For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than ...standard treatment.
We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life.
For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04).
For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life.
The 8
edition UICC/AJCC TNM8 (Tumour, Nodes, Metastasis) melanoma staging system introduced several modifications from the 7
edition (TNM7), resulting in changes in survival and subgroup composition. ...We set out to address the limited validation of TNM8 (stages I-IV) in large population-based datasets.
This retrospective cohort-study included 6,414 patients from the population-based Ontario Cancer Registry diagnosed with cutaneous melanoma between January 1, 2007 and December 31, 2012. Kaplan-Meier curves estimated the melanoma-specific survival (MSS) and overall survival (OS). Cox proportional hazard models were used to estimate adjusted hazard ratios for MSS and OS across stage groups. The Schemper-Henderson measure was used to assess the variance explained in the Cox regression.
In our sample, 21.3% of patients were reclassified with TNM8 from TNM7; reclassifications in stage II were uncommon, and 44.1% of patients in stage III were reclassified to a higher subgroup. Minimal changes in MSS curves were observed between editions, but the stage IIB curve decreased and the stage IIIC curve increased. For TNM8, Stage I (n = 4,556), II (n = 1,206), III (n = 598), and IV (n = 54) had an estimated 5-year MSS of 98.4%, 82.5%, 66.4%, and 14.4%, respectively. Within stage III, IIIA 5-year MSS was 91.7% while stage IIID was 23.5%. HRs indicated that TNM8 more evenly separates subgroups once adjusted for patient- and disease-characteristics. The variance in MSS explained by TNM7 and TNM8 is 18.9% and 19.7%, respectively.
TNM8 performed well in our sample, with more even separation of stage subgroups and a modest improvement in predictive ability compared to TNM7.
ICI therapy has greatly improved patient outcomes in melanoma, but at the cost of immune-related adverse events (irAEs). Data on the chronicity of irAEs, especially in real-world settings, are ...currently limited. We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥ 6 months), transient (resolution over a period < 6 months), or no irAEs. A total of 283 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, fifteen (9.3%) experienced long-term irAEs as their longest-lasting toxicity, thirty-four (21.1%) developed transient irAEs only, and forty-six (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (36.0%) or skin-related (32.4%). Grade 3-4 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still requiring treatment for long-term or permanent irAEs 6 months or more following the completion of ICI therapy, including twenty-four patients on thyroid hormone replacement and twenty-two on oral steroids. ICI treatment was temporarily interrupted for 64 (22.6%) irAEs and permanently discontinued due to irAEs in 38 patients (13.6% of irAEs, 23.6% of patients); additionally, 4 (2.5%) patients died of irAEs. Our findings show that ICI treatment in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients, which should therefore be discussed when obtaining consent for treatment.
•Adjuvant pembrolizumab or nivolumab are effective in cutaneous melanoma.•Ipilimumab is also effective but adverse events are more frequent and severe.•For BRAF v600E/K mutations, dabrafenib plus ...trametinib also improved survival.•Interferon improved survival; benefit is small (3–6%) and it is no longer recommended.•Evidence is insufficient for routine use of adjuvant chemotherapy or vaccines.
Cutaneous melanoma is typically treated with wide local excision and, when appropriate, a sentinel node biopsy. Many patients are cured with this approach but for patients who have cancers with high risk features there is a significant risk of local and distant relapse and death. Interferon-based adjuvant therapy was recommended in the past but had modest results with significant toxicity. Recently, new therapies (immune checkpoint inhibitors and targeted therapies) have been found to be effective in the treatment of patients with metastatic melanoma and many of these therapies have been evaluated and found to be effective in the adjuvant treatment of high risk patients with melanoma. This systematic review of adjuvant therapies for cutaneous and mucosal melanoma was conducted for Ontario Health (Cancer Care Ontario) as the basis of a clinical practice guideline to address the question of whether patients with completely resected melanoma should be considered for adjuvant systemic therapy and which adjuvant therapy should be used.
