Anna Klimczak

The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study

BackgroundGastrointestinal stromal tumors (GIST) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM) or sunitinib (SU). Arterial hypertension (AH) is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+) GIST patients after IM failure.MethodsWe identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2nd line treatment). Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 genes.ResultsOne year progression-free survival (PFS; calculated from the start of SU) rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH vs. 22% (median 17 weeks) in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0.015, respectively).ConclusionsWe confirmed that many advanced GIST patients benefit from SU therapy with OS > 1.5 year. Primary tumor KIT/PDGFRA genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS.NoteThe preliminary data of this study were presented during Annual Meeting of American Society of Clinical Oncology, 4-8 June 2011 and Connective Tissue Oncology Society Meeting, 26-28 October 2011 in Chicago, IL.

Long-term results of therapy with sunitinib in metastatic alveolar soft part sarcoma.

Background Alveolar soft part sarcoma (ASPS) is a rare, highly vascularized soft tissue sarcoma characterized by a high frequency of metastatic disease and resistance to classical chemotherapy. The purpose of our analysis was to assess long-term sunitinib activity in the treatment of metastatic ASPS. Patients and Methods Between 2009 and 2015, 15 patients were diagnosed with metastatic ASPS and received therapy with sunitinib at initial continuous daily dosing of 37.5 mg. Median age was 32 years. The primary tumor sites were lower extremities (8), trunk-retroperitoneum/pelvis (2), upper extremity (3) and other (2). All patients had unresectable disease (primary or relapse in the form of metastases to the lungs ± bones). Five patients received systemic therapy before initiating sunitinib. Median follow-up from start of sunitinib was 38 months (range 5-69 months). Results At the time of analysis 4 patients continue therapy and 9 are still alive. Six patients had RECIST partial remission as best response, 8 had stable disease, and 1 had disease progression. The median progression-free survival was 19 months, with 86% of patients being free of progression at 6 months. Median overall survival was 56 months; the 5-year overall survival rate was 49%. Five patients were treated with sunitinib longer than 2 years. All patients experienced some side effects: 8 patients (53%) had CTCAE grade 3/4 toxicity, 7 patients required dose reduction. The most common toxicities were neutropenia, thrombocytopenia, hypothyroidism, arterial hypertension, and hand-foot syndrome. Conclusions Our analysis confirms the long-term efficacy of sunitinib in patients with advanced ASPS.

Effective treatment of recurrent, advanced dermatofibrosarcoma protuberans by electrochemotherapy

ejd.2013.1992 Auteur(s) : Katarzyna Wiater1 wiater.katarzyna@gmail.com, Marcin Zdzienicki1, Tadeusz Morysinski1, Hanna Kosela1, Anna Klimczak1, Mariusz Obrebski2, Konrad Ptaszynski3, Piotr Rutkowski1 1 Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center, Roentgena Str. 5, 02-781 Warsaw, Poland 2 Department of Surgery, Regional Hospital Plock, Poland 3 Department of Pathology, The Medical Center of Postgraduate Education, Warsaw, Poland In April [...]

Blood neutrophil-to-lymphocyte ratio is associated with prognosis in advanced gastrointestinal stromal tumors treated with imatinib

