Med Oncol (2014) 31:147 DOI 10.1007/s12032-014-0147-9

ORIGINAL PAPER

Interstitial lung disease during targeted therapy in metastatic renal cell carcinoma: a case series from three centres Philipp Ivanyi • Thomas Fuehner • Meike Adam • Christian Eichelberg • Edwin Herrmann • Axel Stuart Merseburger Arnold Ganser • Viktor Gru¨nwald



Received: 22 April 2014 / Accepted: 26 July 2014 / Published online: 15 August 2014 Ó Springer Science+Business Media New York 2014

Abstract Interstitial lung disease (ILD) is an adverse event which occurs also during targeted treatment of patients with metastatic renal cell carcinoma (mRCC). Experiences on ILD-management in mRCC remain limited. mRCC patients treated with everolimus, temsirolimus, or sunitinib at three centres from January 2006 until December 2009 were analysed, retrospectively. Medical records and imaging studies, as well as clinical course, the incidence, diagnostic measures, treatment, and outcome of ILD were assessed. Twenty-six ILD patients (11 %) were identified out of 237 mRCC patients. Median treatment until ILD-diagnosis was 3.8 (range: 1-21.5) months. The ILD-frequency was 2.7 % (n = 6/226) during sunitinib therapy and 19.8 % (n = 20/101) during m-TOR-inhibitor treatment. Cough was the prevailing symptom (69.2 %, n = 18). Bronchoalveolar lavage reviled often

lymphocytic (42.9 %, n = 6/14) or eosinophilic cellularity (28.6 %, n = 4/14). Dose reduction (42.3 %, n = 11), treatment interruption (46.2 %, n = 12) or termination (23.1 %, n = 6), and steroid application (34.6 %, n = 9) were common measures in ILD. Interestingly, eosinophilic ILD required pulsed steroids. Improvement occurred in 73.7 % of symptomatic patients. Continuation of targeted therapies was warranted in 65.4 % of ILD patients. No patient died from ILD. ILD during targeted mRCC treatment is common, and supportive measures should be adapted to the clinical course, and potentially in dependence of BAL findings. Re-exposure to targeted therapies appears feasible.

P. Ivanyi  A. Ganser  V. Gru¨nwald (&) Department of Haematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School Hannover, CarlNeuberg Str. 1, 30625 Hannover, Germany e-mail: [email protected]

Abbreviations AE(s) Adverse event(s) BAL Bronchoalveolar lavage CT(s) Computed tomograph(y)(ies) CTCAE Common terminology criteria for adverse events ILD(s) Interstitial lung disease(s) Kco Diffusion capacity, illustrated through the diffusion coefficient (m)RCC (metastatic) renal cell carcinoma mTOR(i) Mammalian target of rapamycin (inhibitor) n Number(s) NA Not applicable NE Not evaluable NK Not known OD Once daily PFT Pulmonary function test

T. Fuehner Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany M. Adam  C. Eichelberg Department of Urology, University-Hospital-Hamburg Eppendorf, Hamburg, Germany E. Herrmann Department of Urology, University-Hospital-Muenster, Muenster, Germany A. S. Merseburger Department of Urology, Hannover Medical School, Hannover, Germany

Keywords Renal cell carcinoma  Pneumonitis  Interstitial lung disease  Sunitinib  Everolimus  Temsirolimus  Targeted therapy

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147 Page 2 of 10

R TBB VEGFR(i) vs.

Range Trans-bronchial biopsy Vascular endothelial growth factor receptor (inhibitor) Versus

Introduction Small molecules targeting the mammalian target of rapamycin (mTOR), or the vascular endothelial growth factor receptor (VEGFR) signalling pathways, are the mainstay of therapy in metastatic renal cell carcinoma (mRCC) [1–3]. The rapamycin derivates, temsirolimus and everolimus, and inhibit mTOR-signalling by complex binding with FK506-binding-protein-12 (FKBP12), thereby causing changes of cellular metabolism, transcription, translation, proliferation, and angiogenesis [4]. Sunitinib, a VEGFRinhibitor (VEGFRi), is the first clinically approved targeted agent in mRCC, which mainly blocks angiogenesis. Despite its activity on VEGFR, sunitinib also blocks other tyrosine kinases, which is considered as an off-target effect and may contribute to clinical toxicity [5, 6]. Targeted therapies have changed the landscape of mRCC treatment and imply chronic drug exposure. Unusual adverse events (AE) have raised awareness of treating physicians and are often considered important in the use of those agents [5, 7–11]. Interstitial lung disease (ILD), also referred to as non-infectious pneumonitis, is an important AE, and its clinical course ranges from subclinical to fulminate [12]. ILD was described occasionally for gefitinib, imatinib as well as anecdotally for sorafenib and sirolimus, which mainly was used as immunosuppressant in renal transplant recipients [13–17]. Also, recently in the transplant setting, ILD was reported to be associated with everolimus [18]. With the use of mTOR-inhibitors (mTORi) in cancer patients, ILD has become more apparent in cancer treatment than with any other targeted cancer agent [19–23]. Data about the incidence, clinical findings, management, and outcome of ILD during targeted therapies in mRCC are limited, as well as the impact of ILD on sequential targeted treatment strategies in mRCC, particularly, once reflecting a recent meta-analysis, illustrating a surprising incidence of 61.7 % of respiratory infection during mTORi treatment [24]. Therefore, we analysed the clinical course of ILD with exposure to mTORi (everolimus and temsirolimus), as well as during the most common VEGFi (sunitinib) treatment during the study duration in mRCC patients at three German tertiary university centres, reflecting a ‘‘realworld’’ situation.