Immune-related adverse events (iRAEs) are known complications of immune checkpoint inhibitors (ICIs). Early identification and management leads to improved morbidity and mortality. This study seeks ...to address our center's experience with iRAEs in the emergency department (ED).
We performed a retrospective review of patients treated with ICIs in 2018 and 2019 for any indication. All diagnoses of iRAEs were recorded. For all patients who presented to the ED following administration of an ICI, we assessed whether the presenting symptoms were eventually diagnosed as an iRAE. We assessed disposition, time to initiation of corticosteroids and outcomes in these patients.
351 evaluable patients were treated with an ICI, 129 patients (37%) had at least one presentation to the ED, 17 of whom presented with symptoms due to a new iRAE. New iRAE diagnoses were broad, occurred after median 2 cycles, majority irAEs were grade 3 or higher (70.6%), and two patients died due to toxicity. Twelve patients were admitted to the hospital during initial presentation or at follow-up, four required ICU care. All patients required immunosuppressive therapy, and only three were later re-challenged with an ICI. Of the patients who were admitted to the hospital, median time to first dose of corticosteroid was 30.5 h (range 1-269 h).
Patients on ICI have a significant risk of requiring an ED visit. A notable proportion of iRAEs have their first presentation at the ED and often can present in a very nonspecific manner. A standardized approach in the ED at the time of presentation may lead to improved identification and management of these patients.
Immunotherapy has emerged as an effective treatment option for the management of advanced cancers. The effects of these immune checkpoint inhibitors in the older patient population has not been ...adequately assessed.
To understand the impact of aging on CTLA-4 and PDL-1 inhibitors efficacy and immune-related adverse events (irAE) in the context of real-world management of advanced solid cancers.
This retrospective study involved all non-study patients with histologically-confirmed metastatic or inoperable solid cancers receiving immunotherapy at Kingston Health Sciences Centre. We defined ‘older patient’ as age ≥ 75. All statistical analyses were conducted under SPSS IBM for Windows version 24.0.
Study outcomes included immunotherapy treatment response, survival, as well as number, type, and severity of irAEs.
Our study (N = 78) had 29 (37%) patients age <65, 26 (33%) patients age 65–74, and 23 (30%) patients age ≥75. Melanoma, non-small cell lung cancer, and renal cell carcinoma accounted for 70%, 22%, and 8% of the study population, respectively. Distributions of ipilimumab (32%), nivolumab (33%), and pembrolizumab (35%) were similar in the study. The response rates were 28%, 27%, and 39% in the age <65, age 64–74, age ≥75 groups, respectively (P = 0.585). Kaplan-Meier curve showed a median survival of 28 months (12.28–43.9, 95% CI) and 17 months (0–36.9, 95% CI) in the age <65 and age 64–74 groups, respectively; the estimated survival probability did not reach 50% in the age ≥75 group (P = 0.319). There were no statistically significant differences found in terms of irAEs, multiple irAEs, severity of grade 3 or higher, types of irAEs, and irAEs resolution status when comparing between different age groups.
Our results suggest that patients age ≥75 are able to gain as much benefit from immunotherapy as younger patients, without excess toxicity. Our findings suggest that single agent immunotherapy is generally well-tolerated across different age groups with no significant difference in the type, frequency or severity of irAEs. Future studies evaluating aging and combination immunotherapy are warranted.
Some clinical trials have described improved outcomes in patients who develop immune-related adverse events (irAEs) while receiving immune checkpoint inhibitors for advanced melanoma. It is unknown ...if this effect would be seen in a real-world population. This is a single-center retrospective analysis of all patients receiving single-agent PD-1 inhibitor for unresectable stage III or stage IV melanoma between 2012 and 2018. The majority of patients had cutaneous melanoma and were elderly (put in median and range). Totally 33.3% were BRAF mutated and 66.7% had PD-1 inhibitor as first-line treatment for metastatic disease. Also, 22% of patients had brain metastases at presentation. Of the 87 patients included in this analysis, 48 (55%) developed at least one irAE. Dermatologic toxicities were the most common irAE. The median time to develop any irAE was 12 weeks. Only one patient died of immune-related toxicity. Overall survival in the population of patients that had an irAE was significantly greater than those that did not have any toxicity (21.1 vs. 7.5 months; P < 0.001). The development of endocrine toxicity had the strongest correlation with survival as did patient with grade 1 (NCI V.5) toxicity. The development of multiple toxicities did not correlate with survival. In patients with multiple toxicities, the type of irAE that presented initially did not impact the outcome. These findings add to the growing body of literature suggesting an association between irAEs and immune-checkpoint inhibitor efficacy while suggesting that this benefit may depend on the type of toxicity and severity.
