UROLOGICAL ONCOLOGY Responses to Targeted Therapy among Organs Affected by Metastasis in Patients with Renal Cell Carcinoma are Organ-Specific Weixing Jiang1, Hongzhe Shi1*, Lianyu Zhang2, Jin Zhang2, Xingang Bi1, Dong Wang1, Li Wen1, Changling Li1, Jianhui Ma1, Jianzhong Shou1** Purpose: Previous reports showed that targeted therapy efficacy varied due to different metastatic organs in pa- tients with metastatic renal cell carcinoma (mRCC). This study aimed to further evaluate the response and progres- sion-free time (PFT) of individual metastatic organs. Materials and Methods: Data from mRCC patients, who were treated with sunitinib between January 2008 to December 2018, were retrospectively reviewed. Individual metastatic organs were assessed separately by The Response Evaluation Criteria in Solid Tumors criteria. Results: We evaluated response heterogeneity and PFT as characteristics of 281 individual organs affected by mRCC in 213 patients. The objective response rates in these organs were 72.7% in pancreas, 63.7% in spleen, 14.3% in adrenal glands, 13.5% in bone and soft tissue, 11.6% in lymph nodes, 11.6% in lungs, and 9.1% in liver. The median PFT was 15.2 months (95% confidence interval [CI] 2.7–27.7 months) for adrenal glands, 13.2 months (95% CI 3.5–22.9 months) for bone and soft tissue, 9.0 months (95% CI 7.6–10.4 months) for lymph nodes, 8.6 months (95% CI 6.3–10.9 months) for lungs, and 5.2 months (95% CI 2.9–7.5 months) for liver. Median PFT was not reached in pancreas and spleen, but was > 22.8 months and > 20.6 months, respectively. Conclusion: Our results indicated that organs affected by metastasis may have individual responses to sunitinib treatment. The pancreas and spleen may have the best responses, and liver may have the worst response. Further research is needed to verify these findings. Keywords: metastasis; objective response rate; organ; renal cell carcinoma; targeted therapy INTRODUCTION Renal cell carcinoma (RCC) accounts for 3% of malignant tumors in adults; approximately 17% of patients with RCC harbor distant metastases at the time of the initial diagnosis(1-3). The organs most commonly affected by RCC metastasis are the lungs, lymph nodes, and bones(4). Targeted therapy is the mainstay in the treatment of patients with metastatic RCC (mRCC), as it results in improvements in quality of life and surviv- al (5,6). Sunitinib, one of the multitarget receptor-tyros- ine-kinase inhibitors (TKIs), has been the gold-standard first-line treatment for mRCC for over 10 years(7,8). Our clinical practice of sunitinib-based treatment re- vealed the possibility of organ-specific responses to metastatic lesions. To date, there is no published evi- dence relating to this potential response heterogeneity in patients with mRCC who receive targeted therapy. Understanding any organ-specific variations in re- sponse and prognosis would be important for the per- 1Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China 2Department of Imaging, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China *Correspondence: National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Tel: 86-10-87787171. Fax: 86-10-87787363. E-mail: hongzhe_shi@163.com ** National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Tel: 86-10-13601332989. Fax: 86-10-87787170. E-mail: shoujzh@126.com. Received April 2020 & Accepted October 2020 sonalization of mRCC patient treatments. In this paper, we demonstrated organ-specific differences in objec- tive response rates (ORRs) and progression free time (PFT) that were indicative of response heterogeneity. PATIENTS AND METHODS Ethics Statement This retrospective study focused on the evaluation of the efficacy and clinical outcomes of first-line sunitinib treatment in patients with mRCC, and was reviewed and approved by the Ethics Committee of the Domain-Spe- cific Review Board (ID Num: NCC2016XQ-22). Study Population Patients with mRCC who were treated in our institute between January 2008 and December 2018 were ret- rospectively identified. The medical records of all pa- tients