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issn:1549-490
3.  The Cost of Cancer Care—Balancing Our Duties to Patients Versus Society: Are They Mutually Exclusive? 
The Oncologist  2013;18(4):347-349.
doi:10.1634/theoncologist.2013-0078
PMCID: PMC3639518  PMID: 23568002
Health care costs; Ethical issues; Cancer care; Resource allocation; Decision-making
4.  Screening for Breast Cancer-Related Lymphedema: The Need for Standardization 
The Oncologist  2013;18(4):350-352.
This commentary explores the challenges surrounding the development of a standard definition of lymphedema and method of quantification, proposes solutions, and calls for a collaborative effort among providers who care for patients with breast cancer.
doi:10.1634/theoncologist.2012-0387
PMCID: PMC3639519  PMID: 23576481
5.  Adjuvant Therapy With Zoledronic Acid in Patients With Breast Cancer: A Systematic Review and Meta-Analysis 
The Oncologist  2013;18(4):353-361.
A systematic review and meta-analysis of randomized clinical trials estimating the impact on survival outcomes and fracture rates of the use of zoledronic acid versus no use (or delayed use) in the adjuvant treatment of early-stage breast cancer patients is presented.
Background.
The purpose of the study was to estimate the impact on survival and fracture rates of the use of zoledronic acid versus no use (or delayed use) in the adjuvant treatment of patients with early-stage (stages I–III) breast cancer.
Materials and Methods.
We performed a systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meeting searches. All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with zoledronic acid versus nonuse, placebo, or delayed use of zoledronic acid as treatment to individuals who develop osteoporosis were considered eligible. Standard meta-analytic procedures were used to analyze the study outcomes.
Results.
Fifteen studies were considered eligible and were further analyzed. The use of zoledronic acid resulted in a statistically significant better overall survival outcome (five studies, 6,414 patients; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70–0.94). No significant differences were found for the disease-free survival outcome (seven studies, 7,541 patients; HR, 0.86; 95% CI, 0.70–1.06) or incidence of bone metastases (seven studies, 7,543 patients; odds ratio [OR], 0.94; 95% CI, 0.64–1.37). Treatment with zoledronic acid led to a significantly lower overall fracture rate (OR, 0.78; 95% CI, 0.63–0.96). Finally, the rate of osteonecrosis of the jaw was 0.52%.
Conclusion.
Zoledronic acid as adjuvant therapy in breast cancer patients appears to not only reduce the fracture risk but also offer a survival benefit over placebo or no treatment.
doi:10.1634/theoncologist.2012-0261
PMCID: PMC3639520  PMID: 23404816
Zoledronic acid; Adjuvant; Breast cancer; Bisphosphonates
6.  Long-Term Risk Perceptions of Women With Ductal Carcinoma In Situ 
The Oncologist  2013;18(4):362-368.
Recurrence risk perceptions after 5 years were evaluated in women with a history of ductal carcinoma in situ. Many women were found to harbor inaccurate perceptions of their risk for future breast cancer events even 5 years after diagnosis.
Learning Objectives
Identify predictors of excessive risk perception in women with a distant history of DCIS.Explain the importance of educating women with a history of DCIS about reasonable assessments of their risk for future breast cancer.
Introduction.
Previous research has demonstrated that many women with ductal carcinoma in situ (DCIS) overestimate their risk for future breast cancer at the time of diagnosis and soon thereafter. This study aims to evaluate risk perceptions after 5 years.
Patients and Methods.
In a longitudinal cohort study, we mailed long-term follow-up surveys to 315 women who had previously responded to a survey 18 months after they were diagnosed with DCIS, excluding those who had experienced recurrence and those not treated at our institution. We evaluated risk perceptions with items used previously in the cohort.
Results.
One hundred ninety-three women (61%) responded. The median time since diagnosis was 5.9 years. We excluded 12 because of recurrence. Of the 181 remaining, 32% perceived at least a moderate 5-year risk for developing DCIS again, 43% perceived at least a moderate lifetime risk for developing DCIS again, 27% perceived at least a moderate 5-year risk for invasive breast cancer, 38% perceived at least a moderate lifetime risk for invasive breast cancer, and 24% perceived at least a moderate risk for DCIS spreading to other body parts. In a multivariate model, worse financial status and higher perceived risk in the previous survey were the only predictors of at least a moderate perception of risk for DCIS spreading.
Conclusion.
Women with a history of DCIS continue to harbor inaccurate perceptions of their risk for future breast cancer events even 5 years after diagnosis.
doi:10.1634/theoncologist.2012-0376
PMCID: PMC3639521  PMID: 23568001
Carcinoma; Intraductal; Noninfiltrating; Survivors; Anticipation; Psychological; Anxiety
7.  Case Control Study of Women Treated With Chemotherapy for Breast Cancer During Pregnancy as Compared With Nonpregnant Patients With Breast Cancer 
The Oncologist  2013;18(4):369-376.
