Targeted Therapy in the Management of Elderly Patients with Pancreatic Metastases from Renal Cell Carcinoma

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Journal of Cancer Therapy, 2013, 4, 15-21

http://dx.doi.org/10.4236/jct.2013.49A2003 Published Online October 2013 (http://www.scirp.org/journal/jct) 15

Targeted Therapy in the Management of Elderly Patients

with Pancreatic Metastases from Renal Cell Carcinoma*

Keith Chiu1#, Abdul Razack1, Anthony Maraveyas2

1Department of Radiology, Hull and East Yorkshire NHS Trust, Hull, UK; 2The Queen’s Centre for Oncology and Haematology,

Hull and York Medical School, Castle Hill Hospital, Hull, UK.

Email: #[email protected]

Received July 26th, 2013; revised August 24th, 2013; accepted September 1st, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Background: The pancreas is an uncommon but recognizable site for metastases from renal cell carcinoma (RCC).

Isolated pancreatic RCC metastases are still rarer and often present years after initial nephrectomy. Surgical resection

has been the treatment of choice because of superior patient survival compared with traditional immunotherapy. In re-

cent years, the advent of targeted ther apy has transformed the outcomes of p atients with metastatic RCC although little

evidence is available on its effectiveness on this subset of patients. We report our experience of 6 patients with pan-

creatic RCC metastases. Patients and Methods: Between 2007 and 2012, 6 patients (2 men, 4 women; median ag e 78

years) were diagnosed to have pancreatic RCC metastases at our institu te. The clinical featur es, treatment and ou tcomes

were examined. Results: All 6 patients had a primary RCC of clear cell type. The median interval between initial cura-

tive nephrectomy and re-presentation with pancreatic metastases was 12.5 years. Four patients were asymptomatic at

the time of diagnosis, one presented with obstructive jaundice and another with acute gastrointestinal bleed. Four pa-

tients had extra-pancreatic disease. All were deemed unsuitable or unfit for surgical metastasectomy. Five patients had a

Memorial Sloan-Kettering Cancer Center (MSKCC) score of 1 (moderate risk) and the other patient had a score of 0

(good risk). Two patients were commenced on Sunitinib, one received Pazopanib and one received Temsirolimus. Two

patients did not undergo further treatment. Of the 4 patients who underwent targeted therapy, the median follow up was

33 months with a median progression free survival of 16 months. One achieved complete response but recurred soon

after treatment was stopped. Targetted therapy was recommenced and the disease remained stable. A second patient had

long period of stable disease before disease progression. A third achieved partial response since started on targeted

therapy and a fourth had disease progression despite treatment. Of the four patients who underwent systemic therapy,

three are still alive at the time of this report. Conclusion: Pancreatic metastasis from RCC is a unique subgroup of dis-

ease which runs an indolent course, and a higher incidence in an elderly population. Our results demonstrate that tar-

geted therapy can be efficacious in some patients where surgical resection is not suitable or possible.

Keywords: Isolated Pancreatic Metastases; Renal Cell Carcinoma; Targeted Therapy

1. Introduction

Pancreatic metastases are rare and renal cell carcinoma

(RCC) is one of the few known tumour s that metastasize

to this site [1]. They can either present as part of dis-

seminated disease or as isolated metastases. Historically,

disease response and survival rates in patients on immu-

notherapy-type systemic therapy have been disappointing

[2-8], and surgical metastasectomy has been advocated in

patients with resectable disease as they have shown su-

perior outcomes [9-12].

The introduction of targeted therapy has transformed

the outcomes of patients with metastatic RCC (mRCC).

Several clinical trials have shown that multi-targeted

receptor tyrosine kinase (RTK) inhibitor such as sunitinib,

pazopanib or monoclonal antibody avastin based bio-

therapies have improved both the progression free (PFS)

and overall (OS) survival of these patients. For example,

Motzer’s multi-centre randomized phase III trial has shown

that sunitinib doubled the median progression free sur-

vival (PFS) when compared with immunotherapy such as

interferon [13,14]. Similarly, Sternberg and colleagues

*Funding/Grant: N/A.

