AbstractExtramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma that clinicopathologically resembles breast cancer. The prognosis of metastatic EMPD is poor. Although several chemotherapies have been tried, the effects are temporary; better drugs and combinations are required.In the present study, we retrospectively analyze the efficacy and safety of combination of cisplatin, epirubicin, and paclitaxel in five metastatic EMPD cases. The efficacy was better than that for previously reported regimens: 80% partial responses, including two patients who were refractory to taxane‐ and/or platinum‐based regimens. In terms of safety, four patients who were able to continue treatment exhibited acceptable tolerability.This is the first regimen to combine taxane and anthracycline. When treating breast cancer, anthracycline is regarded as the key cytotoxic agent, and anthracycline in combination with taxane constitutes a key chemotherapeutic regimen. Given our results, we speculate both drugs are critical chemotherapeutic agents for the treatment of metastatic EMPD.
Leptomeningeal Carcinomatosis in Chronic Lymphocytic Leukemia: A Case Report and Review of the Literature
AbstractLeptomeningeal disease is a rare complication of chronic lymphocytic leukemia (CLL). We report a case of leptomeningeal disease in CLL with a complete clinical response and clearance of cerebral spinal fluid (CSF) after treatment with ibrutinib and intrathecal rituximab. In a comprehensive review of the published literature since 1976, we found 136 cases of CLL with leptomeningeal spread. We found that leptomeningeal disease in patients with CLL responds favorably to treatment in most cases and is associated with longer overall survival than is expected for other cancers. Clearance of CSF is associated with improved survival. Treatment with rituximab and ibrutinib is more frequently associated with complete response compared with older agents.Implications for Practice.The incidence of leptomeningeal CLL is more common than previously described and can be recognized by attention to certain symptoms and signs. This case presentation and literature review reveals that, in many cases, leptomeningeal lymphomatosis is reversible with the use of rituximab and ibrutinib. The authors show a survival benefit associated with treating to cerebral spinal fluid (CSF) clearance by cytology and compare outcomes with various treatment strategies, focusing on novel agents. Now that there is effective therapy for leptomeningeal lymphoma in CLL, the importance for oncologists to recognize this neurologic complication has become clear.
Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada
AbstractBiosimilar filgrastims are primarily indicated for chemotherapy‐induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%–40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital‐only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the “rebate trap” with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered.Implications for Practice.We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing “rebate traps” where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.
Clinical Activity of Nivolumab for Human Papilloma Virus‐Related Juvenile‐Onset Recurrent Respiratory Papillomatosis
AbstractBackground.Juvenile‐onset recurrent respiratory papillomatosis (JO‐RRP) is a human papilloma virus‐mediated progressive benign neoplasm that affects children and young adults. Primary management consists of regular surgical debulking to maintain airway patency and vocal function. Like condyloma acuminata, JO‐RRP is associated with immune dysregulation, and T cells isolated from papillomas express an anergic phenotype. Therefore, we hypothesized that programmed death protein 1 axis inhibition could stabilize tumor growth.Materials and Methods.We treated two patients with refractory JO‐RRP using nivolumab, with the primary objective of assessing clinical activity. We explored baseline papilloma features using immunohistochemistry and comprehensive genomic profiling.Results.Both patients experienced symptomatic improvement, and interval laryngoscopies revealed a reduction in papillomatosis burden. One patient has not required subsequent surgical debridement for almost 2 years. On pathologic examination of pretreatment papillomas from both cases, infiltrating T cells were evident in the papilloma stroma, and papilloma programmed death ligand 1 expression was absent. Papilloma mutational load ranged between three and six mutations per megabase for each case. From on‐treatment biopsy tissue, a higher amount of intraepithelial T cells and programmed death ligand 1 expression were detected in the papilloma.Conclusion.Nivolumab appears to have promising activity in JO‐RRP, and further clinical investigation with more patients in clinical trials is warranted.Implications for Practice.To the authors' knowledge, this article is the first report describing clinical activity with a programed cell death‐1 (PD‐1) inhibitor to treat a rare but detrimental type of respiratory tract epithelial neoplasm that afflicts young adults. Two patients were treated, and tumor features, such as mutational load, were examined with the intent to stimulate future hypotheses for translational research. The safety and activity of PD‐1 inhibitors in this population still need to be corroborated in clinical trials and should not yet be adopted into clinical practice.
