bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors in osteosarcoma: a critical review.
Authors: Davis A M , Bell R S , Goodwin P J
Published: February 2017

PURPOSE

The purpose of this critical appraisal was to determine the prognostic factors that influence survival in patients with nonmetastatic, high-grade osteosarcoma of the extremities.

DESIGN

A computerized literature search of reports published from January 1973 to March 1992 was conducted to determine those eligible for inclusion in the review. Reports were reviewed blindly by two of the authors; inclusion and scoring were determined according to preestablished criteria.

RESULTS

Eight reports were included in the appraisal. The prognostic variables evaluated were age, sex, anatomic tumor location, tumor size, and tumor necrosis. Tumor size and necrosis following preoperative chemotherapy were significant prognostic variables in relation to survival in univariate analysis. However, only tumor necrosis maintained its significance in multivariate modeling.

CONCLUSION

The most important prognostic variable for patients with osteosarcoma of the extremity was tumor necrosis evident following preoperative chemotherapy. There is no consensus as to any prognostic variable that might be used to stratify patients before the onset of therapy.
Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.
Authors: Cuzick J , Stewart H , Rutqvist L , Houghton J , Edwards R , Redmond C , Peto R , Baum M , Fisher B , Host H
Published: February 2017

PURPOSE

To examine long-term cause-specific mortality in patients irradiated for breast cancer as part of a randomized clinical trial.

PATIENTS AND METHODS

We studied all available information from randomized trials initiated before 1975 in which radiotherapy was the randomized option and surgery was the same for both treatment arms. Eight such trials were identified.

RESULTS

The increased all-cause mortality rate in 10-year survivors previously reported is no longer significant, although a numerical difference in favor of non-irradiated patients remains. This result was strongly influenced by the earliest trials, and more recent trials have found a nonsignificant net benefit in overall mortality associated with radiation therapy. An excess of cardiac deaths was apparent in both early and more recent trials (P < .001), but this was offset by a reduced number of deaths due to breast cancer, especially in more recent trials.

CONCLUSION

The reduction of breast cancer deaths suggests that radiation therapy may have a value beyond the clearly established improvements obtainable for local control. Use of techniques that minimize cardiac dose is important in reducing the risks of adjuvant radiotherapy, especially in good-prognosis patients.
Limited-stage small-cell lung cancer: patterns of intrathoracic recurrence and the implications for thoracic radiotherapy.
Authors: Liengswangwong V , Bonner J A , Shaw E G , Foote R L , Frytak S , Eagan R T , Jett J R , Richardson R L , Creagan E T , Su J Q
Published: February 2017

PURPOSE

This analysis was performed to determine the most appropriate volume that should be encompassed by thoracic radiation treatments (TRTs) for patients with limited-stage small-cell lung cancer (LSSCLC) who have responded to initial chemotherapy.

PATIENTS AND METHODS

A retrospective review of all patients (N = 67) with LSSCLC who were not entered onto a research protocol and were treated at our institution between the years of 1982 and 1990 was performed. Fifty-nine of 67 patients had adequate information regarding the size of the tumor before the start of chemotherapy (computed tomographic [CT] scan of chest or chest x-ray), the size of the tumor before TRT, and the TRT field size based on a simulation radiography. All 59 patients were treated with cyclophosphamide-based chemotherapy, and TRT was generally delivered concomitantly with chemotherapy following two to three cycles of chemotherapy alone.

RESULTS

Of 59 patients, 28 were treated with TRT field sizes that encompassed postchemotherapy tumor volumes, and 31 patients were treated with TRT field sizes that encompassed prechemotherapy tumor volumes (defined as a volume that included at least a 1.5-cm margin on the prechemotherapy tumor volume). Nineteen patients had an intrathoracic recurrence of disease as the first site of recurrent small-cell carcinoma: 10 of 31 patients treated with TRT fields that encompassed prechemotherapy tumor volumes and nine of 28 patients treated with TRT fields that encompassed postchemotherapy tumor volumes. For the 28 patients treated with TRT fields that encompassed postchemotherapy tumor volumes, the greatest distance that the prechemotherapy tumor volume (without margins) extended beyond the edge of the TRT field was 0.5 to 5.0 cm, with a median of 2.5 cm. All 19 of the intrathoracic recurrences were in-field failures, although two patients (one prechemotherapy volume and one postchemotherapy volume) did have concurrent pleural effusions.

CONCLUSION

These results indicate that the use of TRT fields that encompass postchemotherapy tumor volumes does not increase the risk of marginal failures or intrathoracic failures outside the TRT field.
High-dose sequential chemoradiotherapy, a widely applicable regimen, confers survival benefit to patients with high-risk multiple myeloma.
Authors: Gianni A M , Tarella C , Bregni M , Siena S , Lombardi F , Gandola L , Caracciolo D , Stern A , Bonadonna G , Boccadoro M
Published: February 2017

PURPOSE

To assess the toxicity, efficacy, and applicability of high-dose therapy with bone marrow and/or peripheral-blood autotransplantation in high-risk, previously untreated patients with multiple myeloma.

PATIENTS AND METHODS

Thirteen consecutive patients with high-labeling index (LI) multiple myeloma received a novel high-dose sequential (HDS) regimen consisting in the high-dose administration of cyclophosphamide (7 g/m2) followed by vincristine (1.4 mg/m2) plus methotrexate (8 g/m2 with leucovorin rescue), etoposide (2 g/m2) and, finally, total-body irradiation (TBI; 10 Gy) plus melphalan (120 mg/m2) with autografting of peripheral-blood hematopoietic progenitor cells. Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 5 micrograms/kg/d) was continuously infused after cyclophosphamide and etoposide both to accelerate hematopoietic recovery and to expand/mobilize the hematopoietic progenitor-cell pool.

