bluuebunny/crossref_metadata_2025 huggingface dataset:
Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma.
Authors: Kaminski M S , Zasadny K R , Francis I R , Fenner M C , Ross C W , Milik A W , Estes J , Tuck M , Regan D , Fisher S , Glenn S D , Wahl R L
Published: February 2017

PURPOSE

The CD20 B-lymphocyte surface antigen expressed by B-cell lymphomas is an attractive target for radioimmunotherapy, treatment using radiolabeled antibodies. We conducted a phase I dose-escalation trial to assess the toxicity, tumor targeting, and efficacy of nonmyeloablative doses of an anti-CD20 monoclonal antibody (anti-B1) labeled with iodine-131 (131I) in 34 patients with B-cell lymphoma who had failed chemotherapy.

PATIENTS AND METHODS

Patients were first given tracelabeled doses of 131I-labeled anti-B1 (15 to 20 mg, 5 mCi) to assess radiolabeled antibody biodistribution, and then a radioimmunotherapeutic dose (15 to 20 mg) labeled with a quantity of 131I that would deliver a specified centigray dose of whole-body radiation predicted by the tracer dose. Whole-body radiation doses were escalated from 25 to 85 cGy in sequential groups of patients in 10-cGy increments. To evaluate if radiolabeled antibody biodistribution could be optimized, initial patients were given one or two additional tracer doses on successive weeks, each dose preceded by an infusion of 135 mg of unlabeled anti-B1 one week and 685 mg the next. The unlabeled antibody dose resulting in the most optimal tracer biodistribution was also given before the radioimmunotherapeutic dose. Later patients were given a single tracer dose and radioimmunotherapeutic dose preceded by infusion of 685 mg of unlabeled anti-B1.

RESULTS

Treatment was well tolerated. Hematologic toxicity was dose-limiting, and 75 cGy was established as the maximally tolerated whole-body radiation dose. Twenty-eight patients received radioimmunotherapeutic doses of 34 to 161 mCi, resulting in complete remission in 14 patients and a partial response in eight. All 13 patients with low-grade lymphoma responded, and 10 achieved a complete remission. Six of eight patients with transformed lymphoma responded. Thirteen of 19 patients whose disease was resistant to their last course of chemotherapy and all patients with chemotherapy-sensitive disease responded. The median duration of complete remission exceeds 16.5 months. Six patients remain in complete remission 16 to 31 months after treatment.

CONCLUSION

Nonmyeloablative radioimmunotherapy with 131I-anti-B1 is associated with a high rate of durable remissions in patients with B-cell lymphoma refractory to chemotherapy.
Malignant mesothelioma following treatment for Hodgkin's disease.
Authors: Weissmann L B , Corson J M , Neugut A I , Antman K H
Published: February 2017

PURPOSE

Asbestos exposure is the major known risk factor for mesothelioma, but several case reports have suggested a link between radiation therapy and subsequent development of malignant mesothelioma. This report explores a possible association between radiation therapy for Hodgkin's disease and mesothelioma.

PATIENTS AND METHODS

Four cases of malignant mesothelioma were observed following Hodgkin's disease at the Mesothelioma Clinic of the Dana-Farber Cancer Institute. A fifth such patient was found after a review of the literature.

RESULTS

In all five cases, the mesothelioma arose in the field of prior radiotherapy. No history of asbestos exposure was elicited by careful questioning or by review of chest radiographs. Examination of lung tissue in one patient showed 250 ferruginous bodies per gram of lung tissue, consistent with no significant prior exposure. The mean interval between radiation treatment for Hodgkin's disease and development of mesothelioma was 15 years, which emphasizes the need for continued follow-up and evaluation of these patients and supports a causal relationship.

CONCLUSION

Mesothelioma may need to be added to the list of second malignancies that arise following radiation therapy for Hodgkin's disease. Further support is given to a causal link between radiation exposure and mesothelioma.
Cladribine and mitoxantrone dose escalation in indolent non-Hodgkin's lymphoma.
Authors: Saven A , Lee T , Kosty M , Piro L
Published: February 2017

PURPOSE

Since cladribine (2-chlorodeoxyadenosine [2-CdA]) and mitoxantrone both exhibit major activity against indolent lymphoid malignancies and have different mechanisms of action, we performed a dose-escalation study of 2-CdA and mitoxantrone in patients with alkylator-failed indolent lymphoma to determine the maximum-tolerated dose (MTD) of this combination and to make preliminary observations about efficacy.

PATIENTS AND METHODS

Twenty-three patients were treated every 28 to 35 days, in cohorts of at least three patients, with stepwise dose escalations until dose-limiting toxicities (DLTs) were encountered. The initial dose levels were 2-CdA 0.1 mg/kg/d by continuous infusion for 7 days, mitoxantrone 5 mg/m2 intravenously (i.v.) on day 1, and prednisone 100 mg/d on days 1 to 5. Mitoxantrone was dose-escalated in increments of 2.5 mg/m2 i.v. on day 1.

RESULTS

The MTD of the combination was 2-CdA 0.1 mg/kg/d for 7 days, mitoxantrone 7.5 mg/m2 i.v. on day 1, and prednisone 100 mg/d on days 1 to 5. Myelosuppression and infection were the DLTs. The recommended phase II doses were 2-CdA 0.075 mg/kg/d for 7 days mitoxantrone 5 mg/m2 i.v. on day 1; prednisone was omitted to decrease the risk of opportunistic infections. The overall response rate was 70%, with 22% complete responses (CRs) and 48% partial responses (PRs). The median duration of CR was 15 months and PR 5 months.