AbstractBackground.The benefit of repeat lumpectomy for ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery is currently inconclusive.Materials and Methods.Patients with IBTR with definitive surgery were identified in the Surveillance, Epidemiology, and End Results registry between 1973 and 2013. The effect of different IBTR surgeries on overall and cancer‐specific mortality was assessed using risk‐adjusted Cox proportional hazard regression modeling and stratified propensity score‐matching analysis (PSMA).Results.Of the 5,098 patients with IBTR, 4,048 (79.4%) women underwent mastectomy and 1,050 (20.1%) underwent repeat lumpectomy. In multivariable Cox regression analysis, repeat lumpectomy was associated with increased overall mortality (hazard ratio for death [HR], 1.522; 95% confidence interval [CI], 1.317–1.759; p < .001) and cancer‐specific mortality (HR, 1.666; 95% CI, 1.319–2.105; p < .001). Similar HRs were derived from the PSMA cohort. However, we found no significant difference in overall mortality for women who underwent repeat lumpectomy followed by radiation therapy (RT) compared with that for those who underwent mastectomy. Moreover, patients with IBTR with small tumors (≤1 cm) who underwent repeat lumpectomy with RT rather than without had similar overall and cancer‐specific survival rates to those who underwent mastectomy.Conclusion.Our investigation suggests that compared with mastectomy, repeat lumpectomy for IBTR is associated with higher overall and cancer‐specific mortality under real‐world observational conditions. Furthermore, repeat lumpectomy with RT is equivalent to mastectomy with respect to overall mortality and may influence treatment decision making for patients with small IBTR.Implications for Practice.Although mastectomy has been regarded as the standard treatment for ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery, many patients diagnosed with small and early‐detected recurrent tumor might be technically suitable for a less invasive surgical procedure. However, different studies have drawn inconsistent conclusions. The present study is a population‐based analysis, which demonstrated the overall unfavorable impact of repeat lumpectomy over mastectomy on survival outcomes for patients with IBTR. However, patients with small IBTR (≤1 cm) that can tolerate radiation therapy may be the optimal candidates for repeat lumpectomy.
First‐in‐Human Phase I Study of Merestinib, an Oral Multikinase Inhibitor, in Patients with Advanced Cancer
AbstractBackground.The purpose of this nonrandomized, open‐label, phase I study (NCT01285037) was to evaluate the safety and tolerability of merestinib, an oral antiproliferative and antiangiogenic kinase inhibitor, and to determine a recommended phase II dose and schedule for patients with advanced cancer.Materials and Methods.This was a multicenter, nonrandomized, open‐label, phase I study of oral merestinib consisting of six parts: dose escalation (part A), followed by a four‐cohort dose‐confirmation study (part B) and subsequently a four‐part dose expansion and combination safety testing of merestinib with standard doses of cetuximab (part C), cisplatin (part D), gemcitabine and cisplatin (part E), and ramucirumab (part F) in patients with specific types of advanced cancers. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated in all cohorts.Results.The dose escalation, confirmation, and expansion results support the dosing of merestinib at 120 mg once daily, based on acceptable exposure and safety at this dose. One complete response was observed in a patient with cholangiocarcinoma, and three patients with cholangiocarcinoma achieved a partial response. Overall, 60 (32%) of the 186 patients enrolled in the study had a best response of stable disease.Conclusion.This study demonstrates that merestinib has a tolerable safety profile and potential anticancer activity and warrants further clinical investigation.Implications for Practice.Merestinib treatment in patients with advanced cancer demonstrated an acceptable safety profile and potential antitumor activity, supporting its future development in specific disease populations as a monotherapy and/or in combination with other therapies.
