Tumor Shrinkage Rate Research Articles

Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study

BackgroundImmune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are...

Subcellular localization of hTERT in breast cancer: insights into its tumorigenesis and drug resistance mechanisms in HER2-immunopositive breast cancer.

Human telomerase reverse transcriptase (hTERT) is highly expressed in various cancers, including breast cancer. Although telomere elongation is an essential role for hTERT, the nuclear export after oxdative stress has also been shown in several cancer cell lines and is associated with drug-resistance invitro. As only a few reports focused on the subcellular localization of hTERT in clinical specimens, we performed immunohistochemistry (IHC) and analyzed the correlation between intracellular hTERT expression and the clinicopathological characteristics to identify the clinical significance of hTERT subcellular expression in breast cancers. 144 invasive breast cancers classified by IHC subtype without primary systemic therapy (PST), were selected from a surgical resection cohort and were immunostained for hTERT, p-STAT3, p-AKT and p-ERK. The nuclear and/or cytoplasmic staining intensity and proportion of hTERT were scored and compared with clinicopathological parameters. The nuclear hTERT expression was significantly correlated with HER2 expression (p=0.00156), and the scores were significantly correlated with p-STAT3 and p-AKT expression scores (r=0.532, p=0.000587 and r=0.345, p=0.0339, respectively) in the HER2-immunopositive breast cancer including luminal-HER2 and HER2 subtypes. Furthermore, hTERT was expressed more in cytoplasm in the specimens after PST than those before PST, and the score tended to be negatively correlated with tumor shrinkage rate in HER2 subtype (r=-0.593, p=0.0705). These results suggest that nuclear and/or cytoplasmic hTERT may play a different role before and after PST including the tumorigenesis and drug-resistance in breast cancer. Suppression of cytoplasmic hTERT expression may lead to more effective strategy for drug-resistant HER2 subtype in breast cancer.

Early Tumor Shrinkage as a Predictor of Favorable Treatment Outcomes in Patients With Extensive-Stage SCLC Who Received Programmed Cell Death-Ligand 1 Inhibitor Plus Platinum-Etoposide Chemotherapy: A Prospective Observational Study

IntroductionIn recent years, programmed cell death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy was found to have favorable clinical outcomes in patients with extensive-stage SCLC (ES-SCLC). The usefulness of early tumor shrinkage (ETS) has been reported in various types of cancers. Nevertheless, there have been few reports evaluating ETS in ES-SCLC. Therefore, this study aimed to evaluate the role of ETS in the clinical outcomes of patients with ES-SCLC receiving chemoimmunotherapy. MethodsWe prospectively identified 46 patients with ES-SCLC who received PD-L1 inhibitor plus platinum-etoposide chemotherapy at 10 institutions in Japan between September 2019 and October 2021. Of them, 35 patients were selected for analyses. ResultsThe responders (progression-free survival [PFS] ≥ 6.0 mo) had significantly greater tumor shrinkage at the first evaluation than the nonresponders (PFS < 6.0 mo) (65.0% versus 53.7%, p = 0.03). We defined the cutoff value for ETS as a 57% change from the baseline on the basis of the receiver operating characteristic results to determine the optimal tumor shrinkage rate at the first evaluation for identifying responders. The patients with ES-SCLC who achieved ETS had longer PFS and overall survival than those who did not achieve ETS (5.6 versus 4.0 mo, log-rank test p = 0.001 and 15.0 versus 8.3 mo, log-rank test p = 0.02). In the multivariate analyses, ETS was significantly associated with PFS and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.12–0.63, p = 0.002 and hazard ratio = 0.34, 95% confidence interval: 0.13–0.85, p = 0.02). ConclusionsOur prospective observational study indicated that ETS was related to favorable clinical outcomes for patients with ES-SCLC receiving PD-L1 inhibitor plus platinum-etoposide chemotherapy.

EUS-derived maximum tumor thickness and tumor shrinkage rate as independent prognostic factors in locally advanced esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy.