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Patients and methods mRCC patients with everolimus, temsirolimus, or sunitinib treatment of any line at three German centres (Hamburg, Muenster, Hannover) between January 2006 and December 2009 were included. ILD patients were followed until August 2012. Medical records were analysed retrospectively on an anonymous basis. Patients were treated according to institutional standards, which included a formal informed consent to therapy. Analyses were done in concordance with local ethic committee requirements and in concordance with the Declaration of Helsinki. Patients received everolimus (10 mg OD), temsirolimus (25 mg i.v. weekly), or sunitinib (50 mg 4–2 schedule orally). Dose reductions were conducted according to local standards. Computed tomography (CT) scans and chest X-rays were performed according to local standards for routine tumour assessment every 2–3 months or when clinically indicated. The diagnosis of ILD was based on chest CTs (alterations were categorized in four groups: interstitial, nodular, ground glass opacities, or complex). Furthermore, presented symptoms (e.g. cough, dyspnea, fever) and diagnostics were recorded at time of diagnosis. Additional work-up included serological, microbiological, and virological tests, ECG, pulmonary function tests (PFT), and bronchoscopy per institutional standard. For the diagnosis of a drug-induced ILD, no other reason than the therapy at risk had to be apparent as underlying cause. Diagnosis of ILD was performed by the treating physician, a pulmonologist, or specialist for internal medicine. AEs were classified according to the CTC version 3.0. Outcome criteria of the study were incidence of ILD, clinical symptoms, and descriptive parameters of diagnosis and treatment. This included results from PFT, bronchoscopy, bronchoalveolar lavage (BAL), and trans-bronchial biopsies (TBB), as well as ILD-measures and its impact on outcome of ILD. Times to ILD, to clinical improvement, and from pneumonitis to death were evaluated. When available, chest CTs prior to and after ILD-occurrence were analysed as well as subsequent oncological therapies following ILD. Descriptive statistics were employed for calculation of means, medians, and ranges. According to the variable analysed, independent t test, chi-squared test, and F-test were performed (SPSS, USA, v 20).

Results During the observation period, 237 mRCC patients were identified who received 226 courses of sunitinib, 67 courses of everolimus, and 34 temsirolimus courses. Thereof, 26 patients with ILD were identified (Table 1). Each ILD

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Table 1 Baseline characteristics of mRCC patients with ILD Parameter

Number or median

Percentage or [range]

Identified ILD patients

26

11

Median age (years)

63

[44–85]

Table 2 Characteristics of ILD in mRCC patients with targeted therapies Parameter

15

57.7

Female

Number or median

Percentage or [range]

Targeted therapy at ILD-onset

Gender Male

VEGFRi

6/226

2.7

mTORi

20/101

19.8

Median ILD-grade (CTCAE-pneumonitis)

11

42.3

All

2

[1–3]

Nephrectomy

24

92.3

VEGFRi

1

[1–3]

Histology RCC

25

96.2

Papillary RCC Median time to metastasis (months)

mTORi 2 [1–3] Median time from treatment initiation to ILD-onset (months)

1

3.8

All

3.8

[1–21.5]

13.3

[0–156.6]

VEGFRi

6.8c

[1.35–21.5]

mTORi

3.6c

[1–18.7]

MSKCC-scorea

Median therapies prior to ILD-onset

Low

4

15.4

Intermediate

12

46.1

All

1

[0–6]

High

0

0

VEGFRi

0

[0–3]

NE

10

38.5

mTORi

1

[0–6]

Prior therapies to therapy at risk

Sites of metastasis Lung

17

65.4

Immunotherapy

Liver

3

11.5

VEGFRi

18



Renal

4

15.4

Othersa

1



Other

23

88.5

Radiotherapy

1



NE

1

3.8

None

3



4 2

15.4 7.7

Pre-existing pulmonary disease NE Current or history of smoking NE Pathological chest CT prior to targeted therapy at riskb NE

10

NE 2 Median therapies after ILDb





6

23.1

All

1

[0–7]

5

19.2

VEGFRi

2

[0–4]

6

23.1

mTORi

1

[0–7]

ECOG prior to ILD 8

30.8

0

17

65.4

Parameters were evaluated prior to initiation of the targeted therapy associated with ILD

