Mattioli 1885

EuropEan Journal of oncology

Eur. J. Oncol. - Vol. 24 - Suppl. 4 - December 2019 | ISSN 1128-6598

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The European Journal of Oncology is indexed by Excerpta Medica (EMBASE), the Elsevier BioBASE and SCOPUS

Ramazzini Institute

Integration of active surveillance, local and systemic treatments engenders prolonged survival in renal cell carcinoma: a case report

Major and prolonged response to nivolumab in a renal cell carcinoma patient who previously experienced severe renal toxicity while on tyrosine kinase inhibitor: a case report

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01-board.indd 1 24/02/20 16:42

Contents

Volume 24 / Suppl. 4 December 2019

Case reports

3 Integration of active surveillance, local and systemic treatments engenders prolonged survival in renal cell carcinoma: A case report

Matteo Perrino, Paolo Andrea Zucali

11 Major and prolonged response to nivolumab in a renal cell carcinoma patient who previously experienced severe renal toxicity while on tyrosine kinase inhibitor: A case report

Elena Fea

Mattioli 1885 srl - Strada di Lodesana 649/sx43036 Fidenza (Parma)tel 0524/530383fax 0524/82537www.mattioli1885.com

Direttore GeneralePaolo CioniDirettore ScientificoFederico Cioni

Formazione/ECMSimone AgnelloProject ManagerNatalie CerioliMassimo RadaelliEditing ManagerAnna ScottiEditingValeria CeciForeign RightsNausicaa CerioliDistribuzioneMassimiliano Franzoni

Journal Director / Direttore ResponsabileFederico Cioni

Autorizzazione del Tribunale di Parma n. 14/97 del 11/6/1997ISSN 1128-6598La testata fruisce dei ContributiStatali diretti di cui alla legge 7 agosto 1990, n. 250

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Integration of active surveillance, local and systemic treatments engenders prolonged survival in renal cell carcinoma: A case reportMatteo Perrino1, Paolo Andrea Zucali2

1 Humanitas Cancer Center, Humanitas Research Hospital, Rozzano, MI, Italy; 2 Humanitas Cancer Center, Farmacologia Clinica, UO Oncologia Medica e Ematologia, Humanitas Research Hospital, Rozzano, MI, Italy

Summary. Dramatic improvements in survival outcomes have been obtained in renal cell carcinoma (RCC) patients since the availability of tyrosine kinase inhibitors (TKI) with antiangiogenic properties and immune checkpoint blockers (ICB) targeting CTLA-4 and the PD-1/PD-L1 axis. In the current management of advanced RCC, the integration of different treatment modalities represents the crucial element to couple the best survival benefits with the lowest toxicity burden. Oligometastatic and oligoprogressive diseases are the setting where the local and systemic therapies fully integrate in the scenario of a personalized treatment. Here we report the case of a clear cell RCC patient with prolonged survival fostered by active surveillance, multiple surgical approaches, TKI (pazopanib) and ICB (nivolumab) treatments, vouching for the relevance of the current therapeutic armamentarium.

Key words: RCC, surgery, tyrosine kinase inhibitors, immune checkpoint blockers, thyroid metastasis, active surveillance

EUR. J. ONCOL.; Vol. 24, Suppl. 4, pp. 3-9, 2019 © Mattioli 1885

Case report

PATIENT’S MEDICAL HISTORY

Female, 60-year-old, primary school teacher, never-smoker

Family history: Patient’s mother died at the age of 65 years of breast cancer

Past medical history: Arterial hypertension in medical treatment

February 2011: Flank pain and anemia led to radiological diagnosis of left renal cell carcinoma (RCC)

March 2011: Surgical intervention of radical left nephrectomy, partial pancreatic resection and splenec-tomy. Histological examination documented a clear cell RCC (ccRCC) pT3a N0 M1 (pancreatic metastasis).

November 2011: Surgical removal of a metastasis in the adipose tissue of the right posterior pararenal space.

January 2013: Progressive increase of a retroperitoneal lesion and lung nodules. Intermediate risk accord-ing to IMDC score, first-line pazopanib introduced, with prolonged disease control.

February 2017: surgical removal of a voluminous thyroid metastasis, pazopanib maintained.

September 2017: Second-line nivolumab due to hepatic progression led to disease response.