Author Contribution: Chiu K, Razack A and Maraveyas A contributed

equally to this work. All three researched, wrote and edited the

manuscript.

#Corresponding author.

Targeted Therapy in the Management of Elderly Patients with Pancreatic Metastases from Renal Cell Carcinoma

have found that pazopanib doubled the median PFS when

compared with placebo but even more impressively, in

treatment naïve patients, the median PFS quadrupled [15].

More recently, the COMPARZ trial has shown that both

pazopanib and sunitin ib are equally effective [16]. These

agents have now become the current standard of care for

first line treatment of mRCC [17,18].

Pancreatic metastases from RCC tend to be princi-

pally metachronous events. Although these patients may

suffer from particular complications (such as biliary tree

obstruction) due to its complex relation with its sur-

rounding structures, current literature seems to suggest

that they tend to have good prognostic indices and have a

“slow-burning” course [19]. Real world data seem to

suggest that RTK inhibitors can benefit patients across

the spectrum of performance status and age although lit-

tle is known about particular coho rts of patients with rare

metastatic sites like the pancreas [20].

2. Materials and Methods

Between 2007 and 2012, 6 patients (2 men, 4 women;

median age 78 years; range 59 - 80 years) were treated

by the Department of Oncology in Hull and East York-

shire NHS Trust. Primary tumour histology, interval be-

tween primary treatment and re-presentation, presenting

complaints and symptoms, diagnostic imaging and clini-

cal outcomes including response rate and treatment toxi-

city were evaluated. Statistical analysis was performed

with Graphpad Prism 5 statistical software package (Gra-

phPad. Software, La Jolla, CA).

3. Results

The demographics and clinical features of the 6 patients

are summarized in Table 1. The median interval between

initial presentation of primary tumour and diagnosis of

pancreatic metastases was 12.5 years (range: 2 - 22

years). Four patients were asymptomatic at the time of

presentation; three were discovered during routine fol-

low-up CT scans and one was an incidental finding on a

CT for suspected lung carcinoma. Two patients were

symptomatic at presen tation, one with obstru ctive jaund i-

ce and the other acute upper gastrointestinal haemorrhage.

Histological sample was obtained in all 6 patients with 5

underwent endoscopic ultrasonography fine needle aspir-

ation and one percutaneous ultrasound guided pancreatic

biopsy. All 6 patients had clear cell renal cell carcinoma

in their initial tumours and pancreatic metastases (Figure

1).

The patient who presented with obstructive jaundice

had multiple metastases in the pancreas but no extra-

pancreatic disease. He underwent percutaneous cholan-

giography and metallic biliary stent insertion to relieve

his jaundice and was commenced on pazopanib (Figure

2). The other patient who presented with acute upper

gastrointestinal haemorrhage also had diffuse pancreatic

metastases and also single renal metastases in her con-

tralateral kidney. She underwent tumour embolization to

control the bleeding and was treated with sunitinib (Fig-

ure 3).

Of the four asymptomatic patients, one had diffuse

pancreatic metastases and a single liver metastasis. Due

to his extensive cardiac history, he was commenced on

(a) (b)

Figure 1. (a) Histology from endoscopic ultrasound biopsy

demonstrating classical appearance of clear cell RCC meta-

stasis. (b) High expression of membranous claudin-1 pro-

tein in clear cell RCC.

Figure 2. Patient presented with obstructive jaundice. Cor-

onal CT image demonstrated intrahepatic duct dilatation

(black arrow) secondary to metastasis at the head of pan-

creas (white arrow). Biopsy from endoscopic ultrasound

confirmed clear cell RCC metastasis.

Figure 3. Patient presented with acute upper GI haemor-

rhage. Axial CT image showed the lesion has eroded

through into the duodenum (white arrow). Active contrast

extravasion indicating active haemorrhage (black arrow)

was seen in the second and third part of the duodenum. The

patient underwent tumour embolization for haemostasis.

