Discontinuation Of Systemic Therapy Research Articles

Outcomes of Radiotherapy in Oligoprogressive Breast Cancer.

Radiotherapy (RT) shows potential for improving local control in cases of oligoprogressive metastatic breast cancer (mBC). This retrospective analysis aims to evaluate the advantages of RT in such a clinical scenario. We conducted a retrospective analysis including patients with mBC who received radiation therapy (RT) for up to three sites of oligoprogression while continuing systemic therapy. The study took place between January 2014 and December 2021. Our endpoints were progression-free survival after radiotherapy (PFS-AR), the rate of discontinuation of systemic therapy (RDT) at three months post-RT, and overall survival (OS). We used Cox regression analysis to perform multivariate analysis for PFS-AR. Fifty-nine patients met the inclusion criteria. The PFS-AR was 13 months (95% CI 8.5-18.8 months). At three months, the RDT was 3% (two patients). A significant difference in median PFS-AR was observed between patients in the first + second-line group and those in the subsequent line group (p = 0.03). In the multivariate analysis conducted for PFS-AR, the biologically effective dose (BED) with α/β = 4 > 100 Gy emerged as the sole significant variable (p = 0.0017). The median overall survival (OS) was 24.4 months (95% CI 17-24.4 months). This study is the first report on the outcomes of radiotherapy in a cohort of over 50 patients with oligoprogressive metastatic breast cancer (mBC). Our findings emphasize the significant relationship between PFS-AR, the number of ongoing lines of systemic therapy, and the BED of radiotherapy.

Salvage extended surgery after immune-checkpoint inhibitor treatment for advanced non-small cell lung cancer.

We evaluated the surgical outcomes of salvage extended surgery after definitive medical treatment with an immune-checkpoint inhibitor (ICI) for locally advanced or unresectable non-small-cell lung cancer (NSCLC). The subjects of this single-center retrospective analysis were 14 patients who underwent salvage surgery after ICI treatment between May, 2017 and April, 2023 at our institute. We reviewed the comprehensive surgical outcomes, including operative procedures, intraoperative findings, and postoperative morbidities. Overall survival (OS) was calculated using a Kaplan-Meier estimation. The initial clinical stage before medical treatment (c-stage) was stage III in eight patients, stage IV in five patients, and one patient had postoperative lung cancer recurrence. The indications for surgery were as follows: local control for relapse or residual tumor in ten patients and discontinuation of systemic therapy because of treatment-related complications in four patients. The surgical modes were segmentectomy (n = 1), lobectomy (n = 4), bilobectomy (n = 3), pneumonectomy (n = 6), and bronchoplasty (n = 7). Grade 3 or higher postoperative morbidities were observed in six patients, including only one case of 90-day mortality. Our series demonstrated that the surgical outcome of salvage extended surgery after ICI therapy may be positive with careful selection of the procedure and indication.

Psoriasis with facial skin lesions that arose against background of withdrawal of ixekizumab (clinical case)

Facial skin lesions in psoriasis, one of the most common dermatoses, are traditionally considered a relatively rare manifestation of the disease, especially in adult patients, but according to modern data, it is observed in at least 40 % of patients. It is believed that facial skin lesions are more typical for young patients with severe widespread skin lesions, involvement of the nail plates and a protracted course. Localization of rashes on the skin of the face – in a cosmetically and socially significant area – is accompanied by significant impairments in the quality of life of patients. The treatment of facial psoriasis is difficult, and few algorithms have been developed for the management of patients with facial psoriatic lesions. We present a patient with psoriasis involving facial skin that first developed after discontinuation of systemic therapy with an IL-17A inhibitor (ixekizumab). During the follow-up of the patient, it became necessary to re-administer systemic biological therapy with the potential risk of an escape effect. In the article, we discuss the clinical manifestations of facial psoriasis and the impact on the quality of life of patients. A description of the observation of a patient with lesions of the facial skin in severe plaque psoriasis and the role of biological therapy in this direction is presented.

The incidence and predictors of new brain metastases in patients with non-small cell lung cancer following discontinuation of systemic therapy.