with mRCC who were treated with sunitinib were reviewed. Among them, 213 patients with diagnoses of Urology Journal/Vol 18 No. 5/ September-October 2021/ pp. 512-518. [DOI: 10.22037/uj.v16i7.6129] clear-cell RCC (ccRCC) who had detailed imaging data collected every two cycles of sunitinib treatment, and had not received other systemic treatments or metas- tasectomy, were included in the study. Sunitinib was administered at a dosage of 50 mg once daily, on a 4/2 (on/off) schedule. Dosages were reduced or interrupt- ed only in cases of treatment intolerance, in which case stepwise dose reductions occurred in 12.5 mg incre- ments. All patients had complete imaging data and fol- low-up information. Characteristics including age, sex, Memorial Sloan Kettering Cancer Center (MSKCC) criteria, and Eastern Cooperative Oncology Group (ECOG) Performance Status(9). Radiological Assessment Computed tomography (CT) or magnetic-resonance im- aging (MRI) scanning was performed every 4–8 weeks, and the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria were used for evaluation of the responses of the lesions in every organ affected by me- tastasis(10). Patients with measurable disease at baseline were collected. The tumor burden was assessed in cen- timeters of the tumor diameter by the sum of five meas- urable diseases for each metastatic organ at baseline according to RECIST 1.1. The best response of each individual organ was determined (complete response [CR] was better than partial response [PR], which was better than stable disease [SD], which was better than progressive disease [PD]), with the proviso that the re- sponse had to have been maintained for ≥ 28 days. All CT and MRI data were reviewed by two independ- ent genitourinary radiologists. Organs with metastases at the beginning of sunitinib treatment were evaluated throughout the treatment period, and the efficacy was recorded for each individual organ. Metastatic lesions that appeared during sunitinib treatment were consid- ered to be primary drug-resistant lesions, and were not included in the study. Brain metastasis was not in- vestigated, because in our institution nearly all brain metastases were treated with radiotherapy or surgical resection. Evaluation continued until death, the end of follow-up, or the replacement of sunitinib with a sec- ond-line targeted therapy or another systemic therapy. Statistical Analysis The chi-square test was used to compare the difference of distribution data between the groups; non-normally distributed continuous data were compared using the Mann-Whitney U test. PFT for each organ, progres- sion-free survival (PFS) and overall survival (OS) from the initiation of sunitinib were analyzed by the Kaplan– Characteristics n (%) Total patients 213 Gender Male 139 (65.3) Female 74 (34.7) Median age (range), year 55 (17–76) ECOG 0 148 (69.5) 1 53 (24.9) > 1 12 (5.6) MSKCC Good 102 (47.9) Intermediate 72 (33.8) Poor 39 (18.3) Prior surgery Yes 165 (77.5) No 48 (22.5) Sites of disease (by organs) Lung 95 (33.8) Lymph node 69 (24.6) Bone and soft tissue 52 (18.5) Liver 22 (7.8) Adrenal gland 21 (7.5) Pancreas 11 (3.9) Spleen 11 (3.9) Table 1. Patient characteristics at baseline. Metastatic-organ-specific responses to targeted therapy-Jiang et al. Abbreviations: ECOG, Eastern Cooperative Oncology Group; MSKCC, Memorial Sloan-Kettering Cancer Center Figure 1. Responses and maximal tumor shrinkage of lung metastasis (A) and lymph node metastasis (B) assessed by RECIST1.1. The green-shaded area corresponds to follow-up time (months). The positioning of the markers with different colors indicates the point of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The arrow (on therapy) indicates con- tinuing treatment with sunitinib. Vol 18 No 5 September-October 2021 513 Urological Oncology 514 Meier method and the log-rank test. The deadline for follow-up was October 2019. Statistical analysis was performed using SPSS statistics for Windows, version 23.0 (IBM Corp. Armonk, NY, USA), and differences were considered statistically significant if P < 