112 Case report

Renal cell cancer metastases to esophagus and stomach successfully treated with radiotherapy and pazopanib Santiago Cabezas-Camareroa, Javier Puentea, Aránzazu Manzanoa, Juan Antonio Coronab, José Luis González-Larribaa, Israel Bernal-Becerrac, Miguel Soteloa and Eduardo Díaz-Rubioa Renal cell cancer has been rarely reported as a cause of gastric or esophageal metastases. They usually present with gastrointestinal bleeding and most cases have been managed surgically or endoscopically. We report the case of a 38-year-old man with a 4-year history of metastatic renal cell carcinoma admitted to the emergency room with melena and anemia. At endoscopy, three esophageal polypoid lesions (middle and distal thirds) and a 7 cm mass in the gastric fundus were identified. Biopsy revealed esophageal mucosa infiltrated by renal cell carcinoma. Radiotherapy was administered (30 Gy in 10 fractions), followed by pazopanib, with excellent tolerance and without new bleeding episodes. Computed tomography scan showed complete disappearance of the esophageal and fundic lesions at 3 months follow-up. Twenty-four months after being initiated on pazopanib, there is no radiological evidence of disease. This is the first reported case showing

Case A 38-year-old man with a history of metastatic renal cell cancer was admitted to the emergency room in February 2012 with a 24-h history of melena. In October 2008, he had undergone a left radical nephrectomy for a renal cell carcinoma (RCC) of clear cell type, Fuhrman grade 4, pT3b pN1 M0, stage III of the AJCC/UICC. At 3 months follow-up, a ganglionar mediastinal relapse occurred, being classified with a MSKCC intermediate prognostic risk [1]. He initiated treatment with sunitinib (six cycles) and subsequently, upon progression, he received everolimus (10 cycles), sorafenib (seven cycles), and eventually a rechallenge with sunitinib, achieving stable disease after the third cycle but suffering a lymphatic mediastinal and supraclavicular progression after the fifth cycle in November 2011. As the patient was asymptomatic, a therapeutic vacation was initiated, with the next oncologic visit scheduled 3 months later. On examination, he appeared pale and was mildly hypotense. Laboratory tests showed 8.0 g/dl hemoglobin (29% hematocrit). Urgent upper gastrointestinal endoscopy (UGE) showed three polypoid lesions along the esophageal mucosa, at 25, 35, and 38 cm distance from the incisors. The last one, which impeded the passage of the endoscope, was biopsied. Pathological examination revealed esophageal mucosa infiltrated by a RCC of clear cell type (Fig. 1). 0959-4973 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

complete remission of gastric and esophageal metastases after treatment with radiotherapy and pazopanib. AntiCancer Drugs 26:112–116 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Anti-Cancer Drugs 2015, 26:112–116 Keywords: esophagus, metastasis, pazopanib, radiotherapy, renal cell carcinoma, stomach Departments of aMedical Oncology, bRadiation Oncology and cPathology Center affiliated to the “Red Temática de Investigación Cooperativa (RD12/0036/006)”, Instituto Carlos III, Spanish Ministry of Economy and Competitivity, Hospital Clínico San Carlos, 28040 Madrid, Spain Correspondence to Santiago Cabezas-Camarero, MD, Department of Medical Oncology, Hospital Clínico Universitario San Carlos, Profesor Martín Lagos S/N, 28040 Madrid, Spain Tel: + 34 91 330 3649/3546; fax: + 34 91 330 3546; e-mails: [email protected], [email protected] Received 29 March 2014 Revised form accepted 18 June 2014

A second UGE with a pediatric endoscope could surpass the most distal esophageal implant and reach the stomach. A large, friable mass of ∼ 7 cm in diameter grew from the subcardial region toward the fundus, with easy bleeding when touched with the endoscope (Fig. 2). Upper gastrointestinal series confirmed the normal passage of barium contrast (Fig. 2). Computed tomography of the chest, abdomen, and pelvis showed disease progression at the lymphatic level in the supraclavicular, mediastinal, and retroperitoneal regions, as well as at the pulmonary inferior lobe and right adrenal. Implants at the middle and distal esophagus and a big mass in the gastric fundus were also seen (Fig. 2). As there had not been new episodes of melena and hemoglobin remained stable, treatment with pazopanib was initiated, after informing the patient of the increased risk for gastrointestinal bleeding of any antiangiogenic drug in this context. To avoid problems with the passage of oral medication, pazopanib was given diluted at a dose of 400 mg/d (half the approved dosage), as administration of the crushed tablet augments its AUC(0–72) by 46% [2]. Unfortunately, 72 h later, he was admitted to the emergency room of another hospital with ‘coffee-grounds’ vomiting and melena. Laboratory tests showed hemoglobin of 8.0 g/dl and two red blood cell units were transfused. Treatment with pazopanib was ceased and the patient was discharged 2 days later without new DOI: 10.1097/CAD.0000000000000150