CONCLUSION

These results demonstrate the feasibility and safety of combining 2-CdA and mitoxantrone in the treatment of indolent lymphoma, and appear to confirm clinically the mechanistic synergism and rationale for this combination regimen. Prednisone exacerbated the risk of opportunistic infection and was omitted. The overall response rate was high, including durable CRs. Further studies of this combination regimen are warranted in untreated and alkylator-failed indolent lymphoma.
Granulocyte-macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: a randomized trial by the European Organization for Research and Treatment of Cancer Leukemia Cooperative Group.
Authors: Zittoun R , Suciu S , Mandelli F , de Witte T , Thaler J , Stryckmans P , Hayat M , Peetermans M , Cadiou M , Solbu G , Petti M C , Willemze R
Published: February 2017

PURPOSE

To assess the value of granulocyte-macrophage colony-stimulating factor (GM-CSF) for induction treatment of acute myeloid leukemia (AML), both for priming of leukemic cells and for acceleration of hematopoietic recovery.

PATIENTS AND METHODS

GM-CSF was administered 5 micrograms/kg/d by continuous intravenous (i.v.) infusion during induction therapy with daunorubicin (DNR) (days 1 to 3) and cytarabine (ARA-C) (days 1 to 7). A total of 102 patients were randomized onto four arms, as follows: (1) GM-CSF 24 hours before and during chemotherapy (arm +/-); (2) GM-CSF after chemotherapy until day 28 or recovery of polymorphonuclear leukocytes (PMNs) (arm -/+);(3) GM-CSF before, during, and after chemotherapy (arm +/+); or (4) no GM-CSF (arm -/-). Stopping rules were applied in case of an initial WBC count greater than 30 x 10(9)/L or a secondary increase of circulating blast cells. Analyses were performed according to the intention-to-treat principle.

RESULTS

The complete remission (CR) rates were 77% (arm -/-), 72% (arm +/-), 48% (arm -/+), and 46% (arm +/+). Patients randomized to receive GM-CSF after induction (arms -/+ and +/+) had a significantly lower CR rate (P = .008) and a trend toward accelerated recovery of neutrophils, but no fewer infections or induction deaths. The lower CR rate appeared to be related to an increased resistance rate, with persistent leukemia. The main side effects of GM-CSF were fluid retention and hypotension.

CONCLUSION

GM-CSF administered during induction treatment of AML with a DNR/Ara-C combination did not provide any clinical benefit. Furthermore, there was a significant decrease in the CR rate with more persistent leukemia when GM-CSF was administered during the hypoplastic phase after the chemotherapy courses.
Oral cladribine as primary therapy for patients with B-cell chronic lymphocytic leukemia.
Authors: Juliusson G , Christiansen I , Hansen M M , Johnson S , Kimby E , Elmhorn-Rosenborg A , Liliemark J
Published: February 2017

PURPOSE

Purine analogs have wide potential indications in the treatment of hematologic malignancies, but intravenous administration has been required. We previously established that the oral bioavailability of cladribine is 50%. Our aim was to evaluate the efficacy and toxicity of oral cladribine to previously untreated patients with chronic lymphocytic leukemia (CLL).

PATIENTS AND METHODS

Sixty-three patients with symptomatic but previously untreated CLL received cladribine solution 10 mg/m2/d orally for 5 consecutive days in monthly courses.

RESULTS

Complete remission (CR) was achieved in 24 patients (38%), and 23 patients (37%) had a partial response (PR). Most patients, including those in whom there was no remission (NR) achieved normal blood lymphocyte counts. Failure to meet response criteria was mostly due to thrombocytopenia. The median response duration was not reached at 2 years. The median survival time among 13 deceased patients was 322 days, whereas the median observation time of surviving patients is 760 days. The overall survival rate at 2 years is 82%. Response rate was associated with clinical stage. Grade III to IV infectious toxicity occurred in one third of patients.

CONCLUSION

Orally administered cladribine is an effective and feasible therapy for CLL, and produces durable remissions in three quarters of the patients. However, significant toxicity may occur and further studies are required to assess long-term effects and quality-of-life aspects.
Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer.
Authors: Greenberg P A , Hortobagyi G N , Smith T L , Ziegler L D , Frye D K , Buzdar A U
Published: February 2017

PURPOSE

To determine the long-term clinical course of patients with metastatic breast cancer (MBC) who achieved a complete remission with doxorubicin-alkylating agent-containing combination chemotherapy programs.

PATIENTS AND METHODS

To assess the long-term prognosis of MBC, we reviewed our experience with 1,581 patients treated on consecutive doxorubicin and alkylating agent-containing front-line treatment protocols between 1973 and 1982. Treatment was administered for a maximum duration of 2 years. Characteristics of long-term survivors were evaluated, and hazard rates for progression were calculated.

RESULTS

From this group, 263 (16.6%) achieved complete responses (CR) and 49 (3.1%) remained in CR for more than 5 years. After a median duration of 191 months, 26 patients remain in first CR, four patients died in CR at times ranging from 118 to 234 months, 18 patients died of breast cancer, and one is alive with metastatic disease. Compared with the overall CR and total patient populations, the long-term CR group had more premenopausal patients, a younger median age, a lower tumor burden, and better performance status. The hazard function shows a substantial drop in risk of progression after approximately 3 years from initiation of therapy. Ten long-term CR patients developed second primary cancers: breast (3), ovary (2), pancreas (1), endometrium (1), colon (1), head and neck (1), and lung (1).

