Early tumor shrinkage as a predictor of survival in patients with advanced esophageal squamous cell carcinoma treated with first-line checkpoint inhibitors

Introduction

Tumor immunotherapy is a novel treatment method for restoring the normal anti-tumor function of the body by restarting and maintaining the immune response (1). Immune checkpoint inhibitors (ICIs) inhibit the interactions between immunosuppressive molecules on the surface of tumor cells, antigen-presenting cells, and their ligands, thus partially restoring the T-lymphocyte function by improving the tumor immune microenvironment (2). ICIs combined with chemotherapy have become a guideline-recommended, first-line treatment option for patients with advanced esophageal squamous cell carcinoma (ESCC) based on the findings of a landmark KEYNOTE-590 (3) and ESCORT-1st (4) phase-III trial. Moreover, this combination has been reported to result in a longer overall survival (OS) than that resulting from treatment with chemotherapy alone in patients with advanced ESCC, regardless of the programmed death ligand 1 (PD-L1) expression status (5).

Early tumor shrinkage (ETS) has been considered a promising imaging biomarker for evaluating treatment responses and has been proven to predict outcomes in patients with colorectal cancer (6,7), hepatocellular carcinoma (8), melanoma (9), and non-small cell lung cancer (10,11). The significance of ETS is related to the sensitivity to first-line therapy, and it reflects the biological behavior of the tumor (12). An analysis of patients with advanced non-small cell lung cancer treated with ICIs revealed that the percentage of ETS predicted a higher survival (13). Similarly, nivolumab combined with ipilimumab in patients with advanced renal cell carcinoma demonstrated a correlation between ETS and survival (14).

The modified Response Evaluation Criteria in Solid Tumors (RECIST) established a 30% size reduction in the maximum tumor diameter as a partial response (PR). However, immunotherapy may be effective without establishing such a reduction observed on imaging. This is similar to the findings of another retrospective research of clinical trials on ICIs (15). A RECIST response with a threshold of 30% may be related to a loss of ability in prognostic stratification. Thus, an additional threshold for ETS might assist in supplementing the prior response criteria and subsequently support the patient selection and treatment decision.

However, few studies have explored the association between ETS and survival in patients with ESCC treated with ICIs combined with chemotherapy. Our study hypothesized that an ETS with an optimal cut-off value is a promising prognostic imaging parameter for patients with advanced ESCC who receive first-line immunotherapy. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2562/rc).

Methods

Patients

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of The First Affiliated Hospital of Zhengzhou University (No. 2025-KY-0988-002). All patients signed informed consent before the examination.

We retrospectively enrolled 132 patients with unresectable locally advanced ESCC, confirmed histopathologically using gastroscopy, who were treated with first-line immunotherapy at The First Affiliated Hospital of Zhengzhou University between February 2019 and August 2021. None of them had received any prior treatment. The exclusion criteria were as follows: (I) patients who were followed up by imaging assessment after receiving treatment in an external hospital; (II) patients with a poor general condition or severe cardiac, hepatic, or renal comorbidity; and (III) patients with a history of a severe iodine allergy. Finally, 129 patients were enrolled in the study, as summarized in Figure 1.

Figure 1 Flowchart of patient enrollment. ESCC, esophageal squamous cell carcinoma.

Treatment strategies

The patients received ICI combined with chemotherapy (first-line therapy). The treatment regimens included an ICI (Camrelizuma, Hengrui Pharmaceutical Co., Ltd., Jiangsu, China) 200 mg/time, paclitaxel 175 mg/m², and cisplatin 75 mg/m² once every 3 weeks. Treatment was continued until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision, whichever occurred first.