Patients with non-small cell lung cancer (NSCLC) metastatic to the brain are living longer. The risk of new brain metastases when these patients stop systemic therapy is unknown. The authors hypothesized that the risk of new brain metastases remains constant for as long as patients are off systemic therapy. A prospectively collected registry of patients undergoing radiosurgery for brain metastases was analyzed. Of 606 patients with NSCLC, 63 met the inclusion criteria of discontinuing systemic therapy for at least 90 days and undergoing active surveillance. The risk factors for the development of new tumors were determined using Cox proportional hazards and recurrent events models. The median duration to new brain metastases off systemic therapy was 16.0 months. The probability of developing an additional new tumor at 6, 12, and 18 months was 26%, 40%, and 53%, respectively. There were no additional new tumors 22 months after stopping therapy. Patients who discontinued therapy due to intolerance or progression of the disease and those with mutations in RAS or receptor tyrosine kinase (RTK) pathways (e.g., KRAS, EGFR) were more likely to develop new tumors (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.81, p = 2.5 × 10-3; HR 2.51, 95% CI 1.45-4.34, p = 9.8 × 10-4, respectively). The rate of new brain metastases from NSCLC in patients off systemic therapy decreases over time and is uncommon 2 years after cessation of cancer therapy. Patients who stop therapy due to toxicity or who have RAS or RTK pathway mutations have a higher rate of new metastases and should be followed more closely.

Durable discontinuation of systemic therapy in patients affected by chronic graft-versus-host disease.

Successful treatment of chronic graft-versus-host disease (GvHD) often requires long-term systemic therapy (ST). Durable discontinuation of ST reflects the resolution of active chronic GvHD. We evaluated the factors associated with durable ST discontinuation, defined as cessation of all ST for ≥12 months, using data from two prospectively followed cohorts from the Chronic GvHD Consortium (n=684). Transplant sources were peripheral blood (89%), bone marrow (6.6%), and cord blood (4.4%) from HLA matched related (37.6%), HLA matched unrelated (45%), and other donor types (18%). Half of the patients received non-myeloablative conditioning. The median time from transplantation to chronic GvHD diagnosis was 7.7 months (range, 1.0-141.3) and the median time from chronic GvHD onset to enrollment into the cohorts was 0.9 months (range, 0.0-12.0). The cumulative incidence estimate of durable ST discontinuation was 32% (95% confidence interval: 28%-37%) at 10 years after enrollment into the cohort. Among patients who discontinued ST, the median time from chronic GvHD diagnosis to durable ST discontinuation was 3.6 years (range, 1.2-10.5). In multivariate analysis, patients who received myeloablative conditioning, had chronic GvHD manifested as moderate/severe lower gastrointestinal involvement, and had a higher (worse) Lee symptom overall score were less likely to attain durable ST discontinuation. In contrast, mild lower gastrointestinal involvement and cord blood (vs. peripheral blood) as the graft source were associated with a greater likelihood of ST discontinuation. Although a minority of patients can discontinue ST permanently, most patients require prolonged ST. Viewing chronic GvHD in this way has implications for management approaches.

RADI-19. The Incidence of New Brain Metastases in Patients with Non-Small Cell Lung Cancer Following Discontinuation of Systemic Therapy

PurposePatients with non-small cell lung cancer (NSCLC) metastatic to the brain increasingly are living longer due to improvements in systemic therapy and local modalities. The risk of new brain metastases when these patients stop systemic therapy is unknown. Recognizing patterns of new tumor occurrence is necessary to determine the frequency of follow-up and the need for further treatment.MethodsWe included patients in a prospective registry who had non-small cell lung cancer (NSCLC) brain metastases, discontinued systemic therapy for at least 90 days, and underwent active surveillance. 63 patients with 73 off-periods were studied. The risk factors for the development of new tumors were determined using Cox regression and multi-state Markov modeling.ResultsThe median time to new brain metastases off systemic therapy was 16.0 months. The probability of developing an additional new tumor at 6, 12, and 18 months was 26%, 40%, and 53%, respectively. There were no additional new tumors 22 months after stopping therapy. Patients who discontinued therapy due to intolerance or progression of the disease and those with mutations in RAS or receptor tyrosine kinase pathways (e.g. KRAS, EGFR) were more likely to develop new tumors (HR: 2.21, 95% CI: 1.25–3.91, p=6.3 x 10–3; HR: 2.03, 95% CI: 1.09–3.77, p=0.026, respectively).ConclusionThe rate of new brain metastases from NSCLC in patients off systemic therapy decreases over time and is uncommon 2 years after cessation of cancer therapy. Patients who stop therapy due to toxicity or who have RAS or receptor tyrosine kinase pathway mutations have a higher rate of new metastases and should be followed more closely.