This analysis compared disease-free survival, progression-free survival, and overall survival rates for pregnant and nonpregnant patients with breast cancer who were treated with chemotherapy. The survival rates for pregnant patients were comparable to, if not better than, those of nonpregnant women, indicating that pregnant patients should receive appropriate local and systemic therapy for breast cancer.
Learning Objectives
Discuss known data regarding outcomes in pregnancy-associated breast cancer.Evaluate outcomes in a single institution when compared to nonpregnant breast cancer patients.
Background.
The purpose of this analysis was to compare disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) between pregnant and nonpregnant patients with breast cancer.
Methods.
From 1989 to 2009, 75 women were treated with chemotherapy during pregnancy. Each pregnant case was matched on age and cancer stage to two nonpregnant patients with breast cancer (controls). Fisher's exact test, the Kaplan-Meier method, and Cox proportional hazards regression models were used.
Results.
Median follow-up time for patients who were alive at the end of follow-up (n = 159) was 4.20 years (range: 0.28–19.94 years). DFS at 5 years was 72% (95% confidence interval [CI]: 58.3%–82.1%) for pregnant patients and 57% (95% CI: 46.7%–65.8%) for controls (p = .0115). Five-year PFS was 70% (95% CI: 56.8%–80.3%) for pregnant patients and 59% (95% CI: 49.1%–67.5%) for controls (p = .0252). Five-year OS was 77% (95% CI: 63.9%–86.4%) for pregnant patients and 71% (95% CI: 61.1%–78.3%) for controls (p = .0461). Hazard ratio estimates favored improved survival for pregnant patients in univariate analyses and multivariate analyses, controlling for age, year of diagnosis, stage, and tumor grade.
Conclusions.
For patients who received chemotherapy during pregnancy, survival was comparable to—if not better than—that of nonpregnant women. Pregnant patients with breast cancer should receive appropriate local and systemic therapy for breast cancer.
doi:10.1634/theoncologist.2012-0340
PMCID: PMC3639522  PMID: 23576478
Pregnancy; Breast cancer; Chemotherapy; Anthracycline; Survival
8.  Multicenter Phase II Study of Tivozanib (AV-951) and Everolimus (RAD001) for Patients With Refractory, Metastatic Colorectal Cancer 
The Oncologist  2013;18(4):377-378.
Background.
Treatments that target the vascular endothelial growth factor (VEGF) pathway have efficacy in colorectal cancer. We evaluated tolerability and efficacy of tivozanib (an oral VEGF receptor-1, -2, -3 inhibitor) plus everolimus (an oral mammalian target of rapamycin inhibitor).
Methods.
The phase Ib study followed a 3 + 3 dose-escalation design with three dose levels. The primary objective in the follow-on phase II study was improvement in 2-month progression-free survival (PFS) from 30% (historical benchmark) to 50% in patients with refractory, metastatic colorectal cancer.
Results.
Dose-limiting toxicities in the phase Ib study were grade 3 fatigue and dehydration. Oral tivozanib (1 mg daily for 3 of 4 weeks) and oral everolimus (10 mg daily continuously) were advanced to a 40-patient phase II study. The most common grade 3–4 adverse events were thrombocytopenia and hypophosphatemia. The 2-month PFS rate was 50%, with 20 of 40 patients having stable disease (SD). Seven (18%) patients were treated for ≥6 months. Median PFS and overall survival (OS) times were 3.0 months (95% confidence interval [CI]: 1.9–3.6 months) and 5.6 months (95% CI: 4.4–10.6 months), respectively. Patients who developed grade 1+ hypertension had increased SD rates (65.2% vs. 29.4%) and longer OS times (10.6 vs. 3.7 months).
Conclusions.
The oral combination of tivozanib and everolimus was well tolerated, with stable disease achieved in 50% of patients with refractory, metastatic colorectal cancer.
doi:10.1634/theoncologist.2012-0378
PMCID: PMC3639523  PMID: 23580238
9.  A Phase II Randomized Dose Escalation Trial of Sorafenib in Patients With Advanced Hepatocellular Carcinoma 
The Oncologist  2013;18(4):379-380.
Background.
Sorafenib has proven survival benefits in patients with advanced hepatocellular carcinoma (HCC). The viability of continuing sorafenib at a higher dosage in patients who experienced radiologic disease progression was investigated.
Methods.
Patients who experienced disease progression while on sorafenib 400 mg twice daily were randomized to sorafenib 600 mg twice daily (n = 49) or best supportive care (n = 52). The primary end point was progression-free survival (PFS). Time to progression, overall survival, and safety were also evaluated.
Results.
The study did not meet its primary end point. The difference in PFS between the sorafenib arm (3.91 months) and the best supportive care arm (2.69 months) did not reach statistical significance (p = 0.086). Adverse events were mainly grade 1–2 and similar across both groups. In the sorafenib arm, the most frequent events were diarrhea (80%), weight loss (75%), fatigue (67%), hand-foot-skin reaction (49%), abdominal pain (37%), and stomatitis (26%).