September 2019: Prolonged response still ongoing two years from treatment beginning

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M. Perrino, P.A. Zucali4

Introduction

Tyrosine kinase inhibitors (TKI) and immune checkpoint blockers (ICB) represent the elements harboring the major impact in the recent scenario of medical oncology, allowing the achievement of un-precedented survival outcomes in several malignant diseases. Renal cell carcinoma (RCC), a tumor histori-cally targeted with both antiangiogenic TKI and im-munotherapy (1) due to its biological features of hyper-vascularization and tumor-immune interactions (2,3) such as hemangioblastomas and renal carcinomas and their sporadic counterparts, are cystic and well vascu-larized. Mutations of the VHL tumor-suppressor gene and elevated levels of vascular endothelial growth fac-tor (VEGF, respectively, is a meaningful example of the benefit driven by these two classes of agents. Moreo-ver, the biological and clinical behavior of RCC, often including indolent diseases, sustains the role of local treatments (i.e. surgery, radiotherapy, interventional ra-diology techniques) as key players in the global manage-ment of RCC patients (4). In this perspective, surgical procedures are not only addressed to cytoreductive ne-phrectomy (5), but oligometastatic disease (i.e. tumors presenting with few distant metastases) can be suitable for local approaches aiming at removal of all the macro-scopic disease sites. Similarly, the development of soli-tary or isolated metacronous metastases (oligoprogres-sive disease) may be again suitable for local approaches with a radical intent. In this scenario, the continuous discussion of patients’ histories within multidisciplinary tumor boards during their disease course represents the most advantageous way to provide them with the best survival outcomes. The integration of the competences of different specialists involved in RCC patients’ care (oncologist, urologist and radiologist, among the oth-ers) is indeed pivotal to give the best treatment indi-cations and to guarantee the best synergy between the numerous therapeutic strategies currently available.

Here we report the case of an RCC patient still alive eight years after the diagnosis of (oligo)metastatic disease. The harmonization of surgical and systemic treatments during this long period, together with ac-tive surveillance periods, probably contributed to the favorable outcomes, encompassing an excellent quality of life.

Case presentation

The female patient, 60-year-old, is a never-smoker, primary school teacher without a significant medical history except for arterial hypertension treated with medical therapy. Her mother died at the age of 65 years from breast cancer. In February 2011, the patient referred to the emergency room due to the persistency of left flank pain and anemia. The CT scan revealed a large, irregular mass in the left kidney with uneven contrast enhancement and a suspect nodule in the body of the pancreas (Figure 1A and 1B). The persistency of bleeding from the mass required left renal and adre-nal artery selective embolization. In March 2011, the patient underwent a surgical intervention of radical left nephrectomy and of resection of pancreatic body and tail accompanied by splenectomy. The histological examination confirmed the radiological diagnosis of RCC in its clear cell histotype (ccRCC), bifocal, Fuhr-man grade II, with peritumor vascular invasion, venous emboli in the extratumoral space and infiltration of the perirenal adipose tissue. Tumor cells were detected in the pancreatic nodule, leading to a pathological stage pT3aN0 M1. A post-surgical CT scan in April 2011 identified a new centimetric lesion in the adipose tis-sue of the right posterior pararenal space, highly sus-pected for disease recurrence, and hepatic nodules, whose nature was less certain. A wait-and-see strategy was adopted and in July 2011 an abdomen MRI docu-mented the dimensional stability of the right parare-nal nodule, while the liver did not harbor pathologi-cal lesions. The following CT scan in September 2011 documented the dimensional increase of the pararenal nodule (Figure 2), without additional signs of disease in the abdomen and in the thorax. Due to the isolated disease recurrence, the multidisciplinary tumor board endorsed the surgical approach to the lesion that was removed through laparoscopy and was confirmed as a metastasis of ccRCC. The patient was then referred to follow-up. In September 2012, a retroperitoneal and two infracentimetric nodules were considered suspect-ed at the CT scan. Due to the low disease burden and to slow tumor growth kinetics, the multidisciplinary tumor board endorsed a strategy of active surveillance. In January 2013, the CT scan documented a meaning-ful increase of the bilateral lung nodules and of the re-