CONCLUSION

Most patients with MBC treated with systemic therapies have only temporary responses to treatment, but some patients continue in CR following initial treatment. These data show that a small percentage of patients achieve long-term remissions with standard chemotherapy regimens. Remission consolidation strategies are needed.
Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. Dolasetron Comparative Chemotherapy-induced Emesis Prevention Group.
Authors: Hesketh P , Navari R , Grote T , Gralla R , Hainsworth J , Kris M , Anthony L , Khojasteh A , Tapazoglou E , Benedict C , Hahne W
Published: February 2017

PURPOSE

To assess the comparative antiemetic efficacy of single-dose intravenous (IV) dolasetron mesylate and ondansetron in preventing cisplatin-induced nausea and vomiting.

PATIENTS AND METHODS

Cancer patients (n = 609) receiving first-course cisplatin chemotherapy were randomized to one of three treatments: 1.8 or 2.4 mg/kg dolasetron mesylate salt (equivalent to 1.3 and 1.8 mg/kg dolasetron base, respectively) or 32 mg ondansetron. Each treatment was infused over 15 minutes, 30 minutes before cisplatin administration. Patients were stratified to cisplatin doses of > or = 70 and less than 91 mg/m2 (n = 368) or > or = 91 mg/m2 (n = 241), administered over < or = 3 hours. Protocol-defined efficacy criteria included complete response (zero emetic episodes and no rescue medication), major response (1 to 2 emetic episodes and no rescue medication), and patients' report of nausea severity and satisfaction recorded on a 100-mm visual analog scale (VAS).

RESULTS

The three treatments met protocol-specified criteria for equivalence. Complete response rates for dolasetron mesylate 1.8 mg/kg, 2.4 mg/kg, and ondansetron, respectively, were 49.2%, 45.6%, and 50.4% for patients in the lower cisplatin stratum (mean, 74.7 mg/m2) and 36.8%, 31.3%, and 31.8% in the higher cisplatin stratum (mean, 100.6 mg/m2). No significant differences were observed in the extent of nausea with either dolasetron dose compared with ondansetron. Less nausea was noted with 1.8 mg/kg dolasetron compared with the 2.4 mg/kg dose (P = .044) All three antiemetic treatments were well tolerated. Asymptomatic electrocardiogram changes were recorded with both dolasetron and ondansetron.

CONCLUSION

A single IV dose of dolasetron mesylate (1.8 or 2.4 mg/kg) has comparable safety and efficacy to a single 32-mg IV dose of ondansetron in patients receiving cisplatin chemotherapy.
Phase II study of paclitaxel in patients with recurrent malignant glioma.
Authors: Prados M D , Schold S C , Spence A M , Berger M S , McAllister L D , Mehta M P , Gilbert M R , Fulton D , Kuhn J , Lamborn K , Rector D J , Chang S M
Published: February 2017

PURPOSE

To assess the efficacy and toxicity of paclitaxel administered as a 3-hour infusion to patients with recurrent malignant glioma.

PATIENTS AND METHODS

Adult patients with recurrent malignant glioma following radiation therapy, who had received no more than one prior chemotherapy regimen and who had a Karnofsky performance status (KPS) > or = 60, were treated with a 3-hour infusion of paclitaxel every 3 weeks. The initial dose was 210 mg/m2; dose escalation to 240 mg/m2 was allowed. Tumor response was assessed at 6-week intervals using radiographic and clinical criteria. Treatment was continued until documented tumor progression or a total of 12 paclitaxel infusions.

RESULTS

Of 41 eligible patients, all were assessable for treatment toxicity and 40 (98%) were assessable for response. The response rate (disease stabilization or better) was 35%. Twenty-nine patients (71%) underwent dose escalation to 240 mg/m2 without the use of growth factors. Toxicities included alopecia (98%), nausea (22%), arthralgias (32%), CNS toxicity (24%), peripheral neuropathy (15%), cardiac toxicity (7%), and myelosuppression (10% grade 3 or 4 hematologic toxicity). No patient developed febrile neutropenia. There was one allergic reaction (2%).

CONCLUSION

Paclitaxel is well tolerated at this dose schedule in patients with recurrent malignant glioma, and affords a modest response rate. Because minimal myelotoxicity was encountered in our patients, a dose-escalating phase I/II study of paclitaxel is planned to determine the maximal-tolerated dose (MTD).
Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: an Eastern Cooperative Oncology Group Trial.
Authors: Schiller J H , Kim K , Hutson P , DeVore R , Glick J , Stewart J , Johnson D
Published: February 2017

PURPOSE

To determine the response rate and survival of chemotherapy-naive patients with extensive-stage small-cell lung cancer (SCLC) treated with topotecan, and to determine the relationship of topotecan pharmacokinetics with response and toxicity.

PATIENTS AND METHODS

Forty-eight patients with previously untreated, extensive-stage SCLC received 2.0 mg/m2 of topotecan daily for 5 days. The first 13 patients were treated without colony-stimulating factor (CSF) support; the next 35 patients received 5 micrograms/kg of granulocyte-colony-stimulating factor (G-CSF) for 10 to 14 days starting on day 6. Cycles were repeated every 3 weeks for a maximum of four cycles. Patients who had a partial response to topotecan after four cycles, stable disease after two cycles, or progressive disease at any time received salvage chemotherapy with cisplatin and etoposide. Topotecan pharmacokinetics were measured using a four-point sampling scheme.

