Early tumor shrinkage and response assessment according to mRECIST predict overall survival in hepatocellular carcinoma patients under sorafenib

Background The aim of this study was to explore the relationship between follow-up imaging characteristics and overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients under sorafenib treatment. Methods Associations between OS and objective response (OR) by mRECIST or early tumor shrinkage (ETS; ≥20% reduction in enhancing tumor diameter at the first follow-up imaging) were analyzed in HCC patients treated with sorafenib within a multicenter phase II trial (SORAMIC). 115 patients were included in this substudy. The relationship between survival and OR or ETS were explored. Landmark analyses were performed according to OR at fixed time points. Cox proportional hazards models with OR and ETS as a time-dependent covariate were used to compare survival with factors known to influence OS. Results The OR rate was 29.5%. Responders had significantly better OS than non-responders (median 30.3 vs. 11.4 months; HR, 0.38 [95% CI, 0.22–0.63], p < 0.001), and longer progression-free survival (PFS; median 10.1 vs. 4.3 months, p = 0.015). Patients with ETS ≥ 20% had longer OS (median 22.1 vs. 11.4 months, p = 0.002) and PFS (median 8.0 vs. 4.3 months, p = 0.034) than patients with ETS < 20%. Besides OR and ETS, male gender, lower bilirubin and ALBI grade were associated with improved OS in univariate analysis. Separate models of multivariable analysis confirmed OR and ETS as independent predictors of OS. Conclusion OR according to mRECIST and ETS in patients receiving sorafenib treatment are independent prognostic factors for OS. These parameters can be used for assessment of treatment benefit and optimal treatment sequencing in patients with advanced HCC.

Assessing prognostic value of early tumor shrinkage and depth of response in first-line therapy for patients with advanced unresectable pancreatic cancer

Background The prognostic potential of early tumor shrinkage (ETS) and depth of response (DpR) in pancreatic cancer (PC) is unclear. Here, we recruited 90 patients with recurrent and metastatic PC (RMPC) who had received chemotherapy as first-line therapy to assess the prognostic potential of these markers. Methods ETS is characterized as a ≥ 20% depletion in the sum-of-the-longest-diameters (SLD) of measurable tumor lesions at 6–12 weeks than the baseline. DpR is the maximum shrinkage (%) from the baseline to nadir. We evaluated corrections in ETS and DpR with survival. Results Of the 63 patients in which ETS assessment was possible, 21 (33.3%) achieved ETS. We found a significant association between the incidence of ETS and an improved rate of progression-free survival (PFS; 6.5 vs. 2.2 months; p < 0.001) and overall survival (OS; 12.1 vs. 6.0 months; p = 0.014). The median value of DpR was − 23.66%. DpR was also related to improved PFS (9.3 vs. 3.1 months; p < 0.001) and OS (18.2 vs. 7.3 months; p < 0.001). Patients who had distant metastasis, not local recurrence, with ETS showed markedly better outcomes. In a multivariate model, both ETS and DpR were independent predictors of OS in the whole population. Conclusions ETS and DpR may predict favorable outcomes for RMPC patients who had received chemotherapy as first-line therapy, independent of the agents used. Further studies on the exploratory analyses of the optimum ETS cut-off value in recurrent PC patients to predict favorable clinical outcomes are required.

Letter to the Editor from Colle et al

In their article, Fucà et al highlight that early tumor shrinkage and depth of response predict the prognosis of patients with metastatic colorectal cancer (mCRC) microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) treated by immune checkpoint inhibitors (ICI). We are surprised that no cases of pseudoprogression (PSPD) were reported in their study. PSPDs were described under ICI in patients treated for MSI/dMMR mCRC. In a cohort of 123 patients treated with anti-PD1±antiCTL-4 for MSI/dMMR mCRC, we reported 12 patients with PSPD, representing 10% of the cohort. Of 12 patients with PSPD, 8 secondary achieved an objective response and were alive and free of progression at the data lock. Conversely, in Fucà’s article, no PSDP was observed and the patients with primary radiological progression (21.7%) had a poor overall survival. These differences between the two series could be probably explained by the following points. First, Fucà et al use RECIST 1.1 criteria for radiological evaluation. Second, the first imaging was done after 8–9 weeks of treatment in Fucà’s article, which may be late to detect PSPD. In conclusion, if the first evaluation is made during the first 3 months of treatment, using iRECIST criteria seems mandatory to avoid stopping treatment prematurely, especially in patients receiving anti-PD1 alone.