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Integration of active surveillance, local and systemic treatments 5

troperitoneal lesion (Figure 3), that justified a systemic treatment approach; in the same period the patient stopped her work due to poor physical conditions. The patient (ECOG performance status PS = 0) was classi-fied at intermediate risk according to the International Metastatic RCC Database Consortium (IMDC) risk stratification groups (6), and in January 2013 was can-didate to a first-line treatment with pazopanib 800

mg/daily. The treatment was well tolerated, with the exception of grade 2 arterial hypertension, persisting despite the implementation of a medical treatment, and requiring a pazopanib dose reduction to 600 mg/daily. The first radiological evaluation after two months of treatment documented a major response (Figure 4) and the treatment was maintained without further ad-verse events. In November 2014, the CT scan detected a hypovascularized thyroid nodule, which at the cyto-logical examination turned out to be a metastasis from the ccRCC. In April and July 2015, given the persist-

Figure 1. Baseline CT correlates (February 2011). A large, uneven exophytic mass in left kidney (A, red arrow) was accompanied by a nodule in the pancreatic body (B, green arrow)

Figure 2. CT scan of September 2011. The green arrow indi-cates the nodule in the right posterior pararenal space

Figure 3. In January 2013, the dimensional increase of bilateral lung and right retroperitoneal nodules (green arrows) required systemic treatment introduction (pazopanib)

➘

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M. Perrino, P.A. Zucali6

ing small dimensions of the thyroid nodule, not en-gendering a mass-effect symptomatology, no specific treatment indication was addressed by the multidis-ciplinary tumor board. Nevertheless, in January 2016, the thyroid lesion was significantly increased (Figure 5), and the risk of tracheal infiltration fostered its sur-gical removal through right emithyroidectomy (Feb-ruary 2016, metastasis of ccRCC confirmed). Given the lack of symptoms, toxicity and additional disease localizations, the pazopanib treatment was maintained with subsequent disease stability without detectable macroscopic signs of malignancy.

In August 2017, after four years and seven months of pazopanib treatment, the detection of new hepatic lesions (Figure 6) prompted a switch to a second-line

treatment (patient’s ECOG PS = 0). Nivolumab ad-ministration (3 mg/kg every two weeks) started in September 2017 and was well tolerated without the onset of dysimmune toxicities. The first radiological evaluation in November 2017, after the third nivolum-ab cycle, was tricky in its interpretation as the CT scan small nodules (bilateral pulmonary, head of the pancreas, digiunal ansa) and a partial response of liver metastases. The timeframe from baseline CT scan and the beginning of nivolumab treatment was 40 days, suggesting a potential appearance of the nodules cited

Figure 4. After two months of pazopanib treatment (March 2013), a major response was observed (red arrow). Green arrow indicates the dimensional decrease of the right retroperitoneal nodule

Figure 5. In February 2016, the increase of the thyroid metasta-sis (green arrow) required right emithyroidectomy

Figure 6. Hepatic disease progression (hyperdense lesion inside the green circle) in August 2017 led to the switch to second-line therapy with nivolumab.

➘

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Integration of active surveillance, local and systemic treatments 7

above before the immunotherapy onset. Moreover, the excellent clinical conditions and the absence of symp-toms justified the nivolumab continuation. In January 2018, after three additional nivolumab cycles, a partial disease response was documented at hepatic and pul-monary level, while a new, infracentimetric peritoneal lesion was detected. Nivolumab was pursued and in April 2018 a complete lung response and a dimension-al reduction of liver metastases were achieved after a total of 12 cycles. In May 2018, after fifteenth weight-based cycle, bimonthly nivolumab was switched to the dosage of 480 mg flat dose monthly. At the last follow-up in August 2019 (31 nivolumab treatment cycles) excellent clinical conditions are maintained and the patient remains asymptomatic (she resumed teach-ing again), continuing the nivolumab treatment at the dose of 480 mg flat dose monthly.

Discussion

The current availability of several therapeutic op-tions for the treatment of advanced RCC allows for the achievement of a prolonged survival (7). Neverthe-less, the positive outcomes observed in clinical practice are results both of the evidence driven from clinical trials, defining the new standards of care, and of the global treatment strategies to be adopted for every sin-gle patient, in the setting of a personalized therapeutic approach. Here indeed we reported the case of a pa-tient alive eight years after the diagnosis of metastatic ccRCC. The timely management of several therapeu-tic strategies, within a multidisciplinary tumor board, likely represents the key element explaining this suc-cess (Figure 7). Oligometastatic disease at diagnosis (isolated pancreatic metastasis) was approached with radical surgery, followed by active surveillance and