RESULTS

Of 48 patients, none had a complete response and 19 had a partial response, for an objective response rate of 39% (95% confidence interval [CI], 25.2% to 53.0%). The median response duration was 4.8 months (95% CI, 3.0 to 7.3). After a median follow-up duration of 18.2 months, the overall median survival time was 10.0 months (95% CI, 8.2 to 12.7); the 1-year survival rate was 39% (95% CI, 25.2% to 53.0%). Eight of 34 patients (24%) who received salvage chemotherapy responded. Four of 17 patients who did not respond to first-line therapy with topotecan responded to cisplatin and etoposide. The most common toxicity was hematologic. Ninety-two percent of patients treated without G-CSF developed grade 3 or 4 neutropenia, compared with 29% who received G-CSF. However, the incidence of neutropenic fevers was similar between the two groups (8% and 11%, respectively), and one patient in each group died of neutropenic fevers. There were no differences in objective tumor response, duration of response, time to treatment failure, or survival between the 13 patients who entered the study before G-CSF administration was mandated and the 35 patients who entered after and received G-CSF. There was poor correlation between the WBC count and absolute neutrophil counts (ANCs) and both the area under the curve (AUC) and maximum concentration++ (Cmx) of total topotecan in plasma. There was no correlation between the tumor response and either AUC or Cmx of total topotecan.

CONCLUSION

The activity of topotecan in extensive-stage SCLC noted in this study warrants further investigation of this agent in phase III clinical trials.
Bronchioloalveolar carcinoma.
Authors: Barkley J E , Green M R
Published: February 2017

PURPOSE

To review bronchioloalveolar carcinoma (BAC).

MATERIALS AND METHODS

English language articles were identified through a Melvyl Medline Search (1966 to 1995) and through the bibliographies of selected articles.

RESULTS

An increase in BAC appears to be responsible for the observed rise in the incidence of adenocarcinoma of the lung. Patients with BAC tend to be younger at diagnosis, are more likely to be female, and less likely to be cigarette smokers when compared with other patients with non-small-cell lung cancer (NSCLC). The etiology of this disease is unclear, but multiple environmental insults have been implicated. There are three subtypes of BAC and the symptoms and prognosis of the disease depend on the subtype and extent of disease, but are generally similar to other histologic types of NSCLC. The radiographic differential diagnosis is broad and includes both benign and malignant diseases. The treatment approach to patients with BAC is similar to those with other types of NSCLC.

CONCLUSION

BAC appears to be increasing in incidence, especially in young, nonsmoking females. Three subtypes of the disease exist and are responsible for the variable clinical presentations. Further epidemiologic investigation is needed to elucidate the etiology and pathogenesis of this unique disease.
Proposal for classifying the acute emetogenicity of cancer chemotherapy.
Authors: Hesketh P J , Kris M G , Grunberg S M , Beck T , Hainsworth J D , Harker G , Aapro M S , Gandara D , Lindley C M
Published: February 2017

PURPOSE

To propose a classification of the acute emetogenicity of antineoplastic chemotherapy agents, and to develop an algorithm to define the emetogenicity of combination chemotherapy regimens.

METHODS

A Medline search was conducted to identify (1) clinical trials that used chemotherapy as single-agent therapy, and (2) major reviews of antiemetic therapy. The search was limited to patients who received commonly used doses of chemotherapy agents, primarily by short (< 3 hours) intravenous infusions. Based on review of this information and our collective clinical experience, we assigned chemotherapy agents to one of five emetogenic levels by consensus. A preliminary algorithm to determine the emetogenicity of combination chemotherapy regimens was then designed by consensus. A final algorithm was developed after we analyzed a data base composed of patients treated on the placebo arms of four randomized antiemetic trials.

RESULTS

Chemotherapy agents were divided into five levels: level 1 (< 10% of patients experience acute [< or = 24 hours after chemotherapy] emesis without antiemetic prophylaxis); level 2 (10% to 30%); level 3 (30% to 60%); level 4 (60% to 90%); and level 5 (> 90%). For combinations, the emetogenic level was determined by identifying the most emetogenic agent in the combination and then assessing the relative contribution of the other agents. The following rules apply: (1) level 1 agents do not contribute to the emetogenic level of a combination; (2) adding > or = one level 2 agent increases the emetogenicity of the combination by one level greater than the most emetogenic agent in the combination; and (3) adding level 3 or 4 agents increases the emetogenicity of the combination by one level per agent.

CONCLUSION

The proposed classification schema provides a practical means to determine the emetogenic potential of individual chemotherapy agents and combination regimens during the 24 hours after administration. This system can serve as a framework for the development of antiemetic guidelines.
Outpatient high-dose chemotherapy with autologous stem-cell rescue for hematologic and nonhematologic malignancies.
Authors: Meisenberg B R , Miller W E , McMillan R , Callaghan M , Sloan C , Brehm T , Kosty M P , Kroener J , Longmire R , Saven A , Piro L D
Published: February 2017

PURPOSE

A prospective study to determine the feasibility of high-dose chemotherapy (HDC) and autologous stem-cell rescue (ASCR) in the outpatient setting.

METHODS

One hundred thirteen consecutive patients underwent 165 cycles of HDC/ASCR for a variety of malignancies. HDC regimens were disease-specific. Initially, patients were hospitalized for HDC, discharged on completion, and maintained as outpatients unless toxicities required rehospitalization (subtotal outpatient transplantation [STOT]). Once this was established as safe, a total outpatient transplant (TOT) program was developed in which patients received all of the HDC, as well as supportive care, as outpatients. Patients who declined the outpatient programs received the same HDC and supportive care as inpatients.

RESULTS

In 140 of 165 (85%) HDC cycles, patients agreed to participate in one of the outpatient transplant programs. Five patients in the STOT program could not be discharged from the hospital because of toxicities that developed during HDC; thus, 135 patients were monitored the outpatient setting, 95 (70%) of whom were never readmitted. The mean +/- SEM total hospital length of stay (LOS), including all readmissions and excess days after chemotherapy, was 18.33 +/- 5.06 days for patients who refused the outpatient program, 8.22 +/- 5.76 days for patients in the STOT program, and 2.81 +/- 7.66 days for those in the TOT program (P < .001). One treatment-related death occurred in each treatment setting: day 120 inpatient, day 17 STOT, and day 110 TOT.