RESULTS

Among 13 patients, 12 completed the program; 10 (or 77%) achieved a complete response and five are alive and disease-free after a median follow-up duration of 36 months (range, 24 to 52). The durations of both freedom from progression (FFP; median, 38 months) and overall survival (OS; median, 41 months) were significantly superior in the 13 HDS-treated patients as compared with 19 well-matched historical controls.

CONCLUSION

HDS emerges as a highly effective, well-tolerated, and widely accessible regimen capable of imparting a survival benefit to patients with high-LI multiple myeloma. Larger studies using this or similar programs in standard-risk myeloma are clearly warranted.
Phase I study of combined 2-chlorodeoxyadenosine and chlorambucil in chronic lymphoid leukemia and low-grade lymphoma.
Authors: Tefferi A , Witzig T E , Reid J M , Li C Y , Ames M M
Published: February 2017

PURPOSE

We conducted a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) added to a standard fixed dose of chlorambucil to evaluate the toxicity of the combined regimen in patients with chronic lymphocytic leukemia (CLL) and low-grade lymphoma.

PATIENTS AND METHODS

A total of 15 adults with relapsed or refractory CLL or low-grade lymphoma were to receive chlorambucil orally (30 mg/m2) every 2 weeks. Also, groups of three patients were to receive escalating doses of continuous intravenously administered 2-CdA at 1, 2, or 4 mg/m2/d for 7 days repeated at monthly intervals. All patients had pharmacokinetic studies during the first cycle of 2-CdA therapy; the results were compared with other institutional phase I studies in which comparable amounts of 2-CdA were administered by bolus infusion for 5 days.

RESULTS

The maximal-tolerated dose of 2-CdA that could be combined with chlorambucil was 2 mg/m2/d for 7 days for a maximum of two courses. At a higher dose level of 2-CdA or at the maximal-tolerated dose level given for more than two courses, severe and protracted pancytopenia, sometimes associated with life-threatening infections, was noted. Nonhematologic toxicities were limited to moderate degrees of nausea, vomiting, anorexia, and fatigue. Results of the pharmacologic studies suggested that 2-CdA clearance was independent of administration schedule and was unaffected by concomitant administration of chlorambucil.

CONCLUSION

These observations suggest the possibility of combining two cycles of continuous intravenously administered 2-CdA (2 mg/m2/d for 7 days) with standard doses of oral chlorambucil to test the efficacy of the combination regimen in phase II trials.
Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma.
Authors: McLaughlin P , Hagemeister F B , Swan F , Cabanillas F , Pate O , Romaguera J E , Rodriguez M A , Redman J R , Keating M
Published: February 2017

PURPOSE

Fludarabine is an active agent for patients with low-grade lymphoma (LGL) but has mainly been used as a single agent. This trial was designed to define the maximum-tolerated dose (MTD) of a combination of fludarabine, mitoxantrone, and dexamethasone (FND), to identify the toxicities of these agents in combination, and to make preliminary observations about the efficacy of this combination.

PATIENTS AND METHODS

Twenty-one patients with recurrent LGL or follicular large-cell lymphoma were treated, in cohorts of three, at stepwise escalating doses. Patients were required to have adequate marrow function and normal renal, hepatic, and cardiac function.

RESULTS

The MTD of the combination was found to be as follows: fludarabine, 25 mg/m2/d (days 1 to 3); mitoxantrone, 10 mg/m2 (day 1); and dexamethasone, 20 mg/d (days 1 to 5). Each course was administered monthly, and up to eight courses were given. Dose-limiting toxicities were neutropenia and infections. Thrombocytopenia was modest. Nonhematologic toxicity was very modest. Responses were seen at every dose level. The overall response rate was 71%, with a 43% complete remission (CR) rate. The median duration of CR was 18 months (with follow-up duration from 13 to 28+ months).

CONCLUSION

FND was well tolerated in this population. While our primary aim was to define the MTD, our preliminary observations on the efficacy of the regimen were favorable. The overall response rate was high, there was a high fraction of CRs, and our early impression is that these responses are durable.
Small Noncleaved Cell Lymphoma in Adults
Authors: Lopez Timothy M. , Hagemeister Fredrick B. , McLaughlin Peter , Velasquez William S. , Swan Forrest , Redman John R. , Rodriguez Maria A. , Tucker Susan L. , Silvermintz Karen , Johnson Jana , Cabanillas Fernando
Published: February 2017

Table 2 in the 1990 report entitled "Small Noncleaved Cell Lymphoma in Adults: Superior Results for Stages I–III Disease" by Lopez et al (J Clin Oncol 8:615–622, 1990) contained a vincristine dosage error. The table is reprinted here correctly in its entirety.

Please see the PDF for Table.
Randomized study of growth factors post-peripheral-blood stem-cell transplant: neutrophil recovery is improved with modest clinical benefit.
Authors: Spitzer G , Adkins D R , Spencer V , Dunphy F R , Petruska P J , Velasquez W S , Bowers C E , Kronmueller N , Niemeyer R , McIntyre W
Published: February 2017

PURPOSE

To evaluate the clinical value of growth factors (GFs) with peripheral-blood stem cells (PBSC) collected following mobilization with GFs, we randomized patients to receive or not to receive GFs following transplant.

