Chemotherapy in combination with stereotactic body radiation therapy (SBRT) for oligometastatic pancreatic cancer

Abstract

Metastatic pancreatic cancer is characterised by poor prognosis. High toxicity of chemotherapy limits its use in elderly patients with severe comorbidities. Meanwhile, in metastatic disease, local treatment did not show the positive effect on life expectancy. We present a clinical case of a 72-year-old woman with metastatic pancreatic adenocarcinoma tumour, node, metastases (T3N0M1) (according to the seventh TNM classification of the International Union Against Cancer). Chemotherapy led to partial response, but later was stopped due to severe toxicity. Thereafter, consolidating radiosurgical treatment was performed. Dose to pancreatic and liver lesions was 35 Gy in five fractions. After 9 months, only one liver lesion and primary pancreatic tumour, stable in size were determined by MRI. At present time, the patient is alive and in good condition, the disease is stable 50 months after stereotactic body radiation therapy (SBRT). SBRT provides a high level of local control and in combination with systemic treatment can potentially increase survival.

Background

Metastatic pancreatic cancer is characterised by extremely poor prognosis. The median survival of patients with untreated metastatic disease is less than 6 months. Until recently, the standard treatment was monotherapy with gemcitabine, which may result in relief of symptoms and slightly increase survival.¹ Combination of gemcitabine with other cytotoxic drugs showed no significant survival gain. Only the appearance of folinic acid, fluoruracil, irinotekan, oxaliplatin (FOLFIRINOX) scheme has increased the median survival up to 11 months.² However, high toxicity of this scheme limits its use in elderly patients with severe comorbidities. Meanwhile, in patients with metastatic disease, local treatment didn’t show a positive effect on life expectancy. The issue of choosing an effective treatment with low toxicity for such category of patients remains open.

Case presentation

A 72-year-old woman was referred to medical oncologist for further evaluation and treatment with a 4-week history of moderate pain in the epigastrium, diarrhoea, weight loss by 3 kg in 1 month. CT showed a 45×55×63 mm mass in the head of pancreas and two lesions in the liver (18 and 27 mm in greatest dimension, respectively). Core needle biopsy was positive for moderately differentiated adenocarcinoma. Staging showed metastatic pancreatic adenocarcinoma tumour 3, node 0, metastases 1. Initial CA 19–9 was 10.3 U/mL and CEA was 2.1 ng/mL. The patient had moderate Eastern Cooperative Oncology Group (ECOG) performance status (ECOG score=2).

Treatment

Erlotinib–gemcitabine combined chemotherapy was started. Erlotinib was administered at a dose of 100 mg daily without interruption. Gemcitabine (1000 mg/m²) was administered by a 30 min intravenous infusion on days 1, 8 and 15. Cycles were repeated every 28 days. Tumour responses were assessed via CT every 8 weeks (two cycles). After two cycles, the patient was classified as having stable disease. But the CT scan performed after the fourth cycle revealed disease progression (35% increase in the sum of the longest diameter for pancreatic and liver lesions).

It was decided to pursue with chemotherapy consisting of a doublet—capecitabine and oxaliplatin. The patient received capecitabine at 2000 mg/m²/dose on days 1–14 and oxaliplatin at 130 mg/m²/dose on day 1, every 21 days. After two cycles, a CT scan revealed partial response, which persisted also after fourth cycle. Unfortunately, due to severe toxicity (grade III diarrhoea, grade II asthenia) and poor patients performance status (ECOG=3) chemotherapy was stopped. Because of high risk of further progression, it was decided to perform consolidating stereotactic body radiation therapy (SBRT).

SBRT was performed using the Cyberknife, a robotic image-guided radiosurgery system with the synchrony respiratory tracking for moving targets. To monitor displacements of lesions during respiration, one gold fiducial marker was implanted in the tumour of the pancreas and four markers were implanted in the liver around the target volume percutaneously using sono-guided procedure 10 days before the planning CT scan. A contrast simulation CT with slice thickness of 1 mm was performed. For proper tumour volumes delineation, MRI of pancreas and liver was arranged and fused with the planning CT.