0.05. RESULTS Patient characteristics The patient characteristics are summarized in Table 1. A total of 213 metastatic ccRCC patients, with a meas- urable response to sunitinib, were included in the study. This population consisted of 139 men (65.3%) and 74 women (34.7%), with a median age of 55 years (range 17–76 years). The numbers of patients with ECOG scores of 0, 1, and > 1 were 148 (69.5%), 53 (24.9%), and 12 (5.6%), respectively. Good, intermediate, and poor MSKCC risk levels were assessed in 102 (47.9%), 72 (33.8%), and 39 (18.3%) patients, respectively. In 165 patients (77.5%), nephrectomy was performed pri- or to sunitinib treatment. We only statistically analyzed target organs that were identified in >10 participants, which meant that 281 individual organs were availa- ble for analysis. These organs were lung in 95 patients (33.8%), lymph node in 69 (24.6%), bone and soft tissue in 52 (18.5%), liver in 22 (7.8%), adrenal gland in 21 (7.5%), pancreas in 11 (3.9%), and spleen in 11 (3.9%). There was no difference in MSKCC risk distribution between metastatic organs (P = 0.071) (Table 2). The median tumor burden for lung, lymph node, bone and soft tissue, liver, adrenal gland, pancreas, and spleen was 4.3 cm (interquartile range [IQR]: 2.3-5.6), 4.0 cm (IQR: 2.4-5.1), 3.8 cm (IQR: 2.1-4.8), 4.1 cm (IQR: 2.6-5.5), 3.9 cm (IQR: 1.8-4.9), 3.8 cm (IQR: 1.4-5.0), and 3.6 cm (IQR:1.9-4.5), respectively. Difference of tumor burden between metastatic organs was not statis- tically observed (P = 0.068) (Table 2). Organ-specific treatment efficacy for metastasis The treatment responses in each individual organs are shown in Figure 1; the best responses and ORRs for each organ type are summarized in Table 3. For lung metastasis, the median times to CR, PR, and SD were 8.6 months, 7.4 months, and 4.3 months, respectively (Figure 1A). For lymph-node metastasis, the median times to CR, PR, and SD were 5.6 months, 3.6 months, and 4.2 months, respectively (Figure 1B). For bone and soft-tissue metastasis, the median times to CR, PR, and SD were 7.5 months, 8.6 months, and 4.6 months, respectively (Figure 2A). For adrenal metastasis, the median time to CR was 6.4 months, only one patient achieved PR (in 4.3 months), and the median time to SD was 2.6 months (Figure 2B). For liver metastasis, the median times to PR and SD were 6.9 months and 2.6 months, respectively (Figure 3A). For pancreas metastasis, the median times to CR, PR, and SD were 6.9 months, 6.5 months, and 2.4 months, respectively (Figure 3B). For spleen metastasis, the median times to CR, PR, and SD were 10.2 months, 3.0 months, and 2.8 months, respectively (Figure 3C). Clinical Outcomes of Metastases in Different Organs The final follow-up was in October 2019. The medi- an overall follow-up period was 32.0 months (range, 2.6–125.8 months). Median PFS was 10.7 months (95% confidence interval [CI] 9.9–11.4 months) and median OS was 28.3 months (95% CI 26.5–30.1 months) (Sup- plementary file). Dose interruption and reduction due to adverse events were required in 30.5% (65/213) and 47.4% (101/213) of patients, respectively. The rate of dose reduction or treatment discontinuation for lung, lymph node, bone and soft tissue, liver, adrenal gland, pancreas, and spleen was 50.5% (48/95), 47.8% (33/69), 38.5% (20/52), 45.5% (10/22), 52.4% (11/21), 36.4% (4/11), and 27.3% (3/11), respectively. Difference of the rates was not significant (P = 0.714) (Table 2). Kaplan–Meier analysis revealed that median PFT was 8.6 months (95% CI: 6.3-10.9) for lung metastasis, which was similar to lymph node metastasis with 9.0 months (95% CI: 7.6-10.4) (P = 0.762). Median PFT was 13.2 months (95% CI: 3.5-22.9) for bone and soft tissue metastasis, which was slightly shorter than ad- renal metastasis with 15.2 months (95% CI: 2.7-27.7) (P = 0.501). Median PFT of liver metastasis was 5.2 months (95% CI: 2.9-7.5), which was shorter than oth- er organs (P < 0.001). Median PFT was not reached in pancreas and spleen, but was > 22.8 months and > 20.6 months, respectively. An overall comparison of all