PATIENTS AND METHODS

Thirty-seven patients were apheresed after receiving the combination of granulocyte colony-stimulating factor (G-CSF) with granulocyte-macrophage colony-stimulating factor (GM-CSF) at doses of 10 micrograms/kg/d and 5 micrograms/kg/d, respectively, for 6 days before apheresis and during a median of 4 days of collections. One day after the infusion of autologous marrow and PBSC, patients were randomly assigned to receive no GFs or a combination of G-CSF (7.5 micrograms/kg/d) and GM-CSF (2.5 micrograms/kg/d), both as a 2-hour intravenous (i.v.) infusion twice per day until the neutrophil count was greater than 1,500/microL.

RESULTS

The median days to recovery to an absolute neutrophil count (ANC) of 100/microL (9 v 11.5, P = .0005), 500/microL (10 v 16, P = .0004), or 1,000/microL (12 v 21, P = .0008) was shortened with the use of GFs, post-PBSC infusion. In addition, the duration of hospitalization was shorter (19 v 21 days, P = .0112) in the arm receiving GFs post-PBSC infusion. There was no significant difference between the two study arms in the duration of fever, documented septic episodes, or RBC or platelet transfusion requirements.

CONCLUSION

Despite faster neutrophil recovery and shortened duration of hospitalization with GFs administered after PBSC transplantation, the measured clinical variables of febrile days, septic episodes, and transfusion requirements were similar between the study arms. The use of GFs post-PBSC transfusion is associated with a modest clinical benefit.
Use of palliative end points to evaluate the effects of mitoxantrone and low-dose prednisone in patients with hormonally resistant prostate cancer.
Authors: Moore M J , Osoba D , Murphy K , Tannock I F , Armitage A , Findlay B , Coppin C , Neville A , Venner P , Wilson J
Published: February 2017

PURPOSE

This phase II study was designed to assess the effects of mitoxantrone with prednisone in patients with metastatic prostate cancer who had progressed on hormonal therapy. The methods of assessment included quality-of-life analyses, pain indices, analgesic scores, and the National Prostatic Cancer Project (NPCP) criteria.

PATIENTS AND METHODS

Patients received mitoxantrone 12 mg/m2 intravenously every 3 weeks plus prednisone 10 mg orally daily. All had a castrate serum testosterone and Eastern Cooperation Oncology Group (ECOG) performance status < or = 3, and had not received prior chemotherapy. Every 3 weeks, analgesic intake was scored, and a present pain intensity (PPI) record and visual analog scale (VAS) describing pain were collected. Every 6 weeks, the European Organization for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire plus a prostate-specific module were completed. A palliative response was defined as a decrease in analgesic score by > or = 50% or a decrease in PPI by > or = two integers without any increase in the other.

RESULTS

Twenty-seven patients were entered onto the study. Nine of 25 (36%) assessable patients achieved a palliative response maintained for > or = two cycles (range, two to eight or more). Improvements in mean PPI and VAS pain scores after each cycle of therapy (P < .05) were seen. Quality-of-life analysis showed improvements in social and emotional functioning, and in pain and anorexia. Using NPCP criteria, one patient achieved a partial response (PR) and 12 had stable disease; one of seven patients with measurable disease had a PR. No serious nonhematologic toxicity was experienced, and there were no episodes of febrile neutropenia.

CONCLUSION

Mitoxantrone with low-dose prednisone is a well-tolerated treatment regimen that has some beneficial effects on disease-related symptoms and quality of life for patients with advanced prostate cancer.
Effects of PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein, on chemotherapy-induced multilineage myelosuppression in patients with sarcoma.
Authors: Vadhan-Raj S , Papadopoulos N E , Burgess M A , Linke K A , Patel S R , Hays C , Arcenas A , Plager C , Kudelka A P , Hittelman W N
Published: February 2017

PURPOSE

To evaluate the clinical safety and ability of PIXY321, a novel fusion protein of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), to ameliorate chemotherapy-induced multilineage myelosuppression.

PATIENTS AND METHODS

PIXY321 was administered by subcutaneous injection twice daily (25 to 1,000 micrograms/m2/d) over 14 days to 24 chemotherapy-naive patients with sarcoma in a phase I/II study. Three weeks from the initiation of PIXY321, the first cycle of chemotherapy with cyclophosphamide, doxorubicin, and dacarbazine (DTIC) (CyADIC) was administered over 3 days. Four weeks later, a second cycle of CyADIC was administered, followed by 14 days of PIXY321.

RESULTS

Treatment with PIXY321 was well tolerated. Local skin reactions and constitutional symptoms were the main side effects. The dose-limiting toxicity was not encountered; however, headache and fatigue were more frequent at the highest dose (1,000 micrograms/m2). PIXY321 before chemotherapy elicited a modest increase in the WBC count (consisting mainly of mature neutrophils), platelets, and corrected reticulocyte counts (all P < .001). Following chemotherapy, PIXY321 at effective doses (500 to 1,000 micrograms/m2/d), significantly reduced both the degree (mean nadir, 70 v 310/microL; P = .016) and duration (mean days < 500/microL, 6.6 v 3.9 days; P = .002) of neutropenia. Cumulative thrombocytopenia was not observed during the first two cycles of CyADIC (mean nadir platelet count, 103 v 95 x 10(3)/microL, in cycles no. 1 and 2, respectively; P = NS). Compared with our historic control data, the mean nadir platelet count in cycle no. 2 was significantly higher after PIXY321 (1.7-fold, P < .05) than with CyADIC alone or with GM-CSF support. There was a suggestion for a dose response, since the mean percentage change in nadir platelet values from cycle no. 1 to cycle no. 2 increased with the PIXY321 dose (P < .02), with the peak effect observed at 750 micrograms/m2/d.