Safety and Efficacy of Palbociclib (CDK4/6 inhibitor) and Radiotherapy in Metastatic Breast Cancer Patients: Initial Results of a Novel Combination

Palbociclib is a selective CDK4/6 inhibitor approved for metastatic ER+/HER2- breast cancer. Preclinical evidence suggests palbociclib can augment radiotherapy (RT) antitumor effect by 1) preventing cell cycle progression from G1 to the more radioresistant S phase and 2) inhibiting RT-induced DNA double-strand break repair. Despite this potential benefit, clinicians seldom use this combination due to fear that RT may exacerbate palbociclib toxicity, particularly hematologic. The aim of this study is to report the preliminary results of this novel combination in patients with metastatic breast cancer. Records of patients treated with palbociclib at our institution from 2015-2018 were retrospectively reviewed. Patients who received RT for symptomatic metastases concurrently or within 14 days of palbociclib were included. Local treatment effect was assessed by clinical exam and subsequent CT/MRI imaging. Toxicity was graded based on CTCAE v5.0. A total of 16 women (median age: 59.6 years) received palliative RT in close temporal proximity to palbociclib administration. Four patients received palbociclib prior to RT (25.0%), 5 (31.3%) concurrent, and 7 (43.8%) post-RT. The median interval from closest palbociclib use to RT was five (range 0-14) days. The following sites were irradiated in decreasing order of frequency: bone (15 axial skeleton [9-vertebra; 4-pelvis; 2-other]; 3-extremity), brain (4: 3-WBRT & 1-fSRS), and mediastinum (1). The most frequently used RT dose/fractionation by was 30 Gy in 10 fractions. The median follow-up time is 14.7 (range 1.7-38.2) months. Pain relief was achieved in all patients. No radiographic local failure was noted in the 13 patients with evaluable follow-up imaging. Leukopenia, neutropenia, and thrombocytopenia were seen in 4 (25.0%), 5 (31.3%), and 1 (6.3%) patients before RT. Following RT, 5 (31.3%), 1 (6.3%), and 3 (18.8%) patients were leukopenic, neutropenic, and thrombocytopenic, respectively. All but two (Grade 2) hematologic toxicities were Grade 1. No acute or late Grade 2+ cutaneous, neurological, or gastrointestinal toxicities were noted. Toxicity results did not differ based on disease site or palbociclib-RT temporal association. The use of RT in patients receiving palbociclib resulted in minimal Grade 2 and no Grade 3+ toxicities. This preliminary work suggests that symptomatic patients receiving palbociclib may be safely irradiated without discontinuation of systemic therapy. Further studies with larger cohorts are needed to confirm these results.

Abstract PD8-12: Safety and efficacy of palbociclib and radiotherapy in metastatic breast cancer patients: Initial results of a novel combination