CONCLUSION

Outpatient management of HDC/ASCR is safe and acceptable for the vast majority of patients. The STOT program resulted in significant reduction in hospital LOS, while the TOT program appears equally safe and further reduces LOS. Hospitalization for HDC/ASCR is unnecessary in most patients.
Patient preferences for oral versus intravenous palliative chemotherapy.
Authors: Liu G , Franssen E , Fitch M I , Warner E
Published: February 2017

PURPOSE

To assess patient preference for oral versus intravenous (i.v.) palliative chemotherapy (CT). A strong preference would be an important quality-of-life issue.

PATIENTS AND METHODS

A structured interviewer-administered scenario-based questionnaire evaluated incurable cancer patients who would be likely to receive palliative CT in the future. Using probability trade-offs, the preference for route of administration was evaluated against diminishing treatment response.

RESULTS

Of 103 assessable patients, 92 preferred oral CT, 10 preferred i.v. CT, and one had no preference. Patient preferences were not associated with age, sex, site of primary cancer, or previous CT experiences. Major reasons for preferring oral CT were convenience, problems with i.v. access or needles, and a better CT-taking environment (outside of the clinic). Regardless of initial preference, 70% of patients were not willing to accept a lower response rate and 74% were not willing to accept a shorter duration of response to retain their initial preference. Although 99% of patients had a preference, 39% wanted the specific treatment decision made primarily by their physicians, 38% primarily by themselves, and 22% shared equally.

CONCLUSION

Patients with incurable cancer have a clear preference for oral CT, but are generally not willing to sacrifice efficacy for their preference. Almost 40% of patients did not want to make final treatment decisions themselves.
Evaluation of new bone resorption markers in a randomized comparison of pamidronate or clodronate for hypercalcemia of malignancy.
Authors: Vinholes J , Guo C Y , Purohit O P , Eastell R , Coleman R E
Published: February 2017

PURPOSE

To compare the effects of two bisphosphonates on markers of bone resorption in a randomized double-blind trial for the treatment of hypercalcemia of malignancy.

PATIENTS AND METHODS

Thirty-two patients with a serum calcium (sCa) level > or = 2.7 mmol/L that persisted after 48 hours of saline rehydration were randomized to receive pamidronate 90 mg or clodronate 1,500 mg. Bone resorption markers measured included urinary calcium (uCa), hydroxyproline (Hyp), deoxypyridinoline (Dpd), pyridinoline (Pyd), the cross-linking molecule at either the N-telopeptide (NTx) or the C-telopeptide (Crosslaps) regions of type I collagen, and free Dpd.

RESULTS

Both bisphosphonates restored normocalcemia, but the duration of action was longer after pamidronate (P < .01). There was a mean pretreatment sevenfold increase in NTx, fivefold increase in Dpd and Crosslaps, and 2.5-fold increase in free Dpd. The changes in uCa were confounded by an increase in parathyroid hormone (PTH) (P < .05), which, through effects on the kidney, inhibits calcium excretion. Most resorption markers showed a larger decrease after pamidronate than clodronate (P < .01). NTx and Crosslaps showed the greatest decrease, being significantly different from any other marker in both arms (P < .01). There was a significant correlation between Dpd, NTx, and Crosslaps (P < .002), but not with uCa.

CONCLUSION

The superiority of pamidronate in controlling hypercalcemia is mirrored by the changes observed in these markers. uCa is not an accurate bone resorption marker, which reflects the renal handling of calcium by PTH. NTx and Crosslaps showed the largest increase at baseline and the greatest change after treatment, which suggests these new markers may be more sensitive indicators of bone resorption.
Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery.
Authors: Caillot D , Casasnovas O , Bernard A , Couaillier J F , Durand C , Cuisenier B , Solary E , Piard F , Petrella T , Bonnin A , Couillault G , Dumas M , Guy H
Published: February 2017

PURPOSE

The prognosis of invasive pulmonary aspergillosis (IPA) occurring in neutropenic patients remains poor. We studied whether new strategies for early diagnosis could improve outcome in these patients.

PATIENTS AND METHODS

Twenty-three histologically proven and 14 highly probable IPAs in 37 hematologic patients (neutropenic in 36) were analyzed retrospectively.

RESULTS

The most frequent clinical signs associated with IPA were cough (92%), chest pain (76%), and hemoptysis (54%). Bronchoalveolar lavage (BAL) was positive in 22 of 32 cases. Aspergillus antigen test was positive in 83% of cases when tested on BAL fluid. Since October 1991, early thoracic computed tomographic (CT) scans were systematically performed in febrile neutropenic patients with pulmonary x-ray infiltrates. This approach allowed us to recognize suggestive CT halo signs in 92% of patients, compared with 13% before this date, and the mean time to IPA diagnosis was reduced dramatically from 7 to 1.9 days. Among 36 assessable patients, 10 failed to respond (amphotericin B [AmB] plus fluorocytosyne, n = 2; itraconazole + AmB, n = 8) and died of aspergillosis. Twenty-six patients were cured or improved by antifungal treatment (itraconazole with or without AmB, n = 22; voriconazole, n = 4). In 15 of 16 cases, surgical resection was combined successfully with medical treatment. Achievement of hematologic response, early diagnosis, unilateral pulmonary involvement, and highest level of fibrinogen value < 9 g/L were associated with better outcome.