CONCLUSION

These results suggest a potential clinical role for PIXY321 in attenuating the cumulative multilineage hematopoietic toxicity of chemotherapy.
ChlVPP/PABlOE and radiotherapy in advanced Hodgkin's disease. The Central Lymphoma Group.
Authors: Cullen M H , Stuart N S , Woodroffe C , Murphy A , Fletcher J , Blackledge G R , Child J A , Grieve R J , Jones E L
Published: February 2017

PURPOSE

The United Kingdom Central Lymphoma Group (CLG) has modified mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) by substituting mechlorethamine with chlorambucil and dacarbazine with etoposide in the treatment of patients with advanced Hodgkin's disease (HD). Prednisolone is included in the bleomycin-containing combination, and the vinca alkaloids have been switched to balance the myelotoxicity of the two component regimens.

PATIENTS AND METHODS

The resulting ChlVPP/PABlOE regimen is as follows: on days 1 to 14, chlorambucil 6 mg/m2 orally, procarbazine 100 mg/m2 orally, and prednisolone 30 mg/m2 orally; on days 1 and 8, vinblastine 6 mg/m2 intravenously (i.v.); on day 29, doxorubicin 40 mg/m2 i.v.; on days 29 and 36, vincristine 1.4 mg/m2 (maximum, 2 mg) i.v., and bleomycin 10 mg/m2 i.v.; on days 30, 31, and 32, etoposide 200 mg/m2/d orally; on days 29 to 43, inclusive, prednisolone, 30 mg/m2 orally. The second full cycle restarts on day 50. Treatment continues to maximum response plus two full cycles, but with a minimum of three full cycles. Radiotherapy is administered, after chemotherapy, to sites of previously bulky disease. Since 1983, 216 patients with previously untreated, advanced Hodgkin's disease (HD) have entered this study.

RESULTS

The complete remission (CR) rate after chemotherapy was 73% (95% confidence interval [CI], 67% to 79%), and after additional radiotherapy was 85% (95% CI, 80% to 90%). The failure-free survival (FFS) rate at 5 years was 68% (95% CI, 61% to 74%), and the overall actuarial survival at 5 years was 78% (95% CI, 72% to 84%). The CR rate in patients in the poorer prognostic categories was high: 81% in patients with albumin levels less than 37 g/L, 79% in patients older than 40 years of age, 84% in stages IIIB plus i.v. disease, and 79% in patients presenting with B symptoms. As expected, nausea and vomiting were not major problems, although infection, often in the context of myelosuppression, complicated almost half the cases, and 29% of patients required admission at some stage for treatment of infection.

CONCLUSION

In this multicenter study, ChlVPP/PABlOE produced results comparable to those reported for MOPP/ABVD, but with less nausea and vomiting. Treatment duration was shorter than in the original MOPP/ABVD regimen, and than that used in the Cancer and Leukemia Group B (CALGB) trial. It will now be compared with PABlOE alone.
Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma.
Authors: Bajetta E , Di Leo A , Zampino M G , Sertoli M R , Comella G , Barduagni M , Giannotti B , Queirolo P , Tribbia G , Bernengo M G
Published: February 2017

PURPOSE

Some phase II studies have suggested that the combination of interferons (IFNs) with dacarbazine (DTIC) in the treatment of malignant melanoma (MM) increases the antitumor activity of DTIC alone. In an attempt to confirm this hypothesis, a randomized study was performed with the further intent of observing whether low doses of recombinant interferon alfa-2a (rIFN alpha 2a) could be as effective as intermediate doses.

PATIENTS AND METHODS

Two hundred sixty-six patients were randomized onto three different treatment arms: DTIC 800 mg/m2 intravenously (IV) days 1 and 21; DTIC plus rIFN alpha 2a 9 mIU intramuscularly (IM) daily; and DTIC plus rIFN alpha 2a 3 mIU IM three times per week. Major prognostic factors were well balanced among the three arms. Chemotherapy was administered for a maximum of eight cycles. After 6 months of therapy, rIFN alpha 2a was continued until disease progression at 3 mIU three times per week in responding patients who had received the combined treatment.

RESULTS

The percentage of objective responses did not differ among the three groups (20%, 28%, and 23%, respectively), although a significant prolongation of response duration was observed when rIFN alpha 2a was added to DTIC (2.6 v 8.4 v 5.5 months, respectively). However, this improvement in response duration did not translate into an amelioration of overall survival. The addition of rIFN alpha 2a led to the onset of flu-like syndrome, but in no case was it necessary to withdraw the treatment program and no toxic deaths or life-threatening toxicities were reported.

CONCLUSION

In this study, rIFN alpha 2a significantly prolonged response duration, whereas no effects on response rate and survival were observed; rIFN alpha 2a 3 mIU appeared to be equally effective and better tolerated than 9 mIU.
Phase I trial of doxorubicin with cyclosporine as a modulator of multidrug resistance.
Authors: Bartlett N L , Lum B L , Fisher G A , Brophy N A , Ehsan M N , Halsey J , Sikic B I
Published: February 2017

PURPOSE

To study the effects of cyclosporine (CsA), a modulator of multidrug resistance (MDR), on the pharmacokinetics and toxicities of doxorubicin.