Conclusions.
Escalated-dose sorafenib in patients with advanced HCC who progressed while on sorafenib, failed to provide any clinical benefit. Second-line treatment still remains an open issue to be explored in appropriate clinical trials.
doi:10.1634/theoncologist.2012-0221
PMCID: PMC3639524  PMID: 23580239
10.  The Financial Toxicity of Cancer Treatment: A Pilot Study Assessing Out-of-Pocket Expenses and the Insured Cancer Patient's Experience 
The Oncologist  2013;18(4):381-390.
The experiences of insured cancer patients requesting copayment assistance and the impact of health care expenses on well-being and treatment are examined. Insured patients undergoing cancer treatment and seeking copayment assistance were found to experience considerable subjective financial burden and were found to alter care to defray out-of-pocket expenses.
Learning Objectives
Describe the experiences of insured cancer patients requesting copayment assistance in order to better understand the challenges of underinsurance.Describe the impact of costs on the well being of insured cancer patients.Evaluate the impact of costs on the treatment received by insured cancer patients.
Purpose.
Cancer patients carry rising burdens of health care-related out-of-pocket expenses, and a growing number of patients are considered “underinsured.” Our objective was to describe experiences of insured cancer patients requesting copayment assistance and to describe the impact of health care expenses on well-being and treatment.
Methods.
We conducted baseline and follow-up surveys regarding the impact of health care costs on well-being and treatment among cancer patients who contacted a national copayment assistance foundation along with a comparison sample of patients treated at an academic medical center.
Results.
Among 254 participants, 75% applied for drug copayment assistance. Forty-two percent of participants reported a significant or catastrophic subjective financial burden; 68% cut back on leisure activities, 46% reduced spending on food and clothing, and 46% used savings to defray out-of-pocket expenses. To save money, 20% took less than the prescribed amount of medication, 19% partially filled prescriptions, and 24% avoided filling prescriptions altogether. Copayment assistance applicants were more likely than nonapplicants to employ at least one of these strategies to defray costs (98% vs. 78%). In an adjusted analysis, younger age, larger household size, applying for copayment assistance, and communicating with physicians about costs were associated with greater subjective financial burden.
Conclusion.
Insured patients undergoing cancer treatment and seeking copayment assistance experience considerable subjective financial burden, and they may alter their care to defray out-of-pocket expenses. Health insurance does not eliminate financial distress or health disparities among cancer patients. Future research should investigate coverage thresholds that minimize adverse financial outcomes and identify cancer patients at greatest risk for financial toxicity.
doi:10.1634/theoncologist.2012-0279
PMCID: PMC3639525  PMID: 23442307
Neoplasms; Cost; Chemotherapy; Indigency; Medical; Quality of health care; Financial support
11.  Molecular and Therapeutic Advances in the Diagnosis and Management of Malignant Pheochromocytomas and Paragangliomas 
The Oncologist  2013;18(4):391-407.
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare catecholamine-secreting tumors derived from chromaffin cells originating in the neural crest. This review discusses the currently available diagnostic and therapeutic options for patients with malignant PCCs and PGLs and details the molecular rationale and clinical evidence for novel and emerging diagnostic and therapeutic strategies.
Learning Objectives
Discuss the advances in molecular genetics which have uncovered new hereditary and germline mutations contributing to the development of pheochromocytoma and paraganglioma and identify the genotype/phenotype patterns which facilitate more accurate determination of malignant potential.Describe the current imaging modalities used in the diagnosis of pheochromocytoma and paraganglioma and evaluate the efficacy of functional imaging modalities according to tumor genotype.Evaluate the current preclinical molecular research contributing to the selection of targeted therapies for malignant pheochromocytoma and paraganglioma.
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare catecholamine-secreting tumors derived from chromaffin cells originating in the neural crest. These tumors represent a significant diagnostic and therapeutic challenge because the diagnosis of malignancy is frequently made in retrospect by the development of metastatic or recurrent disease. Complete surgical resection offers the only potential for cure; however, recurrence can occur even after apparently successful resection of the primary tumor. The prognosis for malignant disease is poor because traditional treatment modalities have been limited. The last decade has witnessed exciting discoveries in the study of PCCs and PGLs; advances in molecular genetics have uncovered hereditary and germline mutations of at least 10 genes that contribute to the development of these tumors, and increasing knowledge of genotype-phenotype interactions has facilitated more accurate determination of malignant potential. Elucidating the molecular mechanisms responsible for malignant transformation in these tumors has opened avenues of investigation into targeted therapeutics that show promising results. There have also been significant advances in functional and radiological imaging and in the surgical approach to adrenalectomy, which remains the mainstay of treatment for PCC. In this review, we discuss the currently available diagnostic and therapeutic options for patients with malignant PCCs and PGLs and detail the molecular rationale and clinical evidence for novel and emerging diagnostic and therapeutic strategies.
doi:10.1634/theoncologist.2012-0410
PMCID: PMC3639526  PMID: 23576482
Pheochromocytoma; Paraganglioma; Malignant; Therapeutics; Genetic mutation
12.  Toxicity of Bevacizumab in Combination with Chemotherapy in Older Patients 
The Oncologist  2013;18(4):408-414.