CONCLUSION

In febrile neutropenic patients, systematic CT scan allows earlier diagnosis of IPA. Early antifungal treatment, combined with surgical resection if necessary, improves IPA prognosis dramatically in these patients.
Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study.
Authors: Omura G A , Blessing J A , Vaccarello L , Berman M L , Clarke-Pearson D L , Mutch D G , Anderson B
Published: February 2017

PURPOSE

Cisplatin, mitolactol (dibromodulcitol), and ifosfamide have been the most active single agents in squamous carcinoma of the cervix identified so far by the Gynecologic Oncology Group (GOG). Combinations of cisplatin plus ifosfamide and cisplatin plus mitolactol are prospectively compared with cisplatin alone.

PATIENTS AND METHODS

Patients were randomized to receive cisplatin 50 mg/m2 or the same dose of cisplatin plus mitolactol (C + M) 180 mg/m2 orally on days 2 to 6, or cisplatin plus ifosfamide (CIFX) 5 g/m2 given as a 24-hour infusion plus mesna 6 g/m2 during and for 12 hours after the ifosfamide infusion, every 3 weeks for up to six courses. Of 454 patients entered, 438 were eligible and analyzed for response and survival.

RESULTS

CIFX had a higher response rate (31.1% v 17.8%, p = .004) and longer progression-free survival (PFS) time (P = .003) compared with cisplatin alone. The median times to progression or death were 4.6 and 3.2 months, respectively. C + M showed no significant improvement in these parameters compared with cisplatin alone. Survival was associated with initial performance score (PS; 0 was more favorable; P < .001) and with age (younger was unfavorable, P = .025). There was no significant difference in overall survival between cisplatin and either of the combinations. Leukopenia, renal toxicity, peripheral neurotoxicity, and CNS toxicity were more frequent with CIFX (P < .05).

CONCLUSION

CIFX improved the response rate and PFS duration in advanced cervix cancer compared with cisplatin alone, but at the cost of greater toxicity and with no improvement in survival.
Mutational activation of the K-ras oncogene and the effect of chemotherapy in advanced adenocarcinoma of the lung: a prospective study.
Authors: Rodenhuis S , Boerrigter L , Top B , Slebos R J , Mooi W J , van't Veer L , van Zandwijk N
Published: February 2017

PURPOSE

To determine whether the clinical course and the response to chemotherapy of patients with advanced adenocarcinoma of the lung depends on the presence or absence of a ras mutation in the tumor. Mutational activation of K-ras is a strong adverse prognostic factor in stage I or II lung cancer and laboratory studies have suggested that ras mutations lead to resistance against ionizing radiation and chemotherapy.

PATIENTS AND METHODS

Patients with advanced adenocarcinoma of the lung with measurable or assessable disease received chemotherapy with mesna, ifosfamide, carboplatin, and etoposide (MICE). Archival biopsies, fresh biopsies, or fine-needle aspirations were tested for the presence of ras gene mutations. Associations of ras mutations with clinical characteristics, response to chemotherapy, and survival were studied.

RESULTS

The presence or absence of ras gene mutations could be established in 69 of 83 patients (83%). A total of 261 courses of MICE were administered to 62 informative patients, 16 of whom were shown to have a K-ras mutation-positive tumor. The frequency of mutations (26%) and the type of mutations closely matched the pattern we have previously reported in operable disease. Patients with a ras mutation in their tumor were more likely to have a close relative with lung cancer, but other clinical characteristics, such as pattern of metastases, response, and survival, were similar between the ras mutation-positive and ras mutation-negative groups.

CONCLUSION

Patients with advanced lung adenocarcinoma who harbor a ras mutation may have major responses to chemotherapy and have similar progression-free and overall survival as patients with ras mutation-negative tumors. K-ras mutations may represent one of several ways in which early tumors are enabled to metastasize to distant sites.
Phase II study of irinotecan and etoposide in patients with metastatic non-small-cell lung cancer.
Authors: Oshita F , Noda K , Nishiwaki Y , Fujita A , Kurita Y , Nakabayashi T , Tobise K , Abe S , Suzuki S , Hayashi I , Kawakami Y , Matsuda T , Tsuchiya S , Takahashi S , Tamura T , Saijo N
Published: February 2017

PURPOSE

To determine the effects of irinotecan (CPT-11) given in combination with etoposide (VP-16) in metastatic non-small-cell lung cancer (NSCLC), to evaluate response and survival rates, and to determine the qualitative and quantitative toxicities of the combination chemotherapy.

PATIENTS AND METHODS

Sixty-one metastatic NSCLC patients received concurrent administration of CPT-11 and VP-16 for 3 days with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support.

RESULTS

Fifty-nine patients were assessable for response and all 61 patients were assessable for toxicity and survival. Fifty-six patients were treated with two or more courses of chemotherapy. Thirteen patients achieved a partial response (PR), 36 showed no change (NC), and 10 showed progressive disease (PD). The overall response rate was 21.3% (95% confidence interval, 12.9% to 33.1%). The median duration of PRs was 141 days (range, 62 to 299). Of the hematologic toxicities, 14 (23%) and 24 (39%) patients experienced grade 3 or 4 leukopenia and neutropenia, respectively. The toxicities were feasible. Treatment-related death occurred in one patient who suffered hypovolemic shock induced by hematemesis. The median survival time was 10.0 months and the 1-year survival rate was 36.1%.

CONCLUSION

Combination chemotherapy with concurrent administration of CPT-11 and VP-16 with rhG-CSF support was only modestly effective against metastatic NSCLC, with feasible toxicities of moderate diarrhea and pulmonary toxicity. The results were equivalent to those expected with either cisplatin-based chemotherapy or with CPT-11 alone.
Effect of chemotherapy on survival of craniofacial osteosarcoma: a systematic review of 201 patients.
Authors: Smeele L E , Kostense P J , van der Waal I , Snow G B
Published: February 2017

PURPOSE

To evaluate the possible value of chemotherapy in the treatment of craniofacial osteosarcoma (CFOS).

