x CPT-11(3.0) + 20.60 x CPT-11(11.5) + 1,520.53; AUCSN-38 = 5.38 x SN-38(3.5) + 33.61 x SN-38(11.5) - 7.73; and AUCSN-38G = 10.73 x SN-38G9.5 + 20.66 x SN-38G11.5 + 142.69. BI at each time point (denoted BIt) was calculated as CPT-11t x (SN-38t/SN-38Gt). Several promising LSMs were defined by BI3.5 paired with BI7.5 (R2 = .63) or BI9.5 (R2 = .76), or BI5.5 paired with BI9.5 (R2 = .76). Predicted BI from each model (categorized into low, intermediate, or high) accurately predicted observed intestinal toxicity grade (P < or = .005).

CONCLUSION

These LSMs appear to accurately predict PK parameters of CPT-11. Notably, BI, predicted from several LSMs, accurately predicted intestinal toxicity and thus may be useful for future trials that use adaptive control with feedback.
In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission.
Authors: Stein A S , O'Donnell M R , Chai A , Schmidt G M , Nademanee A , Parker P M , Smith E P , Snyder D S , Molina A , Stepan D E , Spielberger R , Somlo G , Margolin K A , Vora N , Lipsett J , Lee J , Niland J , Forman S J
Published: February 2017

PURPOSE

To evaluate in a prospective study the efficacy of autologous bone marrow transplantation (BMT) in adult patients with acute myelogenous leukemia (AML) in first remission, using a single course of high-dose Cytarabine (HD Ara-C) consolidation therapy as in vivo purging.

PATIENTS AND METHODS

Sixty consecutive adult patients with AML in first complete remission (CR) were treated with HD Ara-C consolidation therapy as a method of in vivo purging before marrow collection. High-dose therapy consisted of fractionated total-body irradiation (FTBI) 12 Gy, intravenous etoposide 60 mg/kg, and cyclophosphamide 75 mg/kg, followed by reinfusion of cryopreserved marrow.

RESULTS

Sixty patients underwent consolidation treatment with HD Ara-C with the intent to treat with autologous BMT. Sixteen patients were unable to proceed to autologous BMT (10 patients relapsed, one died of sepsis, one developed cerebellar toxicity, two had inadequate blood counts, and two refused). Forty-four patients underwent autologous BMT and have a median follow-up time of 37 months (range, 14.7 to 68.7) for patients who are alive with no relapse. The cumulative probability of disease-free survival (DFS) at 24 months in the intent-to-treat group is 49% (95% confidence interval [CI], 37% to 62%) and in those who actually underwent autologous BMT is 61% (95% CI, 46% to 74%). The probability of relapse was 44% (95% CI, 31% to 58%) and 33% (95% CI, 20% to 49%) for the intent-to-treat and autologous BMT patients, respectively.

CONCLUSION

This approach offers a relatively high DFS rate to adult patients with AML in first CR. The results of this study are similar to those achieved with allogeneic BMT.
Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol.
Authors: Chang A , Yeap B , Davis T , Blum R , Hahn R , Khanna O , Fisher H , Rosenthal J , Witte R , Schinella R , Trump D
Published: February 2017

PURPOSE

Patients with stage D2 prostate carcinoma are often treated initially with hormones to decrease endogenous testosterone. Therapy with diethylstilbestrol (DES), leuprolide, or bilateral orchiectomy has been reported to be equivalent. DES is the cheapest preparation, but has the potential for serious cardiovascular or thromboembolic complications. Flutamide is a novel antiandrogen with fewer side effects.

PATIENTS AND METHODS

The Eastern Cooperative Oncology Group (ECOG) conducted a double-blind, randomized study to compare the efficacy of flutamide (250 mg three times daily) to DES (1 mg three times daily) as the primary hormonal therapy for patients with stage D2 prostate cancer. Patients were stratified by performance status, disease sites, and history of cardiovascular disease at randomization.

RESULTS

Forty-eight patients received DES and 44 flutamide. Patient characteristics were evenly distributed between the two treatments. The overall response rate was similar (DES, 62%; flutamide, 50%). Grade III or worse cardiovascular or thromboembolic toxicity developed in 33.3% of patients on DES and in 17.6% on flutamide (P = .051). Other toxicities were similar between the two treatment arms. However, DES produced significantly longer time to treatment failure (26.4 v 9.7 months, P = .016) and longer survival than flutamide (43.2 v 28.5 months, P = .040).

CONCLUSION

As the primary hormonal therapy for stage D2 prostate cancer, DES caused more serious cardiovascular or thromboembolic complications than flutamide. Despite this, flutamide was not as active an initial agent as DES. However, the effectiveness of flutamide in conjunction with other agents compared with DES remains undetermined, and the optimal initial hormone therapy of stage D2 prostate cancer requires further studies.
Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1.
Authors: Jäger E , Heike M , Bernhard H , Klein O , Bernhard G , Lautz D , Michaelis J , Meyer zum Büschenfelde K H , Knuth A
Published: February 2017

PURPOSE

To determine the most effective dose of leucovorin (folinic acid [FA]) within a weekly bolus fluorouracil (FU) schedule, we conducted a randomized multicenter trial to compare therapeutic effects and toxicity of high-dose FA versus low-dose FA combined with FU at equal doses in both treatment groups.