Figure 4. Graphical representation of disease course and treatment administration.TKI: Tyrosine kinase inhibitor; ICB: Immune checkpoint blocker

95 months survival (ongoing)

Diagnosis

22 months 55 months 24 months

First-line treatment: TKI

PAZOPANIB

Secon-line treatment: ICB

NIVOLUMAB

Left nefrectomy and partial pancreasectomy (oligometastatic disease)

Resection of a metastasis in the right pararenal space (oligoprogressive disease)

Right emithyroidectomy (oligoprogressive disease)

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M. Perrino, P.A. Zucali8

removal of the nodule in the right posterior parare-nal space. Systemic treatment with pazopanib was introduced after an additional period of wait-and-see, when retroperitoneal and lung metastases had already showed a progressive dimensional increase, in line with the evidence available at the time (year 2013) (8,9) as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy. Again, thyroid oligoprogressive dis-ease was surgically approached after a period of obser-vation, with pazopanib maintenance (10). Of interest, thyroid metastases are rare events in RCC patients and, compared to other sites of metastasis, their oc-currence seems to be associated with prolonged sur-vival (11,12), suggesting a potential kidney-thyroid biological axis of dissemination for indolent tumors. Nivolumab was then introduced when hepatic disease progression was documented and its administration engendered a prolonged disease response, still ongoing after two years since the treatment beginning. Of note, patient’s conditions have always been good (ECOG PS = 0), allowing her to maintain an optimal quality of life and likely favoring the treatment outcomes. The low disease burden at pazopanib beginning has likely contributed to the prolonged action of the TKI (55 months) (13), whereas the G2 arterial hypertension, requiring a dose reduction, does not seem to be cor-related to drug efficacy, up to the latest evidence (14). Our patient initiated nivolumab treatment with a good PS and without bone metastases; nevertheless, she har-bored hepatic localizations and did not develop dysim-mune adverse events. We really hope that the patient will achieve an even more prolonged survival benefit from the treatment strategies adopted and from the nivolumab treatment, which is still ongoing.

Conclusions

Together with the availability of new agents for the treatment of RCC, the global patients’ manage-ment within multidisciplinary tumor board discussion allows the achievement of prolonged survival outcomes even in RCC patients with (oligo)metastatic disease at

diagnosis. The timely integration of local and systemic (TKI, ICB) treatments has indeed been crucial to en-gender the positive results in the case we presented. Nivolumab engendered a prolonged survival even after several years of first line treatment with TKI.

References

1. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lan-cet. 2007;370:2103–11.

2. Brieger J, Weidt EJ, Schirmacher P, et al. Inverse regulation of vascular endothelial growth factor and VHL tumor sup-pressor gene in sporadic renal cell carcinomas is correlated with vascular growth: An in vivo study on 29 tumors. J Mol Med. 1999;77:505–10.

3. Thompson RH, Gillett MD, Cheville JC, et al. Costimula-tory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A. 2004;101:17174–9.

4. Dabestani S, Marconi L, Hofmann F, et al. Local treatments for metastases of renal cell carcinoma: A systematic review. Lancet Oncol. 2014;15:e549-61.

5. Soares A, Maia MC, Vidigal F, et al. Cytoreductive ne-phrectomy for metastatic renal cell carcinoma: How to ap-ply new evidence in clinical practice. Oncology. 2019 Sep-tember 12;1-9 [Epub ahead of print].

6. Ko JJ, Xie W, Kroeger N, et al. The international meta-static renal cell carcinoma database consortium model as a prognostic tool in patients with metastatic renal cell carci-noma previously treated with first-line targeted therapy: A population-based study. Lancet Oncol. 2015;16:293–300.

7. Escudier B, Porta C, Schmidinger M, et al. Renal cell car-cinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30:706–20.

8. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722–31.

9. Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol. 2016;17:1317–24.

10. Santini D, Ratta R, Pantano F, et al. Outcome of oligo-progressing metastatic renal cell carcinoma patients treated with locoregional therapy: A multicenter retrospective anal-ysis. Oncotarget. 2017;8:100708–16.

11. Beutner U, Leowardi C, Bork U, et al. Survival after re-nal cell carcinoma metastasis to the thyroid: Single center experience and systematic review of the literature. Thyroid. 2015;25:314–24.