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Gastric and esophageal metastases in renal cancer Cabezas-Camarero et al. 113

Fig. 1

Pathology slides of the primary tumor and the biopsied esophageal metastasis. Primary renal cancer showing cells forming tubules and nests (a; H&E, × 10), with an eosinophilic and wide cytoplasm and a high nuclear grade (Fuhrman 4) (b; h and e, × 40). Mucosa infiltrated by an epithelial neoplastic proliferation composed of similar cells as the primary tumor (c, d; H&E, × 4 and × 20). Neoplastic cells demonstrate strong and diffuse expression of renal cell carcinoma (e; × 40) and focal expression of CD10 (f; × 40), a pattern coincident with that of the primary tumor (pictures not shown).

evidence of bleeding. After considering the possible options, hemostatic radiotherapy (RT) was administered to the lesions in the esophagus and stomach, delivering a total dose of 30 Gy (3000 cGy) in 10 fractions, 3 Gy/

fraction, 5 days a week (Fig. 2). Tolerance to RT was acceptable, with epigastric pain well controlled with a low dose of major opioids, mild pirosis, and halitosis, all of which resolved soon after finishing treatment. No

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Fig. 2

Roentgenographic and endoscopic images. Upper gastrointestinal endoscopy (UGE) showing the more proximal esophageal metastasis (a) and the more distal one (b), which obstructs the lumen almost entirely. Both have polypoid features and appear ulcerated. A large gastric polypoid mass is seen just below the cardia (c). Computed tomography (CT) scan demonstrating a 7 cm mass (arrow) in the gastric fundus (d). Upper gastrointestinal series demonstrating several submucosal esophageal lesions and a large subcardial mass, which nonetheless permit normal passage of barium contrast (e, f). Radiotherapy planification CT scan showing a single radiotherapy field encompassing the lesions in the distal 2/3 of the esophagus and gastric fundus (g–i). CT scan at 3 months follow-up with disappearance of the large fundic mass (j). UGE at 12 months follow-up, showing no remnants of the gastric mass and no obvious sequeale. The esophagus was reported as normal, but unfortunately no pictures were taken (k, l).

bleeding episodes were reported during or after RT, and he progressively restarted a normal diet with excellent tolerance. Two weeks after finishing RT, treatment with pazopanib 800 mg/day was resumed. An UGE performed 12 months later showed only mild signs of a superficial chronic gastritis (Fig. 2). After 24 months of continuous treatment with pazopanib, his disease showed a complete radiological response at all sites, with excellent tolerance to the drug (mild hypertension well controlled with

lysinopril, grade 1 diarrhea well controlled with the occasional use of loperamide, and hypopigmentation of skin and adnexa).

Discussion Gastric metastases (GM) occur with a reported frequency of 1.7–5.4% among all cancers [3,4]. They are particularly common in breast and lung cancers and in malignant melanoma [3–5], where they are frequently asymptomatic,

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Gastric and esophageal metastases in renal cancer Cabezas-Camarero et al. 115

although sometimes they may present with signs of gastric outlet obstruction or upper gastrointestinal bleeding [5–7]. GM in RCC have been variably reported in autopsy series [3,4], but clinical evidence of their existence comes mainly from case reports; probably because of their highly vascular component, they are especially prone to bleeding, and thus to become symptomatic. In 2011, Eslick and Kalantar [8] reviewed the literature on GM in RCC, finding 44 cases reported since 1980. Namikawa et al. [9] analyzed data from 22 case reports and found melena, anemia, and hematemesis as the most frequent signs at presentation. GM were most often single, had a polyp-like appearance and a median size of 3 cm, developing most frequently in the body of the stomach [9]. Reports on esophageal metastases (EM) in RCC are much more scant. To the best of our knowledge, only six cases of EM in RCC (including our case) have been reported in the English literature since 1960 [10], and our case is the second that shows coincident GM and EM [11]. GM and EM in RCC usually develop upward from the submucosa, and finally reach the mucosa, becoming easily ulcerated by the acid of the stomach or by minor trauma [12]. Therefore, a rapidly hemostatic procedure is warranted. Although surgery has been the most used treatment, a growing number of cases have been treated by endoscopic resection since year 2000, and a rise in less aggressive surgical resections (i.e. wedge resection) is evidenced [8]. Nevertheless, surgical resection is still the primary option for any solitary RCC metastasis without evidence of metastatic disease elsewhere [13]. In the case that we report, RT proved to be an excellent treatment for large, actively bleeding gastric or esophageal RCC metastases that are not amenable to endoscopic resection, thus avoiding the risks and discomfort of a major surgery in a patient with disseminated disease. RT allowed a rapid hemostatic and probably cytoreductive effect, permitting the safe administration of pazopanib – a VEGFR tyrosine kinase inhibitor (TKi) – with a reportedly low risk (< 1%) for gastrointestinal bleeding [2]. Although hemostatic RT has been used for decades in patients with cancer, studies reporting its efficacy are scarce. Regimens of 5 × 4 and 10 × 3 Gy are the most widely used with this indication, and, although definitive evidence is still lacking, total doses less than 30 Gy seem to be less efficacious [14,15]. In our patient, the first radiological reevaluation took place 10 weeks after the initiation of pazopanib, showing complete disappearance of the lesions in the esophagus and stomach. Thus, it is not possible to know which of the treatments – RT or pazopanib – was mainly responsible for this excellent response. RCC is traditionally considered a moderately radioresistant tumor, and, although palliative RT for bone metastases in RCC is common practice, we found no reports of hemostatic RT for RCC metastases in any location of the gastrointestinal tract except a case reported by Nussbaum and Grossman [10] in 1976, where

