Dissociated responses at initial computed tomography evaluation is a good prognostic factor in non-small cell lung cancer patients treated with anti-programmed cell death-1/ligand 1 inhibitors

Tozuka, Takehiro; Kitazono, Satoru; Sakamoto, Hiroaki; Yoshida, Hiroshi; Amino, Yoshiaki; Uematsu, Shinya; Yoshizawa, Takahiro; Hasegawa, Toshiyuki; Uchibori, Ken; Yanagitani, Noriko; Horiike, Atsushi; Horai, Takeshi; Seike, Masahiro; Gemma, Akihiko; Nishio, Makoto

doi:10.1186/s12885-020-6704-z

Cited by 30 publications

(27 citation statements)

References 27 publications

(33 reference statements)

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“…By demonstrating the discordant treatment effects between primary sites and adjacent nodes, this study achieves several ends. First, it supports the findings of other studies demonstrating similar discordance in other solid malignancies, such as lung cancer ( 10 , 11 ). Importantly, however, unlike the aforementioned studies, this research utilizes the gold standard of tumor progression, histopathology, to compare true treatment effect to that which is demonstrated by CT imaging.…”

Section: Discussionsupporting

confidence: 89%

Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect

et al. 2020

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PD-1 blockade represents a promising treatment in patients with head and neck squamous cell carcinoma (HNSCC). We analyzed results of a neoadjuvant randomized window-of-opportunity trial of nivolumab plus/minus tadalafil to investigate whether immunotherapy-mediated treatment effects vary by site of involvement (primary tumor, lymph nodes) and determine how radiographic tumor shrinkage correlates with pathologic treatment effect.Patients and MethodsForty-four patients enrolled in trial NCT03238365 were treated with nivolumab 240 mg intravenously on days 1 and 15 with or without oral tadalafil, as determined by random assignment, followed by surgery on day 31. Radiographic volumetric response (RVR) was defined as percent change in tumor volume from pretreatment to posttreatment CT scan. Responders were defined as those with a 10% reduction in the volume of the primary tumor or lymph nodes (LN). Pathologic treatment effect (PTE) was defined as the area showing fibrosis or lymphohistiocytic inflammation divided by total tumor area.ResultsSixteen of 32 patients (50%) with pathologic evidence of LN involvement exhibited discordant PTE between primary sites and LN. In four patients with widely discordant adjacent LN, increased PTE was associated with increased infiltration of tumor CD8+ T cells and CD163+ macrophages, whereas stromal regulatory T cells were associated with low nodal PTE. RVR correlated with PTE at both primary tumor (slope = 0.55, p < 0.001) and in LN (slope = 0.62, p < 0.05). 89% (16/18) of radiographic non-responders with T1–T3 primary sites had no (n = 7) or minimal PTE (n = 9), whereas 15/17 (88%) of radiographic responders had moderate (n = 12) or complete (n = 3) PTE.ConclusionNivolumab often induces discordant treatment effects between primary tumor sites and metastatic lymph nodes within subjects. This treatment discordance was also demonstrated in adjacent lymph nodes, which may correlate with local immune cell makeup. Finally, although these data were generated by a relatively small population size, our data support the use of early radiographic response to assess immunotherapy treatment effect in HNSCC.

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Section: Discussionsupporting

confidence: 89%

Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect

et al. 2020

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“…Atypical patterns (pseudo-progression + dissociated response) were associated with a better overall survival than true progressions. Another retrospective study including 62 NSCLC patients also observed a dissociated response in 9.2% of patients treated with PD-1/L1 inhibitors, and confirmed the improved OS associated to this pattern compared to homogenous progression (14.0 vs. 6.6 months) (14).…”

Section: Immunotherapies In Solid Cancermentioning

confidence: 62%

Dissociated Response in Metastatic Cancer: An Atypical Pattern Brought Into the Spotlight With Immunotherapy

Humbert

Chardin

2020

Front. Oncol.

