Responses of Renal Cell Carcinoma to 29 Therapies
Responses of Renal Cell Carcinomas to 29 Different Systemic Anti-Cancer Therapies
Ofer N. Gofrit¹, Liat Appelbaum², Vladimir Yutkin¹, Mordechai Duvdevani¹, Guy Hidas¹, Steve Frank³, Yakir Rottenberg³
- Department of Urology, Hebrew University of Jerusalem, Hadassah Medical Center, Faculty of Medicine
- Department of Radiology, Hebrew University of Jerusalem, Hadassah Medical Center, Faculty of Medicine
- Department of Oncology, Hebrew University of Jerusalem, Hadassah Medical Center, Faculty of Medicine
OPEN ACCESS
PUBLISHED: 31 July 2025
CITATION: Gofrit, O. N., et al., 2025. Responses of Renal Cell Carcinomas to 29 Different Systemic Anti-Cancer Therapies. Medical Research Archives, [online] 13(7).
https://doi.org/10.18103/mra.v13i7.6752
COPYRIGHT:© 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI https://doi.org/10.18103/mra.v13i7.6752
ISSN 2375-1924
ABSTRACT
Introduction: The prevailing view is that renal cell carcinomas (RCCs) are resistant to chemotherapy. However, it is essential to periodically reassess this perspective, as RCC is diagnosed concurrently with other malignancies, making treatment priority in these patients. The prognosis for these patients is grim.
RCC is considered chemoresistant. In the metastatic setting, its response to single or combined chemotherapy agents has been examined in several phase II studies. Single agents, including vinca alkaloids, gemcitabine, and fluoropyrimidine derivatives, have shown an objective response rate (ORR) of 0-20%. One study reported an ORR of 26% with acceptable. Combination chemotherapy, particularly involving gemcitabine and fluorouracil, has not been shown to provide a meaningful response in this setting. 4 Immunotherapy, including anti-PD-1 agents, has also shown promise in this regard. The aim of this study was to evaluate the response of RCC to various systemic anti-cancer therapies.
Methods: A retrospective review of patients with renal cell carcinoma (RCC) present at our institution was conducted. The largest diameter of the RCC from the initial pathology report was measured and recorded with the measurements taken at the same location at the follow-up period. Renal pathological specimens were evaluated using the 2002 TNM classification, histologic subclassing according to the 1997 UICC classification, and grading based on Fuhrman’s nuclear grading system. The tumor’s linear growth rate was calculated by subtracting the tumor’s largest diameter in the initial CT (mm) from the largest diameter on the last CT (mm) divided by the time elapsed between the studies (in years). Diameter changes within a 3 mm range were classified as “no change”. The research was approved by the institutional review board.
Keywords: renal cell carcinoma, systemic anti-cancer therapies, chemotherapy, immunotherapy
Introduction
RCC is considered chemoresistant. In the metastatic setting, its response to single or combined chemotherapy agents has been examined in several phase II studies. Single agents, including vinca alkaloids, gemcitabine, and fluoropyrimidine derivatives, have shown an objective response rate (ORR) of 0-20%. One study reported an ORR of 26% with acceptable. Combination chemotherapy, particularly involving gemcitabine and fluorouracil, has not been shown to provide a meaningful response in this setting. 4 Immunotherapy, including anti-PD-1 agents, has also shown promise in this regard. The aim of this study was to evaluate the response of RCC to various systemic anti-cancer therapies.
Materials and Methods
The effects of systemic anti-cancer therapies, not targeted at RCC, were retrospectively evaluated through an archival search for patients with diagnosis of RCC (ICD-9-CM 189.0) and another type of cancer (ICD-9-CM codes 140–239). The initial search yielded 746 results. Patients included in the study met all the following criteria:
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Histologically confirmed non-renal cancer.
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Histologically confirmed RCC.
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A CT scan performed before the initiation of systemic therapy, showing measurable RCC.
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Undergoing chemotherapy or immunotherapy directed at the non-renal cancer, while the RCC received no specific treatment.
Subsequent CT scans conducted at least four months after therapy commencement.
The largest diameter of the RCC from the initial CT scan was recorded and compared with the measurements taken at the same location at the end of the follow-up period. Renal pathological specimens were evaluated using the 2002 TNM classification, histologic subtyping according to the 1997 UICC classification, and grading based on Fuhrman’s nuclear grading system.¹⁹ The tumor’s linear growth rate was calculated by subtracting the tumor’s largest diameter in the initial CT (mm) from the largest diameter on the last CT (mm), then dividing by the time elapsed between the studies (in years). Diameter changes within a 3 mm range were classified as “no change.” The research was approved by the local ethical committee (#302-19-HMO) that waived the requirement for informed consent.
