Comparison of cardiac events associated with liposomal doxorubicin, epirubicin and doxorubicin in breast cancer: a Bayesian network meta-analysis.

BACKGROUND: Anthracyclines play a broad and important role in the care of patients with either operable or metastatic breast cancer. However cardiotoxicity narrows the therapeutic index of this drug class leading to potentially clinically meaningful treatment delays or discontinuations. We conducted a Bayesian network meta-analysis, a validated statistical methodology, allowing direct and indirect comparison of cardiotoxicity of different anthracycline and non-anthracycline regimens. METHODS: We conducted a systematic review of prospective randomised controlled trials through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Google Scholar comparing non-anthracycline based regimens (NON), doxorubicin (DOX), epirubicin (EPI) and liposomal doxorubicin (LD). We included studies published up to 1st January 2014 in both adjuvant and metastatic contexts. Notably, HER2/neu-targeted regimens were excluded. We assessed the studies' eligibility criteria and data collection with consensus of two independent authors. Our primary outcome measure was cardiac events grade 3 or greater (CE3) in accordance with Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. A Bayesian pairwise and network meta-analysis was conducted to estimate pooled Odds Ratio (OR). FINDINGS: Nineteen randomised controlled trials met eligibility criteria and were included in this analysis. We found a trend showing that LD is less cardiotoxic than DOX with an OR of 0.60 (95% confidence interval (CI) 0.34-1.07) There was no difference between Epi and LD with an OR of 0.95 (95%CI 0.39-2.33). DOX is more cardiotoxic than Non with an OR of 1.57 (95%CI 0.90-2.72). INTERPRETATION: DOX has higher CE3 rates than NON does. LD statistically trended to lower cardiac event rates than DOX. Non-statistical significance among EPI, LD and DOX with regard to cardiac toxicity indicates that avoidance of CE3 should not motivate selection of a particular anthracycline in otherwise healthy women in whom total lifetime anthracycline exposure will likely be limited. Overall low incidence of CE3 with any type of anthracycline indicates that we can safely use any anthracycline if cumulative dose limits are not exceeded. While CE3 does not limit our choice of anthracycline LD appears to be the least cardiotoxic. FUNDING: Takeo Fujii is supported by the grant named Young Investigator Award for Study Abroad in Clinical Epidemiology from St. Luke's Life Science Institution.

Effects of denosumab on pain and analgesic use in giant cell tumor of bone: interim results from a phase II study.

BACKGROUND: Giant cell tumor of bone (GCTB) is an aggressive primary osteolytic tumor. GCTB often involves the epiphysis, usually causing substantial pain and functional disability. Denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κΒ ligand (RANKL), is an effective treatment option for patients with advanced GCTB. This analysis of data from an ongoing, open-label study describes denosumab's effects on pain and analgesic use in patients with GCTB. MATERIAL AND METHODS: Patients with unresectable disease (e.g. sacral or spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into Cohort 1 (N = 170), and patients with resectable disease whose planned surgery was associated with severe morbidity (e.g. joint resection, limb amputation, or hemipelvectomy) were enrolled into Cohort 2 (N = 101). Patients received denosumab (120 mg) subcutaneously every four weeks, with additional doses on study days 8 and 15. Patients assessed worst pain severity with the Brief Pain Inventory - Short Form (BPI-SF) at baseline, at each visit for the first six months, and every three months thereafter. RESULTS: Clinically relevant pain improvement was reported by 29% of patients in Cohort 1 and 35% in Cohort 2 during week 1 and by ≥ 50% of patients in each cohort at each study visit from months 2-30. Median time to clinically relevant improvement was 30 (95% CI 16, 57) days in Cohort 1 and 15 (95% CI 15, 29) days in Cohort 2. Results in patients with moderate/severe pain at baseline were similar. Fewer than 30% of patients in Cohort 1 and 10% in Cohort 2 experienced clinically relevant pain worsening at any visit through 27 months. Most patients had no/low analgesic use during the study. CONCLUSION: Most patients treated with denosumab experienced clinically relevant decreases in pain within two months.

Impact of oncology drug shortages on patient therapy: unplanned treatment changes.

