The introduction of imatinib to clinical practice revolutionized therapy of advanced gastrointestinal stromal tumors (GIST), but its long-term results have been only just collected. We have attempted ...to identify factors related to the long-term survival. We have analyzed the data of 430 inoperable/metastatic/recurrent GIST patients treated with imatinib in reference centers, assessed the factors influencing the long-term overall survival (OS), and compared the outcomes in three periods of initiation of imatinib therapy during one decade (2001–2003, 2004–2006, 2007–2010). During analyzed time periods, we have found decrease in median largest tumor size at the start of imatinib therapy: 90.5 mm (2001–2003) versus 74 mm (2004–2006) versus 58 mm (2007–2010) (
p
= 0.002). Median progression-free survival (PFS) on 1st line imatinib was 37.5 months, without differences in PFS between three groups. Median OS was 5.8 years, 8-year OS rate was 43 %, and no difference in OS was demonstrated for patients treated in analyzed time periods. Independent good prognostic factors for longer OS were as follows: surgery of residual disease, initial WHO performance status 0/1, normal baseline albumin level, and the presence of exon 11
KIT
mutations. Current median OS in advanced GIST reaches 6 years. The long-term survivors were characterized by smaller maximal tumors at imatinib start, better blood tests results, better performance status, and the surgical removal of residual disease. The latter might reduce the impact of tumor size and equalize the long-term results of therapy during last decade from introduction of imatinib. After introduction of subsequent lines of therapy (as sunitinib), the effect of primary mutational status on the long-term OS is also less visible.
Background: There are several models that predict the risk of recurrence following resection of localised, primary gastrointestinal stromal tumour (GIST). However, assessment of calibration is not ...always feasible and when performed, calibration of current GIST models appears to be suboptimal. We aimed to develop a prognostic model to predict the recurrence of GIST after surgery with both good discrimination and calibration by uncovering and harnessing the non-linear relationships among variables that predict recurrence. Methods: In this observational cohort study, the data of 395 adult patients who underwent complete resection (R0 or R1) of a localised, primary GIST in the pre-imatinib era at Memorial Sloan Kettering Cancer Center (NY, USA) (recruited 1982–2001) and a European consortium (Spanish Group for Research in Sarcomas, 80 sites) (recruited 1987–2011) were used to train an interpretable Artificial Intelligence (AI)-based model called Optimal Classification Trees (OCT). The OCT predicted the probability of recurrence after surgery by capturing non-linear relationships among predictors of recurrence. The data of an additional 596 patients from another European consortium (Polish Clinical GIST Registry, 7 sites) (recruited 1981–2013) who were also treated in the pre-imatinib era were used to externally validate the OCT predictions with regard to discrimination (Harrell's C-index and Brier score) and calibration (calibration curve, Brier score, and Hosmer-Lemeshow test). The calibration of the Memorial Sloan Kettering (MSK) GIST nomogram was used as a comparative gold standard. We also evaluated the clinical utility of the OCT and the MSK nomogram by performing a Decision Curve Analysis (DCA). Findings: The internal cohort included 395 patients (median IQR age, 63 54–71 years; 214 men 54.2%) and the external cohort included 556 patients (median IQR age, 60 52–68 years; 308 men 55.4%). The Harrell's C-index of the OCT in the external validation cohort was greater than that of the MSK nomogram (0.805 (95% CI: 0.803–0.808) vs 0.788 (95% CI: 0.786–0.791), respectively). In the external validation cohort, the slope and intercept of the calibration curve of the main OCT were 1.041 and 0.038, respectively. In comparison, the slope and intercept of the calibration curve for the MSK nomogram was 0.681 and 0.032, respectively. The MSK nomogram overestimated the recurrence risk throughout the entire calibration curve. Of note, the Brier score was lower for the OCT compared to the MSK nomogram (0.147 vs 0.564, respectively), and the Hosmer-Lemeshow test was insignificant (P = 0.087) for the OCT model but significant (P < 0.001) for the MSK nomogram. Both results confirmed the superior discrimination and calibration of the OCT over the MSK nomogram. A decision curve analysis showed that the AI-based OCT model allowed for superior decision making compared to the MSK nomogram for both patients with 25–50% recurrence risk as well as those with >50% risk of recurrence. Interpretation: We present the first prognostic models of recurrence risk in GIST that demonstrate excellent discrimination, calibration, and clinical utility on external validation. Additional studies for further validation are warranted. With further validation, these tools could potentially improve patient counseling and selection for adjuvant therapy. Funding: The NCI SPORE in Soft Tissue Sarcoma and NCI Cancer Center Support Grants.
There are several models that predict the risk of recurrence following resection of localised, primary gastrointestinal stromal tumour (GIST). However, assessment of calibration is not always ...feasible and when performed, calibration of current GIST models appears to be suboptimal. We aimed to develop a prognostic model to predict the recurrence of GIST after surgery with both good discrimination and calibration by uncovering and harnessing the non-linear relationships among variables that predict recurrence.