Computed tomography (CT) image acquisition

All patients underwent enhanced CT prior to treatment. Baseline CT was performed 28 days before the start of the study. Imaging tests were performed every 6 weeks for 6 months after the start of treatment and every 12 weeks after 6 months until death or the end of the study. All patients had to fast for 6 h before the scan. A chest contrast-enhanced CT scan was performed via a 256-slice CT scanner (SOMATOM Force; SIEMENS Healthcare, Forchheim, Bavaria, Germany). During scanning, the patients’ upper limbs were raised above their heads. The tube voltage was set at 80-kVp and 140-kVp (0.5 ms instantaneous switching) spectral CT scanning mode; the tube current was measured automatically in milliampere-second; and the pitch was 0.984:1. The spacing and thickness of the scanning layers were 5 mm with a noise index of 8.0 and a gantry speed of 0.6 s per rotation. The contrast agent containing 350 mg/mL of iodine (Iodofol; Hengrui Pharmaceutical Co., Ltd., Jiangsu, China) was injected in the cubital vein with a double-barrel high-pressure syringe at a rate of 3 mL/s. Its dose was calculated to be 1.5 mL/kg. When the CT value of the monitored aortic arch reached 100 HU, the scan was triggered; the arterial phase was started with a delay of 30 s, and the venous phase was started with a delay of 60 s after the end of the arterial phase.

Two observers (Y.Z. and M.W.) with 12 and 9 years of CT diagnosis experience in the chest and abdomen, individually evaluated and detected the images in a randomized and blinded manner through an advanced CT workstation (APOGEE^TM automation system insight; SIEMENS Healthcare, Forchheim, Bavaria, Germany). The measurements were re-examined until a consensus was reached in cases of disagreement. Basic patient clinicopathological characteristics, tumor location, tumor metastasis, longest diameter, maximum invasive depth, and contrast-enhanced CT features were recorded.

Follow-ups

All cases have been followed up by telephone (every 12 weeks) until death or until the end of the study. Tumor assessments, incorporating complete response (CR), progressive disease (PD), PR, and stable disease (SD) were performed consistent with the modified RECIST, which have revealed high citation in prior research (5-9). CR was defined as the complete disappearance of all evidence of the target tumor lesions being measured. PR was described as a measurable reduction in the total tumor burden, although not to the extent of complete resolution. PD indicated a measurable increase in tumor burden or the presence of new lesions. SD referred to a state in which the tumor burden neither decreased sufficiently to meet the criteria for PR nor increased significantly enough to qualify as PD. Objective response was calculated as the amount of CR and PR in all patients. Disease control was depicted as the entire number of patients with CR, PR, and SD. ETS was measured as the proportion of decrease or increase in the largest diameter (LD) of the lesion at the first evaluation in contrast to that at baseline. ETS was calculated using the following formula (7):

ETS=LDbaseline−LDfirstevaluationLDbaseline×100%[1]

The median survival time of the cases was calculated. Progression-free survival (PFS) was calculated as the period from the start of ICIs therapy to the occurrence of progression or death for any reason, whichever happened initially. The OS was described as the interval from the date of diagnosis to death for any reason. The ETS value was zero representing no change measured in the tumor’s LD, and the ETS was given a negative value if the tumor size increased (6-9).

Statistical analysis

We performed statistical analyses using the SPSS software (version 23.0; SPSS Inc., Chicago, IL, USA). Continuous parameters were reported as the median combined interquartile range (IQR) or mean together with standard deviation. With regard to the reproducibility of data analysis, inter-observer reliability was assessed by using the intraclass correlation coefficient (ICC) value. ICCs were classified as follows: 0–0.20, no agreement; 0.21–0.40, weak agreement; 0.41–0.60, moderate agreement; 0.61–0.80, good agreement; and 0.81–1, excellent agreement. Highly correlated features (ICC ≥0.90) were identified and selected initially. Fisher’s exact and Mann-Whitney U tests were performed to compare the categorical data and continuous variables, respectively. The survival times were compared using log-rank tests. Youden’s indices were used to calculate the optimal cut-off values. The univariate and multivariate analyses were compared using Cox proportional hazards regression model. The hazard ratio (HR) and 95% confidence interval (CI) were considered to assess the risk factor. Statistical significance was set at P<0.05.