EUS-derived maximum tumor thickness (MTT) pre- and post-neoadjuvant chemoradiotherapy (NCRT) for locally advanced esophageal squamous cell carcinoma (LA-ESCC) indicates treatment response. However, the accuracy of predicting long-term survival remains uncertain. This study aimed to investigate the association between EUS-derived MTT pre- and post-NCRT and tumor shrinkage rate as well as long-term survival in patients with LA-ESCC receiving NCRT. We retrospectively enrolled patients with LA-ESCC who underwent EUS examination from 2017 to 2021. Tumor shrinkage rate was the ratio of the difference between pre- and post-MTT to pre-MTT. The most fitted cutoff values were determined by the receiver operating characteristic curve. Univariate and multivariate Cox regression analyses and Kaplan-Meier curves were used to calculate overall survival (OS) and progression-free survival. Data from another center were also used for external validation testing. Two hundred thirty patients were enrolled. Of the patients, 178 completed the first EUS pre-NCRT and obtained pre-MTT, 200 completed the reexamined EUS post-NCRT and obtained post-MTT, and 148 completed both EUS and achieved tumor shrinkage. For all the patients, the 1- and 3-year OS rates were 93.9% and 67.9%, and progression-free survival rates were 77.7% and 54.1%, respectively. The median follow-up period was 30.6 months. Thinner post-MTT (≤8.8 mm) and EUS responder (tumor shrinkage rate ≥52%) were independently associated with better OS. EUS-derived MTT and tumor shrinkage post-NCRT are independent prognostic factors for long-term survival and may be an alternative method for evaluating tumor response in patients with LA-ESCC after NCRT.

Modified (m)-FOLFOXIRI plus cetuximab versus m-FOLFOXIRI plus bevacizumab as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer: Survival analysis of the phase II randomized DEEPER trial by JACCRO.

120 Background: Triplet regimen, FOLFOXIRI, plus bevacizumab is considered as one of standard first-line treatments in metastatic colorectal cancer (mCRC). On the contrary, FOLFOXIRI plus anti-EGFR antibody has been shown to be a promising regimen with greater depth of response (DpR) in patients with RAS wild-type mCRC from the VOLFI and MACBETH trials (J Clin Oncol 2019, JAMA Oncol 2018). We therefore performed a randomized phase II study, DEEPER trial (JACCRO CC-13) [NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. We have reported a significantly better DpR of m-FOLFOXIRI plus cet compared to bev as the primary endpoint (Tsuji A, et al. ASCO 2021). Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as initial treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05, in per protocol set (PPS) consisted of patients evaluable for the DpR. Secondary endpoints included progression-free survival, overall survival, overall response rate, early tumor shrinkage rate, secondary resection rate, and toxicity. A total of 359 patients were enrolled between July 2015 and June 2019. For the PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), 159 and 162 patients were randomly assigned to the cet and bev arms, respectively. Clinical outcomes will be analyzed according to primary tumor sidedness which is included in the stratification factor. Additionally, we will collect data of BRAF status, and analyze the clinical outcomes in mCRC patients with RAS/ BRAF wild-type tumors and/or left-sided tumors. Pre-planned survival analysis will be performed to compare the two treatment arms at the time of 3 years after last patients’ enrollment using a log-rank test. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant. Statistical analyses will be performed using SAS version 9.4. Clinical trial information: NCT02515734 .

Site-specific patterns of early response to nivolumab plus ipilimumab therapy in advanced renal cell carcinoma patients compared with tyrosine-kinase inhibitors.

This study aimed to identify patterns of early response to nivolumab and ipilimumab combination therapy (Nivo+Ipi) in primary and metastatic sites of advanced renal cell carcinoma (RCC). RCC patients treated with Nivo+Ipi or tyrosine-kinase inhibitors (TKIs) as first-line therapy were included. To exclude selection bias due to patient characteristics, baseline clinical data was adjusted by inverse probability of treatment weighting (IPTW). Overall response rate (ORR) and lesional response rates (LRR) in primary and metastatic sites were determined by measuring tumor diameters on serial CT images according to Response Evaluation Criteria in Solid Tumors, version 1.1. 33 patients were treated with Nivo+Ipi and 39 with TKIs as first-line therapy. After IPTW-adjusted analysis, ORR during the first 24weeks of treatment was significantly higher in Nivo+Ipi group than in TKIs group (45.5% versus 21.7%, p<0.01). LRR of the primary tumor tended to be higher in Nivo+Ipi group than in TKI group (14.8% versus 4.4%, p=0.06). Mean LRR of all metastatic sites was not significantly different between the two groups, but tumor shrinkage rate of lung metastasis was significantly higher in Nivo+Ipi group than in TKIs group (68.5% versus -12.7%, p<0.01). Univariate and multivariate analyses identified lung metastasis as the independent factor associated with prolonged progression-free survival and with higher ORR. Our study found that lung metastasis of advanced RCC exhibited early response to Nivo+Ipi therapy. Further studies are warranted to verify whether site-specific early response predicts overall survival benefit in advanced RCC patients treated with Nivo+Ipi.