Because of asynchronous movement of pancreas and liver during respiration, two separate irradiation plans (one for pancreatic lesion and one for liver lesions) were prepared (figure 1). The gross tumour volume (GTV) of pancreatic lesion was 26.3 cm³. The GTV was expanded to 3 mm in all directions to create the planning target volume. Dose to pancreatic lesion was 35 Gy in five fractions, delivered every other day. Prescribed peripheral isodose was 80%. The dose to two liver lesions was 35 Gy in five fractions, delivered every other day. Prescribed peripheral isodose was 77%. Dose for all critical structures was acceptable in both plans. Nevertheless, during the evaluation of the sum of two plans, it was revealed that dose to stomach and duodenum was outside possible tolerable dose. In order to avoid complications but to deliver the treatment dose and preserve antitumour effect, it was decided to make a 4-week brake between two treatments.

Figure 1.

Dose distribution in irradiation plan for pancreatic (A) and liver (B) lesions.

Outcome and follow-up

The tumour response was evaluated by the change in maximal diameter of the tumour on MRI. During the first follow-up, 3 months after treatment shrinkage of all three lesions was described. Scans, performed 6 months after treatment, showed stable disease. After 9 months only one liver lesion and primary pancreatic tumour, stable in size were determined (figures 2 and 3). The patient remains off treatment for 50 months with surveillance MRI and CT scans every 6 months showing no evidence of recurrence. No grade II, III or IV adverse events were observed. Grade I diarrhoea developed 3 months after irradiation and is controlled with loperamide.

Figure 2.

MRI of pancreatic lesion, performed before (A) and 30 months after (B) SBRT. The primary pancreatic tumor marked by arrow. SBRT, stereotactic body radiation therapy.

Figure 3.

MRI of liver lesion, performed before (A) and 30 months after (B) SBRT. The liver metastases marked by arrows. SBRT, stereotactic body radiation therapy.

Discussion

More than 50% of cases of pancreatic cancer are diagnosed with distant metastasis.³ Although palliative chemotherapy is the standard of care for patients with metastatic disease, management of the subgroup of patients with oligometastatic disease is not clear. Data from multicentre trials suggest the positive role of surgery for patients receiving synchronous hepatic and pancreatic resection compared with patients with liver metastases who did not undergo surgery.^{4 5} Nevertheless, in some cases, lesions are unresectable and the risk of severe complications remains high.

SBRT allows to avoid surgical trauma and possible postoperative complications. On the other side exceeding dose constraints for critical organs may result in severe toxicity, such as gastrointestinal ulcer or fistula. In our case, late toxicity was limited to diarrhoea grade 1 in spite of the fact that dose to stomach and duodenum was higher than acceptable tolerable dose. Potential reason for that is a 4-week brake between two treatments. Such a ‘gapped’ approach theoretically may allow for more sublethal damage repair of normal tissues and a decrease in toxicity. This hypothesis has been studied in several trials describing the use of SBRT in lung cancer, head-and-neck cancer, prostate cancer.^6–8

We describe the first case of oligometastatic pancreatic cancer treated with chemotherapy and SBRT for primary tumour and liver metastasis resulting in long-term survival and no evidence of the disease over 4 years after multimodality treatment. Our patient’s outcome suggests that highly selected patients suffering from oligometastatic pancreatic adenocarcinoma may potentially benefit from SBRT with an acceptable morbidity. Further research is needed to determine the benefit of SBRT as therapeutic option for such group of patients.

Learning points.

• Aggressive local therapy should not be excluded for selected patients with metastatic pancreatic adenocarcinoma.

• Patients with unresectable oligometastatic pancreatic adenocarcinoma may potentially benefit from stereotactic body radiation therapy (SBRT) with an acceptable toxicity.

• Use of increased time gaps between fractions in case of SBRT may reduce the potential for toxicity.