Phase 1 study of concurrent sunitinib and image-guided radiotherapy followed by maintenance sunitinib for patients with oligometastases: acute toxicity and preliminary response

Abstract

Background: To determine the safety and maximum-tolerated dose of concurrent sunitinib and image-guided radiotherapy (IGRT) followed by maintenance sunitinib in oligometastastic patients.

Methods: Eligible patients had 1 to 5 sites of metastatic cancer measuring<or=6 cm. The most common treatment sites were bone, liver, and lung. Patients were treated with concurrent sunitinib (Day 1 through Day 28) and IGRT (40-50 Gy in 10 fractions starting on Day 8) followed by maintenance sunitinib (50 mg daily, 4 weeks on/2 weeks off starting on Day 43). The starting dose was sunitinib 25 mg and IGRT 40 Gy. Doses were escalated in a ping-pong design with incremental increases in either sunitinib or IGRT.

Results: Twenty-one patients with 36 metastatic lesions were enrolled, with a median follow-up of 10 months. No dose limiting toxicities (DLT) were noted at dose levels 1 or 2 (SU 37.5 mg/RT 40 Gy). One of 10 patients at dose level 3 (SU 37.5 mg/RT 50 Gy) and 2 of 5 patients at dose level 4 (SU 50 mg/RT 50 Gy) experienced DLTs comprising grade 4 myelosuppression and grade 3 nausea. At last follow-up, 8 patients are alive without evidence of progression. The 1-year local, progression-free, and overall survival were 85%, 44%, and 75%, respectively.

Conclusions: Addition of SU (25 to 37.5 mg) to IGRT is tolerable in patients with oligometastases, without potentiation of RT toxicity. On the basis of promising antitumor responses observed with this novel combination, a multi-institutional phase 2 trial using SU 37.5 mg/RT 50 Gy is ongoing.

Copyright (c) 2009 American Cancer Society.

Figures

FIGURE 1

Kaplan-Meier estimates of (a) local control, (b) progression-free survival, and (c) overall survival.

FIGURE 2

Complete radiographic and metabolic response of pancreatic adenocarcinoma after concurrent sunitinib and image-guided radiotherapy followed by maintenance sunitinib. A patient with a history of T3N1M0, Stage III pancreatic adenocarcinoma had previously been treated with Whipple procedure (4 positive nodes, perineural invasion, and lymphovascular emboli) followed by adjuvant 5-fluorouracil and concurrent radiotherapy followed by adjuvant gemcitabine. She presented with 3 liver metastases, 1 treated with surgical resection because of proximity to the previously irradiated volume and was subsequently enrolled on this phase 1 trial to address the 2 remaining lesions. (a) Pretreatment CT with arterial contrast (venous phase not shown) demonstrates a new 9 mm enhancing liver lesion in the dome of the liver. (b) Pretreatment T1 fat-saturated MRI with contrast demonstrates second enhancing liver lesions in the dome of the liver. The patient received 50 Gy with 50 mg of sunitinib at dose level 4. (c) Treatment planning CT with superimposed radiation dose distribution. Note fiducial marker placed adjacent to tumor to allow for image-guided radiation delivery. The 5 Gy isodose line covers the gross tumor volumes with excellent sparing of normal tissue. (d) CT performed 9 months after completion of radiation demonstrates a complete radiographic response on CT. Note presence of fiducial markers. We found it interesting that her CA19-9 was rising rapidly during the pretreatment evaluation period and during therapy. (e) CA 19-9 response during treatment course starting with Whipple procedure in 2006. Of note, she developed transient grade 4 thrombocytopenia but was able to complete radiation and continue on maintenance sunitinib at a reduced dose 37.5 mg. Her CA19-9 rapidly declined after therapy. At 5 months follow-up, she underwent CT of the chest, abdomen, and pelvis and there was no enhancing tumor seen. At nearly 10 months follow-up, she remains alive and free of disease with a CA19-9 of 16 compared with a maximum value of 636 and no evidence of disease on PET/CT.

FIGURE 3

Complete radiographic response of metastatic base of tongue squamous cell carcinoma after concurrent sunitinib and image-guided radiotherapy. A patient with a history of base of tongue cancer was treated with surgery and postoperative radiation 6 years ago. He represented 6 months ago with otalgia and was diagnosed with a T3N0M0 recurrence in the base of tongue treated with salvage surgery. He was noted on follow-up PET/CT to have a solitary enlarged subcarinal lymph node measuring 5.5 cm. Fine needle aspiration was positive for metastatic squamous cell carcinoma. (a) Pretreatment CT of the chest demonstrates a bulky subcarinal lymph node. Note fiducial marker placed for image-guided radiation therapy. The patient received 50 Gy with 37.5 mg of sunitinib as part of the expanded cohort of dose level 3. Care was taken to limit the maximum esophagus dose to 40 Gy with IMRT planning, particularly in the region of tumor bulk where no esophageal lumen could be identified. (b) To optimize therapeutic ratio of a tumor immediately adjacent to a critical structure, a simultaneous integrated boost IMRT plan was generated to deliver 4 Gy to the entire target volume while administering 5 Gy to the portion of the tumor that does not abut the esophagus. The maximum esophagus dose is limited to 4 Gy. He tolerated treatment well save for transient cough, grade 3 lymphopenia, and fatigue. (c) Posttreatment CT at 3 months after radiation demonstrated complete resolution of the largeub-carinal mass and interval resolution of the subcarinal mass. The esophageal lumen is now visible and a small air collection measuring 1 cm of uncertain etiology is now present. There is no significant PET activity in this region (not shown).