1

3

11.5

2

4

15.4

NE not evaluable

NE

2

7.7

0

15

57.7

1

5

19.2

2

4

15.4

NE

2

7.7

a

147

MSKCC-score was assessed at first onset of metastatic state

ECOG after ILD

b

Pathological findings other than pulmonary metastasis were assessed

patient suffered only once from ILD, irrespective of subsequent therapies. Prior to therapy at risk, pulmonary metastases were diagnosed in 17 (65.4 %) ILD patients and baseline chest CTs revealed pathological findings other than pulmonary metastasis in 6 (23.1 %) patients. However, pre-existing pulmonary disease or history of smoking remains infrequent in ILD patients (Table 1). Prior to onset of ILD, patients had received a median of 1 [range (r) 0–6] therapy, which predominantly consisted of sunitinib or sorafenib (Table 2).Ninety per cent (n = 18,

Median time ILD-onset to death (months) All VEGFRi

11.1 21.5c

[0.5–36.8]

mTORi

10.8c

[0.5–36.8]

[1.2–32.5]

a

Other therapies: Chemotherapy, study-medication, hormones, vaccination. Radiotherapy: Radiation of upper arm

b

Therapies after ILD: only systemically administered therapies were assessed

c

p [ 0.05

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Fig. 1 Chest CT scans of ILD patients during a mTORi-, and b VEGFRi-therapy. a Patient 21 was treated with mTORi (everolimus, left scan) for 2.5 month until ILD was diagnosed (middle scan) accompanied by cough and fever. Steroid (methylprednisolone) pulse therapy was administered and resulted in resolution of symptoms after 1 month (right scan, 1.4 month after ILD-onset). b Patient 1 was

treated with VEGFRi (sunitinib, left scan). After 8.6 month of VEGFRi routinely performed chest CT revealed ILD (middle scan), only accompanied by a diminished Kco. After interruption of treatment radiological signs of ILD resolved (left scan, 1 month after diagnosis of ILD)

NK = 2) of patients with mTORi-associated ILD were pretreated with sunitinib. Four of five patients with sunitinibassociated ILD received previous immunotherapy. The performance status prior to ILD was mainly good (Table 2). Only one patient had received radiotherapy of the shoulder prior to ILD-occurrence. Twenty-six cases of ILD [median CTCAE-grade: 2 (r 1–3)] were identified in mRCC patients during targeted treatment, reflecting an overall incidence of ILD of 11 % (Table 2). ILD was most common with mTORi treatment, and the ILD-frequency was higher with everolimus (28.4 %, n = 19/67) than with temsirolimus (2.9 %, n = 1/34). Furthermore, ILD was also identified in VEGFitreated patients with a frequency of 2.7 % (n = 6/226) (Table 2, Fig. 1). One of the VEGFi-ILD patients received co-treatment with sirolimus for prevention of renal graft rejection. However, ILD occurred after the sunitinib addition to chronic sirolimus treatment, rendering a sunitinibbased mechanism as most likely. Median time to diagnosis of ILD during causative therapy was 3.8 [r 1–21.5] months, and even though mTORi-associated ILDs were detected earlier than during VEGFRi treatment differences remained insignificant (p = 0.356, Table 2).

In three ILD patients, retrospective analysis identified possible confounding diagnoses that required consideration. In one patient, aspergillus sp. were cultured in the BAL and subsequently lymphangiosis carcinomatosa was suspected. Whether aspergillus infection represented an ILD-complication, or was the underlying cause remained unclear. In two additional patients, a lymphangiosis carcinomatosa was considered as possible confounding diagnosis from clinical course during the follow-up period, even though not confirmed by histological specimen. Four ILD-patterns were apparent on chest CTs: interstitial infiltrations (50 %, n = 13), ground glass opacities (30.8 %, n = 8), nodular infiltrations (11.5 %, n = 3), or a mixture of those patterns, summarized as complex (7.7 %, n = 2) (Table 3; Fig. 1). Three patients exhibited additional pleural effusions. Clinically, cough is the main symptom reported [69.2 %, n = 18, median CTCAEgrade: 2 (r 1–3)], while 23.1 % (n = 6) of the ILD patients were asymptomatic at diagnosis of ILD (Table 3). A total of 15.4 % (n = 4) of the ILD patients suffered from fever [median CTCAE-grade: 1(r 1–3)], and 23.1 % (n = 6) from dyspnea, and both symptoms were often accompanied by cough. Time to ILD-diagnosis tends to be shorter in

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Table 3 Clinical findings at ILD-onset during targeted therapies, performed supportive therapy and outcome in mRCC patients ID

Pneumonitis (grade)

Symptom (grade)

Therapy at ILD

Chest CT pattern

PFT

Diffusion capacity

BAL

TBB

1

I

none

S

interst.

normal

Kco ;

eos

lymph

2

I

none

S

ground glass

normal







3

I

none

E

interst.

restric.

Kco ;

normal

normal

4

I

none

E

ground glass

restric.







5

I

none

E

nod.









6

II

C(II)

E

interst.









7

II

C(I)

S

ground glass

normal



lymph

normal

8

II

C(I)

S

interst.

normal

Kco ;

eos

miscellous

9

II

C(II)

E

complex

restric.



lymph



10

II

C(I)

E

interst.

normal







11

II

C(I), D(II)

E

ground glass

restric.







12

II

C(II)

E

interst.

restric.