Heart disease is more common in those who do not receive bevacizumab. Older patients who receive bevacizumab with chemotherapy have higher odds of developing a grade 3–5 toxicity compared with those who receive chemotherapy alone.
Learning Objectives
Compare characteristics of older patients that receive bevacizumab plus chemotherapy to those treated with chemotherapy alone for advanced NSCLC and CRC.Compare outcomes between older patients treated with bevacizumab plus chemotherapy to chemotherapy alone for advanced NSCLC and CRC.Describe toxicities in older patients treated with bevacizumab plus chemotherapy for advanced NSCLC and CRC.
Background.
Bevacizumab leads to improved survival for patients with metastatic colorectal cancer (CRC) or non-small cell lung cancer (NSCLC) when added to chemotherapy. Little is known about factors associated with receipt of bevacizumab, or whether bevacizamab is associated with increased toxicity when added to chemotherapy.
Patients and Methods.
We conducted a prospective study of patients aged ≥65 years, which evaluated the association between geriatric assessment (GA) metrics and chemotherapy toxicity. We examined differences in characteristics and outcomes of patients with CRC and NSCLC cancers who received bevacizumab with chemotherapy versus chemotherapy alone.
Results.
From a total of 207 patients, 27 (13%) received bevacizumab plus chemotherapy and 180 (87%) received chemotherapy alone. Groups were similar in sociodemographic and cancer characteristics. There were no baseline differences in GA domains except that patients with heart disease were less likely to receive bevacizumab (4% vs. 26%, p = .01). Seventy-eight percent of patients who had bevacizumab had grade 3–5 toxicity compared to only 57% who received chemotherapy alone (p = .06). Patients receiving bevacizumab were more likely to develop grade 3 hypertension than those who received chemotherapy alone (15% vs. 2%, p < .01). In multivariable analysis, factors associated with grade 3 or more toxicity included: bevacizumab (OR: 2.86, p = .04), CRC (OR: 2.54, p < .01), and baseline anemia (OR: 2.58, p = .03).
Conclusion.
Heart disease was more common in those who did not receive bevacizumab. Older patients who receive bevacizumab with chemotherapy have a higher odds of developing a grade 3–5 toxicity compared with those who receive chemotherapy alone.
doi:10.1634/theoncologist.2012-0351
PMCID: PMC3639527  PMID: 23576485
Chemotherapy; Geriatric assessment; Bevacizumab; Drug toxicity; Health services for the aged
13.  Adaptive 3D Image-Guided Brachytherapy: A Strong Argument in the Debate on Systematic Radical Hysterectomy for Locally Advanced Cervical Cancer 
The Oncologist  2013;18(4):415-422.
The outcomes of patients with locally advanced cervical cancer treated with three-dimensional image-guided brachytherapy after concomitant chemoradiation were evaluated. An excellent locoregional control rate with low treatment-related morbidity was observed, justifying the elimination of hysterectomy in the absence of obvious residual disease.
Learning Objectives
Evaluate control rates of IGABT combined with CCRT for the treatment of locally advanced cervical cancer.Describe survival outcomes in patients treated with IGABT combined with CCRT for locally advanced cervical cancer.Describe toxicities in patients treated with IGABT combined with CCRT for locally advanced cervical cancer.
Purpose.
To evaluate the outcomes of patients with locally advanced cervical cancer treated with three-dimensional image-guided brachytherapy (IGABT) after concomitant chemoradiation (CCRT).
Materials and Methods.
Data from patients treated with CCRT followed by magnetic resonance imaging-guided or computed tomography-guided pulsed-dose-rate brachytherapy, performed according to the Groupe Européen de Curiethérapie–European Society for Radiotherapy and Oncology guidelines, were reviewed. At first, stage I or II patients systematically underwent radical hysterectomy or were offered a randomized study evaluating hysterectomy. Then, hysterectomy was limited to salvage treatment.
Results.
Of 163 patients identified, 27% had stage IB, 57% had stage II, 12% had stage III, and 3% had stage IVA disease. The mean dose delivered (in 2-Gy dose equivalents) to 90% of the high-risk clinical target volume was 78.1 ± 9.6 Gy, whereas the doses delivered to organs at risk were maintained under the usual thresholds. Sixty-one patients underwent a hysterectomy. Macroscopic residual disease was found in 13 cases. With a median follow-up of 36 months (range, 5–79 months), 45 patients had relapsed. The 3-year overall survival rate was 76%. Local and pelvic control rates were 92% and 86%, respectively. According to the Common Toxicity Criteria 3.0, 7.4% of patients experienced late grade 3 or 4 toxicity. Most of those had undergone postradiation radical surgery (2.9% vs. 14.8; p = .005).