Results
PATIENTS
Demographics, types of malignancy, and systemic therapy protocols of the 20 patients that met all criteria are detailed in Table 1. The cohort consisted of 14 men and 6 women, with an average age at diagnosis of 61.4 years (SD 10.0 years). Cancer types included lymphoma in 7 patients, lung adenocarcinoma and breast cancer in 4 patients each, and leukemia in 3 patients. Each of the following was present in one patient: colon cancer, melanoma, gastrointestinal stromal tumor, and carcinoma of the gastroesophageal junction. One patient had three types of malignancies (patient #8). After a median follow-up of 56.5 months (Q1 38.75, Q3 97.75), eleven patients died, all from their non-renal cancers.
SYSTEMATIC TREATMENTS
Patients received a total of 29 preparations, administered either as single agents or in combinations. CHOP or R-CHOP combinations were administered to 4 patients. Other commonly prescribed agents included cyclophosphamide and doxorubicin, each given to 5 patients, and vincristine to 4 patients. The complete list of medications is available in Supplementary Document 1.
RENAL CELL CARCINOMA DIRECTED TREATMENTS
Treatments directed at RCC and the patients’ statuses at the end of the follow-up period are shown in Table 2. By the end of the follow-up, 6 patients had undergone radical nephrectomy, 5 had partial nephrectomy, 3 had percutaneous ablation, and one patient had main renal artery embolization (to control bleeding). Five patients received no specific RCC-directed therapy.
RESPONSE OF RENAL CELL CARCINOMA TO SYSTEMIC THERAPY
RCC diameters, time intervals, and growth rates are detailed in Table 3 and Fig. 1. Representative CT images are presented in Fig. 2. The complete set of photos and case histories is available in Supplementary Material 2. The average RCC diameter on the initial CT was 41.9 mm (SD 25.1 mm). After an average follow-up of 28.9 months (SD 29.6 months), the RCC diameter increased in 15 patients (by an average growth rate of 7.3 mm/year, SD 2.9 mm/year). In patients treated with CHOP or R-CHOP, the average growth rate was 8 mm/year (SD 3.0 mm/year). In those treated with cyclophosphamide or doxorubicin, the average growth rate was 5.9 mm/year (SD 4.5 mm/year), and in patients treated with vincristine, the average growth rate was 6.3 mm/year (SD 5.1 mm/year). The RCC diameter remained stable in four patients and decreased in two patients (by 12 mm/year in a tamoxifen-treated patient and by 3.1 mm/year in a patient treated with a combination of bevacizumab, paclitaxel, and cisplatin).
Fig. 1. A: Tumors that increased in size; B: Tumors that remained stable or decreased in size.
Fig. 2.
A: A 40-year-old man diagnosed with mantle cell lymphoma and Fuhrman grade 2 clear cell carcinoma. B: After 10 months and 4 cycles of R-CHOP, the tumor’s diameter increased by 10 mm.
C: A 58-year-old man diagnosed with diffuse large B-cell lymphoma and Fuhrman grade 3 clear cell carcinoma. D: After 11 months and 6 cycles of R-CHOP, the tumor’s diameter increased by 6 mm.
E: A 50-year-old woman with breast cancer and Fuhrman grade 2 clear cell carcinoma. F: After 4 months of tamoxifen, the tumor’s diameter decreased by 2.5 mm.
Supplementary material 2
Medications list (number of patients treated)
aenetoclax
anastrazole
azacitidine
bendamustine
bevacizumab
brentuximab vedotin
capecitabine
Cisplatin (2)
cyclophosphamide (5)
dacarbazine (2)
docetaxel (2)
doxorubicin (5)
etoposide
Fludarabine
fluorouracil
high-dose cytarabine
imatinib
ipilimumab
methotrexate
oxaliplatin
pertuzumab
prednisone (4)
rituximab (3)
rituximab (4)
tamoxifen
trastuzumab
vinblastine
vincristine (4)
vinorelbine
Discussion
In this study, we evaluated the effects of 29 systemic anticancer medications on RCC growth rates in the absence of specific anti-RCC therapy. These medications included some of the most aggressive combinations in hemato-oncology (CHOP and R-CHOP) and some of the latest anticancer agents, such as modern chemotherapeutics, monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates. The general response of RCC to systemic treatment was disappointing. In 14 out of 20 patients, the RCC diameter increased during follow-up (by an average of 6.9 mm/year). Specifically, in the 4 patients treated with CHOP or R-CHOP, the average diameter increase was even higher (8 mm/year), and in the 5 patients treated with cyclophosphamide or doxorubicin, it was 5.9 mm/year.