Induction Chemotherapy with FOLFIRINOX for Locally Advanced Pancreatic Cancer: A Simple Scoring System to Predict Effect and Prognosis

BackgroundEffective chemotherapy (CTx) protocols as induction treatment provide increasing opportunities for surgical resection of locally advanced pancreatic cancer (LAPC). Although improved survival after resection of LAPC with CTx has been reported for selected patients, reliable recommendations on the indication for conversion surgery after induction treatment are currently lacking. We investigated the factors predictive of prognosis in resected LAPC after FOLFIRINOX.MethodsConsecutive patients with LAPC undergoing curative resection after FOLFIRINOX between 2011 and 2018 were identified from a prospectively maintained database. Relevant clinical parameters and CT findings were examined. A scoring system was developed based on the ratio of hazard ratios for overall survival of all significant predictors.ResultsA total of 62 patients with LAPC who underwent oncologic resection after FOLFIRINOX were analyzed. Tumor shrinkage, tumor density, and postchemotherapy CA19-9 serum levels were independently associated with overall survival (multivariate analysis: HR = 0.31, 0.17, and 0.18, respectively). One, two, and two points were allocated to these three factors in the proposed scoring system, respectively. The median overall survival of patients with a score from 0 to 2 was significantly shorter than that of patients with a score from 3 to 5 (22.1 months vs. 53.2 months, P < 0.001).ConclusionsTumor density is a novel predictive marker for the prognosis of patients with resected LAPC after FOLFIRINOX. A simple scoring model incorporating tumor density, the tumor shrinkage rate, and CA 19-9 levels identifies patients with a low score, who may be candidates for additional treatment.

An In Vivo Study of Local Administration of Low-dose Anti-PD-1 Antibody Using an Oral Cancer Cell Line.

The immunotherapy approach using anti-programmed cell death 1 (PD-1) antibody has been demonstrated in oral cancer treatment. However, serious immune-related adverse events (irAE) have been reported. If local administration of small doses of anti-PD-1 antibody via intraarterial chemoradiotherapy could have the same antitumor effect of systemic administration, this can reduce irAE and medical expenses. In this study, we investigate the antitumor effects of local and systemic administration of a small amount of anti-PD-1 antibody, the overall survival (OS), and the immune environment around cancer. A mouse buccal mucosal oral squamous cell carcinoma cell line (Sq-1979) was used, and anti-mouse PD-1 was used as the drug. The cell line was transplanted to mouse, and the drug was locally (30 mg/body) and systemically (300 mg/body) administered in a dose. The tumor shrinkage rate and antitumor effect were examined 21 and 29 days after the start of administration. The OS was also compared in each of the groups. Furthermore, the subcutaneous growth of the tumors was inhibited, and the expressions of PD-L1, CD8T cells, perforin, and granzyme B were examined. We found that the local low-dose and systemic groups had the same antitumor effect, OS also showed a significant prolongation. In addition, indicated that the expression of granzyme B was higher in the local low-dose group. Local low-dose administration of anti-PD-1 antibody showed the same antitumor effect and OS as systemic normal-dose administration. Therefore, local low-dose administration in oral cancer can be useful.

Tumor growth inhibition modeling to support the starting dose for dacomitinib.

Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor for first-line treatment of patients with metastatic non-small cell lung cancer and EGFR-activating mutations. A high rate of dose reductions in the pivotal trial led to an observed inverse exposure-response (ER) relationship with the primary end points. Three ER models were developed to determine if the starting dose from the pivotal trial, 45 mg once daily (q.d.) dose, is appropriate: a longitudinal logistic regression model for adverse event-related dose changes, a Claret tumor growth inhibition (TGI) model, and a Cox model for progression-free survival (PFS) based on the TGI model predictions. This analysis included 266 patients taking dacomitinib with a starting dose of 45 mg (N=250) or 30 mg (N=16) q.d. The ER relationships with the time-varying exposure metrics, most recent maximum plasma concentration (Cmax ) and average concentration (Cavg ) from the first dose, were established for the dose reduction and TGI models, respectively. The TGI model characterized the tumor inhibition over time with constant growth rate (kL =0.0012 years-1 ) and highly variable kill rate (kD =1.002 years-1 /[μg/L]θcavg , coefficient of variation [CV]=89%) and drug resistance (λ=14.47 years-1 , CV=96%) leading to prolonged tumor shrinkage. The ER relationship was characterized using an exposure parameter with a power parameterization (θcavg=0.454, p < 0.0001). The Cox model found that baseline tumor size (p=0.0166) and week 8 tumor shrinkage rate (p=0.0726) were the best predictors of PFS. Simulations of dose reductions and drug interruptions on tumor shrinkage over time showed greater and more prolonged tumor shrinkage with a starting dose of 45 mg q.d.