PURPOSE: Cancer drug shortages have increased considerably over the past 5 years, but quantitative analyses of the scope and effects are limited. We assessed the effects of drug shortages on outpatient medication use in a single New York City university hospital. METHODS: We examined pharmacy records for drug shortages, as defined by the American Society of Health-System Pharmacists. We assessed outpatient records for all patients with cancer treated with infusional antineoplastic medications from April 2010 to September 2010 and April 2011 to September 2011. RESULTS: Twelve medications were in shortage in 2010 and 22 in 2011. Drugs in shortage were used for 170 patients (50.8%) in 2010 and 241 patients (63.6%) in 2011 (P < .001). Of 235 patients treated in August-September 2011, there were 23(9.8%) documented therapy changes due to shortages, compared with zero changes in August-September 2010 (P < .001). Among patients treated in August-September 2010, 24 (11.4%) received paclitaxel and 19 (9.0%) received docetaxel. Among patients treated in August-September 2011, 11 (4.7%) received paclitaxel and 38 (16.2%) received docetaxel, a 69% decrease for paclitaxel and 80% increase for docetaxel from 1 year prior (P = .009, and P = .024, respectively). The estimated cost of a single treatment with paclitaxel for one patient with body-surface area 1.75 was $47.59 versus $858.39 for docetaxel, a 1,704% increase. Surveyed physicians frequently reported lower level evidence (30.4%) and increased risk of toxicity (34.8%) with alternative therapy in drug shortage cases. CONCLUSION: Oncology drug shortages affected the majority of patients in our center and increased at an alarming rate. Drug shortages have substantial economic costs and mandate treatment changes that may affect efficacy and toxicity.

Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514.

BACKGROUND: The use of neoadjuvant and adjuvant chemotherapy in soft tissue sarcomas is controversial. This is a report of long-term (≥5 years) follow-up in patients with high-grade, high-risk soft tissue sarcomas treated with neoadjuvant chemotherapy, preoperative radiotherapy (RT), and adjuvant chemotherapy. METHODS: Patients with high-grade soft tissue sarcoma≥8 cm in diameter of the extremities and body wall received 3 cycles of neoadjuvant chemotherapy (mesna, doxorubicin, ifosfamide, and dacarbazine) and preoperative RT (44 grays administered in split courses), and 3 cycles of postoperative chemotherapy (mesna, doxorubicin, ifosfamide, and dacarbazine). RESULTS: Sixty-four of 66 patients were analyzed. After chemotherapy and RT, 61 patients had surgery; 58 had R0 resections (5 amputations), and 3 had R1 resections. Ninety-seven percent experienced grade 3 or higher toxicity, including 3 deaths. These toxicities were short term. With a median follow-up of 7.7 years in surviving patients, the 5-year rates of locoregional failure (including amputation), and distant metastasis were 22.2% (95% confidence interval [CI], 11.8-32.6) and 28.1% (95% CI, 17.0-39.2). The most common site of metastasis was lung. Estimated 5-year rates of disease-free survival, distant disease-free survival, and overall survival were 56.1% (95% CI, 43.9-68.3), 64.1% (95% CI, 52.3-75.8), and 71.2% (95% CI, 60.0-82.5), respectively. CONCLUSIONS: Although the toxicity was significant, it was limited in its course and for the most part resolved by 1 year. The long-term outcome was better than might be expected in such high-risk tumors.

Management of locally advanced or unresectable head and neck cancer.

The treatment of patients with locoregionally advanced or unresectable squamous cell carcinoma of the head and neck is complex and associated with significant toxicities. During the past 30 years, there has been an ongoing shift in what is perceived as the best treatment approach. Differing radiation techniques have been employed, and chemotherapy has been incorporated in both sequential and concomitant strategies. In this article, we will review the available data regarding many of the advances that have been achieved. We will also discuss the most relevant recent clinical trials, as well as ongoing trials that will hopefully answer some of the questions that remain as we attempt to best treat this patient population

Opioid use and survival at the end of life: a survey of a hospice population.

Concern that opioids hasten death may be among the reasons that pain is treated inadequately in populations with advanced illness. Studies that assess the true risks are needed. To determine whether survival after last opioid dose change is associated with opioid dosing characteristics and other factors, data from the National Hospice Outcomes Project, a large prospective cohort study involving 13 U.S. hospice programs, were analyzed. Of 1,306 patients, 725 received opioids and underwent at least one dose change before death. Subsamples based on maximum opioid dose compared patients receiving usual doses with those receiving high-dose therapy. Spearman rank correlations examined bivariate associations between survival after final dose change and other variables, including dose in morphine equivalent mg and percentage dose increase. Multivariate least squares regression analyses determined associations between survival and other variables, including those significant in bivariate analyses. The mean+/-SD number of days between final dose change and death was 12.46+/-23.11. Multivariate models demonstrated a significant association between shorter survival and higher opioid dose, a cancer diagnosis, unresponsiveness, and pain of <5 on a 0-10 scale, but none of these models explained >10% of the variance in time till death. Analyses of subsamples did not reveal additional effects of dose. This analysis revealed that opioid dosing was associated with time till death, but this factor would explain very little of the variation in survival. In a hospice population, survival is influenced by complex factors, many of which may not be measurable. Based on these findings, concern about hastening death does not justify withholding opioid therapy.