PATIENTS AND METHODS

Patients with measurable inoperable or metastatic colorectal cancer were randomized to receive weekly FU 500 mg/m2 by intravenous (IV) bolus combined with high-dose FA 500 mg/m2 (group A) or low-dose FA 20 mg/m2 (group B) by 2-hour infusion.

RESULTS

Of 291 assessable patients (group A, n = 148; group B, n = 143), we observed, in group A, complete response (CR)/partial response (PR) in 32 (21.6%), no change (NC) in 64 (43.2%), and progressive disease (PD) in 52 (35.1%); and in group B, CR/PR in 25 (17.5%), NC in 63 (44.1%), and PD in 55 (38.5%). The median response duration was 24.8 weeks in group A and 23.1 weeks in group B. Median progression-free intervals were 29.3 weeks (group A) and 30 weeks (group B). The median survival time was 55.1 weeks in group A and 54.1 weeks in group B. Overall toxicity was moderate. Mild nausea and vomiting, and stomatitis were common side effects in both groups. The incidence of World Health Organization (WHO) grade III/IV diarrhea was significantly higher in group A (40 v 23 patients). Severe side effects were observed only in a minority of patients in both arms. WHO grade IV diarrhea was observed in seven patients: four in group A and three in group B. The rate of toxicity-related adjustments of dose and schedule was comparable in both groups.

CONCLUSION

High-dose FA/FU is not superior to low-dose FA/FU within a weekly treatment schedule. Response rates and survival were comparable in both treatment arms. Treatment-related toxicity was higher in group A (high-dose FA). Therefore, low-dose FA combined with weekly FU may be considered the preferred treatment for metastatic colorectal cancer.
Comparative cytotoxicity of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia.
Authors: Ito C , Evans W E , McNinch L , Coustan-Smith E , Mahmoud H , Pui C H , Campana D
Published: February 2017

PURPOSE

The relative cytotoxicity of prednisolone and dexamethasone in acute lymphoblastic leukemia (ALL) is controversial. We therefore compared the direct antileukemic activities of these compounds in stroma-supported cultures of leukemic lymphoblasts.

MATERIALS AND METHODS

Bone marrow samples from children with B-lineage ALL were cultured on allogeneic bone marrow-derived stromal layers and exposed to various concentrations of glucocorticoids. After 4 days of culture, the number of viable leukemic cells was counted by flow cytometry and compared with that in parallel cultures without drugs.

RESULTS

In 28 B-lineage ALL samples tested, the concentration producing 50% cytotoxicity (LC50) of prednisolone ranged from 2.0 to 7,978 nmol/L (median, 43.5 nmol/L), and that of dexamethasone from 0.6 to 327 nmol/L (median, 7.5 nmol/L). Despite the wide variability of responses among samples, there was an excellent correlation between LC50 values obtained with the two drugs (linear r = .99, P < .0001; Spearman rank-order r = .77, P < .0001). The median ratio of dexamethasone to prednisolone LC50 and LC90 values was 1:5.5 (range, 1:1.0 to 1:24.4 for LC50; 1:1.1 to 1:25.5 for LC90). Studies with ALL cell lines demonstrated that both drugs were cytotoxic through induction of apoptosis. Stromal layers did not absorb or inactivate measurable amounts of corticosteroids, which indicates that the assay system did not bias results toward increased drug resistance.

CONCLUSION

In a bone marrow-derived microenvironment, dexamethasone is five to six times more cytotoxic (on a molar basis) than prednisolone, in agreement with the antiinflammatory activities of these drugs. This finding may serve to guide the selection of dexamethasone dosage in the treatment of ALL.
Phase I clinical trial of melphalan and 41.8 degrees C whole-body hyperthermia in cancer patients.
Authors: Robins H I , Rushing D , Kutz M , Tutsch K D , Tiggelaar C L , Paul D , Spriggs D , Kraemer C , Gillis W , Feierabend C , Arzoomanian R Z , Longo W , Alberti D , d'Oleire F , Qu R P , Wilding G , Stewart J A
Published: February 2017

PURPOSE

To evaluate the biologic interactions and toxicities of melphalan (L-PAM) combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes.

PATIENTS AND METHODS

Sixteen patients with refractory cancer were treated (May 1992 to May 1995) with WBH alone during week 1) thereafter patients were randomized to receive either L-PAM alone on week 2 and L-PAM plus WBH on week 5, or the reverse sequence. Patients who demonstrated clinical improvement received WBH plus L-PAM monthly. Dose levels of L-PAM were 10 mg/m2 (n = 3), 15 mg/m2 (n = 3), 17.5 mg/m2 (n = 6), and 20 mg/m2 (n = 4). L-PAM was administered at target temperature; WBH was administered with an Aquatherm radiant-heat device (patent pending; Cancer Research Institute, New York, NY).