Kco ;

lymph



13

II

C(II), D(I)

E

interst.

restric.

normal

lymph



14

II

D(I), F(I)

E

ground glass





eos

gran

15 16

II II

C(II), D(II) C(II)

E E

interst. nod.

– –

– –

normal –

– –

17

III

C(I), D(II)

E

interst.

restric.

Kco ;





18

III

C(III)

T

interst.

normal







19

III

C(I), F(II)

E

ground glass

normal







20

III

C(II)

E

ground glass

restric.

normal





21

III

C(II), F(I)

E

interst.

obstruc.

Kco ;

eos

normal

22

III

C(III), D(I)

S

interst.

normal

Kco ;

lymph

lymph

23

III

C(III), F(I)

S

interst.

restric.

Kco ;

fungal

miscellous

24

NE

C(NE)

E

complex

normal

normal

lymph



25

NE

NE

E

ground glass









26

NE

none

E

nod.





normal



ID

Lymph-angiosis*

Dose re-duction

Interruption of therapy

Duration of interruption (d)

Termination of therapy due to ILD

Steroid dose

Resolution of symptoms

Time to resolution of symptom (d)

1

no

no

no

NA

yes

none





2

no

no

no

NA

no

none





3 4

no no

yes yes

yes no

10 NA

no yes

none none

– –

– –

5

no

no

no

NA

no

none





6

yes

no

no

NA

no

moderate

yes

45

7

no

yes

no

NA

no

none

yes

30

8

no

yes

yes

7

no

moderate

yes

NE

9

no

yes

yes

18

no

none

yes

18

10

no

yes

yes

37

no

none

yes

37

11

no

no

no

NA

no

moderate

yes

7

12

no

yes

yes

25

no

none

yes

72

13

no

yes

yes

25

no

moderate

yes

16

14

no

no

no

NA

yes

HD

yes

5

15

no

NE

NE

NE

NE

NE

NE

NE

16

no

no

no

NA

no

moderate

NE

NE

17

no

no

no

NA

yes

none

no



18 19

no no

yes no

no yes

NA 25

yes no

none none

yes yes

21 NE

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Table 3 continued ID

Lymph-angiosis*

Dose re-duction

Interruption of therapy

Duration of interruption (d)

Termination of therapy due to ILD

Steroid dose

Resolution of symptoms

Time to resolution of symptom (d)

20

no

no

yes

8

no

none

no



21

no

no

yes

38

yes

HD

yes

31

22

yes

no

yes

3

no

moderate

no



23

yes

yes

yes

14

no

none

yes

28

24

no

no

yes

31

no

none

yes

9

25

no

yes

no

NA

no

moderate





26

no

no

no

NA

no

none





* Lymphangiosis carcinomatosa: clinical diagnosis without histological proof. Legend: Roman letters: CTCAE-grades. Symptoms: C: cough, D: dyspnea, F: fever. S: sunitinib, E: everolimus, T: temsirolimus. Patterns of chest CT: ground glass: ground glass opacities, interst.: interstitial infiltrate, nod.: nodular infiltrates. PFT: pulmonary function test (spirometry), restric.: restrictive ventilator disorder, obstruc.: obstructive ventilator disorder. Diffusion capacity is displayed as transfer coefficient (KCO). BAL/TBB: eos: eosinophil cellularity, lymph: lymphocytic cellularity, gran: neutrophil cellularity. Steroid dose: moderate: 1 mg prednisolone/kg body-weight orally, HD: steroid (methylprednisolone) pulse-therapy i.v.. NE not evaluable

symptomatic patients [median: 3.6 (r 2.5–8.6) vs. 4 (r: 1–21.5) months in asymptomatic patients; p = 0.384]. PFT yielded heterogeneous results (Table 3). Restrictive ventilation abnormalities were predominant and associated with or without reduction of the diffusion capacity [median Kco: 67 (r 54–124) mmHg/min/kPA]. In 53.8 % (n = 14) of ILD patients, a bronchoscopy with BAL was performed, revealing predominance of lymphocytic lavage fluid (n = 6), and a few cases of eosinophilia (n = 4). TBB was performed in 30.7 % (n = 8) of the ILD patients, again displaying variable results (Table 3). Therapeutic decisions to manage ILD were taken in an interdisciplinary consensus (Table 3). A high proportion of ILD patients (46.2 %, n = 12) required an interruption of targeted treatment for a median of 21.5 [r 3–38] days. Temporary cessation of therapy was significantly longer in symptomatic patients [median: 0 (r 3–10) days versus 7.5 (r 3–38) days; p = 0.004]. A total of 42.3 % (n = 11) of ILD patients required a dose reduction. Steroids were administered in 34.6 % (n = 9) of patients (intermediate prednisolone: n = 7, methylprednisolone pulse therapy: n = 2). Both mTORi-treated patients with eosinophilic ILD required steroid pulse therapy, because of symptoms severity (Table 3). Termination of the causative therapy was necessary in 23.1 % (n = 6) of the ILD patients, while 11.5 % (n = 3) of ILD patients needed no specific support. In symptomatic patients, supportive measures resulted in a relief from symptoms in 73.7 % (n = 14/19) after a median period of 24.5 [r 7–45] days. No recurrence or deterioration of symptoms was observed during the followup period and follow-up chest CTs, performed in 46.2 % (n = 12, NK = 8) of ILD patients, documented no recurrence of ILD.