AbstractBackground.Our goal was to determine (a) the prevalence of multimorbidity and polypharmacy in patients with cancer and (b) the prevalence, predictability, and preventability of adverse drug reactions (ADRs) causing/contributing to hospitalization.Materials and Methods.We conducted a 12‐month prospective observational study of patients aged ≥16 years admitted to an oncology center. Older adults were aged ≥70 years.Results.We enrolled 350 patients: 52.3% (n = 183) female, mean age 63.6 years (SD 12.1), 36.6% (n = 121) aged ≥70 years. Multimorbidity (≥2 conditions) was identified in 96.9%; 68% had ≥5 conditions. The median number of medications was 6 (interquartile range [IQR] 4–8); 47% were prescribed ≥6 medications and 11.4% ≥11 medications. Older adults had higher numbers of comorbid conditions (7 [IQR 5–10] vs. 5 [IQR 3–7]) and were prescribed more medications (median 7 [IQR 4–9] vs. 4 [IQR 2–7]). ADRs caused/contributed to hospitalization in 21.5% (n = 75): 35.8% (n = 72) of emergency admissions and 4.7% (n = 3) of elective admissions. The most common ADRs were neutropenia with infection (25.3%), dyspepsia/nausea/vomiting (20%), and constipation (20%). Causative medications included systemic anticancer therapies (SACTs; 53.3%), opioids (17.3%), corticosteroids (6.7%), and nonsteroidal anti‐inflammatory drugs (5.3%). ADR prevalence was similar in older and younger adults secondary to SACTs (8.3% vs. 13.1%), non‐cancer medications (10.7% vs. 8.3%), and both (0% vs. 1.3%). ADRs were predictable in 89.3% (n = 67), definitely avoidable in 29.3% (n = 22), and possibly avoidable in 33.3% (n = 25). No association was identified between ADRs and age, gender, daily medication number, length of stay, or death. No ADR predictor variables were identified by logistic regression.Conclusion.More than 21% of admissions to an oncology service are ADR‐related. ADRs are caused by both SACTs and non‐cancer‐specific medications. The majority are predictable; ≥60% may be preventable. Patients with cancer have high levels of multimorbidity and polypharmacy, which require vigilance for related adverse outcomes.Implications for Practice.A diagnosis of cancer often occurs in patients with multimorbidity and polypharmacy. Cancer can cause an altered physiological environment, placing patients at risk of drug‐drug interactions, drug‐disease interactions, and adverse drug reactions (ADRs). This study identified that ADRs caused or contributed to one in five hospital admissions of patients with cancer. ADRs were caused by systemic anticancer therapies (SACTs) in 53.3% of cases and non‐cancer medications in 45.4% of cases, and a combination of both in 1.3%. ADRs occurred in similar frequencies in older and younger patients secondary to SACTs (8.3% vs. 13.1%, p = .295), non‐SACTs (10.7% vs. 8.3%, p = .107), and a combination of both (0% vs. 1.3%, p = .240). The majority of ADRs were predictable (89.3%) and potentially preventable (62.6%). These findings support the need for increased awareness of medication‐related adversity in patients with cancer and interventions to minimize their occurrence, thus supporting the American Society of Clinical Oncology guidelines that recommend adults ≥65 years of age receiving chemotherapy have geriatric assessment to identify medical and medication issues.
AbstractBackground.Enrichment of patients based on molecular biomarkers is increasingly used in early phase clinical trials. Molecular profiling of patients with advanced cancers can identify specific genomic alterations to inform decisions about investigational treatment(s). Our aim was to evaluate the outcomes of new patient referrals to a large academic solid tumor phase I clinical trial program after the implementation of molecular profiling.Materials and Methods.Retrospective chart review of all new referrals to the Princess Margaret Cancer Centre (PM) phase I clinic from May 2012 to December 2014. Molecular profiling using either MALDI‐TOF hotspot mutation genotyping or targeted panel DNA sequencing was performed for patients at PM or community hospitals through the institutional IMPACT/COMPACT trials.Results.A total of 971 new patient referrals were included for this analysis. Twenty‐seven percent of referrals assessed in clinic were subsequently enrolled in phase I trials. Of all new referrals, 41% had prior molecular profiling, of whom 11% (n = 42) were enrolled in genotype‐matched trials. Patients with prior molecular profiling were younger, more heavily pretreated, and had more favorable Princess Margaret Hospital Index (PMHI) scores. Eastern Cooperative Oncology Group (ECOG) performance status 0–1 (p = .002), internal referrals within PM (p = .002), and PMHI (p ≤ .001) were independently associated with successful trial enrollment in multivariable analysis.Conclusion.Although nearly half of new patients referred to a phase I clinic had prior molecular profiling, the proportion subsequently enrolled into clinical trials was low. Prior molecular profiling was not an independent predictor of clinical trial enrollment.Implications for Practice.The landscape of oncology drug development is evolving alongside technological advancements. Recently, large academic medical centers have implemented clinical sequencing protocols to identify patients with actionable genomic alterations to enroll in therapeutic clinical trials. This study evaluates patient referral and enrollment patterns in a large academic phase I clinical trials program following the implementation of a molecular profiling program. Performance status and referral from a physician within the institution were associated with successful trial enrollment, whereas prior molecular profiling was not an independent predictor.