Endoscopic ultrasound fine-needle aspiration in the staging of non-small-cell lung cancer.

Precise mediastinal staging of non-small-cell lung cancer is extremely important, as mediastinal lymph node metastases generally indicate unresectable disease. Reliance on computed tomography (CT) and positron-emission tomography (PET) alone to stage and determine resectability is limited by false-positive results. Whenever possible, pathologic confirmation of metastases is desirable. Mediastinoscopy and transbronchial fine-needle aspiration are widely established but imperfect modalities. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) has emerged as a diagnostic and staging tool because of its safety, accuracy, and patient convenience. We reviewed 13 prospective studies evaluating the comparative performance of EUS for staging lung cancer. We conclude that EUS is a valuable staging modality. Further studies of the role of EUS compared to other modalities such as integrated PET/CT and endobronchial ultrasound (EBUS) are forthcoming.

Primary systemic therapy of breast cancer.

Primary systemic therapy (PST) or neoadjuvant therapy is used in nonmetastatic breast cancer to treat systemic disease earlier, decrease tumor bulk ideally to a complete pathological response (pCR), and reduce the extent of surgery. The multitude of clinical trials using PST in breast cancer patients has not proven the fundamental hypotheses of improved overall survival and disease-free survival that drove the investigation of PST. The other potential advantages of PST, which include increasing the rate of breast-conserving surgery and predicting outcome to a particular chemotherapy regimen, are also not conclusively established. We examined the published literature on PST for breast cancer and predominantly focused our review on data from large, randomized clinical trials comparing primary systemic chemotherapy with adjuvant chemotherapy, different primary systemic chemotherapy regimens, primary systemic chemotherapy with hormonal therapy, and different preoperative hormonal therapies. Although the optimal neoadjuvant chemotherapy regimen has not been established, a combination of four cycles of an anthracycline followed by four cycles of a taxane appears to produce the highest pCR rate (22%-31%). In patients with HER-2-positive breast cancer, concurrent use of neoadjuvant trastuzumab with an anthracycline-taxane combination has produced provocative results that require further confirmatory studies. Preoperative hormonal therapy is associated with low pCR rates and should be reserved for patients who are poor candidates for systemic chemotherapy. The optimal management of patients with residual disease after the administration of maximum neoadjuvant therapy remains to be defined. The surgical approach, including the role of sentinel node biopsy and delivery of radiation therapy after PST in breast cancer patients, is evolving. Ongoing clinical trials will help identify the subset of patients who would most benefit from the use of PST, establish the most effective PST regimen, and determine the optimal multidisciplinary approach in the management of breast cancer.

Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514.

PURPOSE: On the basis of a positive reported single-institution pilot study, the Radiation Therapy Oncology Group initiated phase II trial 9514 to evaluate its neoadjuvant regimen in a multi-institutional Intergroup setting. PATIENTS AND METHODS: Eligibility included a high-grade soft tissue sarcoma > or = 8 cm in diameter of the extremities and body wall. Patients received three cycles of neoadjuvant chemotherapy (CT; modified mesna, doxorubicin, ifosfamide, and dacarbazine [MAID]), interdigitated preoperative radiation therapy (RT; 44 Gy administered in split courses), and three cycles of postoperative CT (modified MAID). RESULTS: Sixty-six patients were enrolled, of whom 64 were analyzed. Seventy-nine percent of patients completed their preoperative CT and 59% completed all planned CT. Three patients (5%) experienced fatal grade 5 toxicities (myelodysplasias, two patients; infection, one patient). Another 53 patients (83%) experienced grade 4 toxicities; 78% experienced grade 4 hematologic toxicity and 19% experienced grade 4 nonhematologic toxicity. Sixty-one patients underwent surgery. Fifty-eight of these were R0 resections, of which five were amputations. There were three R1 resections. The estimated 3-year rate for local-regional failure is 17.6% if amputation is considered a failure and 10.1% if not. Estimated 3-year rates for disease-free, distant-disease-free, and overall survival are 56.6%, 64.5%, and 75.1%, respectively. CONCLUSION: This combined-modality treatment can be delivered successfully in a multi-institutional setting. Efficacy results are consistent with previous single-institution results.

Severe action tremor related to interferon-alpha 2b therapy for malignant melanoma.