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Presence of ILD was not associated with a significant deterioration in performance status (Table 2; p = 0.32). Furthermore, 65.4 % (n = 17) of ILD patients were switched to subsequent targeted therapies [median: 1 (r 0–7)], other than the therapy at risk, without any ILD-reoccurrence during the duration of follow-up. Our data indicate that ILDoccurrence may not predispose to ILD with other agents in later lines of therapies. Patients who did not receive further therapies after ILD were either not eligible for other agents, or not accessible. Twenty ILD patients (76.9 %) died after a median period of 11.1 [r 0.5–36.8] months after ILD-onset. None of the patients died as a result of ILD.

Discussion Here, we retrospectively analysed mRCC patients with ILD exposed to targeted agents with everolimus, temsirolimus, or sunitinib. ILD was assessed by an independent review by an oncologist and pulmonologist. Even though this study is limited by its retrospective nature, implications of our results are relevant to clinical routine. To our knowledge, this analysis is the first series to describe ILD in mRCC patients as a result of sunitinib treatment. Albeit the ILD incidence in mTORi-treated patients is abundantly higher (19.8 %) than in sunitinib-treated patients (2.7 %), this finding illustrates that ILD is not an exclusively mTORi-associated adverse event. This is of particular importance, simply due to the fact that most treating oncologists are aware of ILD during mTORi, but in fact, ILD may also occur with other agents, such as sorafenib or bevacizumab, and require clinical awareness [13, 25].

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The identified ILD-frequency of 19.8 % during mTORi treatment is consistent with prior reports [19, 20, 22, 26– 28]. In general, the reported incidence of ILD in mTORipatients, either organ transplanted (5–15 %) or cancer patients (3–49 %) varies strongly, while the reported incidence for mRCC patients remains modest (3–30 %) [3, 15–20, 22, 28–30]. The wide variation of incidence may in part result from different patient cohorts. However, a dose relation has been discussed for mTORi and the incidence of ILD. The fact that doses for mTORi in cancer patients are considerably higher compared to those used in transplant recipients may explain a proportion of the observed differences. None the less, the main proportion of the higher ILD-frequency in mTORi-treated cancer patients may also simply be reflected by the radiological staging protocols we used and the reliance on highly sensitive CT scans as opposed to conventional chest X-rays, a fact which previously was suggested [19]. ILD is often diagnosed during routine radiological tumour assessment or extended work-up after occurrence of pneumonitis symptoms such as cough, dyspnea, or fever [22]. In this series, ILD was diagnosed incidentally (i.e. without symptoms) on routine chest CT in 6 out of 26 patients. Symptomatic ILD was associated with early detection by provoked alertness of the treating clinician. Again, the reported incidence of symptoms during ILDdiagnosis varies from 30 to 50 % of ILD patients, potentially temsirolimus showed a lower incidence of symptoms than everolimus [23]. Therefore, tools of ILD-diagnostic are of importance [20, 22, 23, 31]. Prior works did not identify any suggestive diagnostics for ILD, despite radiological findings. Here, further findings have to be pointed out. A slight dominance of interstitial ILD-pattern in CT was found, while prior work of only mTORi-associated ILD often found a slight dominance of ground glass opacities [19, 22, 31, 32]. Over all, here pleural effusion is uncommon. Furthermore, hardly any value was ascribed to PFT for the diagnosis of ILD in cancer patients [19, 22]. In our study, restriction in vital capacity or diminished diffusion capacity occurred often during ILD. Particularly, a diminished KCO was associated with an interstitial chest CT pattern in ILD patients. Doubtless, no baseline PFTs were preformed routinely in this study, and a proportion of the patient had pre-existing pulmonary alterations (e.g. metastaseis or history of smoking). It remains undefined whether comorbidities may predispose to pneumonitis and whether PFTs are considered a valuable ILD screening tool [22, 31]. Therefore, further analyses should be encouraged to clarify the role of PFTs in ILD-diagnosis. BAL and TBB provided inconsistent findings, but were subsidiary tools of a diagnostic-algorithm, particularly considering the reported high rates of pulmonary infections during mTORi treatment [24]. Here, three cases were