12. Jackson G, Fino N, Bitting RL. Clinical characteris-tics of patients with renal cell carcinoma and metastasis to the thyroid gland. Clin Med Insights Oncol. 2017;11:

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Integration of active surveillance, local and systemic treatments 9

1179554917743981. 13. Cecere SC, Rossetti S, Cavaliere C, et al. Pazopanib in met-

astatic renal cancer: A “real-world” experience at National Cancer Institute “Fondazione G. Pascale.” Front Pharma-col. 2016;7: 287.

14. Goldstein D, Rosenberg JE, Figlin RA, et al. Is change in blood pressure a biomarker of pazopanib and sunitinib ef-ficacy in advanced/metastatic renal cell carcinoma? Eur J

Cancer. 2016;53:96–104.

Correspondence: Paolo Andrea ZucaliHumanitas Cancer Center, Farmacologia Clinica, UO Oncologia Medica e Ematologia, Humanitas Research Hospital, Rozzano, MI, ItalyE-mail: paolo.zucali@cancercenter.humanitas.it

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Major and prolonged response to nivolumab in a renal cell carcinoma patient who previously experienced severe renal toxicity while on tyrosine kinase inhibitor: A case reportElena FeaUO Oncologia, Ospedale Antonio Carle, Cuneo

Summary. The introduction of immune checkpoint inhibitors (ICI) has opened a new era for the treatment of a wide range of malignancies, including renal cell carcinoma (RCC). ICI are characterized by remark-able activity and efficacy, together with a favorable safety profile, still conditioned by the potential onset of dysimmune adverse events. Here we report the case of a patient suffering from clear cell RCC with several large bone disease localizations and bilateral lung metastases at the beginning of a second-line treatment with nivolumab (an anti-PD-1 agent). Of note, the patient had experienced renal toxicity in terms of a grade 4 proteinuria while receiving first-line pazopanib. Nivolumab administration engendered a rapid, symptomatic, deep and sustained disease response, without the recurrence of renal toxicity. Both the efficacy and the lack of substantial adverse events emerging during nivolumab treatment vouch for the good quality of life feasible with this agent for the treatment of metastatic RCC.

Key words: renal cell carcinoma, nivolumab treatment, quality of life

EUR. J. ONCOL.; Vol. 24, Suppl. 4, pp. 11-15, 2019 © Mattioli 1885

Case report

PATIENT’S MEDICAL HISTORY

Male, 69-year-old, retired professor of physical education

Past medical history: Arterial hypertension.

November 2011: Left radical nephrectomy. Histological examination: clear cell renal cell carcinoma (ccRCC), pT2a N0.

2015: Surgical resection of lung metastases.

March 2016: En bloc resection of a wide disease localization in the left humerus.

May 2016: Radiofrequency on a lung nodule.

September 2016: Multisite progression (bone and lung) led to first-line pazopanib treatment (intermedi-ate risk score)

December 2016: Hospitalization for renal toxicity with grade 4 proteinuria, definitive withdrawal of pa-zopanib.

March 2017: Second-line treatment with nivolumab engendered a rapid and impressive disease response.

April 2017: Clear clinical benefit was observed

April 2019: Ongoing disease response without symptoms or signs of renal impairment. On going treat-ment with nivolumab 480 mg monthly (flat dose).

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E. Fea12

1. Introduction

Renal cell carcinoma (RCC) figures among the most incident malignancies and the development of metastatic disease is the principal cause of mortality. In the last decades, therapeutic opportunities have signif-icantly moved forward for RCC patients. Antibodies directed against the vascular endothelial growth fac-tor (VEGF; i.e. bevacizumab), multi-tyrosine kinase inhibitors (TKI) involved in angiogenesis disruption (i.e. sunitinib, pazopanib, cabozantinib, axitinib) and mTor inhibitors (i.e. temsirolimus, everolimus) have represented the standard of care for the treatment of metastatic RCC. Since their introduction, these agents have changed patients’ management and diseases’ courses. Nevertheless, the disease control exerted by these drugs is usually not sustained and toxicities may significantly hamper the quality of life (1) the treat-ment of mRCC, metastatic Renal Cell Carcinoma, has become more and more complex due to the approval of a great number of effective systemic treatments that have significantly improved the prognosis of patients suffering from such disease. An additional knowledge of the genetic aberrations and the molecular pathways alterations that underlie RCC, has promoted the de-velopment of several novel agents, known as target therapies (TTs. Assuming TKI administration as the consolidated first-line treatment, second-line options after their failure were less frequently associated with disease response, while stabilizations were more com-mon.