PATIENTS AND METHODS

Nineteen patients with incurable malignancies entered this phase I trial. Initially patients received doxorubicin alone (60 or 75 mg/m2) as a 48-hour continuous intravenous (i.v.) infusion. Patients whose tumors did not respond received CsA as a 2-hour loading dose of 6 mg/kg and a 48-hour continuous infusion of 18 mg/kg/d with doxorubicin. Target CsA levels were 3,000 to 4,800 ng/mL (2.5 to 4.0 mumol/L). Doxorubicin doses were reduced to 40% of the prior dose without CsA, and then escalated until myelosuppression equivalent to that resulting from doxorubicin alone was observed. Doxorubicin pharmacokinetics were analyzed with and without CsA.

RESULTS

Thirteen patients received both doxorubicin alone and the combination of doxorubicin and CsA. Mean CsA levels were more than 2,000 ng/mL for all cycles and more than 3,000 ng/mL for 68% of cycles. Dose escalation of doxorubicin with CsA was stopped at 60% of the doxorubicin alone dose, as four of five patients at this dose level had WBC nadirs equivalent to those seen with doxorubicin alone. Nonhematologic toxicities were mild. Reversible hyperbilirubinemia occurred in 68% of doxorubicin/CsA courses. The addition of CsA to doxorubicin increased grade 1 and 2 nausea (87% v 47%) and vomiting (50% v 10%) compared with doxorubicin alone. There was no significant nephrotoxicity. Paired pharmacokinetics were studied in 12 patients. The addition of CsA increased the dose-adjusted area under the curve (AUC) of doxorubicin by 55%, and of its metabolite doxorubicinol by 350%.

CONCLUSION

CsA inhibits the clearance of both doxorubicin and doxorubicinol. Equivalent myelosuppression was observed when the dose of doxorubicin with CsA was 60% of the dose of doxorubicin without CsA. Understanding these pharmacokinetic interactions is essential for the design and interpretation of clinical trials of MDR modulation, and should be studied with more potent MDR modulators.
Dose-ranging evaluation of the serotonin antagonist dolasetron mesylate in patients receiving high-dose cisplatin.
Authors: Kris M G , Grunberg S M , Gralla R J , Baltzer L , Zaretsky S A , Lifsey D , Tyson L B , Schmidt L , Hahne W F
Published: February 2017

PURPOSE

This dose-ranging trial of intravenous dolasetron mesylate (MDL73,147EF) was performed to determine its adverse and antiemetic effects in patients receiving cisplatin at doses > or = 100 mg/m2.

PATIENTS AND METHODS

Eighty-nine patients treated with initial cisplatin received a single intravenous dose of dolasetron mesylate administered over 20 minutes beginning 30 minutes before chemotherapy. The following four dose levels were studied: 1.8, 2.4, 3.0, and 5.0 mg/kg. Emesis and adverse effects were measured for 24 hours after cisplatin.

RESULTS

All adverse effects were mild and transient including loose stools, headache, serum AST/ALT elevations, and asymptomatic prolongation of ECG intervals. Among the dose levels, no-emesis rates from 24% to 52% were observed, and the percentage of patients having zero, one, or two emetic episodes ranged from 48% to 82%. Complete control of vomiting increased as the dose was escalated to 2.4 mg/kg, but did not improve further with higher doses.

CONCLUSION

Dolasetron mesylate can be administered safely at doses up to 5.0 mg/kg, with comparable complete protection rates and increased adverse effects at doses greater than 2.4 mg/kg. Antiemetic activity was seen after cisplatin. Trials comparing single infusions of dolasetron mesylate and ondansetron are under way.
Neoadjuvant chemotherapy and partial cystectomy for invasive bladder cancer.
Authors: Herr H W , Scher H I
Published: February 2017

PURPOSE

This clinical trial evaluated a bladder-sparing strategy using a combined modality approach of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy followed by a partial cystectomy for patients with invasive (T2-4N0M0) bladder cancer.

PATIENTS AND METHODS

One hundred eleven surgical candidates received a median of four cycles of neoadjuvant M-VAC. Following treatment, of those with a favorable response to chemotherapy based on cystoscopic examination, 26 underwent a partial cystectomy.

RESULTS

Of 26 patients, 17 (65%) are alive beyond 5 years (median, 6.9 years; range, 4 to 8), including 14 (54%) with an intact, functioning bladder. Twelve patients (46%) developed bladder recurrences, which were invasive in five (18%) and superficial in seven (26%). Patients with no (P0) or noninvasive (Pis) tumor in their surgical specimens had a 5-year survival rate of 87% (14 of 16), compared with 30% (three of 10) among patients with residual invasive cancer. The majority of deaths was attributed to preexisting metastases.

CONCLUSION

Neoadjuvant M-VAC chemotherapy permitted bladder-sparing surgery in selected responding patients with invasive bladder neoplasms. The bladder remained at risk for new tumor development, but local recurrences were treated successfully by local therapy or salvage cystectomy.
Surgical treatment of primary lung cancer in patients less than 40 years of age.
Authors: Shimono T , Hayashi T , Kimura M , Yada I , Namikawa S , Yuasa H , Kusagawa M
Published: February 2017

PURPOSE AND METHODS

The major purpose of this study was to determine whether the survival rate in young lung cancer patients after surgical treatment differs from that in older patients. An analysis was performed for all patients with bronchogenic carcinoma who underwent surgery at Mie University Hospital from 1965 to 1990.

