Iwona Ługowska

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.

Follow-up in soft tissue sarcomas

The strategy for the follow-up of soft tissue sarcomas (STS) after therapy is tailored to the individual risk of recurrence and based on efficient rather than sophisticated methods of observation. Along with advances in the treatment of sarcomas, earlier detection of a less advanced and resectable recurrent disease (local or metastasis—especially to the lungs) can prolong patient survival. Since the majority of STS relapses occur within 5 years after treatment (approximately 80 % of metastases to the lung and close to 70 % of local recurrences within the first 2–3 years), in the period between 2 and 3 years after treatment, it is mandatory to follow-up patients every 3 months and perform careful history and physical examination (especially scars after surgery of the primary site) and a chest X-ray. There is no reason to perform other studies in asymptomatic patients (unless the patient reports symptoms). In case of retroperitoneal or intraperitoneal STS (including gastrointestinal stromal tumor), contrast-enhanced computed tomography of the abdomen and pelvis is recommended as the follow-up modality of choice. In this paper we outline the current recommendations for the follow-up strategy.

Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas

BACKGROUND The primary treatment of soft tissue sarcomas (STS) is a radical resection of the tumor with adjuvant radiotherapy. Conventional fractionation of preoperative radiotherapy is 50 Gy in fraction of 2 Gy a day. The purpose of the conducted study was to assess the efficacy and safety of hypofractionated radiotherapy in preoperative setting in STS patients. METHODS 272 patients participated in this prospective study conducted from 2006 till 2011. Tumors were localized on the extremities or trunk wall. Median tumor size was 8.5 cm, 42% of the patients had tumor larger than 10 cm, whereas 170 patients (64.6%) had high grade (G3) tumors. 167 patients (61.4%) had primary tumors. Patients were treated with preoperative radiotherapy for five consecutive days in 5 Gy per fraction, with an immediate surgery. Median follow up is 35 months. RESULTS 79 patients died at the time of the analysis, the 3-year overall survival was 72%. Local recurrences were observed in 19.1 % of the patients. Factors that had a significant adverse impact on local recurrence were tumor size of 10 cm or more and G3 grade. 114 patients (42%) had any kind of treatment toxicity, vast majority with tumors located on lower limbs. 7% (21) of the patients required surgery for treatment of the complications. CONCLUSION In this non-selected group of locally advanced STS use of hypofractionated preoperative radiotherapy was associated with similar local control (81%) when compared to previously published studies. The early toxicity is tolerable, with small rate of late complications. Presented results warrant further evaluation.

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.

Genetic polymorphisms may influence the vertical growth rate of melanoma

Background: Identification of new predictive markers in melanoma is of great clinical importance. This study was aimed to analyze association between selected common variants in the cancer susceptibility genes and melanoma progression at the time of diagnosis. Material and Method: The study included 243 consecutive patients with melanoma. Genotyping was performed using real-time PCR. Results: Our data revealed modest association between xeroderma pigmentosum complementation group D (XPD) codon 312 polymorphism and tumor thickness (as defined by Breslow score; XPD D312N CC: 3.00 ± 3.78mm, CT: 1.71 ± 2.48mm, TT: 2,53 ± 3,24mm, P=0.023). The CT genotype in XPD D312N polymorphism was more frequently represented in non-invasive melanomas compared to deeply penetrating tumors. None of the common SNPs in cyclin dependent kinase inhibitor 2A (CDKN2A), vitamin D receptor (VDR), melanocortin 1 receptor (MC1R) were associated with Breslow depth. Conclusion: These findings suggest that genetic alteration in XPD contributes to melanoma progression and may be a potential diagnostic and molecular prognostic marker.

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.

Soft tissue sarcomas in adults

SOFT TISSUE SARCOMAS.................................................................................................................................................. 182 Epidemiology and aetiology ................................................................................................................................................... 182 Diagnostics .............................................................................................................................................................................. 182 Symptoms and physical examination............................................................................................................................... 182 Imaging studies ................................................................................................................................................................. 182 Pathological assessment ................................................................................................................................................... 183 Prognostic factors and staging ......................................................................................................................................... 184 Treatment ................................................................................................................................................................................ 186 Surgical treatment ............................................................................................................................................................. 186 Adjuvant radiotherapy...................................................................................................................................................... 187 Adjuvant (preoperative or postoperative) chemotherapy ............................................................................................ 188 Treatment of metastatic disease ...................................................................................................................................... 189 Special clinical situations ...................................................................................................................................................... 190 Soft tissue sarcomas of the breast ................................................................................................................................... 190 Uterine sarcomas .............................................................................................................................................................. 190 Fibromatosis (aggressive fibromatosis, desmoid-type fibromatosis) ........................................................................... 190 Rehabilitation .......................................................................................................................................................................... 192 Follow-up after treatment ...................................................................................................................................................... 192 GASTROINTESTINAL STROMAL TUMOURS ................................................................................................................ 194 Epidemiology ........................................................................................................................................................................... 194 Diagnostics .............................................................................................................................................................................. 194 Symptoms and physical examination............................................................................................................................... 194 Imaging studies ................................................................................................................................................................. 194 Pathological assessment ................................................................................................................................................... 194 Treatment ................................................................................................................................................................................ 195 Primary surgical treatment ............................................................................................................................................... 195 Assessment of the risk of relapse and the principles of observation after primary therapy ...................................... 196 Adjuvant therapy .............................................................................................................................................................. 197 Treatment in an advanced stage ...................................................................................................................................... 197 References ................................................................................................................................................................................ 200

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.

Follow-up in melanoma patients

Due to lack of evidence from prospective clinical trials, the diagnostic procedures, their frequency, as well as the length of the follow-up period in cutaneous melanoma patients should be based on the individual risk of disease recurrence, which is strongly dependent on the stage of disease at the time of diagnosis. In the paper we propose the current recommendations for follow-up strategy. Nowadays, new effective treatment options with biological agents justify the closer monitoring of high risk melanoma patients.