DESIGN

In a systematic review, data of 201 patients (age, 36.6 +/- 19.0 years [mean +/- SD]) from 20 uncontrolled series on CFOS indexed in Medline and Excerpta Medica between 1974 and 1994 were pooled; 180 patients had undergone surgery. Various chemotherapy regimens had been given to 71 patients. Radiotherapy was used in 69 patients. All patients had data for overall survival, and 182 had data for disease-free survival analysis. Cumulative survival distributions were estimated by the product-limit method, and a multiple regression analysis was performed.

RESULTS

Patients' overall and disease-free survival rates were significantly improved by treatment with chemotherapy. This was confirmed for patients with complete surgical removal, as well as for those with incomplete removal of tumor. In a proportional hazards model, complete surgical removal and chemotherapy were independent significant factors for overall and disease-free survival. The effect of radiotherapy was insignificant. No prognostic factors could be identified among age groups, sex, and subsites.

CONCLUSION

Evidence exists that chemotherapy improves survival in CFOS. We advocate the adoption of the chemotherapy protocols used for OS of the long bones for CFOS.
Phase I clinical and laboratory evaluation of topotecan and cytarabine in patients with acute leukemia.
Authors: Seiter K , Feldman E J , Halicka H D , Traganos F , Darzynkiewicz Z , Lake D , Ahmed T
Published: February 2017

PURPOSE

To determine the maximal-tolerated dose (MTD) of topotecan with cytarabine in acute leukemia patients, and to evaluate leukemia cell apoptosis in these patients.

PATIENTS AND METHODS

Fifty-three patients with acute leukemia not responsive to standard therapy were treated at eight dose levels of topotecan (2.5 mg/m2/d to 7.75 mg/m2/d). Topotecan was given as a 30-minute infusion daily with cytarabine 1 g/m2/d, both for 5 days. Using a flow-cytometric technique, the percent apoptotic cells in blood and bone marrow samples was determined, and the cell cycle distribution of the leukemic cells studied.

RESULTS

Oropharyngeal mucositis was dose-limiting. The MTD of topotecan was 4.75 mg/m2/d for 5 days in high-risk patients and 7.0 mg/m2/d for 5 days in low-risk patients. The mean percent apoptotic cells in the peripheral blood reached a peak of 18.8%, a median of 48 hours following the first dose of topotecan. Patients with higher S-phase fractions, either before treatment or following cytarabine, were more likely to achieve bone marrow aplasia than those with lower S-phase fractions (P = .01 and P < .05, respectively). Clinical responses were seen in four of 39 patients with acute myelogenous leukemia (AML; of whom 32 had received prior high-dose cytarabine), three of six with acute lymphoblastic leukemia (ALL), and one of eight with chronic myelogenous leukemia in blast phase (CML-BP).

CONCLUSION

The recommended phase II dose of topotecan with intermediate-dose cytarabine is 4.75 mg/m2/d for high-risk patients and 7.0 mg/m2/d for low-risk patients. The percentage of cells in S phase was important in determining response to treatment.
Anthracycline dose in childhood acute lymphoblastic leukemia: issues of early survival versus late cardiotoxicity.
Authors: Sorensen K , Levitt G , Bull C , Chessells J , Sullivan I
Published: February 2017

PURPOSE

Late abnormalities of left ventricular (LV) performance occur in most survivors of childhood acute lymphoblastic leukemia (ALL) treated with moderate anthracycline doses. We studied the prevalence of late cardiotoxicity in patients treated with lower anthracycline doses and related this to survival.

PATIENTS AND METHODS

Echocardiograms were performed in 50 normal children and 120 relapse-free ALL survivors 6.2 +/- 2.0 years after the end of cumulative daunorubicin doses of 90 mg/m2 (n = 40), 180 mg/m2 (n = 40), or 270 mg/m2 (n = 40) on UKALL X pilot (1982 to 1984) or UKALL X (1985 to 1989) protocols. Age at treatment onset was 4.7 +/- 2.8 years. Cardiac abnormalities were reviewed in light of the UKALL X 5-year disease-free survival rates of 57% (95% confidence interval [CI], 51% to 63%), 61% to 62% (95% CI, 56% to 68%), and 71% (95% CI, 66% to 76%) for the groups that received 90, 180, and 270 mg/m2 of daunorubicin, respectively.

RESULTS

ALL survivors had reduced LV fractional shortening (FS) compared with normal (32.3% +/- 4.4% v 35.9% +/- 4.2%, P < .005), which was accounted for by increased LV end-systolic stress (49.4 +/- 13.5 v 42.2 +/- 9.1 g/cm2, P < .001), whereas LV contractility independent of loading conditions was normal for the group as a whole. Of 27 patients (23%) with cardiac abnormalities, 25 (21%) had increased end-systolic stress, whereas only two (2%) had reduced contractility. The proportion with cardiac abnormality was similar in the three dose groups. Anthracycline dose, age at treatment, sex, follow-up duration, growth hormone, pubertal status, hemoglobin level, and total WBC count at presentation were not predictive of increased LV end-systolic stress.