Predictors and histological effects of preoperative chemoradiotherapy for rectal cancer and control of lateral lymph node metastasis

IntroductionStandard treatment strategy for low rectal cancer in Japan is different from Western countries. Total mesorectum excision (TME) + lateral lymph node dissection (LLND) is mainly carried out in Japan, whereas neoadjuvant chemoradiotherapy (nCRT) + TME is selected in Western countries. There is no clear definition of preoperative diagnosis of lateral lymph node metastasis. If we can predict lateral lymph node swelling that can be managed by nCRT from lateral lymph node swelling that require surgical resection, clinical benefit is significant. In the current study we assessed characteristics of the lateral lymph node recurrence (LLNR) and LLND that can be managed by nCRT.Patients and MethodsPatients with low rectal cancer (n = 168) underwent nCRT between 2009 and 2016. We evaluated CEA, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lateral lymph node short axis pre and post nCRT, respectively, and also evaluated tumor shrinkage rate, tumor regression grade (TRG). We evaluated the relationship between each and LLNR.ResultsLLND was not carried out all patients. Factors associated with LLNR were PLR and lymph node short axis pre and post nCRT. (p = 0.0269, 0.0278, p < 0.0001, p < 0.0001, respectively). Positive recurrence cut-off values of lateral lymph node short-axis calculated were 11.6 mm pre nCRT and 5.5 mm post nCRT.ConclusionResults suggest that PLR before and after CRT was associated with control of LLNR, and LLND should be performed on lateral lymph nodes with short-axis of 5 mm and 11 mm pre and post nCRT.

Personalized Gamma Knife radiosurgery for cavernous sinus hemangiomas: A Chinese single-center retrospective study for 10 years of 187 patients.

The aim of this study is to retrospectively review the effectiveness and safety of personalized Gamma Knife radiosurgery (GKRS) for cavernous sinus hemangiomas (CSHs) and to summarize experience of personalized GKRS treatment for different volume of CSHs. 187 CSHs patients who received personalized GKRS treatment in our center from January 1, 2011 to December 31, 2020 were enrolled in this study and classified into small and medium CSHs (<20 ml), large CSHs (20-40 ml) and giant CSHs (≥40 ml) according to tumor volume. The personalized GKRS treatment strategy included single GKRS and staged GKRS. Tumor shrinkage rate, clinical symptoms response, and complications after GKRS were recorded during the follow-up period. Multivariate factors influencing clinical symptoms response were analyzed after personalized GKRS treatment. After a mean follow-up duration of 28 months (range 12-124 months), the tumor control rate was 100%, and the mean shrinkage rate of CSHs was 93.2% (61.3%-100%) in the last follow-up. Of the 115 patients with preexisting symptoms, 43 (37.5%) patients showed symptom disappearance, 17 (14.7%) patients demonstrated improvement, and 55 (47.8%) patients remained with no change. Previous surgical resection of CSHs (OR = 0.025, 95% CI 0.007-0.084, P = .000) was identified to be an independent risk factor for no symptom improvement after GKRS treatment. Personalized GKRS is an effective and safe treatment for different volume of CSHs, which is capable of shrinking the tumor and improving symptoms with extremely low incidence of adverse effects and might be considered as the primary treatment strategy for CSHs.

Tumor shrinkage patterns of nivolumab monotherapy in metastatic renal cell carcinoma

To investigate the tumor shrinkage patterns of patients with metastatic renal cell carcinoma treated with nivolumab monotherapy. Forty-four consecutive patients with metastatic renal cell carcinoma treated with nivolumab monotherapy (81 metastatic and four primary lesions) between September 2013 and December 2020 were retrospectively analyzed. The tumor shrinkage rate of individual visceral and lymph node metastatic lesions and the primary site lesions treated with nivolumab monotherapy, as well as the association between overall survival and pretreatment tumor size, were statistically assessed. Pretreatment tumor size for the total and individual target lesions, which included kidneys, lungs, pancreas, and lymph nodes, were not correlated with tumor shrinkage rate. The tumor shrinkage rate was found to have no significant association with pretreatment tumor size between any organ. In addition, there is no significant difference in tumor shrinkage rate between larger (>median value) and smaller (<median value) pretreatment tumor size in any organ. Finally, there was no significant difference in overall survival between larger and smaller pretreatment tumor size. Pretreatment tumor size was not associated with the tumor shrinkage rate and overall survival in nivolumab monotherapy.