In this observational cohort study, the data of 395 adult patients who underwent complete resection (R0 or R1) of a localised, primary GIST in the pre-imatinib era at Memorial Sloan Kettering Cancer Center (NY, USA) (recruited 1982–2001) and a European consortium (Spanish Group for Research in Sarcomas, 80 sites) (recruited 1987–2011) were used to train an interpretable Artificial Intelligence (AI)-based model called Optimal Classification Trees (OCT). The OCT predicted the probability of recurrence after surgery by capturing non-linear relationships among predictors of recurrence. The data of an additional 596 patients from another European consortium (Polish Clinical GIST Registry, 7 sites) (recruited 1981–2013) who were also treated in the pre-imatinib era were used to externally validate the OCT predictions with regard to discrimination (Harrell's C-index and Brier score) and calibration (calibration curve, Brier score, and Hosmer-Lemeshow test). The calibration of the Memorial Sloan Kettering (MSK) GIST nomogram was used as a comparative gold standard. We also evaluated the clinical utility of the OCT and the MSK nomogram by performing a Decision Curve Analysis (DCA).
The internal cohort included 395 patients (median IQR age, 63 54–71 years; 214 men 54.2%) and the external cohort included 556 patients (median IQR age, 60 52–68 years; 308 men 55.4%). The Harrell's C-index of the OCT in the external validation cohort was greater than that of the MSK nomogram (0.805 (95% CI: 0.803–0.808) vs 0.788 (95% CI: 0.786–0.791), respectively). In the external validation cohort, the slope and intercept of the calibration curve of the main OCT were 1.041 and 0.038, respectively. In comparison, the slope and intercept of the calibration curve for the MSK nomogram was 0.681 and 0.032, respectively. The MSK nomogram overestimated the recurrence risk throughout the entire calibration curve. Of note, the Brier score was lower for the OCT compared to the MSK nomogram (0.147 vs 0.564, respectively), and the Hosmer-Lemeshow test was insignificant (P = 0.087) for the OCT model but significant (P < 0.001) for the MSK nomogram. Both results confirmed the superior discrimination and calibration of the OCT over the MSK nomogram. A decision curve analysis showed that the AI-based OCT model allowed for superior decision making compared to the MSK nomogram for both patients with 25–50% recurrence risk as well as those with >50% risk of recurrence.
We present the first prognostic models of recurrence risk in GIST that demonstrate excellent discrimination, calibration, and clinical utility on external validation. Additional studies for further validation are warranted. With further validation, these tools could potentially improve patient counseling and selection for adjuvant therapy.
The NCI SPORE in Soft Tissue Sarcoma and NCI Cancer Center Support Grants.
The neutrophil-to lymphocyte ratio (NLR) has been proven to be correlated with outcomes in various cancer types, including gastrointestinal stromal tumors (GIST). There is limited data regarding the ...clinical value of NLR during second line therapy after failure of imatinib and there is an urgent need for more precise predictive factors for therapy. The aim of this study was to assess the association of the pretreatment NLR with progression free survival (PFS) and overall survival (OS) in patients with unresectable/metastatic GIST treated with sunitinib in a second line of treatment. In this analysis 146 out of 230 patients with unresectable/metastatic GIST were included, who were treated between 2005 and 2016 with sunitinib after failure of imatinib, with complete clinical data. In all patients, the NLR was assessed at baseline. The NLR cutoff of 2.4 was selected. The Kaplan-Meier method with the long-rank test and Cox proportional hazards model were applied for statistical analysis. Median PFS was 12.4 months with a 2-year rate of 27.1% and a 5-year rate of 4.8%. Median OS was 22.8 months, whereas 2- and 5-year rates were 47.8 and 13.8%, respectively. Patients with NLR>2.4 had significantly shorter OS: Median OS was 30 months for NLRless than or equal to2.4 vs. 16.4 months for NLR>2.4 (P=0.002); median PFS was 18.2 vs. 9.6 (P=0.075), respectively. In a multivariate model adjusted for mitotic index, primary location of tumor and driver mutation in KIT exon 11, NLR was proven to be independently associated with OS (HR 1.92, 95% CI 1.27-2.9, P=0.002) but not PFS (HR 1.31, 95%CI 0.89-1.93, P=0.17). The present data demonstrate that NLR can serve as an independent prognostic factor for patients with advanced GIST treated with sunitinib.
GIST is the most common mesenchymal tumour of gastrointestinal tract arising from mutation of KIT or PDGFRA gene. Surgery is the primary method of treatment, however a targeted therapy with imatinib ...is necessary due to recurrence. The aim of the study was to evaluate efficacy of the targeted chemotherapy in advanced gastrointestinal stromal tumours with non-exon 11 KIT mutations.