Conclusion.
IGABT combined with CCRT provides excellent locoregional control rates with low treatment-related morbidity, justifying the elimination of hysterectomy in the absence of obvious residual disease. Distant metastasis remains an important first relapse and may warrant more aggressive systemic treatment.
doi:10.1634/theoncologist.2012-0367
PMCID: PMC3639528  PMID: 23568003
Cervical cancer; Image-guided adaptive brachytherapy; Chemoradiation; Optimization; Dose escalation
14.  A Study to Evaluate the Cause of Bone Demineralization in Gynecological Cancer Survivors 
The Oncologist  2013;18(4):423-429.
The prevalence of low bone mineral density in premenopausal women treated for gynecological cancer is explored and the direct effect of cancer treatment versus that of hormone withdrawal on the bone health of gynecological cancer survivors is evaluated.
Learning Objectives
Describe the potential contributors to bone demineralization in patients receiving systematic treatment for gynecological malignancies.Define what is meant by “osteopenia” and “osteoporosis” and describe their relevance to fracture risk.Explain the importance of preventing and managing bone mineral loss and its complications in gynecological cancer survivors.
Background.
An association between treatment for gynecological cancers and risk of osteoporosis has never been formally evaluated. Women treated for these cancers are now living longer than ever before, and prevention of treatment-induced morbidities is important. We aimed to distinguish, in gynecological cancer survivors, whether cancer therapy has additional detrimental effects on bone health above those attributable to hormone withdrawal.
Methods.
We performed a retrospective cross-sectional analysis of dual energy x-ray absorptiometry (DEXA) scan results from 105 women; 64 had undergone bilateral salpingo-oophorectomy (BSO) followed by chemotherapy or radiotherapy for gynecological malignancies, and 41 age-matched women had undergone BSO for benign etiologies. All were premenopausal prior to surgery.
Results.
The median age at DEXA scan for the cancer group was 42 years, and 66% had received hormonal replacement therapy (HRT) following their cancer treatment. For the benign group, the median age was 40 years, and 87% had received HRT. Thirty-nine percent of cancer survivors had abnormal DEXA scan results compared to 15% of the control group, with the majority demonstrating osteopenia. The mean lumbar spine and femoral neck bone mineral densities (BMDs) were significantly lower in cancer patients. A history of gynecological cancer treatment was associated with significantly lower BMD in a multivariate logistic regression.
Conclusions.
Women treated for gynecological malignancies with surgery and adjuvant chemotherapy have significantly lower BMDs than age-matched women who have undergone oophorectomy for noncancer indications. Prospective evaluation of BMD in gynecological cancer patients is recommended to facilitate interventions that will reduce the risk of subsequent fragility fractures.
doi:10.1634/theoncologist.2012-0416
PMCID: PMC3639529  PMID: 23363808
Gynecological cancer; Osteoporosis; Bone diseases; Metabolic; Bone density; Survivors
15.  Antiangiogenic Therapies for Advanced Hepatocellular Carcinoma 
The Oncologist  2013;18(4):430-438.
Proangiogenic cytokines such as vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor may play crucial roles in the treatment of hepatocellular carcinoma. Recent clinical and preclinical data along with ongoing studies are discussed in this review.
Hepatocellular carcinoma (HCC) is a significant cause of death worldwide. HCC is a highly vascular tumor, and proangiogenic cytokines such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor may play crucial roles in this disease. Sorafenib, a multikinase inhibitor that blocks VEGF and PDGF signaling, was the first systemic therapy to demonstrate improved survival in patients with advanced HCC. Several other drugs targeting VEGF are in development. Because of the anticipation of eventual resistance to anti-VEGF therapies, drugs that also target alternative proangiogenic pathways are being investigated. Recent clinical and preclinical data along with ongoing studies are reviewed.
doi:10.1634/theoncologist.2012-0388
PMCID: PMC3639530  PMID: 23576483
Hepatocellular carcinoma; Vascular endothelial growth factor; VEGF; FGF; Angiogenesis
16.  A Phase II Study of Amrubicin as a Third-Line or Fourth-Line Chemotherapy for Patients With Non-Small Cell Lung Cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0901 
The Oncologist  2013;18(4):439-445.
The efficacy and safety of amrubicin for patients with advanced non-small cell lung cancer as a third- or fourth-line therapy were evaluated. Amrubicin showed significant clinical activity with manageable toxicities.