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initially identified as drug-induced ILD, but were shown to have potential alternative aetiologies during extended work-up, indicating the range and importance of other diagnosis of ILD. Particularly, lymphangiosis carcinomatosa was hardly distinguishable from ILD, if based on radiological findings only. Interestingly, in one patient, we identified a cofounding recurrence of aspergillus supp. Infection was also reported in 2 out of 8 ILD patients in other series with mTORi treatment [31]. We therefore believe that bronchoscopy with lavage or biopsy adds diagnostic precision and is a valuable tool in ILD-diagnosis (Fig. 2). According to the pathophysiology of ILD, our BAL findings are of interest, particularly since in prior works, the reported incidences of bronchoscopy were considerably low [20]. Here, the BAL often revealed lymphocellular intra-alveolar infiltrates, which was also identified often in renal transplant recipients with ILD and mTORi treatment [15, 33]. Those findings were thought to be associated with either an induced autoimmune response, or a delayed T-cell-mediated hypersensitivity [15, 33]. Intriguingly, both cases of identified eosinophilic ILD in mTORi-treated patients may suggest a distinct pathogenesis, reflected by the severe clinical course, which required steroid pulse therapy. Even though speculative, the lymphocellular ILD might reflect a delayed hypersensitivity, while the eosinophilic cellularity reflects a severe eosinophilic drug reaction, which required a more aggressive treatment. To our understanding, steroid therapy is more urgently to considerer in eosinophilic ILD, particularly during mTORi treatment, whereas it remains optional with lymphocytic ILD. The pathomechanism of sunitinib-associated ILD remains elusive, since there are no prior considerations, as well as our identified numbers are too small for definite conclusions. Risk factors, as well as the ILD-pathogenesis during targeted treatment in mRCC, have not yet been elucidated. For gefitinib-associated ILD, prior lung diseases was supposed as a risk factor [34]. In our work, as well as in previous studies of mTORi and ILD, the percentage of patients with lung diseases or active smoking was low and no coincidences with ILD were observed [19, 21]. Radiotherapy, which proceeds targeted drug exposure, is one potential event that may trigger ILD. In our study, only one patient with ILD received radiotherapy at a non-thoracic site prior to ILD, suggesting that this parameter may not be a common risk factor. Recently, the sequence of administration of targeted agents was speculated to be a risk parameter for ILD-onset [35]. Here, our data do not illustrate a final conclusion. Nonetheless, similar ILD incidence during everolimus treatment of mRCC patients within different therapeutic sequences (RECORD 1 and 3 trial) most likely illustrates that the therapeutic line of

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Fig. 2 Diagnostic and therapeutic measures for targeted-agentassociated ILD in mRCC patients. The algorithm based on experiences of three centres during the treatment with everolimus, temsirolimus, and sunitinib in mRCC patients. Once ILD is suspected other diagnosis, as well as laboratory and radiological analyses as

described in the material and method part, should be considered. For grading of clinical severity, we suggest the CTCAE of the chief complain, rather than a pneumonitis grading itself. After diagnosis of ILD, PFT might be useful for clinical monitoring. Particularly in mTOR-associated eosinophilic ILD, steroid therapy is mandatory

administered-targeted agent does not influence the ILDoccurrence [27, 36]. The impact of systemic oncological treatment prior or beyond to ILD is not precisely defined. Reports suggested a switching of targeted therapy after ILD as a feasible approach [37]. Here, the occurrence of ILD with subsequent switch to targeted agents other than the therapy at risk in later lines of therapy was feasible without recurrence of ILD. Whether occurrence of ILD is a surrogate marker of tumour response, as hypothesized for mTORi, can hardly be evaluate in our cohort [21, 28]. Currently, no agreed standard for supportive strategies of targeted-therapy-associated ILD has been defined, even though empiric recommendations exist [11, 19, 22, 32]. Our observation is based on patients with mRCC, but it seems conceivable that it may apply to other indications as well [38, 39]. Our reliance on supportive therapy appeared

to offer a feasible solution in managing clinical symptoms and facilitate subsequent continuation of systemic therapy in most patients. We chose to implement a combination of measures, including interruption or cessation of targeted drugs, and the addition of steroids, particularly in severe cases, irrespective form the class of agent causing the ILD. This approach proved efficacious and feasible, and indeed in mild ILD, no action was required [11, 19]. This approach ensured a low need for treatment cessation of targeted therapy once ILD occurred. Therefore, based on our retrospective analyses, we suggest a diagnostic and therapeutic algorithm for ILD (Fig. 2). Drug-induced ILD is estimated to occur with an overall incidence of 10–20 % in cancer patients [12, 40]. Also, with targeted therapies, ILD requires consideration and a high index of suspicion as illustrated by our report. Early chest CTs in symptomatic patients during targeted therapy

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may open a therapeutic window for early intervention, which sometimes might require intensified steroid treatment urgently. Besides clinical visits, specific routine ILDmonitoring is not recommended in asymptomatic patients, provided that chest CTs are performed every 2–3 months throughout the course of treatment for staging purposes. However, ILD is a diagnosis of exclusion, and the full spectrum of differential diagnosis needs to be considered. Particularly, carcinomatous lymphangiosis is difficult to distinguish from interstitial radiological alterations of other cause and may require BAL or TBB for diagnosis, which is recommended anyway prior to steroid administration. A strict interdisciplinary management with early evaluation in patients with airway symptoms is warranted throughout the course of targeted agents. Acknowledgments We are grateful to numerous colleagues at the three German tertiary care university centres for the excellent clinical support of the patients, as also the constructive discussion in each novel identified ILD patient. For constructive discussion and improvement of the written manuscript, we are grateful to Michael Morgan, PhD. Conflict of interest PI received a travel Grant by Novartis; TF declares none conflict of interest; CE has been an investigator for clinical trials initiated/sponsored by Bayer, Pfizer, Roche, Wilex, Novartis and an invited speaker for Bayer, Pfizer and Roche; MA declares none conflict of interest; EH declares none conflict of interest; AM was involved as principle investigator and subinvestigator for: Novartis, Bayer, Pfizer, Wyeth, Ipsen, TEVA, Astellas, Jannssen, GSK; and AM was a member of the advisory Board of Ipsen, Novartis, Astellas, Janssen, Bayer, Pfizer, TEVA. Further on, a grant was received by Wyeth, AG declares none conflict of interest and VG Advisory Board: Novartis, Pfizer, GSK, Bayer, Genentech, Roche, Aveo, and Astellas. Honoraria for lecture: Novartis, Pfizer, GSK, Roche, and Astellas.