Interferon (IFN)-alpha 2b is used for adjuvant therapy in malignant melanoma. Neurotoxicity as a side effect has been well described. Resting and action tremor related to interferon have been reported but are relatively uncommon. We report a case of a delayed-onset interferon-related action tremor in a patient with malignant melanoma.

Integrated PET-CT: evidence-based review of oncology indications.

Over the past few years, positron-emission tomography (PET) has been increasingly used in oncology. More recently, the fusion of the functional imaging provided by PET with the anatomic information of, computed tomography (CT) has resulted in a powerful new imaging tool. In practice, the PET-CT image fusion can be done visually, with the help of special software, or through hardware incorporating both PET and CT. We performed a review of disease-specific studies using integrated PET-CT or PET-CT with visual or software fusion and found that PET-CT offers a significant benefit in improving the diagnosis, staging, and therapeutic monitoring of patients with cancer. Integrated PET-CT improves characterization of equivocal lesions and decreases intraobserver variability; it also has the potential to significantly affect treatment planning by guiding biopsies and surgical interventions, defining target volumes for radiation therapy fields, and monitoring response to treatment. More promising clinical applications will likely be possible with other fluorine-18-based isotopes.

Long-term survival in patients with human immunodeficiency virus-associated small non-cleaved cell lymphoma: the role for short course intensive chemotherapy.

While intensive chemotherapy is recommended for the treatment of non-HIV related adult small non-cleaved lymphoma (SNCL), including Burkitt's and Burkitt-like lymphoma, optimal treatment for patients with HIV-associated SNCL is not known. We assessed remissions and survival in a cohort of 44 consecutive HIV positive patients diagnosed with SNCL at our hospital between June 2000 and November 2001 using chart and pathology data. Median follow-up, survival and survival at the median follow-up time were 4.5 months, 4 months and 49% respectively. Of this cohort 39% were complete responders (CR) and 36% were long-term lymphoma-free survivors. Two patients relapsed from CR. Short course intensive chemotherapy (McMaster) was administered to 23 patients; 17 received less intensive conventional combination chemotherapy; and four received single-agent chemotherapy or no treatment. In the McMaster group, 38% (9/23) achieved CR with no relapses. Seven patients (30%) died of toxicity compared with one (6%) in the less intensively treated group. Of the stage I patients, 75% (6/8) achieved long-term CR with half being treated conventionally. Conventional chemotherapy may be curative for early stage HIV-SNCL. In advanced disease, McMaster chemotherapy was found to be associated with substantial early mortality but was curative in a significant number of patients.

The multidisciplinary approach to bone metastases.

With recent advances in the management of cancer, the clinical course of patients with metastatic bone disease is more likely to be prolonged and accompanied by morbidity, including severe pain, hypercalcemia, pathologic fracture, and spinal cord and/or nerve root compression. The early identification of patients at higher risk for developing bone metastases enables practitioners to be proactive in their diagnosis and treatment. A multidisciplinary approach that integrates the diagnosis and treatment of the cancer, symptom management, and rehabilitation ensures optimal care. Bisphosphonates can reduce the number of skeletal-related complications, delay the onset of progressive disease in bone, and relieve metastatic bone pain caused by a variety of solid tumors with a resulting enhanced quality of life. The complexity of the clinical problem and the need to involve an array of health-care providers present a logistical and clinical challenge. A strong argument is made for a thematically integrated bone metastases program as part of the primary care of patients with cancer.

Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group.

BACKGROUND: The current study was conducted to evaluate the antitumor activity and toxicity of gemcitabine in patients with advanced sarcoma. METHODS: Twenty-five patients with advanced sarcomas, who previously were untreated for metastatic disease, were treated on an Eastern Cooperative Oncology Group Phase II study. Patients ranged in age from 27 to 79 years, with a median age of 59 years. The most common histology was leiomyosarcoma (54%). The grades of the tumors were high in 40%, moderate in 24% and low in 12%. Gemcitabine was given at a dose of 1250 mg/m(2) as a 30-minute infusion weekly for 3 weeks followed by 1 week of rest. RESULTS: One of the 25 patients (4%) (90% confidence interval [90% CI], 0-18%) achieved a partial response lasting 8 months. The estimated overall median survival was 15 months. The 1-year estimated survival rate was 63% (90% CI, 47-84%). The estimated median progression-free survival (PFS) was 13 months with a 1-year PFS rate of 56% (90% CI, 41-76%). Grade 3-4 toxicities (by CTC criteria) were observed in all 25 patients. No lethal toxicity (Grade 5) related to treatment was found. CONCLUSIONS: The results of the current study demonstrated that gemcitabine given at this schedule and dose in this population of patients with advanced sarcoma had limited activity.