Amrubicin, a third-generation synthetic anthracycline agent, has favorable clinical activity and acceptable toxicity for the treatment of patients with non-small cell lung cancer (NSCLC) and small cell lung cancer. We conducted this study to evaluate the efficacy and safety of amrubicin for advanced NSCLC patients as a third- or fourth-line therapy. Eligible patients had recurrent or refractory advanced NSCLC after second- or third-line therapy. Patients received amrubicin, 35 mg/m2 i.v. on days 1–3 every 3 weeks. The primary endpoint was the disease control rate (DCR). Secondary endpoints were the overall survival (OS) time, progression-free survival (PFS) time, response rate, and toxicity profile. Of the 41 patients enrolled, 26 received amrubicin as a third-line and 15 received it as a fourth-line therapy. The median number of treatment cycles was two (range, 1–9). Objective responses were complete response (n = 0), partial response (n = 4), stable disease (n = 21), progressive disease (n = 15), and not evaluable (n = 1), resulting in a DCR of 61.0% (95% confidence interval, 46.0%–75.9%). The overall response rate was 9.8% (95% confidence interval, 0.6%–18.8%). The median PFS interval was 3.0 months, median OS time was 12.6 months, and 1-year survival rate was 53.7%. Grade 3 or 4 hematological toxicities were neutropenia (68%), anemia (12%), thrombocytopenia (12%), and febrile neutropenia (17%). Nonhematological toxicities were mild and reversible. No treatment-related deaths were observed. Amrubicin showed significant clinical activity with manageable toxicities as a third- or fourth-line therapy for patients with advanced NSCLC. This study provides relevant data for routine practice and future prospective trials evaluating third- or fourth-line treatment strategies for patients with advanced NSCLC.
doi:10.1634/theoncologist.2012-0308
PMCID: PMC3639531  PMID: 23442308
Amrubicin; Chemotherapy; Fourth line; Non-small cell lung cancer; Third line
17.  Association of Anthracycline-Related Cardiac Histological Lesions With NADPH Oxidase Functional Polymorphisms 
The Oncologist  2013;18(4):446-453.
A retrospective case–control design was used to evaluate cardiac histological lesions and NADPH genotype (polymorphisms rs1883112, rs4673, and rs13058338) in 97 consecutive decedents with a cancer diagnosis. rs4673 protected against focal myocardial necrosis, whereas rs1883112 was strongly associated with cardiac fibrosis.
Objective.
Treatment with anthracyclines may cause cardiac dysfunction, but the sequence of anthracycline-induced heart lesions has been incompletely characterized. NADPH oxidase, a key mediator of oxidative cardiac damage and remodeling, modulates anthracycline clinical cardiotoxicity. Our aim was to determine which cardiac histological lesions are specifically induced by anthracycline treatment and to investigate the role of NADPH functional genetic polymorphisms in their development.
Patients and Methods.
Using a retrospective case–control design, we evaluated cardiac histological lesions and NADPH genotype (polymorphisms rs1883112, rs4673, and rs13058338) in 97 consecutive decedents with a cancer diagnosis (48 treated with anthracyclines).
Results.
Myocytolysis (60%), patched myocardial necrosis (19%), and myocardial fibrosis (diffuse and patched; 62% and 23%, respectively) were associated with anthracycline treatment. In patients receiving anthracyclines, NADPH oxidase polymorphism rs4673 protected against focal myocardial necrosis (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.20–0.63) whereas rs1883112 was strongly associated with cardiac fibrosis (OR, 5.11; 95% CI, 1.59–16.43), which was present in all homozygotes.
Conclusion.
Anthracyclines induce a cardiac remodeling pattern characterized by interstitial or patched fibrosis. The contribution of the functionally relevant NADPH polymorphisms rs1883112 and rs4673 to anthracycline-related heart lesions provides a plausible explanation for their modulation of cardiotoxicity. If confirmed, these findings may lead to better individualized strategies for early detection and prevention of anthracycline cardiotoxicity.
doi:10.1634/theoncologist.2012-0239
PMCID: PMC3639532  PMID: 23576480
Anthracyclines; Secondary myocardial diseases; Genotype; Myocardial fibrosis; NADPH
18.  High-Resolution Computed Tomography Findings for Patients With Drug-Induced Pulmonary Toxicity, With Special Reference to Hypersensitivity Pneumonitis-Like Patterns in Gemcitabine-Induced Cases 
The Oncologist  2013;18(4):454-459.
This retrospective study examines the incidence and causes of drug-induced pulmonary toxicity and classifies high-resolution computed tomography findings for antitumor-therapy associated pulmonary toxicity based on characteristic patterns and pathological considerations, with a special focus on gemcitabine-induced pulmonary toxicity.
Background.
Gemcitabine (GEM) is widely used as a chemotherapeutic agent. However, pulmonary toxicity has been rarely observed with GEM use. This article aims to determine the incidence and causes of drug-induced pulmonary toxicity, and to classify the high-resolution computed tomography (HRCT) findings for antitumor therapy-associated pulmonary toxicity based on characteristic patterns and pathological considerations, with a special focus on GEM-associated pulmonary toxicity (GAPT).