Evaluation of Miracle Mouthwash plus Hydrocortisone Versus Prednisolone Mouth Rinses as Prophylaxis for Everolimus‐Associated Stomatitis: A Randomized Phase II Study
AbstractBackground.Mammalian target of rapamycin (mTOR) inhibitor‐associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid‐based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus.Materials and Methods.This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor‐positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1–2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks.Results.A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% (n = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse‐related toxicity.Conclusion.Prophylactic use of steroid‐containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse.Implications for Practice.This prospective phase‐II study showed that two steroid‐containing mouthrinses substantially reduced incidences of all‐grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose‐delays and/or dose‐reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy.Prophylactic use of steroid mouth rinse provides a cost‐effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor‐associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor.
AbstractBackground.Current guidelines include the use of adjuvant oxaliplatin in clinical stage II or III rectal adenocarcinoma. However, its efficacy is supported by a single phase II trial. We aimed to examine whether oxaliplatin confers survival benefit in this patient population.Methods.Using the National Cancer Database (2006–2013) we identified 6,868 individuals with clinical stage II or III rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy. We used multivariate Cox regression to evaluate survival differences according to treatment intensity and change from clinical to pathological stage.Results.We demonstrated an association with improved overall survival with the use of doublet adjuvant chemotherapy in pathological stage III rectal adenocarcinoma (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67–0.92). This association was confirmed in patients with clinical stage III and subsequent pathological stage III disease (HR, 0.69; 95% CI, 0.57–0.83) and was not observed in patients who progressed from clinical stage II to pathological stage III disease. Doublet adjuvant chemotherapy was not associated with improved overall survival in patients with pathological stage 0 or I disease, regardless of their clinical stage.Conclusion.Adjuvant oxaliplatin following neoadjuvant chemoradiotherapy in rectal adenocarcinoma was confirmed in patients with clinical stage III and subsequent pathological stage III disease. Omission of oxaliplatin can be considered in pathological complete response or pathological stage I disease.Implications for Practice.Current guidelines include the use of oxaliplatin as part of adjuvant chemotherapy (AC) in patients with clinical stage II or III rectal adenocarcinoma (RAC). However, its efficacy is supported only by a single phase II trial. This study found an association with improved overall survival with the use of doublet AC in patients diagnosed with clinical stage III and subsequent pathological stage III, and not in patients with pathological stage 0 or I, regardless of their clinical stage. Therefore, omission of oxaliplatin can be considered in patients with either pathological complete response or pathological stage I RAC, thereby avoiding oxaliplatin‐induced neuropathy.
AbstractImmune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organization's pharmacovigilance database of individual‐case‐safety‐reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP (n = 68) and HA (n = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab‐based therapy (monotherapy or combination with anti‐programmed death‐1 [PD‐1]) was associated with earlier onset (median 23 vs. 47.5 days, p = .006) than anti‐PD‐1/programmed death ligand‐1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms.Key Points. Immune‐mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune‐mediated hematologic toxicities.Further research is needed to define patient‐specific risk factors and optimal management strategies for hematologic toxicities.