hemostatic RT was delivered for an EM, unfortunately without a durable effect. As gastrointestinal metastases in RCC seem to grow toward the lumen without deep infiltration through the wall and because of their highly vascular component, which may be especially sensible to RT, lower RT doses could be as efficacious and potentially less toxic. When a complete endoscopic resection is not technically viable but lesions are nonbleeding and measure 2 cm or less [16], the upfront and cautious initiation of any of the currently approved molecularly targeted agents for RCC would be an option as reported in two cases treated with sunitinib and everolimus [17,18], although assuming a probably higher risk for gastrointestinal bleeding. In contrast, as was shown with our patient, these agents should not be initiated before the proper hemostatic control of gastrointestinal metastases when lesions are large or bleed profusely. There are also several reports of RCC metastases to the small intestine [19] and colon [20], but, in contrast to reports on GM and EM, metastases to these sites usually present with signs of acute intestinal obstruction and/or bleeding, which can be successfully managed with local surgical excisions. It is noteworthy that our patient always showed partial responses or at least stable disease with each TKi treatment used, even after sunitinib rechallenge, and eventually achieved a complete remission after 18 months of pazopanib. After 24 months of continuous treatment with pazopanib, he is still in complete remission, making this case exceptional. Such a protracted response is unusual for any molecularly targeted therapy in RCC, especially in a fifth line of treatment. In fact, the reported median progression-free survival for pazopanib as first line treatment is 8.4 months [21]. Several case reports and case series of patients achieving complete remission with TKis, mainly with sunitinib and sorafenib, have been published [17,21]. However, complete responses with any targeted therapy in RCC are unusual. In a recent study comparing the efficacy and safety of pazopanib versus sunitinib as first line therapy [22], there was only one complete response in the pazopanib group (n = 554) and three complete responses in the sunitinib group (n = 548). It is a matter of debate whether patients achieving a complete response should be maintained on treatment or whether it should be stopped. Arguments to stop treatment would be to minimize the risk of developing drug resistances and to avoid toxic effects and therapy costs. In favor of continuing treatment would be to avoid regrowth of residual cancer cells and the potential for a theoretical ‘rebound effect’ after stopping treatment with a TKi [21]. In our patient, it was decided to continue ‘on’ treatment due to the excellent tolerance to the drug and the presumed high risk for relapse in a patient who had previously progressed to four lines of treatment.

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Finally, there is not a clear anatomic explanation for GM or EM in RCC. Suárez Fonseca et al. [23] proposed a metastatic route by the thoracic duct and azygos system and their connections with the vertebral veins. In our patient, a lymphatic progression in the mediastinal and supraclavicular regions was diagnosed 3 months earlier, a possible indirect evidence of an etiologic role of this route of dissemination. Conclusion

Gastric and EM in RCC usually present with signs of gastrointestinal bleeding, which may preclude the safe use of molecularly targeted therapies. A local hemostatic procedure is advisable before initiating these agents. The occurrence of metastases in the gastrointestinal tract is expected to grow in an era of better diagnostic techniques and increased survival of patients with RCC. We report the first patient showing complete disappearance of gastric and EM using RT and pazopanib. Radiotherapy was well tolerated, leaving no long-term sequelae, and pazopanib demonstrated an exceptionally prolonged response, achieving a complete remission. The rarity of this presentation and its unique management prompted us to report this case.



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Acknowledgements The authors are grateful to Dr Sonia Izquierdo for providing the endoscopy images and for help with their interpretation.



Conflicts of interest

There are no conflicts of interest.


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Renal cell cancer metastases to esophagus and stomach successfully treated with radiotherapy and pazopanib.

Renal cell cancer has been rarely reported as a cause of gastric or esophageal metastases. They usually present with gastrointestinal bleeding and mos...
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