RESULTS

Comparisons of mean WBC count and platelet nadirs for L-PAM alone and L-PAM plus WBH demonstrated that the addition of WBH resulted in nadir counts that were, on average, 25% lower. There were no instances of febrile neutropenia or bleeding. Toxicities allowed for escalation of L-PAM to 20 mg/m2; all four patients at this level experienced grade 4 myelosuppression. No significant myelosuppression was observed at 10 and 15 mg/m2. Grade 3 myelosuppression was observed in two of six patients at 17.5 mg/m2. Responses included complete remission (CR) of pancreatic cancer (10 mg/m2), partial remission (PR) of malignant melanoma in two patients (20 mg/m2), and transient clinical and/or serologic improvement in five patients. The pharmacokinetics of L-PAM were not altered by WBH. Observed cytokine induction by WBH is also discussed in detail.

CONCLUSION

We conclude that L-PAM with 41.8 degrees C WBH is well tolerated. Clinical results are consistent with preclinical predictions and provide a foundation for second-generation trials now in progress.
Influence of age on the outcome of 500 autologous bone marrow transplant procedures for hematologic malignancies.
Authors: Kusnierz-Glaz C R , Schlegel P G , Wong R M , Schriber J R , Chao N J , Amylon M D , Hu W W , Negrin R S , Lee Y , Blume K G , Long G D
Published: February 2017

PURPOSE

To determine the effect of age on the outcome of autologous bone marrow transplantation (ABMT) and/or peripheral-blood progenitor-cell (PBPC) transplantation.

PATIENTS AND METHODS

A retrospective analysis was performed on 500 consecutive patients who ranged in age from 1 to 65 years (median, 40) with non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), multiple myeloma (MM), or acute nonlymphoblastic leukemia (AML) who underwent autologous hematopoietic-cell transplant procedures at Stanford University Medical Center.

RESULTS

The actuarial 5-year event-free survival (EFS) rate was 44%, the relapse rate 47%, and the regimen-related mortality (RRM) rate 8.6%. Disease status at time of transplantation, categorized as either minimal or advanced disease, was the strongest predictive factor for EFS (relative risk (RR) for advanced-disease group, 1.8; P < .0003) and relapse rate (RR for advanced-disease group, 1.9; P < .0004). Patients with minimal or advanced disease had an EFS rate of 48% and 30% and relapse rates of 43% and 72%, respectively. The EFS rate of patients less than 50 years verus > or = 50 years of age was 46% versus 34% (P = .03). Cox regression analysis showed that age was predictive for EFS (RR for patients 50 to 65 years, 1.4; P = .03). The actuarial RRM rate for these age groups was 7.4% versus 12.7% (P = .07), respectively. Multivariate analysis demonstrated that age (odds ratio [OR] for patients 50 to 65 years, 1.9; P < .05) and period of transplantation (OR for most recent years [1991 to 1995], 0.6; P = .06) were the most predictive factors for RRM.

CONCLUSION

Although age greater than 50 years is associated with an inferior outcome following autologous hematopoietic-cell transplantation, it does not appear to be warranted to limit this potentially curative procedure based solely on age. The upper age limit of high-dose therapy with autologous progenitor-cell and/ or bone marrow support remains to be defined.
Increasing prostate-specific antigen profile following definitive radiation therapy for localized prostate cancer: clinical observations.
Authors: Lee W R , Hanks G E , Hanlon A
Published: February 2017

PURPOSE

To examine the natural history of patients who have received definitive radiation therapy alone for clinically localized prostate cancer and have an increasing prostate-specific antigen (PSA) profile.

PATIENTS AND METHODS

One hundred fifty-one men with an increasing PSA profile after definitive radiotherapy were identified. The subsequent natural history of these men, including local recurrence, distant metastasis, and survival, was examined. In 119 men, posttreatment PSA doubling times (PSADT) were calculated using linear regression. Cox regression models were used to examine the effect of clinical and treatment variables on clinical failure and survival.

RESULTS

Patients with high pretreatment PSA values, high Gleason scores, and T3 tumors were more likely to develop a PSA elevation. The median calculated post-treatment PSADT was 13 months, and 95% of patients had posttreatment PSADT of less than 3 years. PSADT was correlated with tumor stage and Gleason score. Five years after PSA elevation, the estimated rate of clinical local recurrence is 26% and the estimated rate of distant metastases is 47%. Rapid PSADT (< 12 months) and a short interval from the end of treatment to PSA elevation (< 12 months) were significant independent predictors of distant metastases. The estimated rates of overall and cause-specific survival 5 years after PSA elevation are 65% and 76%, respectively. Gleason grade is the only significant independent predictor of overall and cause-specific survival after PSA elevation.

CONCLUSION

The natural history of men who have an increasing PSA profile following definitive radiotherapy is heterogeneous. In the absence of salvage therapy, at least three quarters of men will have clinical evidence of recurrent disease 5 years after a PSA elevation is detected. Men with a rapid posttreatment PSADT and a short interval from the end of treatment to an increasing PSA profile are at a very high risk of developing distant metastasis within 5 years of PSA elevation.