Are these growth rates typical for untreated RCC, or does chemotherapy had some effect on tumor’s growth rate? Much of the literature on the growth rate of untreated RCC stems from surveillance studies in patients with solid-enhancing renal masses. A meta-analysis of 10 studies involving 234 patients with untreated enhancing renal masses reported an average growth rate of 3 mm/year.¹² This figure might underestimate the actual growth rates as it is based on evaluations of small tumors (average diameter of 2.6 cm at presentation) in elderly patients (average age 71 years) without histological confirmation in many cases. However, the growth rate in patients with histologically confirmed RCC was not significantly higher (4 mm/year). When larger tumors were monitored, the growth rate was remarkably similar to the rates observed in the current series (5.7–8.0 mm/year).²⁰,²¹ Thus, it is reasonable to conclude that most anticancer medications administered in the current study did not modify the natural growth of RCC.
Several mechanisms have been associated with RCC’s resistance to chemotherapy among them are: Overexpression of p-glycoprotein MDR1/ABCB1 transporters that actively pump chemotherapeutic agents out of the cells.²² Rapid drug inactivation through enhanced cytochrome p450 CYP1B1 activity that leads to drug inactivation before cellular damage is done.²³ Hypoxic induced deactivation of p53. This is facilitated by the loss of the von Hippel-Lindau (VHL) tumor suppressor protein, leading to Hdm2-mediated suppression of p53.²⁴ Additionally, dysregulation of the PI3K/AKT/mTOR
pathway, frequently observed in RCC, leads to the downregulation of anti-angiogenic factors like thrombospondin-1, contributing to this phenomenon.²⁵ Changes in the detoxification pathway for reactive oxygen within the glutathione redox cycle and activation of the ATP-dependent drug efflux pump via the membrane-bound P-170 glycoprotein also contribute to the primary resistance of chemotherapy in RCC models.²⁶
In four patients, RCC diameter remained stable during follow-up, and in two patients, it decreased. The most significant case of shrinkage involved a 50-year-old woman with metastatic breast cancer and a 63 mm Fuhrman grade 2 clear cell carcinoma. She was treated solely with tamoxifen, a mixed estrogen receptor agonist and antagonist known for its low toxicity and some anti-RCC activity, which previously led to the regression of lung metastases.²⁷ These observations had established tamoxifen as the standard of care in control groups for clinical trials of immunotherapy.²⁸ However, due to its low response rate, its use was eventually discontinued.²⁹ More recently, mitochondrially targeted tamoxifen (MitoTam) has shown promise, stabilizing disease in four patients and inducing partial responses in one after three lines of therapy.³⁰ Another patient treated with a combination of bevacizumab, docetaxel, and cisplatin experienced a decrease in diameter by 3.1 mm/year. We hypothesize that tumor shrinkage was mediated by inhibition of the vascular endothelial growth factor pathway by bevacizumab, which has demonstrated meaningful clinical benefits in metastatic RCC in both first- and second-line settings. A randomized phase II trial among cytokine-refractory patients showed a doubling of the time to disease progression compared with the control (4.8 vs. 2.5 months; P < .001).³¹
Our findings are consistent with previous studies demonstrating RCC’s resistance to chemotherapy. Yet, other agents such as anti-angiogenic agents and tamoxifen may exhibit some activity against RCC. Four patients with hematologic malignancies exhibited stable renal masses. This corroborates the findings of Johnson et al., who reported on six patients with concurrent RCC and hematologic malignancies, noting a 50% 1-year mortality rate, none of which were related to RCC.³² In any case, the strategy of prioritizing treatment for the other malignancy before addressing the RCC appears to be appropriate.
This study is limited by its retrospective methodology and small sample size. Additionally, despite attempts to meticulously measure cancer diameters, slight deviations could slightly modify the results.
Conclusions
This study evaluated the response of RCC to 29 systemic chemotherapeutic agents, including both traditional and modern agents and several of the most toxic combinations used in hemato-oncology. No solid conclusion regarding any agent can be reached with this methodology. The remarkable resistance of RCC to chemotherapy was confirmed. Nevertheless, the use of tamoxifen, a time-honored and well-tolerated medication, can be reconsidered in combination with modern agents. Similarly, bevacizumab is worth further investigation. This methodology can be adopted in other situations in which there are two clinical conditions, and one takes priority over the other.
Conflict of Interest:
None
Funding:
None
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