Data from 279 patients with advanced GIST treated with imatinib between 2001 and 2011 were analysed in the study. Exon 11 KIT mutation was found in 192 patients (68.7%), non-exon 11 KIT mutation was found in 87 patients (31.3%): this group included lack of mutation - wild-type, exon 9 KIT mutations, exon 18 PDGFRA D842V mutations, non-D842V PDGFRA mutations as well as non-exon 9 and 11 KIT mutations. Analysis of progression-free survival and overall survival were done for the entire group of patients and for patients with particular mutations, and then effects on progression-free survival and overall survival of such factors as sex, age, imatinib dose were evaluated.
Occurrence of non-exon 11 KIT mutation increases the risk of disease progression by 20% in comparison to the presence of exon 11 KIT mutation, however it does not increase the risk of patient's death. Percentage of 5-year progression-free survivals is the greatest in the case of PDGFRA mutation other than D842V mutation. Percentage of 5-year survivals in case of the presence of D842V PDGFRA mutation is more than twice worse than in the case of the other mutations. Lesion location in the gastrointestinal tract affected the risk of death, with the greatest percentage of 5-year survival for lesions located in the stomach. Such factors as sex, age at diagnosis (<50, ≥50 years) and imatinib dose did not affect the risk of disease progression and the risk of patient's death.
The ratio of overall survival of patients with advanced GIST with a mutation other than exon 11 KIT mutation treated with imatinib is similar to the ratio of overall survival of patients with GIST with exon 11 KIT mutation. An exception is the group of patients with GIST in whom the presence of D842V PDGFRA mutation was found. In general, longer survival has been found in patients with GIST located in the stomach in comparison to the small intestine or other less frequent locations. Percentage of 5-year progression-free survivals is the greatest in the case of PDGFRA mutation other than D842V mutation.
OBJECTIVE
To compare outcomes of patients with clinical nodal melanoma metastases that occurred without a detectable primary tumor (melanoma of unknown primary site; MUP) with those with a known ...primary site (KPM).
METHODS
We included data from 459 consecutive patients treated from 1994 to 2007 with radical therapeutic lymph node dissection (LND; stage IIIB, C) due to clinically palpable and pathologically confirmed lymph node metastases (229 axillary; 230 ilioinguinal). The median follow‐up was 49 months.
RESULTS
LND was performed in 59 cases (12.9%; 29 men, 30 women) due to MUP nodal metastases, including 33 axillary (14.4%) and 26 ilioinguinal (11.3%). In the MUP group, the 3‐ and 5‐year survival rates were 48% and 41%, respectively. Similar rates were observed in patients with KPM, even with matched‐pair analyses. Established prognostic factors (number of metastatic nodes, p=.005; extracapsular extension of metastases, p=.002) influenced survival in the MUP group. Relapses occurred in 31 (53%) and 299 (74.7%) cases in the MUP and KPM groups, respectively.
CONCLUSIONS
Survival rates in the MUP and KPM groups were similar, and the same prognostic factors affected both. Thus, all MUP cases should be treated as standard stage III melanomas.
The authors have indicated no significant interest with commercial supporters.
Cutaneous melanoma with nodal metastases in elderly people Rutkowski, Piotr; Nowecki, Zbigniew I.; Zdzienicki, Marcin ...
International Journal of Dermatology,
August 2010, Letnik:
49, Številka:
8
Conference Proceeding, Journal Article
Recenzirano
Background The impact of age on melanoma patient outcomes is uncertain.
Objective The aim of the study was to analyze the characteristics and treatment outcomes in cutaneous melanoma patients ≥ 65 ...years of age with lymph node metastases.
Methods We analyzed data from 849 consecutive patients with stage III cutaneous melanoma who were treated between 1994 and 2007 at one institution. Of these, 225 (26.5%) were ≥ 65 years of age. The characteristics and disease‐specific survival (DSS) from lymph node dissection (LND) date of patients ≥ 65 years of age were compared with those of younger patients. Median follow‐up time was 49 months (range: 6–140 months).
Results In the ≥ 65 years group (51.6% men), the median Breslow thickness was 5.0 mm and 70% was ulcerated. The 5‐year DSS rate was significantly lower in older patients (34%). Multivariate analysis identified older age as an independent prognostic factor for DSS in the overall group. Independent negative prognostic factors of DSS in the group of older stage III patients were identified as features of nodal metastases (extracapsular invasion, HR = 1.74, P = 0.009; and ≥ 4 involved lymph nodes, HR = 1.5; P = 0.008) and male sex (HR = 1.5; P = 0.039).
Conclusions This analysis showed that melanoma patients ≥ 65 years of age are characterized by a higher primary tumor stage and worse prognosis in the presence of regional node metastases than younger patients. Additionally, the results indicate that the same radical surgical therapy is necessary for patients ≥ 65 years old as in younger patients.
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