RESULTS

Of 803 patients, 24 (2.99%) were 33 to 39 years old. At the time of surgery, the disease was diagnosed as stage I in seven patients (29%), stage II in four (17%), stage IIIa in seven (29%), stage IIIb in two (8%), and stage IV in four (17%), while 46.3% of the patients older than 40 years of age had either stage IIIa, IIIb, or IV disease. All of the 24 patients less than 40 years of age underwent thoracotomy: curative resection in 14 cases, palliative resection in sex, and probe-thoracotomy in four. The 5-year survival rate for all stages of disease was 31.4% in these 24 patients, and 41.9% in 603 patients greater than 40 years of age. The 5-year survival rate for stage I disease was 35.7% in the seven younger patients and 78.0% in the 207 older patients; for stage II, it was 25.5% in the four younger patients and 40.6% in the 98 older patients; for stage III, it was 33.3% in the nine younger patients and 15.6% in the 250 older patients; and for stage IV, it was 25% in the four younger patients and 6.6% in the 48 older patients. There were no significant differences in survival rate between the two age groups for all patients or for those with each stage of disease.

CONCLUSION

Although younger patients tended to have more advanced disease, long-term survival in these patients did not differ from that of older patients.
Cisplatin, vinblastine, and hydrazine sulfate in advanced, non-small-cell lung cancer: a randomized placebo-controlled, double-blind phase III study of the Cancer and Leukemia Group B.
Authors: Kosty M P , Fleishman S B , Herndon J E , Coughlin K , Kornblith A B , Scalzo A , Morris J C , Mortimer J , Green M R
Published: February 2017

PURPOSE

To assess the chemotherapy regimen of cisplatin, vinblastine, and hydrazine sulfate administered to patients with non-small-cell lung cancer (NSCLC) in a randomized, placebo-controlled double-blind phase III study.

PATIENTS AND METHODS

Between July 25, 1989 and February 1, 1991, 291 patients with stage IIIB or IV NSCLC and performance status 0 or 1 were randomized to receive cisplatin 100 mg/m2 intravenously (IV) every 28 days, vinblastine 5 mg/m2 IV per week times five, then every 2 weeks; and either hydrazine sulfate 60 mg three times per day orally or placebo. The concurrent use of corticosteroids, medroxyprogesterone, or other appetite stimulants was not permitted. Treatment groups were comparable for known prognostic variables. The primary end point of this study was survival; however, the influence of hydrazine sulfate on nutritional status, performance status, and quality of life was also assessed.

RESULTS

Analysis of 266 eligible patients showed a median survival duration of 7.78 months for the hydrazine sulfate-treated group compared with 7.70 months for the placebo-treated group (P = .65, log-rank). Objective response rates were similar for the two groups, with 4% complete responses, 20% partial responses, and 2% regressions in those treated with hydrazine sulfate; 3% complete responses, 23% partial responses, and 2% regressions in those who received placebo. The major toxicity was severe or life-threatening neutropenia, which occurred in 65% of hydrazine sulfate patients and 63% of placebo patients. There were no differences noted between the two groups in degree of anorexia, weight gain or loss, or overall nutritional status. Sensory and motor neuropathy occurred significantly more often in patients treated with hydrazine sulfate. Quality of life was significantly worse in patients who received hydrazine sulfate.

CONCLUSION

This study suggests no benefit from the addition of hydrazine sulfate to an effective cytotoxic regimen.
Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer.
Authors: Loprinzi C L , Goldberg R M , Su J Q , Mailliard J A , Kuross S A , Maksymiuk A W , Kugler J W , Jett J R , Ghosh C , Pfeifle D M
Published: February 2017

PURPOSE

Hydrazine sulfate, an agent that appears to inhibit gluconeogenesis, has been studied in cancer patients for approximately 20 years. There was a recent resurgence of interest in this drug when subset analysis of a small placebo-controlled, double-blind, clinical trial reported improved survival among non-small-cell lung cancer patients with a good performance status who were randomized to receive this drug along with standard chemotherapy.

PATIENTS AND METHODS

Patients on this trial had newly diagnosed, unresectable non-small-cell lung cancer and were treated with cisplatin and etoposide. In addition, they were randomized to receive hydrazine sulfate or placebo in a double-blind manner.

RESULTS

A total of 243 patients were randomized. Response rates were similar in the two treatment arms. There were trends for worse time to progression and survival in the hydrazine sulfate arm. No significant differences were noted in the two study arms with regard to toxicity or quality of life (QL).

CONCLUSION

This trial failed to demonstrate any benefit for patients who received hydrazine sulfate.
Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma--reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.
Authors: Bramwell V , Rouesse J , Steward W , Santoro A , Schraffordt-Koops H , Buesa J , Ruka W , Priario J , Wagener T , Burgers M
Published: February 2017

PURPOSE

To evaluate the benefit of adjuvant chemotherapy in adult patients with soft tissue sarcomas. The principal end points were freedom from local recurrence and/or metastases and overall survival.

PATIENTS AND METHODS

Between January 1977 and June 1988, 468 patients entered this randomized study and 317 were considered eligible. Following complete surgical resection with or without radiotherapy, outcome in 145 eligible patients receiving cyclophosphamide 500 mg/m2 intravenously (IV) bolus on day 1, vincristine 1.4 mg/m2 IV bolus on day 1, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) 50 mg/m2 IV bolus on day 1, and dacarbazine (DTIC) 400 mg/m2 by 1-hour infusion on days 1 to 3 (CYVADIC) cycles repeated every 28 days for eight courses was compared with that in 172 control patients.