Results

Baseline characteristics

A total of 129 cases were included in the final analysis. The inter-observer agreement was favorable for data reproducibility with calculated mean ICCs are shown in Table 1. The basic clinicopathological features of the patients are summarized in Table 2. The median value of ETS was 29.5% (IQR, 5.2–43.3%). The correlation of ETS values along with clinicopathological and imaging features are described in Table 3, and patient examples are shown in Figure 2. No significant associations were observed in the ETS values based on the baseline characteristics, except for higher ETS values in patients with ESCC with the longest diameter and clear tumor margins. Waterfall plots of ETS values according to tumor assessments for individual patients are presented in Figure 3A. For patients with PR (n=68, 52.7%), the median ETS value was 42.3% (IQR, 30.5–65.2%). For patients with SD, the median ETS value was 5.5% (IQR, −9.4% to 17.6%) (n=57, 44.2%). Patients with PD (n=4, 3.1%) had a median increase of 60.3% in tumor burden (IQR, −29.1% to −19.9%; P<0.001) (Figure 3B).

Figure 2 Examples of patients with advanced ESCC who received first-line immunotherapy. A 76-year-old woman with advanced ESCC in the middle third of esophagus. The ETS was 70.6% from baseline (A) to the first follow-up visit (B,C), showing PR after treatment; a 56-year-old man with advanced ESCC in the middle third of esophagus. The ETS was −37.4% from baseline (D) to the first follow-up (E,F), showing PD after treatment. ESCC, esophageal squamous cell carcinoma; ETS, early tumor shrinkage; PD, progressive disease; PR, partial response.

Figure 3 ETS distribution among patients with different responses to first-line immunotherapy according to the modified RECIST for ESCC. (A) Waterfall plot displaying the ETS and treatment response; (B) boxplot illustrating the ETS in each patient group. ESCC, esophageal squamous cell carcinoma; ETS, early tumor shrinkage; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.

Survival analysis

Optimal stratification was achieved using an optimal cut-off value of 10% for ETS. Moreover, ETS was associated with a longer PFS (10.7 vs. 20.7 months; HR =2.26, 95% CI: 1.21–4.24; P=0.009; Figure 4A) and OS (17.7 vs. 25 months; HR =2.27, 95% CI: 1.11–4.65; P=0.025; Figure 4B). Table 4 describes the associations between ETS, objective response, and disease control with clinical outcomes. PFS and OS were significantly longer in patients with an objective response or disease control than in non-responders or those with no disease control (P<0.05).

Figure 4 Kaplan-Meier curves show PFS and OS of patients treated with first-line immunotherapy for ESCC, stratified based on the cut-off value of ETS. (A) PFS; (B) OS. ESCC, esophageal squamous cell carcinoma; ETS, early tumor shrinkage; OS, overall survival; PFS, progression-free survival.

We performed univariate and multivariate analyses of various variables, containing ETS, to exactly estimate the association with survival outcomes. Tables 5,6 show the associations between various parameters with PFS and OS. An ETS with a 10% cut-off value was significantly correlated to PFS in the univariate analysis (HR =2.26; 95% CI: 1.21–4.24; P=0.009). In addition, the longest diameter, maximum invasive depth, central necrosis on enhanced CT, enhanced pattern, and ETS values were statistically significant factors for OS in the univariate analysis. In the multivariate analysis, the maximum invasive depth and ETS with a 10% cut-off value were independently predictive factors for OS (HR =0.22, 95% CI: 0.09–0.52, P=0.001; HR =2.93, 95% CI: 1.41–6.06, P=0.004).