AbstractBackground.There are limited data to predict which novel childhood cancer therapies are likely to be successful. To help rectify this, we sought to identify the factors that impact the success of phase II clinical trials for pediatric malignancies.Materials and Methods.We examined the impact of 24 preclinical and trial design variables for their influence on 132 phase II pediatric oncology clinical trials. Success was determined by an objective assessment of patient response, with data analyzed using Fisher's exact test, Pearson's chi‐square test, and logistic regression models.Results.Trials that evaluated patients with a single histological cancer type were more successful than those that assessed multiple different cancer types (68% vs. 47%, 27%, and 17% for 1, 2–3, 4–7, and 8+; p < .005). Trials on liquid or extracranial solid tumors were more successful than central nervous system or combined trials (70%, 60%, 38%, and 24%; p < .005), and trials of combination therapies were more successful than single agents (71% vs. 28%; p < .005). Trials that added therapies to standard treatment backbones were more successful than trials testing novel therapies alone or those that incorporated novel agents (p < .005), and trials initiated based on the results of adult studies were less likely to succeed (p < .05). For 61% of trials (80/132), we were unable to locate any relevant preclinical findings to support the trial. When preclinical studies were carried out (52/132), there was no evidence that the conduct of any preclinical experiments made the trial more likely to succeed (p < .005).Conclusion.Phase II pediatric oncology clinical trials that examine a single cancer type and use combination therapies have the highest possibility of clinical success. Trials building upon a standard treatment regimen were also more successful. The conduct of preclinical experiments did not improve clinical success, emphasizing the need for a better understanding of the translational relevance of current preclinical testing paradigms.Implications for Practice.To improve the clinical outcomes of phase II childhood cancer trials, this study identified factors impacting clinical success. These results have the potential to impact not only the design of future clinical trials but also the assessment of preclinical studies moving forward. This work found that trials on one histological cancer type and trials testing combination therapies had the highest possibility of success. Incorporation of novel therapies into standard treatment backbones led to higher success rates than testing novel therapies alone. This study found that most trials had no preclinical evidence to support initiation, and even when preclinical studies were available, they did not result in improved success.
Cost of Disease Progression in Patients with Chronic Lymphocytic Leukemia, Acute Myeloid Leukemia, and Non‐Hodgkin's Lymphoma
AbstractIntroduction.To reduce health care costs and improve care, payers and physician groups are switching to quality‐based and episodic or bundled‐care models. Disease progression and associated costs may affect these models, particularly if such programs do not account for differences in disease severity and progression risk within the cohort. This study estimated the incremental cost of disease progression in patients diagnosed with chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), and non‐Hodgkin's lymphoma (NHL) and compared costs among patients with and without progression.Methods.This was a retrospective study using U.S. administrative claims data from commercial and Medicare Advantage health care enrollees with evidence of CLL, AML, and NHL and systemic antineoplastic agent use from July 1, 2006 to August 31, 2014. Outcome measures included disease progression, 12‐month health care costs, and 3‐year cumulative predictive health care costs.Results.Of 1,056 patients with CLL, 514 patients with AML, and 7,601 patients with NHL, 31.1% of patients with CLL, 63.8% of those with AML, and 36.9% of those with NHL had evidence of disease progression. Among patients with CLL and NHL, adjusted and unadjusted health care costs were significantly higher among progressors versus nonprogressors. Per‐patient‐per‐month costs, accounting for variable follow‐up time, were almost twice as high among progressors versus nonprogressors in patients with CLL, AML, and NHL. In each of the three cancer types, the longer disease progression was delayed, the lower the health care costs.Conclusion.Progression of CLL, AML, and NHL was associated with higher health care costs over a 12‐month period. Delaying cancer progression resulted in a substantial cost reduction in patients with all three cancer types.Implications for Practice.Data on the rates and incremental health care costs of disease progression in patients with hematologic malignancies are lacking. This study estimated the incremental costs of disease progression in patients diagnosed with chronic lymphocytic leukemia, acute myeloid leukemia, and non‐Hodgkin's lymphoma and compared health care costs in patients with and without evidence of disease progression in a real‐world population. The data obtained in this study will assist future studies in quantifying the cost impact of decreased progression rates and will inform payers and physician groups about setting rates for episode and bundled payment programs.