Methods.
Medical records of all patients with drug-induced pulmonary toxicity seen at Kyorin University hospital between April 2006 and December 2011 were retrospectively reviewed. The study examined correlations between HRCT and the assessed pathological or clinical findings, with a specific focus on antitumor drugs.
Results.
We identified 66 patients with drug-induced pulmonary toxicity. Among the antitumor drugs, GEM was the primary offending agent (n = 8) for pulmonary toxicity followed by docetaxel and gefitinib. HRCT patterns for the eight GAPT patients included the non-specific interstitial pneumonia (NSIP; n = 5) and the hypersensitivity pneumonitis (HP)-like pattern (n = 3). In contrast, four patients in the study were found to have the HP-like pattern, with three cases associated with GEM and one case associated with imatinib mesylate. The transbronchial lung biopsy or video-assisted thoracic surgery specimens for these patients showed granuloma or organizing tissue with a random distribution that was independent of the respiratory bronchiole. These results appeared to correspond to the HRCT-determined centrilobular nodules.
Conclusion.
GEM was the leading cause of drug-induced pulmonary toxicity in the patients examined in this study. This toxicity appears as NSIP or an HP-like pattern during HRCT examinations. This HP-like pattern may be useful for diagnosing GEM-induced pulmonary toxicity, as well as demonstrating granuloma or organizing tissue during lung pathology examinations.
doi:10.1634/theoncologist.2012-0248
PMCID: PMC3639533  PMID: 23404815
Pulmonary toxicity; Gemcitabine; Hypersensitivity pneumonitis; High-resolution CT; Antitumor drugs; Lung pathology
19.  Approval Summary: Cetuximab in Combination With Cisplatin or Carboplatin and 5-Fluorouracil for the First-Line Treatment of Patients With Recurrent Locoregional or Metastatic Squamous Cell Head and Neck Cancer 
The Oncologist  2013;18(4):460-466.
The present cetuximab U.S. Food and Drug Administration submission seeks to expand the squamous cell head and neck cancer indication to include recurrent locoregional or metastatic disease. Cetuximab, in combination with platinum-based therapy and 5-fluorouracil (FU), is compared to platinum-based therapy and 5-FU alone.
Learning Objectives
Compare survival outcomes among patients with SCCHN treated with a platinum/5 -FU regimen with and without cetuximab.Compare adverse event profiles among patients with SCCHN treated with a platinum/5 -FU regimen with and without cetuximab.Describe potential risk-benefit issues identified in the EU and US studies.
On November 7, 2011, the U.S. Food and Drug Administration approved cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer. Approval was based on a randomized study of 442 patients conducted outside the U.S. Cisplatin (100 mg/m2 intravenously) or carboplatin (area under the curve 5 intravenously) on day 1 with 5-fluorouracil (1,000 mg/m2/day continuous intravenous infusion days 1–4) were administered every 3 weeks. Cetuximab, 400 mg/m2 intravenously, was administered initially followed by cetuximab, 250 mg/m2 intravenously weekly. After completion of six planned treatment courses, cetuximab patients without progression continued cetuximab 250 mg/m2 weekly. The study used European Union (EU)-approved cetuximab rather than U.S.-approved cetuximab. U.S.-approved cetuximab provides approximately 28% higher exposure relative to EU-approved cetuximab in a pharmacokinetic comparability study in monkeys. Overall survival, the primary efficacy endpoint, was significantly improved in cetuximab-treated patients (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.64–0.98; p = .034, stratified log-rank test). Median survival times were 10.1 and 7.4 months, respectively. Progression-free survival (PFS) was also significantly improved in patients receiving cetuximab (HR: 0.57; 95% CI: 0.46–0.72; p < .0001). Median PFS times were 5.5 and 3.3 months, respectively. Response rates were 35.6% and 19.5% (odds ratio: 2.33; 95% CI: 1.50–3.60; p = .0001). Adverse reactions (≥25%) from cetuximab plus chemotherapy treatment included nausea, anemia, vomiting, neutropenia, rash, asthenia, diarrhea, and anorexia. Conjunctivitis occurred in 10% of cetuximab patients. Other adverse reactions, sometimes severe, included infusion reactions, hypomagnesemia, hypocalcemia, and hypokalemia.
doi:10.1634/theoncologist.2012-0458
PMCID: PMC3639534  PMID: 23576486
Cetuximab; Erbitux; Head and neck cancer; Advanced disease
20.  Factors Associated With Fatigue After Surgery in Women With Early-Stage Invasive Breast Cancer 
The Oncologist  2013;18(4):467-475.
This study investigated factors correlated with cancer-related fatigue before surgery and just before subsequent adjuvant therapy in patients with breast cancer. Results suggest that worsening fatigue after surgery for breast cancer is associated with a decrease in physical functioning and an increase in psychological distress.