CONCLUSION

There was a reduced incidence and severity of cardiac abnormalities with the lower anthracycline dose protocols (90 to 270 mg/m2) studied compared with previous reports in which subjects had received moderate anthracycline doses (approximately 300 to 550 mg/m2). Cumulative anthracycline dose within the range 90 to 270 mg/m2 did not relate to cardiac abnormalities. This suggests that there may be no safe anthracycline dose to avoid late cardiotoxicity, but reinforces the use of the protocol that affords best survival within the dose range studied.
Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children's Cancer Group.
Authors: Provisor A J , Ettinger L J , Nachman J B , Krailo M D , Makley J T , Yunis E J , Huvos A G , Betcher D L , Baum E S , Kisker C T , Miser J S
Published: February 2017

PURPOSE

The specific aims of this study were to improve event-free survival (EFS) in patients with newly diagnosed nonmetastatic osteosarcoma of an extremity using the histologic response to neoadjuvant chemotherapy to determine postoperative chemotherapy; to evaluate a uniform histologic grading system that measures tumor response; and to identify patient characteristics that might influence EFS and survival.

PATIENTS AND METHODS

Two hundred sixty-eight patients with nonmetastatic osteosarcoma of the extremity were entered between August 1983 and October 1986. Preoperative chemotherapy consisted of four courses of high-dose methotrexate (MTX) and one course of bleomycin, cyclophosphamide, and dactinomycin (BCD). Histologic response to preoperative chemotherapy was determined by morphometric analysis. Good histologic responders (< 5% residual viable tumor) were treated postoperatively with MTX, BCD, and doxorubicin (DOX); poor histologic responders were treated with BCD, DOX, and cisplatin (CDDP).

RESULTS

The 8-year EFS and survival rates were 53% and 60%, respectively. Two hundred six patients had their tumors assessed for histologic response: 28% displayed a good histologic response to preoperative chemotherapy. Good histologic responders had an 8-year postoperative EFS rate of 81% and survival rate of 87%; those with a poor histologic response had an 8-year postoperative EFS rate of 46% and survival rate of 52%. A primary tumor site in the proximal humerus or proximal femur and an elevated serum alkaline phosphatase level were associated with an increased risk of an adverse event, whereas the type of surgical procedure was not.

CONCLUSION

EFS and survival appear to be directly related to histologic response to neoadjuvant chemotherapy.
Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial.
Authors: Ranson M R , Carmichael J , O'Byrne K , Stewart S , Smith D , Howell A
Published: February 2017

PURPOSE

A multicenter phase II study to determine the activity and toxicity of Caelyx (Doxil; Sequus Pharmaceuticals Inc, Menlo Park, CA) in patients with metastatic breast cancer.

PATIENTS AND METHODS

Seventy-one patients with stage IV breast cancer were treated with Caelyx at doses of 45 to 60 mg/m2 every 3 to 4 weeks for a maximum of six cycles. Twenty-eight patients had received prior chemotherapy with a nonanthracycline regimen. Fifty-two patients had disease at multiple sites. Hepatic and pulmonary disease were the predominant metastatic site in 50 patients. Response was assessable in 64 cases.

RESULTS

Sixteen patients achieved a partial response and a complete response (overall response rate, 31%; (95% confidence interval, 20% to 43%). Twenty patients (31%) had stable disease on treatment. Neutropenia > or = grade 3 occurred in 10% of cycles (27% of patients) and mucositis > or = grade 3 in 10% of cycles (32% of patients). Significant alopecia was rare and routine prophylactic antiemetics were not required. At doses of 60 mg/m2 every 3 weeks, seven of 13 patients had > or = grade 3 skin toxicity; overall, this toxicity complicated 25% of treatment cycles. The incidence of > or = grade 3 skin toxicity was greatly reduced at doses of 45 mg/m2 every 4 weeks, occurring in five of 32 patients and affecting only 5% of 126 treatment cycles.

CONCLUSION

Caelyx is an active agent in advanced breast cancer with a safety profile that differs markedly from nonliposomal doxorubicin. A regimen of 45 mg/m2 every 4 weeks was well tolerated in this cohort of women with advanced poor-prognosis breast cancer. The mild myelosuppression seen with this regimen would favor its use in combination chemotherapy.
Breast cancer patients' attitudes about rationing postlumpectomy radiation therapy: applicability of trade-off methods to policy-making.
Authors: Palda V A , Llewellyn-Thomas H A , Mackenzie R G , Pritchard K I , Naylor C D
Published: February 2017

PURPOSE

Along with evidence, clinical policies must take patients' values into account. Particularly where evidence is limited and where assumptions of utility-maximizing behavior may not be valid, new methods such as trade-off techniques (TOTs), which allow elicitation of patients' treatment alternatives, might be useful in policy formulation. We used TOTs to assess breast cancer patients' attitudes toward two clinical policies designed to ration adjuvant postlumpectomy breast radiation therapy.

METHODS

Cross-sectional interviews were performed in a tertiary cancer center. A total of 102 patients were presented with information about the side effects and benefits associated with two hypothetical decisions: (1) willingness to receive treatment elsewhere to shorten the wait for radiation therapy, and (2) foregoing radiation therapy in the face of small marginal benefits. For each scenario, a TOT was used to identify the maximal acceptable wait time (MAWT) for therapy and the benefit threshold at which the patient would forego therapy. Associations of clinical and demographic factors with these decisions were determined by regression analysis.

RESULTS

Patients would be willing to wait, on average, 7 weeks before wanting to leave their city for radiation therapy, less than the 13-week delay our patients actually faced. Older patients were less willing to wait (P = .013); 46% of patients would not give up radiation therapy, even in the face of no stated benefit. Willingness to give up radiation therapy was predicted by willingness to accept delay (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.05 to 3.37) and being employed (OR, 2.61; 95% CI, 1.08 to 6.54). Patients with larger tumors were less willing to give up radiation therapy (OR, 0.57; 95% CI, 0.31 to 0.97).

CONCLUSION

Even in difficult decisions such as rationing postlumpectomy breast cancer radiation therapy, TOTs can inform policy formulation by indicating the distributions of patients' preferences.