Upfront Surgical Resection of Melanoma Brain Metastases Provides a Bridge Toward Immunotherapy‐Mediated Systemic Control
AbstractBackground.Immune checkpoint blockade has systemic efficacy in patients with metastatic melanoma, including those with brain metastases (MBMs). However, immunotherapy‐induced intracranial tumoral inflammation can lead to neurologic compromise, requiring steroids, which abrogate the systemic efficacy of this approach. We investigated whether upfront neurosurgical resection of MBM is associated with a therapeutic advantage when performed prior to initiation of immunotherapy.Material and Methods.An institutional review board‐approved, retrospective study identified 142 patients with MBM treated with immune checkpoint blockade between 2010 and 2016 at Massachusetts General Hospital, of whom 79 received surgery. Patients were classified based on the temporal relationship between immunotherapy, surgery, and development of central nervous system metastases. Overall survival (OS) was calculated from the date of diagnosis of MBM until death from any cause. Multivariate model building included a prognostic Cox model of OS, the effect of immunotherapy and surgical sequencing on OS, and the effect of immunotherapy and radiation sequencing on OS.Results.The 2‐year overall survival for patients treated with cytotoxic T‐lymphocyte antigen 4, programmed death 1, or combinatorial blockade was 19%, 54%, and 57%, respectively. Among immunotherapy‐naïve melanoma brain metastases, surgery followed by immunotherapy had a median survival of 22.7 months (95% confidence interval [CI], 12.6–39.2) compared with 10.8 months for patients treated with immunotherapy alone (95% CI, 7.8–16.3) and 9.4 months for patients treated with immunotherapy followed by surgery (95% CI, 4.1 to ∞; p = .12). On multivariate analysis, immunotherapy‐naïve brain metastases treated with immunotherapy alone were associated with increased risk of death (hazard ratio, 1.72; 95% CI, 1.00–2.99) compared with immunotherapy‐naïve brain metastases treated with surgery followed by immunotherapy.Conclusion.In treatment‐naïve patients, early surgical resection for local control should be considered prior to commencing immunotherapy. A prospective, randomized trial comparing the sequence of surgery and immunotherapy for treatment‐naïve melanoma brain metastases is warranted.Implications for Practice.In this retrospective study of 142 patients with melanoma brain metastases treated with immune checkpoint blockade, the development of melanoma brain metastases following immunotherapy was associated with decreased survival compared with diagnosis of immunotherapy‐naïve brain metastases. The benefit of surgical intervention was seen in immunotherapy‐naïve brain metastases in contrast to brain metastases that developed on immunotherapy. These results suggest that upfront local control with surgery for immunotherapy‐naïve melanoma brain metastasis may provide a bridge toward immunotherapy‐mediated systemic control.
AbstractIntroduction.To reduce health care costs and improve care, payers and physician groups are piloting value‐based and episodic or bundled‐care payment models in oncology. Disease progression and associated costs may affect these models, particularly if such programs do not account for disease severity and progression risk across patient populations. This study estimated the incremental cost of disease progression in patients diagnosed with metastatic breast cancer (mBC), colorectal cancer (mCRC) and lung cancer (mLC) and compared costs among patients with and without progression.Methods.This was a retrospective study using U.S. administrative claims data from commercial and Medicare Advantage health care enrollees with evidence of mBC, mCRC, and mLC and systemic antineoplastic agent use from July 1, 2006, to August 31, 2014. Outcome measures included disease progression, 12‐month health care costs, and 3‐year cumulative predictive health care costs.Results.Of 5,709 patients with mBC, 3,707 patients with mCRC, and 5,201 patients with mLC, 56.8% of patients with mBC, 58.1% of those with mCRC, and 80.3% of those with mLC patients had evidence of disease progression over 12 months. Among patients with mBC and mCRC, adjusted and unadjusted health care costs were significantly higher among progressors versus nonprogressors. Per‐patient‐per‐month costs, which accounted for variable follow‐up time, were almost twice as high among progressors versus nonprogressors in patients with mBC, mCRC, and mLC. In each of the three cancer types, delays in progression were associated with lower health care costs.Conclusion.Progression of mLC, mBC, and mCRC was associated with higher health care costs over a 12‐month period. Delayed cancer progression was associated with substantial cost reductions in patients with each of the three cancer types.Implications for Practice.Data on the rates and incremental health care costs of disease progression in patients with solid tumor cancers are lacking. This study estimated the incremental costs of disease progression in patients diagnosed with lung cancer, breast cancer, and colorectal cancer and compared health care costs in patients with and without evidence of disease progression in a real‐world population. The data obtained in our study quantify the economic value of delaying or preventing disease progression and may inform payers and physician groups about value‐based payment programs.
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