Discussion

First-line immunotherapy for advanced or metastatic esophageal carcinoma was limited to specific populations, such as patients with a PD-L1 combined positive score of >10%, before the publication of CheckMate 648 (5). Researchers demonstrated that, in the entire population of randomly assigned groups, the OS of first-line treatment (nabulizumab combined with chemotherapy or nabulizumab combined with ipilimumab) was significantly longer than that of chemotherapy alone (5). The CheckMate 648 conclusion indicated that immunotherapy combined with chemotherapy or dual immunotherapy has achieved OS benefits in all populations without restricting PD-L1 expression. However, the appropriate therapeutic regimen and treatment time points in immunotherapy for advanced ESCC are still being explored. Therefore, available evidence suggests that early tumor size reduction is a remarkable prognostic parameter supporting subsequent clinical decisions (16).

In our study, we provided an innovative demonstration of the prognostic significance of tumor response in patients with ESCC receiving first-line ICIs. Notably, we demonstrated that the ETS distribution among patients with ESCC was related to the tumor response to immunotherapy. Patients with PR had significantly increased ETS values, consistent with the modified RECIST. Similarly, the ETS showed potential in identifying patients who would benefit from therapy and those who would be sensitive to the subsequent treatment (13).

Our findings were similar to those of an analysis that explored ETS in patients with advanced esophageal carcinoma who underwent docetaxel combined with cisplatin plus fluorouracil by Ura et al., who identified a substantial association between ETS and tumor response (17). Furthermore, they described that ETS was highly correlated to PFS and OS, which are calculated from the time of treatment initiation (17). Similar findings have been previously concluded in patients with advanced melanoma treated with immunotherapy (9).

ETS is a prospective prognostic imaging biomarker in patients undergoing immunotherapy for several cancers. In our study, ETS was correlated with the longest diameter at baseline, indicating that the longer the longest diameter at baseline, the more significant the reduction in tumor size. However, this correlation was not predictive of patient survival. This is consistent with current clinical studies’ results, suggesting no significant correlation between OS and initial tumor diameter (18). In contrast, ETS showed no statistically significant difference between groups with different maximum depths of tumor invasion; however, it was considered an independent prognostic factor for OS in patients with ESCC. We suggested that advanced tumors have an increased depth of invasion and a relatively heavy tumor burden. Advanced tumors sensitive to first-line immunotherapy showed a higher range of ETS changes. Moreover, the measurement of tumor size reduction is based on the description of the longest diameter, which is a different concept used to describe tumor morphology.

In previous studies, the cut-off values for ETS varied according to the tumor type, cell biological behavior, and treatment modalities. Ura et al. demonstrated that nearly 66% of patients with an ETS of ≥20% illustrated an objective response, based on the modified RECIST. Additionally, they described that ETS showed highly predictive ability in patients with metastatic or advanced esophageal carcinoma treated with chemotherapy (17). In another recent study on ETS in patients with hepatocellular carcinoma treated with immunotherapy, Müller et al. recommended a cut-off value of 10.0% for patient stratification (19). In our study, patients with an ETS of ≥10.0% had prolonged survival compared with that of patients with an ETS of <10.0% (PFS: 10.7 vs. 20.7 months; OS: 17.7 vs. 25 months). Thus, the optimal cut-off in our cohort was 10%, which was the same as that previously published by Müller et al. (19). This suggested that a tumor reduction of less than 10% or 20% demonstrates an improved survival advantage under normative immunotherapy.

Therefore, ETS reflects the sensitivity of tumors to first-line immunotherapy. In addition, it is associated with the efficacy of anti-tumor regimens. Moreover, tumor shrinkage at the time of initial evaluation was correlated with the efficacy of subsequent treatment regimens. First-line treatment can increase the sensitivity of tumors to second-line treatment and create favorable preconditions for subsequent treatments.