Learning Objectives
Describe the effect of worsening fatigue after breast cancer surgery on physical functioning and psychological distress.Better identify women at risk for developing cancer-related fatigue.Direct target interventions to patients most in need.
Purpose.
Fatigue is one of the most frequent symptoms in patients with cancer. However, the precise determinants of fatigue are still unknown. This study was conducted to investigate factors correlated with cancer-related fatigue before surgery and just before subsequent adjuvant therapy.
Methods.
Patients completed the Multidimensional Fatigue Inventory (MFI-20), the European Organization for Research and Treatment of Cancer 30-item quality-of-life questionnaire before and after surgery, the Trait Anxiety Inventory and the Life Orientation Test before surgery, and the State Anxiety Inventory before the start of adjuvant therapy. Multiple regression analysis of determinants of change in MFI-20 total score after surgery was conducted.
Results.
A series of 466 eligible patients with stage I–III breast cancer with planned surgery were recruited. An increase in MFI-20 total score after surgery was significantly correlated with higher preoperative fatigue and lower role functioning before surgery; a decrease in role functioning, physical functioning, and cognitive functioning after surgery; an increase in insomnia after surgery; and a higher state anxiety after surgery. Disease stage, lymph node metastases, surgical procedure, and demographic characteristics (e.g., age, marital status, having children, educational level) were not correlated with fatigue in multivariate analysis.
Conclusion.
These results suggest that worsening fatigue after surgery for breast cancer is associated with a decrease in physical functioning and an increase in psychological distress rather than with the cancer characteristics. Therefore, screening measures should be implemented at the time of diagnosis—before starting treatment—to identify psychologically vulnerable patients and to offer them professional support.
doi:10.1634/theoncologist.2012-0300
PMCID: PMC3639535  PMID: 23404818
21.  Impact of a Home-Based Walking Intervention on Outcomes of Sleep Quality, Emotional Distress, and Fatigue in Patients Undergoing Treatment for Solid Tumors 
The Oncologist  2013;18(4):476-484.
In this study, the impact of a home-based walking intervention during cancer treatment was evaluated. Patients who exercised during cancer treatment experienced less emotional distress than those who were less active. Exercise was also associated with less fatigue and more vigor.
Learning Objectives
Describe the benefits and limited risks of a low-cost, home-based exercise program.Impart to patients information on an easily implemented, sustainable, at-home exercise intervention.
Purpose.
Exercise use among patients with cancer has been shown to have many benefits and few notable risks. The purpose of this study was to evaluate the impact of a home-based walking intervention during cancer treatment on sleep quality, emotional distress, and fatigue.
Methods.
A total of 138 patients with prostate (55.6%), breast (32.5%), and other solid tumors (11.9%) were randomized to a home-based walking intervention or usual care. Exercise dose was assessed using a five-item subscale of the Cooper Aerobics Center Longitudinal Study Physical Activity Questionnaire. Primary outcomes of sleep quality, distress, and fatigue were compared between the two study arms.
Results.
The exercise group (n = 68) reported more vigor (p = .03) than control group participants (n = 58). In dose response models, greater participation in aerobic exercise was associated with 11% less fatigue (p < .001), 7.5% more vigor (p = .001), and 3% less emotional distress (p = .03), after controlling for intervention group assignment, age, and baseline exercise and fatigue levels.
Conclusion.
Patients who exercised during cancer treatment experienced less emotional distress than those who were less active. Increasing exercise was also associated with less fatigue and more vigor. Home-based walking is a simple, sustainable strategy that may be helpful in improving a number of symptoms encountered by patients undergoing active treatment for cancer.
doi:10.1634/theoncologist.2012-0278
PMCID: PMC3639536  PMID: 23568000
Exercise; Walking; Emotional distress; Fatigue; Vigor; Cancer treatment
22.  Breast Cancer Genomics: Challenges in Interpretation and Application 
The Oncologist  2013;18(4):e11-e12.
doi:10.1634/theoncologist.2013-0116
PMCID: PMC3639537  PMID: 23633449
23.  Debate: The Biology of Breast Cancer in Young Women Is Unique 
The Oncologist  2013;18(4):e13-e15.
doi:10.1634/theoncologist.2013-0118
PMCID: PMC3639538  PMID: 23633450
24.  Geographic Tongue Induced by Angiogenesis Inhibitors 
The Oncologist  2013;18(4):e16-e17.
doi:10.1634/theoncologist.2012-0320
PMCID: PMC3639539  PMID: 23576484
Geographic tongue; Bevacizumab; Sunitinib; Sorafenib; Benign migratory glossitis
25.  In Reply 
The Oncologist  2013;18(4):e18.
This reply to the letter by Hubiche et al. further discusses the hypothesis that geographic tongue is a novel entity related to bevacizumab therapy.
doi:10.1634/theoncologist.2012-0421
PMCID: PMC3639540  PMID: 23576479

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