Abstract Purpose: Palbociclib is a selective CDK4/6 inhibitor approved for the treatment of metastatic ER+/HER2- breast cancer. Inhibition of CDK4/6 prevents cell cycle progression from G1 to the more radioresistant S phase, raising the possibility of an enhanced therapeutic effect if combined with radiotherapy (RT). Despite this potential benefit, clinicians seldom use this combination due to fear that RT may exacerbate palbociclib toxicity, particularly leukopenia. Our aim is to report the preliminary results of patients with metastatic breast cancer who received RT while receiving palbociclib. Methods: We retrospectively reviewed records of all patients who were treated with palbociclib at our institution from 2015-2018. Patients who received RT for symptomatic metastases concurrently or within 14 days of last drug administration were included in our analysis. Local treatment effect was assessed by clinical exam and subsequent CT or MRI imaging, if applicable. Toxicity was graded based on CTCAE v5.0. Results: A total of 16 females received palliative RT in association with palbociclib. The median age of the treated patients was 59.6 (range 33.3-91.0) years. The median time of closest palbociclib use to RT administration was 5 (range 0-14) days. The following sites were treated in order of frequency: bone (10-axial skeleton [8-vertebra]; 1-ilium), brain (4: 3-WBRT & 1-SRS), and mediastinum (1). RT dose/fractionation for bone was 30 Gy/10 fxn (7), 35 Gy/14 fxn (2), 37.5 Gy/15 fxn (1), and 18 Gy/1 fxn (1). WBRT dose/fractionation was 30 Gy/10 fxn for all patients. SRS brain dose was 25 Gy/5 fxn. The patient treated to the mediastinum received 36 Gy/18 fxn. At most recent follow-up, 12 patients are still living. The median time from RT to last known follow-up or death is 10.3 (range 1.7-29.6) months. Pain relief was achieved in 15 of 16 (93.8%) patients. No radiographic local failure was noted in the 13 patients with evaluable follow-up imaging. The combination of RT and palbociclib was well-tolerated. Grade 1 fatigue, dermatitis, and nausea was noted in 5, 3, and 1 patient, respectively. One patient with WBRT developed Grade 1 headache. Six of 16 patients were leukopenic prior to RT initiation. Following RT, 7 patients were observed to have a drop in WBC count, of which 2 dropped into the leukopenic range. Only a total of 5 patients were leukopenic following RT, of which 3 were leukopenic before receiving RT. No acute or late Grade 2 or higher cutaneous, neurological, gastrointestinal, or hematologic toxicities were noted. Conclusions: The use of RT in patients receiving palbociclib resulted in minimal Grade 1 and no Grade 2+ toxicities, including leukopenia. This treatment can be used safely in symptomatic patients without discontinuation of systemic therapy. Further larger prospective studies with longer follow-up are needed to confirm these results. Citation Format: Chowdhary M, Sen N, Chowdhary A, Usha L, Cobleigh M, Patel KR, Wang D, Barry PN, Rao RD. Safety and efficacy of palbociclib and radiotherapy in metastatic breast cancer patients: Initial results of a novel combination [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD8-12.

Predictors for Permanent Discontinuation of Systemic Immunosuppression in Severely Affected Chronic Graft-Versus-Host Disease Patients

Predicting the duration of systemic therapy in patients with chronic graft-versus-host disease (cGVHD) is of critical clinical importance when counseling patients and for treatment planning. cGVHD characteristics associated with this outcome have not been studied in severely affected patients. The National Institutes of Health (NIH) cGVHD scoring provides a standardized set of organ severity measures that could represent clinically useful and reproducible predictive characteristics. We analyzed 227 previously treated patients most with moderate (n = 54) or severe (n = 170) cGVHD defined by NIH criteria who were prospectively enrolled in a natural history protocol (NCT00092235). Patients received a median of 4 prior systemic therapy regimens and were seen at the NIH for a single time-point visit and were then monitored for survival and ability to discontinue cGVHD systemic therapy. With a median follow-up of 71.1 months, the cumulative incidence of systemic therapy discontinuation was 9.5% (95% confidence interval, 6.0% to 13.9%) at 2 years and 27.7% (95% confidence interval, 20.9% to 34.8%) by 5 years after the initial visit. Factors associated with a higher incidence of immunosuppression discontinuation included lower NIH global severity (P = .019) and lung (P = .030) scores and less extensive deep sclerosis (<37% body surface area, P = .024). Lower patient- and clinician-reported 0 to 10 severity NIH scores and noncyclosporine prophylaxis regimens were also associated with higher incidence of immunosuppression discontinuation (P < .05). In conclusion, we found low success rates for immune suppression discontinuation in previously treated patients who were severely affected with cGVHD. NIH scoring and clinical measures provide new standardized disease-specific tools to predict discontinuation of systemic therapy.

Adverse events associated with discontinuation of the biologics/classic systemic treatments for moderate-to-severe plaque psoriasis: data from the Spanish Biologics Registry, Biobadaderm.

