To determine the safety and maximum-tolerated dose of concurrent sunitinib and image-guided radiotherapy (IGRT) followed by maintenance sunitinib in oligometastastic patients.
To determine the safety and maximum-tolerated dose of concurrent sunitinib and image-guided radiotherapy (IGRT) followed by maintenance sunitinib in oligometastastic patients.
Eligible patients had 1 to 5 sites of metastatic cancer measuring ≤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.
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.
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. Cancer 2009; 115:3571–80. © 2009 American Cancer Society.
Cancer is the second leading cause of death in the United States, predominantly due to the inability to control progressive metastatic disease.1 Save for notable exceptions such as germ cell tumors, drug therapy alone is not curative therapy for adult patients with solid tumors with gross disease.2 However, not all patients with metastatic cancer die to their disease. Surgery and chemotherapy have resulted in long-term, disease-free survival in approximately 25% of patients with colorectal cancer and isolated liver metastases.3 In addition, some patients with isolated pulmonary metastases, most notably soft tissue sarcoma, are rendered disease-free with resection and chemotherapy.4 Supported by these observations, the presence of oligometastases has been proposed by Hellman.5 Although some tumors have spread widely before clinical detectability and others never metastasize, for the majority of cancers, metastatic capacity evolves during the clinical phase of tumor growth. During this evolutionary process, there may be an oligometastatic state when metastases are limited in number and location because metastatic capacity has not fully evolved.5 If this hypothesis is valid, then these patients would benefit from effective local therapy in addition to systemic therapy. Recent advances in cytotoxic chemotherapy and biological therapy have resulted in improved overall survival and disease-free survival for the most common metastatic cancers including breast, prostate, colorectal and lung cancer.6-12 However, there is no evidence that chemotherapy or biological therapy alone results in an appreciable long-term cure rate. The median progression-free survival for the 4 most common metastatic tumor types (lung, breast, prostate, and colorectal) with chemotherapy alone ranges from 2 to 11 months, depending on primary tumor site and degree of pretreatment.6-12 In a recent pattern of failure analysis, 38 patients with metastatic lung cancer treated on a phase 2 trial of oxaliplatin and paclitaxel were carefully analyzed. Fifty percent of patients presented with ≤3 metastatic sites and 50% had stable disease or progressed only within initially involved sites on follow-up, suggesting a potential benefit for local therapy could exist in selected patients.13
Although conventional chemotherapy has been limited by low therapeutic index, poor drug penetration through tissue and multidrug resistance, targeted therapies are hindered by genetic heterogeneity within tumors and the multiple genetic abnormalities associated with solid tumors.14-16 Multitargeted tyrosine kinase inhibitors, such as sunitinib, are a promising approach toward overcoming some of these barriers to cure. Angiogenesis inhibitors, including sunitinib, have been shown to significantly enhance radiation response by selectively targeting tumor vasculature in preclinical studies.17-18 With advances in radiation planning and tumor imaging, it is now possible to safely target sites of gross metastatic disease with high dose, image-guided radiation therapy.19-20 We hypothesize that combining effective local therapy to gross disease with effective biological therapy for micrometastatic disease represents a potentially curative approach. Recent data from University of Rochester suggests that stereotactic hypofractionated radiotherapy to a dose of 40 to 50 Gy in 10 fractions is well tolerated and renders approximately 20% of patients with 1 to 5 distant metastases free of disease at 4 years.21 With the ultimate goal of improving upon the local (60%) and distant (25%) control of radiation alone, we embarked on a phase 1 trial investigating a novel treatment combination of sunitinib and image-guided radiotherapy.21
Patients were eligible if they had histologically or cytologically documented advanced solid tumor malignancy with radiographic evidence of 1 to 5 sites of active metastatic disease on whole body imaging (Positron emission tomography [PET] or computed tomography [CT] chest, abdomen, pelvis and bone scan) measuring ≤6 cm in maximum dimension. Other key eligibility criteria included age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and adequate hematologic, hepatic, and renal function. Adequate hematologic, hepatic, and renal function was defined as hemoglobin greater than 9.0 g/dl, absolute neutrophil count (ANC) greater than 1500/mL, platelet count greater than 100,000/mL, serum creatinine and bilirubin within institutional limits, serum albumin greater than 2.9 g/dl, serum alkaline phosphatase less than 2.5 times the upper limit of normal, and serum AST and ALT less than 2.5 times the upper limit of normal. Eligibility required prior chemotherapy or radiation to be discontinued for at least 2 weeks before study entry. Three patients received chemotherapy within 3 months of starting radiation and all had evidence of progression before starting sunitinib. Patients were excluded if they had uncontrolled brain metastases, malignant pleural or pericardial effusion, life expectancy <3 months, prior radiation to volume encompassed by planning target volume (PTV), or uncontrolled intercurrent illness defined as ongoing active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Between February 2007 and May 2008, 21 patients who received informed consent were enrolled on the study. The study was reviewed by the Mount Sinai School of Medicine Institutional Review Board, which was conducted in accordance to federal and institutional guidelines.