There are several shortcomings in this study. First, due to a retrospective design, there might have been some bias. Second, the ETS is not sufficient to fully reflect the dynamic process of tumor response to treatment, including the combination of tumor response and treatment time points. The tumor size reduction pattern, morphological response based on imaging, and other factors might be related to the patient’s prognosis. Third, other imaging parameters, such as depth of response, require a longer observation time to reach the lowest time point of tumor size reduction, which might increase the follow-up duration and change the values of PFS and OS. Furthermore, although immunotherapy represents a promising treatment modality, its application still necessitates individualized evaluation based on each patient’s specific clinical profile. Regarding the potential correlation between tumor burden and ETS, this remains a preliminary hypothesis derived from our single-center study. Further multi-center studies with larger sample sizes are warranted to validate and explore this relationship. Last, future studies should focus on the application of tumor shrinkage in dual immunotherapy for esophageal cancer, such as LAG3 monoclonal antibody combined with PD-1 monoclonal antibody, CTLA4 antibody combined with PD-1 monoclonal antibody, and immune combined targeted therapy (e.g., erlotinib/romatinib/apatinib combined with PD-1 monoclonal antibody). Although the sample size was small, research in the field of esophageal cancer is expected in the future.

Conclusions

ETS is significantly associated with survival outcomes in patients with advanced ESCC treated with immunotherapy. Early tumor size shrinkage of at least 10% can be regarded as a promising biomarker predictive for PFS and OS. ETS can support clinical decisions by identifying patients who are likely to benefit from immunotherapy.

Acknowledgments

We would like to thank the assistance of State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer from Zhengzhou University. This study was presented as an oral presentation at the European Congress of Radiology on 2024, and an oral presentation at the Academic Conference on Abdominal Imaging of the Radiology Branch of the Chinese Medical Association on 2023, and a poster presentation at the National Radiology Academic Conference of the Chinese Medical Association on 2023.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2562/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2562/dss