Role of anlotinib in the treatment of early advanced osteosarcoma of limbs in children.

e23509 Background: The prognosis of advanced or early advanced osteosarcoma during neoadjuvant chemotherapy is unfavorable. Many patients can only accept brutal amputation without a new and reliable limb rescue solution. There are no clinical data on the efficacy and safety of anlotinib in the treatment of osteosarcoma in children and adolescents. We investigate the efficacy of anotinib plus first-line chemotherapy (platinum + doxorubicin liposome/ifosfamide) in the treatment of early advanced osteosarcoma in children and adolescents. Methods: Early advanced osteosarcoma in this study was defined as pathologically identified osteosarcoma that progressed within 6 months after radical surgery, with neoadjuvant chemotherapy or adjuvant chemotherapy. 11 cases of limb osteosarcoma with Enneking stage IIB (8 cases in the lower femur and 3 cases in the upper tibia), aged 8-15 years, were selected from February 2018 to December 2021. After 1 cycle of first-line neoadjuvant chemotherapy, patients locally advanced received anlotinib (12mg/d) combined with first-line chemotherapy for 1-2 cycles. The tumor shrinkage rate, limb salvage rate, disease-free survival time (DFS), progression-free survival time (PFS), disease control rate (DCR), and safety were analyzed. Results: 9 patients had locally advanced during neoadjuvant chemotherapy. After 2 cycles of anlotinib combined with first-line chemotherapy, the tumor shrunked and was well demarcated from surrounding tissue. All patients underwent limb salvage surgery Postoperative chemotherapy lasted for 4-6 cycles, with a median DFS of 12 months. 2 patients who developed recurrence or metastasis after radical surgery continued to complete at least 8 cycles of standard first-line chemotherapy combined with anlotinib, PFS showed separately 6 months and 8 months. The tumor shrinkage rate was 54.55% and the DCR was 72.73%. The adverse reactions associated with anlotinib were epistaxis (8 cases, 72.72%) and oral ulcer (1 case, 9.09%), which were controlled immediately after withdrawal. Conclusions: Combination of anlotinib with first-line chemotherapy can shrink the tumor, improve limb salvage rate for children with early advanced osteosarcoma, and delay disease progression for children with recurrence and metastasis after radical surgery. The toxicity of anlotinib combined with first-line chemotherapy were tolerated which is expected to be a new approach for the treatment of early advanced osteosarcoma.

The effect of anlotinib on unresectable differentiated thyroid cancer (T4): A retrospective study.

6096 Background: Though the majority of differentiated thyroid cancer (DTC) patients obtained a good prognosis after standardized therapy, approximately 15% of DTC patients will progress to unresectable disease. Part of locally advanced (T4) thyroid cancer patients with progressive invasion into vasculature/windpipe/esophagus lost the surgery opportunity because of difficult in achieving R0/R1 resection. The study aimed to evaluate the efficacy and safety of anlotinib in T4 PTC. Methods: Retrospectively included T4 papillary thyroid cancer (PTC) patients from West China Hospital of Sichuan University between Sep. 2020 and Feb. 2022. The patients were prescribed with Anlotinib (12 mg orally daily, two weeks on/one week off) at least two courses. The tumor response was defined by RECIST v. 1.1. The primary endpoint was objective response rate (ORR). Results: The study included 22 T4 PTC patients, including 8 patients with lung metastasis. The median age of patients was 59.2 years, 8/22 patients were male. The median follow-up was 5.5 months (2-13 months). Totally, the ORR was 68.2% (CR: 9.1%; PR: 59.1%), disease control rate (DCR) was 95.5% (SD: 27.3%), one patient progressed (PD). 8 patients with lung metastasis, the ORR was 75% (6/8). The average tumor shrinkage rate was 42.1%. And two female patients (T4aN1M1 and T4bN1M0 respectively) obtained CR. Additionally, one juvenile patient (14 y) also response to Anlotinib treatment with 55.2% tumor shrinkage, and no obvious AE was observed in this patient. Most adverse events (AEs) were grade 1 or 2. Common AEs of all grades were hypertension (68.2%), hypertriglyceridemia (36.4%), proteinuria (31.8%), and tended to discontinue when treatment ceased. Conclusions: Anlotinib demonstrated antitumor activity in the treatment of unresectable T4 PTC; Juvenile PTC patients also response to Anlotinib treatment; Anlotinib treatment was tolerable in T4 PTC patients.

Long-term outcomes of staged Gamma Knife radiosurgery for giant cavernous sinus hemangiomas: a single-center retrospective study.