Appropriate surveillance of patients with melanoma treated with curative intent is vital to improve patient outcomes. A systematic review was conducted to capture locoregional recurrence and ...metastatic disease, and to evaluate the effectiveness of various surveillance strategies.
MEDLINE, EMBASE, PubMed, Cochrane Database of Systematic Reviews, and National Cancer Institute Clinical Trials Database were searched. Randomized controlled trials (RCTs) and comparative studies reporting at least one patient-related outcome were included. Exclusion criteria included: published in non-English or recruited >20 % or an uncertain percentage of non-target patients without conducting a subgroup analysis for the target patients. This review was registered at PROSPERO (CRD42021246482).
Among 17,978 publications from the literature search, one RCT and five non-randomized comparative studies were included and comprised 4016 patients. The aggregate evidence certainty was low for the RCT and very low for the comparative studies, as assessed by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. For patients with stage IA–IIC melanoma, a reduced follow-up schedule with clinical follow-up strategies alone may be safe and cost-effective. For stage IIC–IIIC patients, at least two serial PET/CT or whole-body CT and brain MRI imaging within a median follow-up of 31.2 months may detect 50 % of recurrences that lead to additional management, such as surgery. PET/CT may have a higher positive predictive value and lower false positive rate compared with CT alone in detecting recurrence in stage I–III patients.
Surveillance protocols should be based on individual risk of recurrence and established best practices when formulating follow-up strategies, as suggested by the studies reviewed. Future high-quality studies are needed to clarify the frequency of imaging follow-up strategies, especially in patients with high-risk stage II melanoma.
•The first journal publication of a systematic review on surveillance in melanoma.•A reduced follow-up schedule may be feasible for stage IA–IIC melanoma.•Annual/biannual CT/PET-CT may be suitable in stage IIIA-D as clinically indicated.•Established individual risk of recurrence is the key to surveillance protocols.
Clinicians may read only the abstract of an article to keep abreast of newly published randomized controlled trials (RCTs). However, discordances have been noticed in summary conclusions in the ...abstracts and the main body of some articles. This article evaluated such discordances in detail.
RCTs of systemic therapy for lung cancer published between 2004 and 2009 were considered. Conclusions in the body of the articles and those in the abstracts were graded by using a 7-point Likert scale; 1 for strong endorsement of the control arm, 4 for a neutral statement, and 7 for strong endorsement of the experimental arm. Conclusions were classified as discordant if the difference in scores was ≥ 2. χ(2) tests and logistic regression were used to identify factors associated with discordance.
From among 114 eligible RCTs identified (90 for non-small-cell and 24 for small-cell lung cancer), 11 (10%) articles presented discordant conclusions in the abstract and in the body of the articles. Discordance was most common when the experimental arm was strongly supported in the abstract but not in the body of the article (nine of 11; 82%); however, the converse was much less common (two of 11; 18%; P < .001). Intraclass correlations for the two reviewers were ≥ 0.9. The discordances were found to be independent of trial-related factors.
Conclusive statements in the abstract can differ from those in the full text. Clinicians should use caution when they consider making changes in their practice on the basis of reading only the abstract of a published RCT.
PDF
![[18F]‐FDG PET/CT in the sta...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0008-543X_1045-7410_1097-0142/small "[18F]‐FDG PET/CT in the staging and management of indolent lymphoma: A prospective multicenter PET registry study")