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When evaluating metastatic tumor response to systemic therapies, dissociated response is defined as the coexistence of responding and non-responding lesions within the same patient. Although commonly observed on interim whole-body imaging, the current response criteria in solid cancer do not consider this evolutive pattern, which is, by default, assimilated to progression. With targeted therapies and chemotherapies, dissociated response is observed with different frequencies, depending on the primary cancer type, treatment, and imaging modality. Because FDG PET/CT can easily assess response on a lesion-by-lesion basis, thus quickly revealing response heterogeneity, a PET/CT dissociated response has been described in up to 48% of women treated for a metastatic breast cancer. Although some studies have underlined a specific prognostic of dissociated response, it has always ended up being described as an unfavorable prognostic pattern and therefore assimilated to the "Progressive Disease" category of RECIST/PERCIST. This dichotomous imaging report (response vs. progression) provides a simple information for clinical decision-support, which probably explains the relatively low consideration for the dissociated response pattern to chemotherapies and targeted therapies until now. With immune checkpoint inhibitors, this paradigm is quickly changing. Dissociated response is observed in around 10% of advanced lung cancer patients and appears to be associated to treatment efficiency. Indeed, for this subset of patients, a clinical benefit of immunotherapy and favorable prognosis are usually observed. This specific pattern should therefore be considered in the future immunotherapy-adapted criteria for response evaluation using CT and PET/CT, and specific clinical managements should be evaluated for this response pattern.

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“…Third, target lesions selected for calculation of TGR might not represent the whole tumor burden as new lesions and non-target lesions were not taken into account. Dissociated or mixed response phenomenon may confound the accurate tumor kinetics assessment after treatment initiation (32). Fourth, Limited to the retrospective nature of our work, we were unable to estimate predictive value of PD-L1 status and TMB level for only 3 patients had detected these two items.…”

Section: Discussionmentioning

confidence: 88%

Pre-Treatment Tumor Growth Rate Predicts Clinical Outcomes of Patients With Advanced Non-Small Cell Lung Cancer Undergoing Anti-PD-1/PD-L1 Therapy

Zhang

et al. 2021

Front. Oncol.

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Tumor growth rate (TGR; percent size change per month [%/m]) is postulated as an early radio-graphic predictor of response to anti-cancer treatment to overcome limitations of RECIST. We aimed to evaluate the predictive value of pre-treatment TGR (TGR0) for outcomes of advanced non-small cell lung cancer (aNSCLC) patients treated with anti-PD-1/PD-L1 monotherapy. We retrospectively screened all aNSCLC patients who received PD-1 axis inhibitors in Sun Yat-Sen University Cancer Center between August 2016 and June 2018. TGR0 was calculated as the percentage change in tumor size per month (%/m) derived from two computed tomography (CT) scans during a “wash-out” period before the initiation of PD-1 axis inhibition. Final follow-up date was August 28, 2019. The X-tile program was used to identify the cut-off value of TGR0 based on maximum progression-free survival (PFS) stratification. Patients were divided into two groups per the selected TGR0 cut-off. The primary outcome was the difference of PFS between the two groups. The Kaplan-Meier methods and Cox regression models were performed for survival analysis. A total of 80 eligible patients were included (54 [67.5%] male; median [range] age, 55 [30-74] years). Median (range) TGR0 was 21.1 (-33.7-246.0)%/m. The optimal cut-off value of TGR0 was 25.3%/m. Patients with high TGR0 had shorter median PFS (1.8 months; 95% CI, 1.6 - 2.1 months) than those with low TGR0 (2.7 months; 95% CI, 0.5 - 4.9 months) (P = 0.005). Multivariate Cox regression analysis revealed that higher TGR0 independently predicted inferior PFS (hazard ratio [HR] 1.97; 95% CI, 1.08-3.60; P = 0.026). Higher TGR0 was also significantly associated with less durable clinical benefit rate (34.8% vs. 8.8%, P = 0.007). High pre-treatment TGR was a reliable predictor of inferior PFS and clinical benefit in aNSCLC patients undergoing anti-PD-1/PD-L1 monotherapy. The findings highlight the role of TGR0 as an early biomarker to predict benefit from immunotherapy and could allow tailoring patient’s follow-up.

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Dissociated responses at initial computed tomography evaluation is a good prognostic factor in non-small cell lung cancer patients treated with anti-programmed cell death-1/ligand 1 inhibitors

Cited by 30 publications

References 27 publications

Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect

Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect

Dissociated Response in Metastatic Cancer: An Atypical Pattern Brought Into the Spotlight With Immunotherapy

Pre-Treatment Tumor Growth Rate Predicts Clinical Outcomes of Patients With Advanced Non-Small Cell Lung Cancer Undergoing Anti-PD-1/PD-L1 Therapy

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