Cavernous sinus hemangiomas (CSHs) are rare benign tumors originating from the cavernous sinus. Gamma Knife radiosurgery (GKRS) has been recommended as a primary treatment for small- to medium-sized CSHs. The optimal treatment for giant CSHs is still controversial. In this study, the authors retrospectively reviewed the effectiveness and safety of staged GKRS treatment for giant CSHs. Twenty-two patients with giant CSH who received staged GKRS treatment in the Gamma Knife Treatment Center of Henan Province during the period from January 1, 2011, to December 31, 2018, were enrolled in this study. Six patients had received microsurgery before GKRS, the other 16 patients were diagnosed according to clinical symptoms and MR images. All of the enrolled patients received 2-stage GKRS, and the mean interval between the two GKRS treatments was 6.5 months (range 6-12 months). For the first GKRS, the median isodose line was 48% (range 45%-50%), the median marginal dose was 13 Gy (range 11.5-14 Gy), and the median coverage of CSHs was 80% (range 70%-88%). For the second GKRS treatment, the median isodose line was 50% (range 45%-55%), the median marginal dose to the CSHs was 10.5 Gy (range 9-12.5 Gy), and the median coverage of the CSHs was 88% (range 80%-94%). All of the patients received an outpatient review of an enhanced MR image of the head and a clinical physical check every 6 months after the first GKRS treatment. The mean follow-up duration was 52 months (range 24-84 months). The tumor control rate was 100% 24 months after staged GKRS, and at the last follow-up the mean tumor shrinkage rate was 96.7% (range 90.6%-100%) and the mean residual CSH volume was 2.1 ml (range 0-8.5 ml). Twenty patients suffered central nervous system (CNS) injury symptoms to varying degrees before staged GKRS treatment. Complete symptom recovery was found in 11 (55%) patients, improved symptoms in 5 (25%) patients, and no change in 4 (20%) patients after treatment. Only 1 patient suffered temporary preexisting headache aggravation and 1 patient suffered temporary preexisting diplopia aggravation 1 week after receiving the first GKRS treatment. Subacute or chronic complications were not detected after staged GKRS. Staged GKRS is an effective treatment for giant CSHs. Because of the impressively low incidence of adverse effects, staged GKRS may be considered as a primary treatment for giant CSHs.

Abstract P2-12-23: Changes in 18F-FDG-PET uptake after the first course of DTX reflect response to preoperative chemotherapy and prognosis in breast cancer

Abstract [Purpose] It is important to make early decisions about treatment changes in treatment-resistant groups. The aim of this study is to extract non-responders among preoperative chemotherapy using 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) in primary breast cancer. We hypothesized that early evaluation of FDG PET after the first course of docetaxel (DTX) would predict treatment resistant group by the relationship between changes on FDG accumulation and tumor diameter on magnetic resonance imaging (MRI). [Patients and Methods] Thirty-seven of 41 patients were evaluated. Clinical stage was T1-4, N0-3, and M0 between August 2007 and December 2010. Four courses of DTX were administered followed by 4 courses of fluorouracil/epirubicin/cyclophosphamide (FEC) followed by surgery. FDG-PET evaluation was performed by the maximum standardized uptake value (SUVmax). FDG-PET scans were performed at baseline, at 15 days after the first course of DTX (C1D15), and at 15 days after 4 courses of DTX (C4D15). Tumor reduction rate was measured on MRI at baseline and at C4D15 according to Response Evaluation Criteria in Solid Tumors (RECIST). ROC analysis was performed by between SUVmax of C1D15 and MRI of C4D15. Changes of SUVmax C1D15 were divided into high and low group by ROC analysis. Core needle biopsy (CNB) was performed to evaluate the treatment effect pathologically after 4 courses of DTX (C4CNB). The pathological treatment effect of surgical specimens after 4 courses of FEC (C4FEC) was also examined. The difference in progression-free survival (PFS) rate or overall survival (OS) rate between the low and high SUVmax of C1D15 change rate was calculated using Kaplan-Meier survival curves and compared by log-rank test. The protocol of the study was approved by the Ethics Committee of the Gunma Prefectural Cancer Center (ECGPCC), and all patients gave their written informed consent before enrollment (No. 19011). The observational study was also approved by ECGPCC (No. 30087). [Results] There were ER+HER2-:17, ER+HER2+:4, ER-HER2-:11, and ER-HER2+:5 cases. SUVmax change rate C1D15 correlated with the SUVmax change rate C4D15 and tumor shrinkage rate on MRI C4D15 in univariate (SUVmax C4D15: γ=.567, p&amp;lt;.001, MRI C4D15: γ=.748, p&amp;lt;.001) and in multivariate analysis (SUVmax C4D15: γ=414, p=.002, MRI C4D15: γ=.616, p&amp;lt;.001). The SUVmax change rate C1D15 correlated with pathological effect of C4CNB (γ=.392, p=.032) and of surgical specimen C4FEC (γ=.440, p=.006) in univariate analysis. From ROC analysis based on SUVmax C1D15 and MRI C4D15 (AUC=.924, 95% CI: .828-1.000, p&amp;lt;.001), the SUVmax C1D15 were divided into two groups with high and low SUVmax changes. The mean SUVmax in the low group (&amp;lt;30%) (n=15) was 15.8% (±9.7). The mean SUVmax in the high group (≥30%) (n=22) was 50.8% (±11.7). The mean of MRI change rate of C4D15 was 20.4% (±5.4) in the low SUVmax change group and 69.2% (±5.8) in the high SUVmax change group, showing a significant difference between the two groups (p&amp;lt;.001). The low SUVmax change group showed shorter PFS than the high SUVmax group (median 80.9 vs 93.7 months, p=.050), but there was no difference in OS (p=.719). [Conclusion] Changes less than 30% of 18F-FDG uptake after the first course of DTX may reflect the treatment resistance and poor prognosis in primary breast cancer. Citation Format: Tomoko Hirakata, Yasuhiro Yanagita, Tomomi Fujisawa, Teruhiko Kinoshita, Hiroyuki Horikoshi, Nariyuki Oya, Tsukasa Akiyoshi, Misa Iijima, Takeshi Miyamoto, Keiko Yanai, Hiroshi Matsumoto, Kenichi Inoue, Rie Horii, Takaaki Fujii, Ken Shirabe. Changes in 18F-FDG-PET uptake after the first course of DTX reflect response to preoperative chemotherapy and prognosis in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-23.