Immunotherapy represents a revolutionary step ahead in the management of metastatic RCC patients. The phase III study CheckMate 025 randomized 821 metastatic RCC patients, who had previously received an anti-angiogenic agent, to receive either nivolumab (an anti-PD-1 agent) or everolimus. Objective re-sponse rate was respectively 25% vs. 5% [odds ratio 5.98, 95% confidence interval (CI) 3.68-9.72, p < 0.001] and overall survival (OS) was longer in the ex-perimental arm with nivolumab (median 25 vs. 19.6 months, hazard ratio 0.73, 98.5% CI 0.57-0.93, p = 0.002) (2). In addition, quality of life assessments gave better results in nivolumab compared to everolimus arm. By virtue of its benefit in terms of survival and of its favorable toxicity profile, nivolumab is among the

preferred second-line treatments for metastatic RCC patients (3). Real-world data provided evidence that nivolumab is active even within particular populations, such as in patients suffering from bone or brain me-tastases (4).

Here we describe the case of a patient suffer-ing from metastatic RCC with bone metastases in anatomic sites at risk of demolition surgery. First-line TKI had engendered grade 4 renal toxicity, prompting a switch to second-line nivolumab administration. The patient experienced an impressive disease response, as major remission of all disease sites and complete re-sponse at bone level were obtained, without recurrence of renal impairment.

2. Case presentation

A 69-year-old man, with arterial hypertension in his past medical history, underwent left radical ne-phrectomy in November 2011. Histological analysis allowed the diagnosis of invasive ccRCC, Fuhrman grade III. According to the 7th TNM 2009 edition, the pathological staging was pT2a (8 cm) N0 (no positive lymph nodes out of the nine resected). The patient was then referred to clinical and radiological follow-up.

Four years later (2015), a CT scan documented suspected lung lesions. Atypical resections of the up-per left lobe and double in the lower left lobe were performed. Pathological examination confirmed the radiological diagnosis of metastases from ccRCC, and surgical margins were negative for malignant cell infil-tration. The patient was referred again to clinical and radiological follow-up.

In January 2016, the patient complained of the abrupt onset of severe pain in the left arm and a mas-sive destructive lesion was detected in the left humerus (Figure 1A). At re-staging in January 2016, the total-body CT confirmed the left humerus lesion, this rep-resented the only macroscopic bone localization, ac-companied by a nodule in the posterior segment of the upper lobe of the left lung. In March 2016, the patient underwent an en-bloc resection of the proximal left humeral epiphysis with endoprosthetic replacement (Figure 1B) and excision of the axillary nerve, encased in the malignant mass. This latter was confirmed as a

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Major and prolonged response to nivolumab in a renal cell carcinoma 13

metastasis of ccRCC, conditioning a massive patho-logical fracture, while surgical margins were not infil-trated. In May 2016, radiofrequency therapy on the nodule of the upper left lung lobe was performed.

In September 2016, a CT scan documented mul-tiple lung metastases (lung nodules of diameter of 1 cm) and bone progression, with peri-prosthetic disease recurrence and new localizations at the second and third cervical vertebrae, at the left elbow and in the left ileo-pubic ramus with involvement of the acetabular fundus. Antalgic radiotherapy (20 Gy) was admin-istered on the vertebral lesions. The patient was no longer able to carry out his usual daily physical activi-ties as walks and small exercises. Given the disease ex-tent, the patient was candidate for a first-line systemic treatment. The patient was rated at intermediate risk according to the International Metastatic RCC Da-tabase Consortium (IMCD) risk stratification groups (5), and pazopanib at the dose of 800 mg daily was administered since the beginning of October 2016. From the end of October to the half of November 2016 the patient was hospitalized due to a suspected peri-prosthetic infection of the left humerus. Microbi-ological analysis confirmed the diagnostic hypothesis and pazopanib administration was suspended. In ad-dition, the ultrasound-guided needle aspiration of the lesion allowed the cytological detection of malignant cells. After clinical improvement, with normalization