Targeted Therapy in the Management of Elderly Patients with Pancreatic Metastases from Renal Cell Carcinoma

Temsirolimus. Another patient also had multiple pancre-

atic metastases but no extra-pancreatic disease. She was

commenced on sunitinib. One of the remaining two pa-

tients had a solitary pancreatic metastasis but also a syn-

chronous metastasis in the contralateral kidney. This pa-

tient was not suitable for systemic therapy due to her

neurological comorbidities (several episodes of strokes)

but underwent two radiofrequency ablation of the renal

metastasis in her contralateral kidney. The other patient

that did not receive any systemic therapy had multiple

pancreatic metastases and also a liver metastasis. She

was anephric due to nephrectomies for RCC on previous

occasions and was on permanent haemodialysis.

The median follow-up of the cohort was 33 months

(range 11 - 72 months) after diagnosis of pancreatic RCC

metastases. Of the four patients who received systemic

therapy, the median follow up was 26 months (range 11 -

72 months). They underwent regular CT scans to assess

treatment response. Of the two patients who did not re-

ceive any systemic therapy, one continued to have regu-

lar follow-up CT scans for assessment of response from

RFA. One patient had no further imaging and was only

followed-up clinically and treated palliatively. The pa-

tient who was given pazopanib had partial response with

a PFS of 9 months. The patient developed stent related

biliary sepsis 20 months after initial diagnosis and died

from biliary sepsis. The patient who received temsi-

rolimus had a PFS of 21 months before disease progres-

sion but is alive at the time of this report (33 month s fol-

low-up). Of the two patients who received sunitinib, one

achieved complete response after 24 months and sunit-

inib was stopped. Twelve months after sunitinib was

stopped, the patient had recurrence and she was restarted

on sunitinib, achiev ing a partial response and her disease

remained stable. The other patient who received sunitinib

had stable disease and remained so on follow up after 11

months (Figure 4).

Overall, the median PFS for patients on systemic ther-

apy was 16 months (range: 9 - 26 months) and the me-

dian overall survival (OS) was 33 months (range 11 - 72

months). Only one patient who was on systemic therapy

died in our series as described above. The two patients

who did not receive any systemic treatment passed away

31 and 34 months after initial diagnosis respectively.

4. Discussion

Renal cell carcinoma (RCC) is relatively uncommon,

representing 2% of all adult malignancies [21]. Due to

the lack of any early warning signs, they often present

late with advanced local or metastatic disease. At diag-

nosis, around 20% - 30% of patients have synchronous

metastases with a further 40% initially having localized

disease will develop metachronous disease [1,22,23 ]. Th e

pancreas is an unusual site for metastases, accounting for

Figure 4. Partial response to sunitinib. On the selected pre-

treatment axial CT image, a large pancreatic metastasis

(white arrow) and a contralateral metastasis in the right

kidney (white arrow) were seen. Six months after com-

mencing on sunitinib, both lesions have dec reased in size.

only 2% - 4% of all pancreatic lesions with colon, lung,

breast, malignant melanoma along with RCC being the

most common primary tumours [10,24,25].

Although pancreatic metastases are often considered

as end stage events, there is a small but distinct group of

patients that present with isolated pancreatic RCC meta-

stases. The majority of them are from clear cell type

[26-28], and they often present years after initial treat-

ment [9,10,12].

The mechanism with which metastatic RCC sp reads to

the pancreas is poorly understood. Sellner and colleagues

have analyzed a large cohort of pancreatic metastases

from RCC and have concluded that haematological

spread is the most likely mechanism due to diffuse dis-

tribution of pancreatic metastases irrespective of the site

of RCC and absence of concurrent metastases to other

organs [9].