Efficacy and safety exposure-response analyses of entrectinib in patients with advanced or metastatic solid tumors.

Entrectinib is an anti-cancer agent that inhibits TRKA/B/C, ROS1, and ALK. Secondary pharmacokinetic (PK) exposure parameters for entrectinib derived from a previously described population PK model were used to characterize exposure-response relationships in patients treated with entrectinib. Data were pooled from Phase 1 and 2 studies of entrectinib (600-800mg/day in adults, 250-750mg/m2/day in children) in 293 patients with NTRK-, ROS1-, or ALK-positive, locally advanced or metastatic tumors. Efficacy was evaluated by the changes in sum of target lesion diameters and best overall response defined by RECIST1.1. A longitudinal nonlinear mixed-effect model described the relationship between entrectinib exposure and tumor size data in patients with ROS1-positive non-small-cell lung cancer (NSCLC) or NTRK fusion-positive solid tumors. The relationship between exposure and treatment-emergent (TEAEs) or serious (SAEs) adverse events was assessed by logistic regression in all patients for whom secondary PK parameter estimates were derived. Among the 89 patients with evaluable efficacy data included in the exposure-efficacy analysis, 73% (65/89) achieved a complete or partial response. Entrectinib exposure distribution was similar in responders and non-responders. Model-described tumor shrinkage rates were 8-12 times greater than growth rates in both ROS-1-positive NSCLC patients and NTRK fusion-positive solid tumor patients, with no relationship between exposure and these rates. The probability of experiencing a Grade ≥ 3 TEAE or SAE increased with exposure, primarily at doses > 600mg/day. These analyses supported that entrectinib at 600mg/day provides an acceptable benefit-risk ratio in adults with NTRK-, ROS1-, or ALK-positive tumors, considered as rare disease.

Equivalent efficacy assessment of QL1101 and bevacizumab in nonsquamous non-small cell lung cancer patients: A two-year follow-up data update.

ObjectiveAnti-vascular endothelial growth factor (VEGF) monoclonal antibodies are an effective means of treating non-small cell lung cancer (NSCLC). Here, we aim to update the equivalent efficacy assessment between QL1101 and bevacizumab based on two-year follow-up data.MethodsIn total, 535 eligible NSCLC patients were enrolled in this randomized controlled trial. Patients were randomly assigned 1:1 to the QL1101 group and the bevacizumab group. The full end time of this study was defined as 24 months after the last enrolled patient was randomized. The primary endpoint was the objective response rate (ORR); equivalence was confirmed if the two-sided 90% confidence interval (90% CI) of the relative risk was within the range of 0.75−1.33. The secondary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsThe two-year updated data showed similar ORR (QL1101 vs. bevacizumab: 53.1% vs. 54.3%; relative risk=0.977; 90% CI: 0.838−1.144), PFS (235 d vs. 254 d, log-rank P=0.311), and OS (577 d vs. 641 d, log-rank P=0.099) results between the QL1101 group and the bevacizumab group. The mean shrinkage ratio of targeted lesions was also similar between the QL1101 group and the bevacizumab group (22.5% vs. 23.5%). For patients who received QL1101 maintenance therapy, similar results were shown between the QL1101 group (n=157) and the bevacizumab group (n=148) (PFS: 253 d vs. 272 d, log-rank P=0.387; OS: 673 d vs. 790 d, log-rank P=0.101; mean tumor shrinkage rate: 26.6% vs. 27.5%). ConclusionsThis study reported that QL1101 had similar efficacy in treating nonsquamous NSCLC in terms of ORR, PFS and OS based on two-year updated data, providing a basis for the clinical application of QL1101.