Phase II Study of Ifosfamide+Doxorubicin in Patients With Advanced Synovial Sarcomas (E1793): A Trial of the Eastern Cooperative Oncology Group.

Purpose Because we had observed in the synovial sarcoma subgroup of a broad phase III advanced soft tissue sarcoma study a significantly greater objective regression rate from ifosfamide+doxorubicin (88%) than from doxorubicin alone (20%) (P = 0.02), the Eastern Cooperative Oncology Group (ECOG) decided to further assess this two drug combination in a subsequent Phase II study.Patients Between 1994 and 1999, twelve adult patients with advanced synovial sarcomas were enrolled to receive, as their initial chemotherapy, ifosfamide 7.5 gm/m(2) plus doxorubicin 60 mg/m(2), given intravenously over two consecutive days every 3 weeks.Methods Each day for 2 days doxorubicin 30 mg/m(2) was infused over 5 min through a running i.v., followed by ifosfamide 3750 mg/m(2) over 4 h. Continuous i.v. fluid was infused at 300 mL/h for 3 h on day 1, before chemotherapy was begun; then the infusion was continued at 100 mL/h for a total of 3 days. Mesna 750 mg/m(2) was given 15 min before ifosfamide and at 4 and 8 h after ifosfamide on days 1 and 2 of each treatment cycle. Filgrastim (G-CSF) 5 mug/kg was given subcutaneously each day for 14 days beginning on day 3 of each treatment cycle to limit the severity of neutropenia.Results Five of our 12 patients (42%) experienced partial regression of their advanced synovial sarcomas; however, this first stage result was borderline for proceeding to the second planned stage of accrual and our case accrual was quite poor. Thus, the study was closed after stage one accrual. Our patients received a median of four cycles of chemotherapy (range: 1 to 6). All patients experienced at least grade 3 neutropenia (grade 4 in nine of them), and one patient died of treatment-related sepsis following the initial cycle of chemotherapy. Median survival was 11 months.

Study of either ifosfamide or teniposide compared to a standard chemotherapy for extensive disease small cell lung cancer: an Eastern Cooperative Oncology Group randomized study (E1588).

This randomized study of previously untreated patients with extensive disease small cell lung cancer was designed (a) to compare the survival of patients treated with either effective standard chemotherapy or an investigational anti-cancer drug as initial therapy and (b) to evaluate response rates and toxic effects of such therapies. One hundred and thirty-five patients were randomly assigned to receive as initial therapy, either the standard CAV regimen--cyclophosphamide (1000 mg/m(2)), doxorubicin (50 mg/m(2)) and vincristine (1.4 mg/m(2)) every 3 weeks--or the phase II drugs ifosfamide (1.5 gm/m(2)/days 1-5) with mesna (300 mg/m(2)) dose at 0, 4 and 8 h after IV daily ifosfamide every 3 weeks or teniposide (60 mg/m(2)/days 1-5) every 3 weeks. Nonresponders received salvage chemotherapy-etoposide (120 mg/m(2) on days 1, 2 and 3) and cisplatin (60 mg/m(2) on day 1), repeated every 3 weeks. Among the 46 patients on CAV, there were two complete and 24 partial responses (56%). Among the 43 patients on ifosfamide, there were three complete and 18 partial responses (49%), while among the 46 patients on teniposide, there were two complete and 18 partial responses (43%). Eighty-three of the patients proceeded onto salvage regimen, of which 81 were analyzable for response and toxicity. Among the 81 patients who continued on salvage therapy and were evaluable for response, the overall best response rate was 61% for CAV+salvage, 54% for ifosfamide+salvage, and 53% for teniposide+salvage. These rates were not significantly different (P=0.962). Of the 135 analyzable patients, 130 (96%) have died. The estimated median survival time was 42 weeks for CAV patients, 43 weeks for ifosfamide, and 38 weeks for teniposide. Seven patients survived longer than 2 years (four on CAV, one on ifosfamide and two on teniposide). There were 29 life-threatening complications to the induction regimen (22 (48%) on CAV, four (9%) on ifosfamide and three (7%) on teniposide) and seven lethal complications (two on CAV, four on ifosfamide and one on teniposide). The treatments were significantly different with respect to the overall degree of toxicity (P < 0.0001) with CAV being more toxic. The data of this study, like the previous ECOG study suggests that the administration of a new agent followed by effective salvage chemotherapy in the treatment of extensive disease small cell lung cancer may have no adverse effect on survival.