the PFT curves for each organ is shown in Figure 4. DISCUSSION It is clear that different therapeutic effects of targeted therapy in the treatment of patients with mRCC are partly correlated with individual metastatic organs. In this study, we further evaluated the response and PFT of each organ individually. We found that metastasis in different organs resulted in organ-specific PFTs and responses to sunitinib. Tumor burden has been shown to be a prognostic fac- tor in mRCC(11-13). In this study, we evaluated the tumor burden separately based on the metastatic organs. The results showed that the median tumor burden between different organs was relatively consistent with 4.3 cm Table 2. The distribution of MSKCC scores, tumor burden, and dose changes based on different metastatic organs Metastatic organs n (%) MSKCC risk classification Median tumor burden (IQR), cm Dose reduction or interruption n (%) Low Intermediate Poor Lung 46 (48.4) 31 (32.6) 18 (19.0) 4.3 (2.3–5.6) 48 (50.5) Lymph node 38 (55.1) 21 (30.4) 10 (14.5) 4.0 (2.4–5.1) 33 (47.8) Bone and soft tissue 19 (36.5) 15 (28.9) 18 (34.6) 3.8 (2.1–4.8) 20 (38.5) Liver 6 (27.3) 6 (27.3) 10 (45.4) 4.1 (2.6–5.5) 10 (45.5) Adrenal gland 7 (33.3) 8 (38.1) 6 (28.6) 3.9 (1.8–4.9) 11 (52.4) Pancreas 3 (27.3) 5 (45.4) 3 (27.3) 3.8 (1.4–5.0) 4 (36.4) Spleen 3 (27.3) 3 (27.3) 5 (45.4) 3.6 (1.9–4.5) 3 (27.3) P value 0.071 0.068 0.714 Abbreviations: MSKCC, Memorial Sloan-Kettering Cancer Center; IQR, interquartile range. Metastatic-organ-specific responses to targeted therapy-Jiang et al. Vol 18 No 5 September-October 2021 515 in lung, 4.0 cm in lymph node, 3.8 cm in bone and soft tissue, 4.1 cm in liver, 3.9 cm in adrenal gland, 3.8 cm in pancreas, and 3.6 cm in spleen. However, the effica- cy of sunitinib varied among organs. Previous results have suggested that the biological behaviors of organs affected by metastasis and the corresponding microen- vironments may be related to the efficacy of antiangi- ogenic therapy(14-16). In the present study, although all of the metastases originated from ccRCC, the thera- peutic responses were organ specific. The ORRs were from 72.7% in the pancreas to 9.1% in the liver. The wide range of ORRs may reflect heterogeneity among the metastatic tumors or the relationship between the growth of metastatic tumors and neovascularization in the various organs. Identification of organ-specific dif- ferences in the efficacy of targeted therapies may ena- Figure 2. Responses and maximal tumor shrinkage of bone and soft tissue metastasis (A) and adrenal metastasis (B) assessed by RE- CIST1.1. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. Figure 3. Response and maximal tumor shrinkage of liver metastasis (A), pancreas metastasis (B) and spleen metastasis (C) assessed by RECIST1.1. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. Metastatic-organ-specific responses to targeted therapy-Jiang et al. Urological Oncology 516 ble a breakthrough in individualized therapy. The lung is the primary major target organ of metastasis in mRCC, as it is involved in ~45% of cases(4). In a pre- vious study of patients with mRCC and metastases sole- ly to the lung(17), targeted therapy was found to result in a relatively stable PFS (10.6 months), which is similar to that observed in our study (8.6 months). The lung is an organ with an abundant blood supply, and an anti-an- giogenic probably could be more effective. However, we found that lung metastasis had a worse response and shorter PFT than bone and soft tissue, adrenal gland, spleen, or pancreas metastasis. In addition, lymph-node metastasis had a similar PFT to lung metastasis, with a median PFT of 9.0 months. It has previously been sug- gested that surgical resection is beneficial for isolated lymph-node metastases(18). In our population, patients with lymph-node metastasis receiving sunitinib most- ly had metastases to retroperitoneal lymph nodes that were accompanied by metastases to other organs. For these patients, metastatic lymph node excision may not benefit from surgery. From the above