Introduction: Neutrophil-to-lymphocyte ratio (NLR) was shown to be prognostic in several solid malignancies. There are limited data about predictive/prognostic value of NLR during targeted therapy of patients with advanced gastrointestinal stromal tumors (GIST). The aim of this study was to asses a clinical value of this ratio in patients with advanced GIST. Methods: Between 2001 and 2016, 385 patients with metastatic/unresectable GIST treated initially with imatinib were included in the analysis. In all patients, the NLR was assessed at the baseline, after 3 months of treatment, and upon disease progression (or last observation). The cutoff values for NLR were set at 2.7 and 5.4. Kaplan-Meier survival probability estimation with log-rank test and Cox proportional hazards model were used for analysis. Results: Median progression-free survival (PFS) on imatinib treatment was 44.8 months, 5-year rate 43%; median overall survival (OS) 87.2 months, 10-year rate 36.3%. NLR >2.7 at baseline was significantly associated with poorer OS and PFS: median OS was 89.3 months (95% confidence interval [CI] 80.2-115) for NLR ratio ≤2.7 vs 59.4 months (95% CI 48.6-82) for NLR >2.7 (p < .001); median PFS was 59.4 vs 32.7 (p < .001), respectively. In multivariate model adjusted for mitotic index and driver mutation in the tumor (KIT exon 11 mutation versus other), NLR ratio was proven to be statistically significant (hazard ratio 1.09; 95% CI 1.01-1.19; p = .030). Among patients with disease progression, NLR >2.7 assessed at the third month of treatment was linked with significantly shorter median time to progression (7.5 vs 19 months). Conclusions: Our results demonstrate the usefulness of NLR as a prognostic and predictive marker as well as a marker for treatment monitoring in patients with advanced GIST treated with imatinib.

Treatment outcomes in older patients with advanced gastrointestinal stromal tumor (GIST)

BACKGROUND The aim of the study was to analyze the treatment results of advanced GIST in the largest, homogenous series of older patients. METHODS Between 2001 and 2016, 686 patients with metastatic/unresectable GIST were treated initially with imatinib and 656 were included in the analysis. Subsequently 232 patients were treated with sunitinib after imatinib failure. We have analyzed the outcomes of patients who have been treated with the tyrosine kinase inhibitor at the age ≥ 70 years and compared to control group of patients younger than 70 years old. RESULTS In the group of patients treated with imatinib, 139 (21%) started therapy at the age of at least 70 years (median age of the entire cohort: 60). Median progression-free survival (PFS) on 1st line imatinib did not differ between patients ≥70 yo (years old) and < 70yo (38.5 vs 44.9 months), but median overall survival (OS) was significantly better for younger patients (81 months vs. 50; p = 0.0001; although disease-specific survival - DSS was similar). Distribution of primary tumor mutational status was generally similar in older and younger patients. Permanent dose reduction (300-100 mg/day) was required for 23 patients (16.9%) in the older group and was significantly more frequent as compared to younger patients (5%). Drug-related adverse events were mainly of grades 1/2, but grade 3/4 toxicity occurred more frequently in older (14.7%) than in younger patients (3.8%). Similarly in group of patients treated with second-line sunitinib median PFS and DSS were comparable in groups of patients ≥70 yo (n = 55) and < 70yo (9.7 months vs 10.3 months; p = 0.7, and 21.5 vs 22.9 months). >40% of patients in both groups required dose adjustments to 37.5-25 mg daily. CONCLUSIONS Our study confirms that current therapy of advanced GIST with tyrosine kinase inhibitors (both in 1st and 2nd line) in older patients enable to achieve the similar disease control rate and final outcomes as in younger patients, but it demands close cooperation of experienced oncologist with patients for dose modifications and side effects management. Limitation of our study is that the patients did not undergo a comprehensive geriatric assessment, what might be helpful for personalized management of patients. Nevertheless, we confirm that older patients with GIST should not receive less treatment irrespective of comorbidities.

The analysis of the long-term outcomes of sorafenib therapy in routine practice in imatinib and sunitinib resistant gastrointestinal stromal tumors (GIST)*

Aim of the study was to analyze the outcome of treatment and factors predicting results of sorafenib therapy in inoperable/metastatic CD117-positive GIST patients after failure on imatinib and sunitinib. Material and methods We identified 60 consecutive patients (40 men, 20 women) with advanced inoperable/metastatic GIST after failure on at least imatinib and sunitinib treated in one sarcoma center with sorafenib at initial dose 2 × 400 mg daily in 2007–2015 (in 56 cases it was 3rd line therapy). Median follow-up time was 39 months. Results One year progression-free survival (PFS; calculated from the date of the start of sorafenib to disease progression) rate was 23% and median PFS = 7.7 months. The median overall survival (OS) was 13.5 months calculated from sorafenib start (1-year OS rate = 57%) and 7 years from imatinib start. Three patients (5%) had objective partial responses to therapy, 31 patients (52%) had stabilization of disease > 4 months. Primary tumor mutational status was known in 43 cases (73%), but we have not identified the differences in PFS between tumors carrying different KIT/PDGFRA mutations. The most common adverse events were: diarrhoea, hand and foot syndrome, fatigue, loss of weight and skin reactions; grade 3–5 toxicity occurred in 35% of patients. 23 patients required sorafenib dose reductions due to AEs. Conclusions We confirmed that many advanced GIST patients benefit from sorafenib therapy after imatinib/sunitinib failure with OS > 1 year.