Geometrical Comparison and Quantitative Evaluation of 18F-FDG PET/CT- and DW-MRI-Based Target Delineation Before and During Radiotherapy for Esophageal Squamous Carcinoma.

Background and PurposeThis study aimed to evaluate the geometrical differences in and metabolic parameters of 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET-CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) performed before and during radiotherapy (RT) for patients with esophageal cancer based on the three-dimensional CT (3DCT) medium and explore whether the high signal area derived from DW-MRI can be used as a tool for an individualized definition of the volume in need of dose escalation for esophageal squamous cancer.Materials and MethodsThirty-two patients with esophageal squamous cancer sequentially underwent repeated 3DCT, 18F-FDG PET-CT, and enhanced MRI before the initiation of RT and after the 15th fraction. All images were fused with 3DCT images through deformable registration. The gross tumor volume (GTV) was delineated based on PET Edge on the first and second PET-CT images and defined as GTVPETpre and GTVPETdur, respectively. GTVDWIpre and GTVDWIdur were delineated on the first and second DWI and corresponding T2-weighted MRI (T2W-MRI)-fused images. The maximum, mean, and peak standardized uptake values (SUVs; SUVmax, SUVmean, and SUVpeak, respectively); metabolic tumor volume (MTV); and total lesion glycolysis(TLG) and its relative changes were calculated automatically on PET. Similarly, the minimum and mean apparent diffusion coefficient (ADC; ADCmin and ADCmean) and its relative changes were measured manually using ADC maps.ResultsThe volume of GTVCT exhibited a significant positive correlation with that of GTVPET and GTVDWI (both p < 0.001). Significant differences were observed in both ADCs and 18F-FDG PET metabolic parameters before and during RT (both p < 0.001). No significant correlation was observed between SUVs and ADCs before and during RT (p = 0.072–0.944) and between ∆ADCs and ∆SUVs (p = 0.238–0.854). The conformity index and degree of inclusion of GTVPETpre to GTVDWIpre were significantly higher than those of GTVPETdur to GTVDWIdur (both p < 0.001). The maximum diameter shrinkage rate (∆LDDWI) (24%) and the tumor volume shrinkage rate (VRRDWI) (60%) based on DW-MRI during RT were significantly greater than the corresponding PET-based ∆LDPET (14%) and VRRPET (41%) rates (p = 0.017 and 0.000, respectively).ConclusionBased on the medium of CT images, there are significant differences in spatial position, biometabolic characteristics, and the tumor shrinkage rate for GTVs derived from 18F-FDG PET-CT and DW-MRI before and during RT for esophageal squamous cancer. Further studies are needed to determine if DW-MRI will be used as tool for an individualized definition of the volume in need of dose escalation.

Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab.

Empirical time-varying clearance models have been reported for several immune checkpoint inhibitors, including avelumab (anti-programmed death ligand 1). To investigate the exposure-response relationship for avelumab, we explored semimechanistic pharmacokinetic (PK)-tumor growth dynamics (TGD) models. Plasma PK data were pooled from three phase I and II trials (JAVELIN Merkel 200, JAVELIN Solid Tumor, and JAVELIN Solid Tumor JPN); tumor size (TS) data were collected from patients with metastatic Merkel cell carcinoma (mMCC) enrolled in JAVELIN Merkel 200. A PK model was developed first, followed by TGD modeling to investigate interactions between avelumab exposure and TGD. A PK-TGD feedback loop was evaluated with simultaneous fitting of the PK and TGD models. In total, 1,835 PK observations and 338 TS observations were collected from 147 patients. In the final PK-TGD model, which included the bidirectional relationship between PK and TGD, avelumab PK was described by a two-compartment model with a positive association between clearance and longitudinal TS, with no additional empirical time-varying clearance identified. TGD was described by first-order tumor growth/shrinkage rates, with the tumor shrinkage rate decreasing exponentially over time; the exponential time-decay constant decreased with increasing drug concentration, representing the treatment effect through tumor shrinkage inhibition. We developed a TGD model that mechanistically captures the prevention of loss of antitumor immunity (i.e., T-cell suppression in the tumor microenvironment) by avelumab, and a bidirectional interaction between PK and TGD in patients with mMCC treated with avelumab, thus mechanistically describing previously reported time variance of avelumab elimination.