Little is known about the adverse events (AEs) that lead to suspension of systemic treatments for psoriasis in clinical practice. The study aimed to investigate AEs associated with discontinuation of systemic therapy in patients with psoriasis in a clinical setting (Biobadaderm). Multicentre, prospective, cohort study of patients with moderate-to-severe plaque psoriasis receiving systemic therapies from January 2008 to November 2015, in 12 hospitals in Spain. The incidence rate (IR) was used to compare biologics and classic systemic therapies. A total of 4218 courses of treatment were given to 1938 patients. A total of 447 (11%) treatments were discontinued due to AEs. The IR of AE associated with discontinuation of systemic therapies was 13 events/100 patient-years (PY) (95% CI: 12.14-13.93), 9.34 events/100 PY (95% CI: 8.44-10.33) for biologics and 19.67 (95% CI: 17.9-21.6) events/100 PY for classics (P<0.001). Of 810 discontinuation-related AEs, 117 (14%) were serious. The highest IRs were for cyclosporine [49.18/100 PY (95% CI: 41.91-57.72)] and infliximab [26.52/100 PY (95% CI: 20.98-33.51). Ustekinumab presented the lowest IR (2.6/100 PY (95% CI: 1.83-3.69). Observational study with potential selection bias. Biologic therapies are associated with a lower rate of discontinuation-related AEs than are classic therapies in real clinical practice. Ustekinumab showed the lowest incidence.

Adrenal cortex function in asthmatic patients following the discontinuation of chronic therapy with systemic glucocorticosteroids.

To estimate the time it takes for adrenal cortex function in asthmatic patients to return to normal after discontinuation of chronic therapy with systemic glucocorticosteroids (GCs) and to assess the relationship between the duration of the disease, chronic therapy, and the return of the normal adrenal cortex functioning. The study involved 58 asthmatic patients and 31 healthy volunteers (aged 20-69 years). Adrenal cortex function was evaluated with the Synacthen short test, and determining serum and urinary free cortisol levels after 1, 3, 6, 12, 18, and 21 months following the discontinuation of systemic therapy with GCs. A decreased adrenal reserve was observed 1 month after withdrawal of GCs in 50% of the chronically treated patients. Adrenal cortex function returned to normal in 55% of patients within 6 months, in 24% within 12 months, and in 14% within 15 months of discontinuation of systemic GCs administration. A significant positive correlation between the time taken for return to normal adrenal cortex function and duration of the disease and of GCs therapy was found. Symptoms of adrenal failure may develop in about 50% of asthmatic patients. In the majority of patients treated long term with systemic GCs, adrenal cortex function returns to normal within 6 months following discontinuation of GCs. The time of such return depends on the duration of the disease and of therapy with systemic GCs.

Impaired recovery of hypothalamic-pituitary-adrenal axis function and hypoglycemic seizures after high-dose inhaled corticosteroid therapy in a toddler

Corticosteroids are the treatment of choice for children with persistent reactive airway disease. In these patients, taper and discontinuation of systemic therapy is often facilitated by transition to high-dose inhaled corticosteroid treatment. To report a case of impaired hypothalamic-pituitary-adrenal (HPA) axis recovery and adrenal crisis associated with prolonged high-dose inhaled therapy after long-term systemic corticosteroid treatment. A 32-month-old child with severe airway obstruction and wheezing was treated with long-term daily systemic (intravenous and oral) corticosteroids followed by high-dose inhaled fluticasone (440 to 1,320 microg/day). This child presented in adrenal crisis, as evidenced by severe hypoglycemia and seizures, I day after receiving the influenza vaccine. After hydrocortisone replacement and a long taper of fluticasone, the child's adrenal function returned to normal. At the time of seizure, the serum glucose was 1 mg/dL. An electroencephalogram, computed tomographic scan, and magnetic resonance imaging of the brain were normal. Adrenal insufficiency was documented (morning serum cortisol, 0.6 microg/dL; after adrenocorticotrophic hormone stimulation, 8.4 microg/dL). Repeat evaluation 3 weeks after discontinuation of all corticosteroid therapy demonstrated normal HPA axis function. After treatment with long-term systemic steroids, high-dose inhaled corticosteroid therapy can impair recovery of the HPA axis and place patients at risk for adrenal crisis.