References 1. Di Lorenzo G, Autorino R. Sternberg CN: metastatic renal cell carcinoma: Recent advances in the targeted therapy era. Eur Urol. 2009;56:959–71. 2. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584–90. 3. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–81. 4. Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene. 2000;19:6680–6. 5. Maitland ML, Ratain MJ. Terminal ballistics of kinase inhibitors: there are no magic bullets. Ann Intern Med. 2006;145:702–3.

Page 9 of 10

147

6. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25:884–96. 7. Ivanyi P, Winkler T, Grosshennig A, Reuter C, Merseburger AS, Ganser A, Grunwald V. Treatment with tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma is associated with drug-induced hyperparathyroidism: a single center experience in 59 patients. World J Urol. 2010;28:311–7. 8. Ivanyi P, Winkler T, Ganser A, Reuter C, Grunwald V. Novel therapies in advanced renal cell carcinoma: management of adverse events from sorafenib and sunitinib. Dtsch Arztebl Int. 2008;105:232–7. 9. Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, Morgan JA, Dychter SS, Larsen PR, Demetri GD, Alexander EK. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med. 2006;145:660–4. 10. Grunwald V, Soltau J, Ivanyi P, Rentschler J, Reuter C, Drevs J. Molecular targeted therapies for solid tumors: management of side effects. Onkologie. 2009;32:129–38. 11. Di Lorenzo G, Porta C, Bellmunt J, Sternberg C, Kirkali Z, Staehler M, Joniau S, Montorsi F, Buonerba C. Toxicities of targeted therapy and their management in kidney cancer. Eur Urol. 2011;59:526–40. 12. Snyder LS, Hertz MI. Cytotoxic drug-induced lung injury. Semin Respir Infect. 1988;3:217–28. 13. Ide S, Soda H, Hakariya T, Takemoto S, Ishimoto H, Tomari S, Sawai T, Nagashima S, Furukawa M, Nakamura Y, Kohno S. Interstitial pneumonia probably associated with sorafenib treatment: an alert of an adverse event. Lung Cancer. 2010;67:248–50. 14. Ohnishi K, Sakai F, Kudoh S, Ohno R. Twenty-seven cases of drug-induced interstitial lung disease associated with imatinib mesylate. Leukemia. 2006;20:1162–4. 15. Morelon E, Stern M, Israel-Biet D, Correas JM, Danel C, Mamzer-Bruneel MF, Peraldi MN, Kreis H. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation. 2001;72:787–90. 16. Champion L, Stern M, Israel-Biet D, Mamzer-Bruneel MF, Peraldi MN, Kreis H, Porcher R, Morelon E. Brief communication: Sirolimus-associated pneumonitis: 24 cases in renal transplant recipients. Ann Intern Med. 2006;144:505–9. 17. Weiner SM, Sellin L, Vonend O, Schenker P, Buchner NJ, Flecken M, Viebahn R, Rump LC. Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome–a single-centre experience and review of the literature. Nephrol Dial Transplant. 2007;22:3631–7. 18. Baas MC, Struijk GH, Moes DJ, van den Berk IA, Jonkers RE, de Fijter JW, Homan van der Heide JJ, van Dijk M, Ten Berge IJ, Bemelman FJ: Interstitial pneumonitis caused by everolimus: a case-cohort study in renal transplant recipients. Transpl Int 2014. 19. White DA, Camus P, Endo M, Escudier B, Calvo E, Akaza H, Uemura H, Kpamegan E, Kay A, Robson M, Ravaud A, Motzer RJ. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med. 2010;182:396–403. 20. White DA, Schwartz LH, Dimitrijevic S, Scala LD, Hayes W, Gross SH. Characterization of pneumonitis in patients with advanced non-small cell lung cancer treated with everolimus (rad001). J Thorac Oncol. 2009;4:1357–63. 21. Dabydeen DA, Jagannathan JP, Ramaiya N, Krajewski K, Schutz FA, Cho DC, Pedrosa I, Choueiri TK. Pneumonitis associated with mtor inhibitors therapy in patients with metastatic renal cell carcinoma: incidence, radiographic findings and correlation with clinical outcome. Eur J Cancer. 2012;48:1519–24. 22. Albiges L, Chamming’s F, Duclos B, Stern M. Motzer RJ, Ravaud A, Camus P: incidence and management of mtor inhibitorassociated pneumonitis in patients with metastatic renal cell carcinoma. Ann Oncol. 2012;23:1943–53.