Phase II study of panitumumab monotherapy in chemotherapy-naïve frail or elderly patients with unresectable, RAS wild type colorectal cancer: OGSG 1602, survival update data.

3558 Background: We previously reported the result of the phase II OGSG1602 study in which single agent of panitumumab (Pmab) demonstrated 76.5% and 50% of disease control rate (DCR), primary endpoint, and response rate (RR), respectively, in chemotherapy-naïve frail or elderly patietns (pts) with wild-type (wt) RAS unresectable colorectal cancer (CRC). Here, we reports the survival analysis including overall survival (OS) and progression free survival (PFS) in terms of sidedness and early tumor shrinkage (ETS). Methods: Thirty-six pts aged ≥76 years, or ≥65 considered unsuitable for intensive chemotherapy were enrolled and received Pmab 6 mg/kg intravenously every 2 weeks. Primary tumors located in the cecum to transverse colon were coded as right-sided tumors (RST), while tumors located from the splenic flexure to rectum were considered left-sided tumors (LST). Early tumor shrinkage (ETS) was determined as tumor reduction of 20% at week 8 compared to baseline. Results: Of total of 36 enrolled pts, 34 pts were included in the efficacy analysis, with pts with LST vs. RST being 26 vs. 8 cases, while pts who achieved ETS (ETS+) vs. those who did not achieve ETS (ETS-) being 15 vs. 19 cases. Among the evaluable 34 pts, the median PFS (mPFS) and median OS (mOS) were 6.0 months (95% Confidence Interval [CI]: 5.4-10.0) and 17.5 months (95%CI, 13.8-24.3), respectively, with the median follow-up of 17.0 months. For PFS, there were no significant differences between pts with LST vs. RST [6.6 months (95%CI, 5.4-11.5) vs. 4.9 months (95%CI, 1.9-NA), p = 0.120] but between pts with ETS+ vs. ETS- [10.4 months (95%CI, 7.4-NA) vs. months (95%CI, 2.1-7.9), p = 0.001]. Furthermore, OS was significantly different either in pts with LST vs. RST [19.3 months (95%CI, 14.2-NA) vs. 12.3 (95%CI, 9.9-NA), p = 0.043] or in pts with ETS+ vs. ETS- [ months (n = 15, 95%CI, 19.6-NA) vs. 10.1 months (n = 19, 95%CI, 6.8-21.8), p < 0.001]. Conclusions: Pmab monotherapy showed the favolable OS in the frail or elderly pts with RAS wt, unresectable CRC. Our data also confirmed the prognostic value of sidedness as well as predictive value of ETS in this setting. Clinical trial information: UMIN000024528. [Table: see text]