results, we con- sidered that patients with lung and lymph node metasta- sis treated with sunitinib may have poor prognosis, and be more suitable for immunotherapy or immunotherapy combined with targeted therapy. However, clinical re- search validation with large cohorts is needed. Previous studies reported that some selected patients with adrenal-gland metastasis underwent surgery as an alternative treatment option(19,20). Differently, in our study we found that the organ-specific median PFT for adrenal-gland metastasis was 15.2 months longer than lung, lymph node, and liver metastasis; this suggested that surgical treatment of adrenal-gland metastasis may be not a priority and can be postponed if other metas- tases are also well controlled. Bone and soft-tissue me- tastasis had a similar response to adrenal-gland metas- tasis, with a median PFT of 13.2 months. Bone and soft tissue metastasis has previously been shown to have a negative effect on the outcome in patients with ccRCC who are treated with sunitinib, due to skeletal-related events, including pain, impending fractures, nerve com- pressions, hypercalcemia, and pathological fractures(21). Considering the relatively long PFT and stable response associated with bone metastasis in patients with mRCC, we suggest that local therapy may prevent the occur- rence of skeletal-related events and may improve the therapeutic effects associated with targeted therapy. In this regard, radiotherapy has been shown to have prom- ising effects on short-term pain control, prevention of fractures, and avoidance of the need for surgery in pa- tients with RCC and multiple bone metastases(22). In our study population, the ORR and PFT for liver me- tastasis were only 9.1% and 5.2 months, respectively. The association of poor outcomes with liver metastasis in patients with mRCC who are undergoing targeted therapy is supported by previous findings(23,24). There- fore, it may be beneficial for patients with liver metas- tasis to also receive adjuvant treatment, such as surgery, transarterial chemoembolization, or radioablation(25-27). In addition, immune checkpoint inhibitors may also be applicable. The pancreas and spleen are infrequently affected by metastasis in mRCC, and published reports relating to these types of metastasis involve cases of isolated and metachronous lesions, for which surgical resections have been recommended(28-32). However, we found that metastases in the pancreas and spleen had favorable responses to sunitinib, compared with other organs, suggesting that targeted therapy is a suitable treatment for these lesions, and that surgery or other systematic therapies may not be necessary. A limitation of our study was that it was a retrospective study involving a limited number of cases. A prospec- tive, observational study with a larger population may be needed to confirm (or refute) our findings. In addi- tion, further exploration of the possible mechanisms underlying the organ-specific responses of metastases is needed. CONCLUSIONS The present study found organ-specific responses of Figure 4. Kaplan–Meier analysis of organ-specific progression free time. Metastatic-organ-specific responses to targeted therapy-Jiang et al. Vol 18 No 5 September-October 2021 517 metastases to sunitinib treatment. Metastases in the pancreas and spleen may have the best responses, and liver metastasis may have the worst. We suggest that other therapies may be explored for the optimal treat- ment of liver, lung, and lymph-node metastasis. Further prospective validation is needed to confirm these find- ings. ACKNOWLEDGEMENT FUNDING This work was supported by the Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine [2016-I2M-1-007] and the Beijing Hope Run Special Fund of the Cancer Foundation of China [LC2018L02]. Availability of Data and Materials The datasets used and/or analyzed in the current study are available from the corresponding author on reason- able request. CONFLICT OF INTEREST The authors report no conflict of interest. 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