RESULTS

With a median follow-up duration of 80 months (range, 39 to 165), actuarial percentage survival figures at 7 years were compared. Relapse-free survival rates were higher for CYVADIC, 56% versus 43% (P = .007), and local recurrence was significantly reduced in the CYVADIC arm at 17% versus 31% (P = .004). In contrast, distant metastases occurred with similar frequency in both arms, 32% for CYVADIC versus 36% for control patients (P = .42), and overall survival rates were not significantly different at 63% versus 56% (P = .64). A reduction in local recurrence was only apparent in the group of head, neck, and trunk sarcomas (P = .002), but not in limb tumors (P = .31).

CONCLUSION

Adjuvant chemotherapy with CYVADIC cannot be recommended outside the context of a clinical trial. Experience from this study has been used to plan a trial of neoadjuvant chemotherapy with doxorubicin/ifosfamide, which is currently in progress.
Incidence of neutropenic fever in patients treated with standard-dose combination chemotherapy for small-cell lung cancer and the cost impact of treatment with granulocyte colony-stimulating factor.
Authors: Nichols C R , Fox E P , Roth B J , Williams S D , Loehrer P J , Einhorn L H
Published: February 2017

PURPOSE

We sought to determine the incidence of neutropenic fever associated with the use of standard-dose combination chemotherapy for small-cell lung cancer (SCLC) and to use these data as a template to analyze the costs and benefits of the routine use of granulocyte colony-stimulating factor (G-CSF).

PATIENTS AND METHODS

We retrospectively reviewed records of 137 consecutive, unselected patients with SCLC treated with combination chemotherapy from January 1987 to March 1992. Admission criteria for neutropenic fever were temperature > or = 38.5 degrees C and an absolute neutrophil count < or = 500/microL. Neutropenic fevers were managed with a 25% dose reduction of the myelosuppressive drugs in subsequent cycles. Charge estimates for hospitalization ($1,244 per day) and G-CSF use ($2,027 per course) were estimated by reviewing charges to patients at Indiana University hospitalized for neutropenic fever or treated with outpatient G-CSF. We imposed assumptions from the Neupogen (filgrastim; Amgen Inc, Thousand Oaks, CA) licensing trial regarding the effectiveness of G-CSF and the Indiana University charge estimates on three models of G-CSF use: (1) preemptive--with all courses of chemotherapy, (2) reactive--with all cycles of chemotherapy following a neutropenic fever, and (3) dose reduction only (no G-CSF)--to derive charge estimates for G-CSF use.

RESULTS

Records of 137 patients with SCLC were identified and reviewed. The incidence of neutropenic fever was 12% in the first cycle of chemotherapy, and 18% overall, compared with the placebo- and G-CSF-treated arms of the Neupogen licensing trial, in which the incidence of neutropenic fever was 77% and 40%, respectively. Other therapeutic outcomes, such as neutropenic septic deaths, response rates, and survival, were comparable. We derived the following charge estimates for the three models of G-CSF: (1) preemptive--total charges = $1,287,481; (2) reactive--total charges = $276,154; and (3) dose reduction only--total charges = $192,820.

CONCLUSION

The incidence of neutropenic fever with standard-dose chemotherapy for SCLC was 18%. Routine use of G-CSF in SCLC patients treated with standard-dose chemotherapy appears to be expensive and is not associated with an obvious therapeutic benefit or cost savings. We suggest that careful analysis of the incidence of infectious complications, rather than granulocyte nadir and duration, be performed, and that clinical guidelines for the use of these effective, but expensive, products be developed.
Adjuvant chemotherapy for breast cancer: discordance between physicians' perception of benefit and the results of clinical trials.
Authors: Rajagopal S , Goodman P J , Tannock I F
Published: February 2017

PURPOSE

Decisions about management of patients depend on the perception of physicians about the results of clinical trials. We therefore determined whether physicians would recommend adjuvant chemotherapy for specified patients with breast cancer, and whether the perceived levels of benefit that led to these decisions were supported by the results of clinical trials.

METHODS

We mailed a questionnaire that presented two clinical scenarios to 515 American and European oncologists. Scenario A depicted a premenopausal woman with node-negative, estrogen receptor-negative (ER-) breast cancer, and scenario B depicted a post-menopausal woman with node-positive, ER- disease. Respondents were asked about the evidence that they required from clinical trials to recommend adjuvant chemotherapy for these patients.

RESULTS

Replies were received from 307 oncologists. American respondents were more likely to recommend adjuvant chemotherapy than Europeans (A, 93% v 68%; B, 85% v 67%; P < .001 for both comparisons). Opinion was evenly divided as to whether improvement in the relapse-free survival (RFS) rate was sufficient to recommend treatment, or whether improvement in overall survival was necessary. Mean values of 12.9% to 14.6% improvement in RFS at 3 years, or 10.7% to 12.4% improvement in overall survival at 5 years, were required to offer treatment. An overview analysis of clinical trials suggests that adjuvant chemotherapy achieves absolute improvements of 6% to 9% in RFS rates at 3 years and 3% to 4% in overall survival rates at 5 years for patients in these scenarios.