of inflammation indexes following an antibiotic treat-ment, pazopanib administration was reintroduced. At the beginning of December 2016, another hospitaliza-tion was required due to a weight gain of 10 kg, with worsening of the renal function and severe proteinuria (grade 4, G4), compatible with nephrotic syndrome, whose etiology was ascribed either to pazopanib, or to the prolonged antibiotic therapy. Pazopanib adminis-tration was suspended and a diuretic therapy was in-troduced, leading to a rapid global improvement. In December 2016 a CT scan documented the recurrence of the peri-prosthetic infection in the left humerus, symptomatic for edema, heat and pain. Just before discharge, pazopanib was reintroduced at the reduced dose of 400 mg daily, definitively suspended after a few days due to recurrence of proteinuria (G2). The patho-genic role of pazopanib in engendering renal damage was confirmed by a careful nephrological evaluation. After an initial stabilization of both inflammation in-dexes and clinical parameters for one month, in Feb-ruary 2017, the increase of inflammation indexes was accompanied by the onset of pain in the left arm. The orthopedic indication consisted in demolition surgery (i.e. left arm disarticulation), due to the impossible management of the infection through an antibiotic treatment, as the tumor mass completely embedded the prosthesis itself (Figure 1C). As a final attempt to obtain tumor regression through a medical therapy,

Figure 1. Magnetic resonance imaging (MRI; A, C, D) and 99mTc-methylene diphosphonate (MDP) bone scintigraphy of the left humeral metastasis (Fig. B). A: Massive destruction lesion at first detection in January 2016; B: After endoprosthetic replacement (March 2016); C: Peri-prosthetic disease recurrence (February 2017); D: Complete response engendered by nivolumab (October 2018).

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second-line nivolumab at the dose of 3 mg/kg every two weeks was introduced at the beginning of March 2017. Renal function remained normal and proteinuria recurrence was not observed. In April 2017, after three nivolumab therapy cycles, a clear clinical benefit was observed, with reduction of left arm edema and pain, concomitantly to the normalization of inflammatory indexes. In July 2017 the first CT scan evaluation doc-umented a partial disease response in all known disease sites, whereas since the second CT scan of Novem-ber 2017, prolonged complete all bone sites response and partial lung response were obtained. In May 2018 nivolumab was switched to the dosage of 480 mg flat dose monthly. In October 2018 the patient experi-enced a full recovery in motility of the left arm (Figure 1D), regaining complete autonomy and an active life. Nivolumab was well tolerated. At the last follow-up in April 2019, the patient is still on treatment with nivolumab 480 mg flat dose monthly.

3. Discussion

In the last decade, TKI have been the treatment of choice in the first-line setting of metastatic RCC patients. Renal adverse events are frequently reported with TKI and the underlying mechanisms are com-plex, involving damages to the microcirculation and to glomerular, tubular and interstitial structures. Clinical manifestations range from asymptomatic proteinuria to renal insufficiency (6, 7).

In the phase III COMPARZ clinical trial, rand-omizing metastatic ccRCC patients to receive either sunitinib either pazopanib in the first-line setting, all-grade and grade 3-4 proteinuria occurred respectively in 10% and 3% of treated patients (8). Sorich and colleagues (9) pooled the data regarding proteinuria emerging from COMPARZ and VEG105192 (pa-zopanib vs. placebo in treatment-naive and cytokine-pretreated advanced RCC patients) (10) phase III tri-als. Authors reported that the median time to onset of all-grade and grade 3-4 proteinuria induced by either sunitinib or pazopanib was 32 and 100 days, respec-tively, without any significant difference between the two TKI with reference to the incidence of this specific toxicity.

Nivolumab is the only immune checkpoint in-hibitor (ICI) approved in the second-line setting of metastatic RCC, after first-line TKI failure or unac-ceptable toxicity (3).

4. Conclusions

Here we reported the peculiar case of a rapid, ma-jor and prolonged response to nivolumab in a meta-static ccRCC patient previously experiencing TKI-re-lated G4 renal toxicity. Of note, a complete regression of wide and symptomatic bone lesions was obtained, including a peri-protesic metastasis that would have otherwise required demolition surgery. Nivolumab ad-ministration did not engender renal adverse events.

This case documents that nivolumab can act rapidly and deeply in patients with RCC and symp-tomatic bone metastases with a good toxicity profile, therefore leading to a significant improvement of the quality of life.

Nivolumab can give rapid and deep responses in patients with RCC and bone metastases.

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Correspondence: Elena FeaUO Oncologia, Ospedale Antonio Carle, CuneoE-mail: elenafea@libero.it

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