Prognostic impact of early tumor shrinkage and depth of response in patients with microsatellite instability-high metastatic colorectal cancer receiving immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (ICIs) are the new standard of care in microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). Since tumor response dynamic parameters already shown a strong association with survival outcomes in patients with mCRC treated with first-line therapy, we investigated the association of early tumor shrinkage (ETS) and depth of response (DoR) in patients with MSI-H/dMMR mCRC treated with ICIs.MethodsThis is a retrospective, multicenter, cohort study in patients with dMMR and/or MSI-high mCRC treated with ICIs (anti-PD-1/PD-L1 with or without anti-CTLA-4 agents) with measurable disease and at least one post-baseline radiological disease reassessment. The Kaplan-Meier method and Cox proportional-hazards regression models were used for survival analyses. A maximally selected statistics method in a Cox regression model for progression-free survival (PFS) was used to determine the optimal cut-offs for ETS and DoR.ResultsWe included a total of 169 patients: 116 (68.6%) were treated with anti-PD-1 monotherapy, whereas 53 (31.4%) with anti-PD-1 plus anti-CTLA-4 agents. Patients with primary progressive disease (N=37, 21.9%), experienced an extremely poor overall survival (OS) and were evaluated separately. In patients with clinical benefit, we observed a significant association between ETS and DoR with both OS and PFS, and we identified a relative reduction of at least 1% as the optimal cut-off for ETS and a relative reduction of at least 50% as the optimal cut-off for DoR.ConclusionsETS and DoR are important prognostic factors in patients with MSI-high mCRC treated with ICIs that might be useful to design treatment intensification/deintensification strategies. A prospective validation of both is warranted.

Analysis of early tumor shrinkage and depth of response in patients with advanced biliary tract cancer treated with gemcitabine plus cisplatin or gemcitabine plus S-1: An exploratory analysis of JCOG1113.

301 Background: JCOG1113 is a randomized phase III trial to confirm the non-inferiority of gemcitabine (GEM) plus S-1 (GS) compared with GEM plus cisplatin (GC) regarding overall survival (OS) in patients with advanced biliary tract cancer (BTC). Although the non-inferiority of GS to GC was demonstrated, the difference in the nature of tumor shrinkage effects between GC and GS is not clear. Early tumor shrinkage (ETS) and depth of response (DpR) are considered as on-treatment markers that reflect the anti-tumor effect to chemotherapy and have been reported to be associated with survival in metastatic colorectal cancer. However, there are few studies assessing ETS or DpR in advanced BTC. Therefore, we evaluated the association between ETS, DpR, and clinical outcomes in JCOG1113. Methods: We conducted an exploratory analysis of JCOG1113, which included chemotherapy-naïve patients with recurrent or unresectable BTC. ETS was defined as tumor reduction in the sum of the longest diameters of the target lesions at week 6 when compared with that at baseline. DpR was defined as the maximum tumor shrinkage observed until 12 weeks from enrollment. Survival curves were estimated using the Kaplan–Meier method. Progression-free survival (PFS) and OS for ETS and DpR were estimated from week 6 and 12 (landmarks) after enrollment, respectively. Multivariable analyses for PFS and OS, adjusted for baseline factors, were performed using a stratified Cox regression model. Results: Of the 354 registered patients in JCOG1113, 277 patients in the ETS group and 230 patients in the DpR group were included in this study. Seventy-seven patients (27.8%) achieved ETS ≥ 20% (ETS high group) and 52 patients (22.6%) achieved DpR ≥ 40% (DpR high group). The proportion of ETS high group (GC, 25.4%; GS, 30.4%) and DpR high group (GC, 21.2%; GS, 24.1%) was similar between the arms. The patient characteristics of ETS high group were not different between GC and GS. The hazard ratio (HR) of the ETS high group compared with the ETS low group for PFS and OS was 0.76 (95% confidence interval [CI] 0.58–1.00) and 0.80 (95% CI 0.60–1.07), respectively. The impact of ETS was higher in GC (HR 0.64, 95% CI 0.43–0.95) than GS (HR 0.88, 95% CI 0.60–1.28) in PFS. The HR of DpR high group compared with DpR low group for PFS and OS was 0.75 (95% CI 0.55–1.03) and 0.79 (95% CI 0.57–1.09), respectively. The impact of DpR was higher in GC (HR 0.63, 95% CI 0.40–0.998) than GS (HR 0.88, 95% CI 0.57–1.37) in PFS. ETS and DpR were significantly associated with both PFS and OS in the multivariable analyses. Conclusions: ETS and DpR may be useful as on-treatment markers associated with PFS and OS in patients with advanced BTC, especially in those treated with GC. Clinical trial information: UMIN000010667.