123

147 Page 10 of 10 23. Maroto JP, Hudes G, Dutcher JP, Logan TF, White CS, Krygowski M, Cincotta M, Shapiro M, Duran I, Berkenblit A. Drugrelated pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus. J Clin Oncol. 2011;29:1750–6. 24. Kaymakcalan MD, Je Y, Sonpavde G, Galsky M, Nguyen PL, Heng DY, Richards CJ, Choueiri TK. Risk of infections in renal cell carcinoma (rcc) and non-rcc patients treated with mammalian target of rapamycin inhibitors. Br J Cancer. 2013;108:2478–84. 25. Tamura S, Kusaba H, Kubo N, Ijichi K, Tsuchihashi K, Komoda M, Uchino K, Ariyama H, Akashi K, Baba E. Interstitial pneumonia during bevacizumab-based chemotherapy for colorectal cancer. Med Oncol. 2014;31:856. 26. Grunwald V, Karakiewicz PI, Bavbek SE, Miller K, Machiels JP, Lee SH, Larkin J, Bono P, Rha SY, Castellano D, Blank CU, Knox JJ, Hawkins R, Anak O, Rosamilia M, Booth J, Pirotta N, Bodrogi I. An international expanded-access programme of everolimus: Addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. Eur J Cancer. 2012;48:324–32. 27. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase iii trial. Lancet. 2008;372:449–56. 28. Atkinson BJ, Cauley DH, Ng C, Millikan RE, Xiao L, Corn P, Jonasch E, Tannir NM: Mtor inhibitor associated noninfectious pneumonitis in patients with renal cell cancer: Management, predictors, and outcomes. BJU Int 2013. 29. Morelon E, Stern M, Kreis H. Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients. N Engl J Med. 2000;343:225–6. 30. Chhajed PN, Dickenmann M, Bubendorf L, Mayr M, Steiger J, Tamm M. Patterns of pulmonary complications associated with sirolimus. Respiration. 2006;73:367–74. 31. Duran I, Siu LL, Oza AM, Chung TB, Sturgeon J, Townsley CA, Pond GR, Seymour L, Niroumand M. Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur J Cancer. 2006;42:1875–80. 32. Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, Creel P, Dickow B, Fischer P, Gornell SS, Meloni F,

123

Med Oncol (2014) 31:147

33.

34.

35.

36.

37.

38.

39.

40.

Motzer RJ. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer. 2011;47:1287–98. Pham PT, Pham PC, Danovitch GM, Ross DJ, Gritsch HA, Kendrick EA, Singer J, Shah T, Wilkinson AH. Sirolimus-associated pulmonary toxicity. Transplantation. 2004;77:1215–20. Ando M, Okamoto I, Yamamoto N, Takeda K, Tamura K, Seto T, Ariyoshi Y, Fukuoka M. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2006;24:2549–56. Kushima H, Ishii H, Kadota JI: Sunitinib-related interstitial pneumonia after treatment with temsirolimus: a case of possible recall phenomenon. Int J Urol 2013. Motzer RJ BC, Kim TM, Falcon S, Cosgriff T, Harker WG, Pittman KB, Sabbatini R, Rha SY, Flaig TW., Page RD, Bavbek SE, Beck JT, Patel PM, Schiff E, Vaury A, Niolat J, Gogov, Anak SO, Knox J.: Record-3: Phase ii randomized trial comparing sequential first-line everolimus (eve) and second-line sunitinib (sun) versus first-line sun and second-line eve in patients with metastatic renal cell carcinoma (mrcc). J Clin Oncol 2013;31. Rehm B, Keller F, Mayer J, Stracke S. Resolution of sirolimusinduced pneumonitis after conversion to everolimus. Transplant Proc. 2006;38:711–3. Peddi PF, Shatsky RA, Hurvitz SA. Noninfectious pneumonitis with the use of mtor inhibitors in breast cancer. Cancer Treat Rev. 2014;40:320–6. Pritchard KI, Burris HA III, Ito Y, Rugo HS, Dakhil S, Hortobagyi GN, Campone M, Csoszi T, Baselga J, Puttawibul P, Piccart M, Heng D, Noguchi S, Srimuninnimit V, Bourgeois H, Gonzalez Martin A, Osborne K, Panneerselvam A, Taran T, Sahmoud T, Gnant M. Safety and efficacy of everolimus with exemestane vs. Exemestane alone in elderly patients with her2negative, hormone receptor-positive breast cancer in bolero-2. Clin Breast Cancer. 2013;13:421–32 e428. Christensen S, Pedersen L, Grijota M, Kornum JB, Beiderbeck A, Sorensen HT. Incidence of interstitial pneumonitis among breast cancer patients: a 10-year danish population-based cohort study. Br J Cancer. 2008;98:1870–5.

Interstitial lung disease during targeted therapy in metastatic renal cell carcinoma: a case series from three centres.

Interstitial lung disease (ILD) is an adverse event which occurs also during targeted treatment of patients with metastatic renal cell carcinoma (mRCC...
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