Surgical resection has been advocated by many studies

as the treatment of choice [2-4,9,10,12]. Many case se-

ries have demonstrated that resection of metastases in

other organs such as liver, lung and brain have improved

survival and quality of life [29,30]. In a recent systematic

review, Tanis have shown that this is also the case in

pancreas. They reviewed 311 patients who underwent

pancreatic metastasectomy for mRCC and compared

them with 73 patients who were managed medically and

have shown that the overall 2 and 5 year survival were

significantly higher for the surgical group (80.6% and

72.6% compared to 41% and 14% respectively) [12].

The main reasons cited for non-operative management

were local irresectability, poor performance status and

the presence of extra-pancreatic disease [12]. However,

most patients presented with isolated pancreatic metasta-

ses usually possess one or more of these factors. The me-

dian age for pancreatic metastases from RCC occurs in

the 7th decade of life and between 20% - 45% of these

metastases are multifocal [31]. Our cohort reflects the

“real-life” situation where the patients are elderly, and

not suitable for surgical intervention due to other co-

morbidities. The median age at presentation in our co hort

was 78 years. In 5 out of our 6 patients, there were dif-

Targeted Therapy in the Management of Elderly Patients with Pancreatic Metastases from Renal Cell Carcinoma 19

fuse pancreatic metastases. Three patients had multiple

comorbidities precluding them from surgery (one had

cardiac disease, one was anephric on haemodialysis after

both kidneys were removed due to RCC and another had

debilitating neurological co-morbidities as a result of

previous episodes of strokes). Four patients had extra-

pancreatic disease involving the liver, contralateral kid-

ney and lung metastases.

For patients who were not suitable for surgery, they

were traditionally treated by immunotherapy such as in-

terleukin-2 or IFNa since RCC is not responsive to tradi-

tional chemotherapy. However, the response rate with

these agents were often poor (as low as 5% - 20%) with

the median survival of these patients of usually 12 mon-

ths and a 5 year survival rate of around 10% [3,5-8]. In

recent years, the emergence of targeted therapy has trans-

formed the management and outcomes of patients with

mRCC [14,15,32-34]. The three systemic therapies that

were used in our patients have all shown encouraging

results. In a randomized phase III trial with 750 patients,

Motzer and colleagues had showed the median PFS in

patients receiving sunitinib, an oral multi-targeted recap-

tor tyrosine kin ase (RTK) inhibitor, have more than dou-

bled that of IFNa (11 vs 5 months). The OS had also in-

creased by nearly 5 months (26.4 vs 21.8 months) [14].

Similarly, Sternberg and colleagues had demonstrated

that pazopanib, another RTK inhibitor, had significantly

prolonged the median PFS compared with placebo in

treatment naïve patients (9.2 months vs 2.8 months) and

achieved a tenfold increase in response rate (30% vs. 3%)

[15]. As for temsirolimus, a mTOR inhibitor, it was

shown to double the median PFS (3.8 vs 1.9 months)

months and increased median OS (10.9 vs 7.3 months)

when compared to IFNa in a ph ase III trial [32].

Some of the drawbacks in this study are the small

number of patients and the heterogeneous treatment they

received with different targeted therapies used. However,

isolated pancreatic RCC metastases are rare and alth ough

our cohort is small, our results suggest a significant sur-

vival benefit when compared to survival of 41% at 2

years and 14% at 5 years for the non-surgically treated

group in Tanis’ systematic review [12], particularly if

one factors in the median age and “real world” characte-

ristics of our cohort. With a median PFS of 15 months

and median OS of 31 months our data is generally com-

parable to results from other clinical trials [13-15 ]. Of the

4 patients who underwent systemic therapy, 3 are still

alive at the time of th is study with a median follow-up of

26 months (range 9 - 70 months). The two patients who

did not receive any further treatment had survived 31 and

34 months after diagnosis underscoring the recognized

indolence of the metastatic disease in th is group, running

a much less aggressive course and having particularly

long median overall surviv al [31].

5. Conclusion

Our results in this rare group of patients demonstrate that

targeted treatments can be used safely in elderly patients

who are usually unfit for surgery or their disease is un-

suitable for pancreatic resection and can improve out-

comes even in these better prognosis metastatic patients.

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