Efficacy of regorafenib in gastrointestinal stromal tumors (GISTs) – a case report.

The systemic treatment of gastrointestinal stromal tumors is based on targeted therapies such as imatinib, sunitinib, sorafenib or regorafenib. The important treatment option is recruitment onto clinical trials specially in late stage of disease. The presented case concerns the 62 year-old woman with metastatic GIST. In 2008 after gastrectomy she was recruited to EORTC 62024 clinical trial. Here she was randomly assigned to the observational arm. In 2009 due to non-resectable recurrence, the imatinib therapy was started and continued until 2014. At this time, she experienced disease progression so imatinib dose was doubled, and due to further progression – she received sunitinib. The tolerance of imatinib was satisfactory, but after sunitinib therapy - the dose modification was necessary due to toxicity at grade CTC3. In 2015, because of the further progression she received sorafenib over 12 months, and next re-treatment with imatinib and chemotherapy according to the ADIC with 4 months of response. Considering patient’s good performance status regardless the fifth line of treatment she was proposed the regorafenib treatment. After the first course, patient reported a definite improvement of quality of life and pain control. The main complications was the hand-foot syndrome and diarrheas (grade CTC2). The best response was partial response, nowadays patient disease is stable. In the case of further progression a clinical trial will be proposed. Conclusions: In GIST patients, regorefenib as an single agent administered after progression on imatinib, sunitinib and sorafenib is effective and well tolerated treatment leading into clinical and radiological response.

The efficacy and safety of trabectedin in patients with advanced liposarcomas and leiomyosarcomas (L-sarcomas)

Wstep . Trabektedyna jest lekiem zarejestrowanym do leczenia chorych z rozpoznaniem zaawansowanych miesakow tkanek miekkich. Badania wykazaly jej skutecznośc w leczeniu paliatywnym, zwlaszcza w tluszczakomiesakach (LPS — liposarcoma ) i mieśniakomiesaku gladkokomorkowym (LMS — leiomyosarcoma ). Celem badania byla analiza wynikow leczenia trabektedyną pacjentow leczonych w jednym ośrodku. Materialy i metody . Od kwietnia 2008 roku do października 2013 roku leczono trabektedyną 50 pacjentow (23 kobiety, 27 mezczyzn) z rozpoznaniem miejscowo zaawansowanych przerzutowych miesakow tkanek miekkich (20 — LMS, 30 — LPS, w tym 13 myxoid LPS — MLPS). Mediana wieku w momencie leczenia wyniosla 51 lat. Prawie wszyscy chorzy (49/50) otrzymali wcześniejsze leczenie systemowe oparte na doksorubicynie. 14 (28%) pacjentow otrzymywalo trabektedyne w 2. linii leczenia, 23 (46%) w 3. linii, 13 (26%) w > 3. linii. Odpowiedź na leczenie wedlug kryteriow RECIST oceniano co 3 miesiące za pomocą badania tomografii komputerowej (CT). Wyniki . Mediana liczby podanych cykli leczenia wynosila 5 (zakres 2–40); 18 chorych (36%) otrzymalo ≥ 10 cykli. U 4 pacjentow (8%) stwierdzono cześciową odpowiedź, u 23 (46%) stabilizacje choroby (przez minimum 3 miesiące), u 23 (46%) — progresje choroby. Po pol roku leczenia 47% pacjentow bylo wolnych od progresji choroby (PFS — progression-free survival ), wiecej w grupie chorych z rozpoznaniem LPS — 66% w porownaniu z 27% w grupie LMS (p = 0,023). PFS byl istotnie dluzszy u pacjentow otrzymujących trabektedyne w 2. lub 3. linii leczenia (mediana 7 miesiecy) niz > 3. linii leczenia (mediana 2 miesiące) p = 0,038. Mediana przezycia calkowitego (OS — overall survival ) wynosila 13 miesiecy. Stezenie hemoglobiny oraz aktywnośc LDH przy rozpoczeciu leczenia nie mialo wplywu na wyniki terapii. 34 pacjentow otrzymalo kolejne linie leczenia po niepowodzeniu leczenia trabektedyną. W momencie analizy 37 chorych zmarlo. Podtyp histologiczny mial wplyw na OS (p = 0,008), prawie 70% pacjentow z rozpoznaniem MLPS zylo dluzej niz rok. Toksycznośc terapii byla umiarkowana. Nie obserwowano zgonow spowodowanych leczeniem. 30 (60%) pacjentow doznalo jakiejkolwiek toksyczności leczenia, w wiekszości w stopniu 1. i 2. Trzech pacjentow wymagalo redukcji dawki leku. Wnioski . Przeprowadzona analiza potwierdza skutecznośc stosowania trabektedyny w paliatywnym leczeniu u chorych na L-miesaki. Zastosowanie leku pozwala na uzyskanie dlugotrwalej kontroli choroby przy dobrej tolerancji leczenia. Najdluzszy czas calkowitego przezycia stwierdzono w grupie chorych z rozpoznaniem MLPS.