Funding: This study was supported by the Basic Research and Applied Basic Research, Zhengzhou Science and Technology Bureau (Zhengzhou, Henan, China) (No. 2024ZZJCYJ007), and the Scientific and Technological Research Project of the Department of Science and Technology of Henan Province (Henan, China) (No. 252102310073).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2562/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of The First Affiliated Hospital of Zhengzhou University (No. 2025-KY-0988-002). All patients signed informed consent before the examination.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Ayoub M, Eleneen Y, Colen RR. Cancer Imaging in Immunotherapy. Adv Exp Med Biol 2020;1244:309-24. [Crossref] [PubMed]
2. Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol 2020;17:807-21. [Crossref] [PubMed]
3. Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 2021;398:759-71. Erratum in: Lancet 2021;398:1874. [Crossref] [PubMed]
4. Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, et al. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA 2021;326:916-25. [Crossref] [PubMed]
5. Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med 2022;386:449-62. [Crossref] [PubMed]
6. Manca P, Corallo S, Randon G, Lonardi S, Cremolini C, Rimassa L, et al. Impact of early tumor shrinkage and depth of response on the outcomes of panitumumab-based maintenance in patients with RAS wild-type metastatic colorectal cancer. Eur J Cancer 2021;144:31-40. [Crossref] [PubMed]
7. Fucà G, Corti F, Ambrosini M, Intini R, Salati M, Fenocchio E, et al. Prognostic impact of early tumor shrinkage and depth of response in patients with microsatellite instability-high metastatic colorectal cancer receiving immune checkpoint inhibitors. J Immunother Cancer 2021;9:e002501. [Crossref] [PubMed]
8. Öcal O, Schinner R, Schütte K, de Toni EN, Loewe C, van Delden O, Vandecaveye V, Gebauer B, Zech CJ, Sengel C, Bargellini I, Gasbarrini A, Sangro B, Pech M, Malfertheiner P, Ricke J, Seidensticker MSORAMIC study group. Early tumor shrinkage and response assessment according to mRECIST predict overall survival in hepatocellular carcinoma patients under sorafenib. Cancer Imaging 2022;22:1. [Crossref] [PubMed]
9. Almansour H, Afat S, Serna-Higuita LM, Amaral T, Schraag A, Peisen F, Brendlin A, Seith F, Klumpp B, Eigentler TK, Othman AE. Early Tumor Size Reduction of at least 10% at the First Follow-Up Computed Tomography Can Predict Survival in the Setting of Advanced Melanoma and Immunotherapy. Acad Radiol 2022;29:514-22. [Crossref] [PubMed]
10. Wei M, Ye Q, Wang X, Wang M, Hu Y, Yang Y, Yang J, Cai J. Early tumor shrinkage served as a prognostic factor for patients with stage III non-small cell lung cancer treated with concurrent chemoradiotherapy. Medicine (Baltimore) 2018;97:e0632. [Crossref] [PubMed]
11. Ooki A, Morita S, Tsuji A, Iwamoto S, Hara H, Tanioka H, Satake H, Kataoka M, Kotaka M, Kagawa Y, Nakamura M, Shingai T, Ishikawa M, Miyake Y, Suto T, Hashiguchi Y, Yabuno T, Ando M, Sakamoto J, Yamaguchi K. Impact of early tumor shrinkage on quality of life in patients treated with first-line cetuximab plus chemotherapy for unresectable metastatic colorectal cancer: results of Phase II QUACK trial. BMC Cancer 2022;22:711. [Crossref] [PubMed]
12. Colloca GA, Venturino A, Guarneri D. Early tumor shrinkage after first-line medical treatment of metastatic colorectal cancer: a meta-analysis. Int J Clin Oncol 2019;24:231-40.
13. Heinemann V, Stintzing S, Modest DP, Giessen-Jung C, Michl M, Mansmann UR. Early tumour shrinkage (ETS) and depth of response (DpR) in the treatment of patients with metastatic colorectal cancer (mCRC). Eur J Cancer 2015;51:1927-36. [Crossref] [PubMed]
14. Miyake H, Miyazaki A, Imai S, Harada K, Fujisawa M. Early Tumor Shrinkage Under Treatment with First-line Tyrosine Kinase Inhibitors as a Predictor of Overall Survival in Patients with Metastatic Renal Cell Carcinoma: a Retrospective Multi-Institutional Study in Japan. Target Oncol 2016;11:175-82. [Crossref] [PubMed]
15. Mushti SL, Mulkey F, Sridhara R. Evaluation of Overall Response Rate and Progression-Free Survival as Potential Surrogate Endpoints for Overall Survival in Immunotherapy Trials. Clin Cancer Res 2018;24:2268-75. [Crossref] [PubMed]
16. Tsuji A, Sunakawa Y, Ichikawa W, Nakamura M, Kochi M, Denda T, Yamaguchi T, Shimada K, Takagane A, Tani S, Kotaka M, Kuramochi H, Furushima K, Koike J, Yonemura Y, Takeuchi M, Fujii M, Nakajima T. Early Tumor Shrinkage and Depth of Response as Predictors of Favorable Treatment Outcomes in Patients with Metastatic Colorectal Cancer Treated with FOLFOX Plus Cetuximab (JACCRO CC-05). Target Oncol 2016;11:799-806. [Crossref] [PubMed]
17. Ura T, Hironaka S, Tsubosa Y, Mizusawa J, Kato K, Tsushima T, Fushiki K, Chin K, Tomori A, Okuno T, Matsushita H, Kojima T, Doki Y, Kusaba H, Fujitani K, Seki S, Kitagawa Y. Early tumor shrinkage and depth of response in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil: an exploratory analysis of the JCOG0807. Esophagus 2023;20:272-80. [Crossref] [PubMed]
18. Woodford C, Yartsev S, Dar AR, Bauman G, Van Dyk J. Adaptive radiotherapy planning on decreasing gross tumor volumes as seen on megavoltage computed tomography images. Int J Radiat Oncol Biol Phys 2007;69:1316-22. [Crossref] [PubMed]
19. Müller L, Gairing SJ, Kloeckner R, Foerster F, Schleicher EM, Weinmann A, Mittler J, Stoehr F, Halfmann MC, Düber C, Galle PR, Hahn F. The prognostic role of early tumor shrinkage in patients with hepatocellular carcinoma undergoing immunotherapy. Cancer Imaging 2022;22:54. [Crossref] [PubMed]