CONCLUSIONS

Most oncologists recommended treatment in these scenarios, but require a level of treatment effect that has not been demonstrated in clinical trials. Our results suggest that oncologists' perceptions of the results of clinical trials overestimate the therapeutic gain from use of adjuvant chemotherapy for breast cancer.
Psychosocial adjustment among women with breast cancer stages I and II: six-year follow-up of consecutive patients.
Authors: Omne-Pontén M , Holmberg L , Sjödén P O
Published: February 2017

PURPOSE

To evaluate, in a long-term follow-up study of consecutive patients (N = 99), the impact of surgery--breast-conserving treatment (BCT) versus mastectomy (MT)--on psychosocial adjustment among women with breast cancer, pTNM stage I/II.

PATIENTS AND METHODS

Semistructured interviews were conducted at a median of 6 years (range, 5.8 to 8.1) after primary surgery. Sixty-six women were available for the long-term follow-up study. Twenty-six women had been treated with BCT and 40 with MT.

RESULTS

No statistically significant differences were found between the two groups concerning psychosocial adjustment, as measured by the Social adjustment Scale (SAS). In general, the levels of maladjustment were lower than at 13 months postoperatively, but 10% still showed maladjustment. Sixty percent of the women were unwilling to show themselves naked, and 22% felt that they had become less attractive because of the surgical treatment. In an explorative part of the interview, 68% of the women complained about how they had been informed of the diagnosis. A tendency toward a significant difference was found in the relation between previous maladjustment and a negative experience at the time of diagnosis (P = .07).

CONCLUSION

Few data are available on long-term follow-up results with regard to psychosocial adjustment among women after breast cancer surgery. This study provides the important information that there are no differences in patient psychosocial adjustment that can be ascribed to the type of surgery at 6-year follow-up evaluation.
Fundamental dilemmas of the randomized clinical trial process: results of a survey of the 1,737 Eastern Cooperative Oncology Group investigators.
Authors: Taylor K M , Feldstein M L , Skeel R T , Pandya K J , Ng P , Carbone P P
Published: February 2017

PURPOSE

We studied oncologists' attitudes and behavior with regard to their participation in randomized clinical trials.

METHODS

We surveyed the 1,737 physician members of the Eastern Cooperative Oncology Group (ECOG) using the Physician Orientation Profile (POP), a self-administered mailed questionnaire. A response rate of 86% was achieved (1,485 of 1,737); each physician's actual patient accrual was recorded.

RESULTS

All respondents indicated that they had a systematic pattern of patient preselection for entry onto trials beyond the formal inclusion/exclusion trial criteria. Eighty-nine percent stated that improving patient quality of life rather than prolonging survival was more personally satisfying. Sixty-two percent did not enter a single patient during the 12-month period following the survey, while 10% entered 80% of all patients during that time. Physicians overestimated their accrual rate by a factor of 6. Eighty-three percent defined randomization and adherence to trial protocol as a serious challenge to their ability to make individualized treatment decisions.

CONCLUSION

This study raises questions regarding the following: (1) the perceived generalizability of trial findings, (2) the role of end points other than survival for clinical trials, (3) the consequences of physician overestimation of patient accrual, and (4) the impact of randomized trials on the behavior of clinicians. Further investigation into these critical issues will provide meaningful recommendations to enhance the future design, implementation, and conduct of randomized clinical trials in cancer.
Phase I and pharmacologic study of irinotecan and etoposide with recombinant human granulocyte colony-stimulating factor support for advanced lung cancer.
Authors: Masuda N , Fukuoka M , Kudoh S , Matsui K , Kusunoki Y , Takada M , Nakagawa K , Hirashima T , Tsukada H , Yana T
Published: February 2017

PURPOSE

We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) support because of the overlapping neutrophil toxicity of both drugs. The aim was to determine the maximum-tolerated dose of CPT-11 combined with a fixed dose of etoposide in patients with advanced lung cancer, as well as the dose-limiting toxicities of this combination.

PATIENTS AND METHODS

Twenty-five patients with stage III or IV lung cancer, 15 (60%) with prior chemotherapy, were treated at 4-week intervals using CPT-11 (90-minute intravenous infusion on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3). In addition, rhG-CSF (2 micrograms/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. The starting dose of CPT-11 was 60 mg/m2, and it was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached.

RESULTS

The maximum-tolerated dose of CPT-11 was 90 mg/m2, since two of the three patients developed grade 3 to 4 leukopenia or grade 3 to 4 diarrhea during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the dose-limiting toxicities, while thrombocytopenia was only a moderate problem. Elimination of CPT-11 was biphasic, with a mean +/- SD beta half-life of 18.17 +/- 9.09 hours. The mean terminal half-life of 7-ethyl-10-hydroxycamptothecin (SN-38; the major metabolite of CPT-11) was 43.40 +/- 37.84 hours. There was one complete response (5%) and eight partial responses (38%) among 21 assessable patients, for an overall response rate of 43%. The response rates for small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) were 58% (seven of 12 patients) and 22% (two of nine patients), respectively.

CONCLUSION

The combination of CPT-11 and etoposide with rhG-CSF support seems to be active against lung cancer, especially SCLC, with acceptable toxicity. The recommended dose for phase II studies in previously untreated patients is 80 mg/m2 of CPT-11 (days 1, 8, and 15) and 80 mg/m2 of etoposide (days 1 to 3) plus 2 micrograms/kg of rhG-CSF (days 4 to 21, except when CPT-11 is given). In addition, 70 mg/m2 of CPT-11 appears to be the appropriate dose for previously treated patients receiving this regimen.