Results for advanced melanoma therapy with vemurafenib in a Polish drug programme

Introduction. Melanoma is a heterogeneous group of tumours with poor prognosis if the disease is metastatic. More than half of patients with melanoma of the skin have detectable mutations in the BRAF gene. Vemurafenib is the BRAF kinase inhibitor used in the treatment of patients with advanced melanoma with the BRAF mutation. This improves time to progression-free survival and overall survival in patients with this diagnosis. The aim of the study was to analyse the results of treatment and safety of vemurafenib in patients treated during the Polish drug programme. Materials and methods .Between October 2013 and April 2015 a total of 189 patients were treated, 90 women and 99 men, who had previously been diagnosed with unresectable/metastatic melanoma with BRAF V600 mutation. Patients received vemurafenib in 960 mg dose twice per day. The estimated progression-free survival, overall survival and adverse events were assessed. For the survival analysis the Kaplan-Meier method and log-rank test (log-rank) for multi-factor analysis were used. Results. In the first evaluation of the effectiveness of treatment, 8 patients (4.3%) had a complete response, 75 patients (39.7%) partial response, 62 patients (32.8%) had stable disease, and 44 patients (23.2%) had progression of the disease. The disease was controlled in 76.7% of patients. After progression during the therapy with vemurafenib 27% of the patients received subsequent lines of systemic therapy. Twenty-eight patients received chemotherapy and 22 patients immunotherapy with ipilimumab. During the last analysis dated 5 September 2015, the median observation time for still living patients was 8 months (range 3–26). Median progression-free survival was 6.7 months. The median overall survival was 12 months. 146 patients (77%) had adverse events, mostly in the form of dermal toxicity of Grades 1 and 2. Thirty-two patients (17%) presented with side effects of the 3rd and 4th grades of toxicity. Two patients had to stop the treatment due to the toxicity. There were no deaths reported due to the toxicity of treatment. Conclusions. The multicentre analysis confirmed the efficacy and safety of vemurafenib in routine clinical practice in a heterogeneous group of advanced melanomas with BRAF mutation. We confirmed the importance of the known prognostic factors for overall survival in this group of patients, such as lactate dehydogenaze activity (LDH) and ECOG performance status. The current survival of patients with the metastatic melanomas with BRAF mutations are longer than those observed in historical groups.