Sunitinib was administered orally once daily in 6-week cycles comprising 4 weeks of treatment followed by 2 weeks without treatment. Pfizer, the sponsor of the trial, provided sunitinib. Patients were monitored weekly during treatment for toxicity and premedication was not routinely prescribed with the exception of 5-HT3 inhibitors for patients receiving gastric radiation. If unexpected grade ≥3 toxicity occurred, sunitinib was temporarily discontinued but restarted at the next lower dose level when the toxicity has resolved to grade 2 or lower. For patients with persistent dose-modifying toxicities despite dose reduction, sunitinib was discontinued and radiation was continued at the discretion of the treating physician. After completion of the first treatment cycle, the treating medical oncologist had the option of continuing on maintenance sunitinib for additional cycles if there was no unacceptable toxicity or progression for up to 2 years.
Radiation was administered concurrently with the first cycle of sunitinib during Day 8 to Day 19. Each patient's treatment was individualized with respect to immobilization and radiation planning technique to optimally cover the target volume, adequately account for organ motion, and meet strict normal tissue dose and volume limits. Briefly, all patients underwent CT simulation before the first treatment using appropriate site-specific immobilization. For sites with significant respiratory motion, maximum inspiratory, expiratory, and free-breathing CT scans were fused to document the maximum amplitude of tumor motion. Relaxed end expiratory breath holding, forced shallow breathing and/or external optical tracking was used to ensure minimal internal organ motion during radiotherapy. The gross tumor volume (GTV) was defined as gross tumor on CT, magnetic resonance imaging [MRI], and/or PET. The clinical target volume (CTV) was defined as GTV with 0-5 mm margin. PTV was defined as CTV with adequate margin for internal tumor motion and setup uncertainty, generally between 3 mm and 10 mm. We prescribed to the isodose line covering ≥95% of the PTV that was not immediately adjacent to a critical structure.
Patients were treated on either a Novalis Tx radiosurgery system (n = 15) or Varian linear accelerator with on-board portal imaging capability (n = 6). Depending on treatment site, treatment planning comrpised conformal arcs, intensity modulated radiation, or 3-dimensional forward planning using Novalis Brainscan (version 5.3) and Varian Eclipse (version 8.0) planning systems. Intensity modulation was not used for targets shown to have ≥1cm organ motion. Pencil beam algorithm is used for both planning systems and the percentage depth dose/tissue maximum ratio (PDD/TMR) curves are fitted reasonably well with measured data in the buildup region. All the lesions we treated in this study locate beyond the buildup region and phantom measurements show ≤1% deviation between measured and modeled PDD/TMR. Daily kilovoltage or megavoltage image guidance was mandatory using either implanted fiducial markers into tissue immediately adjacent to the tumor or fusion of the bony anatomy in the vicinity of the tumor. The attending physician was present for verification of the first treatment. Subsequent treatments were administered in accordance with a standardized protocol defining thresholds for either performing calculated shifts or calling the attending physician and physicist. The attending physician regularly reviewed all shifts and portal images. Strict normal tissue dose and volume limits based on available published data were used to ensure patient safety (Table 1).22
|Spinal cord||Maximum spinal cord dose ≤30 Gy; Same segment of spinal cord must not be in more than 1 treatment field|
|Skin||Maximum skin dose ≤40 Gy|
|Lung||Volume receiving >20 Gy less than 30%|
|Liver||Volume receiving >30 Gy less than 50%|
|Kidney||Volume receiving >20 Gy (both kidneys) less than 50%|
|Esophagus/ stomach/bowel||Maximum dose ≤40 Gy|
|Heart||Volume >25 Gy less than 60% and maximum heart dose <40 Gy|
|Major vessels||Maximum dose 40 Gy|
|Bone marrow||Must limit the radiation to <30% of bone marrow|
|Bladder/rectum||Maximum dose 40 Gy|
Sunitinib and radiation doses were sequentially escalated using a ping-pong strategy according to a 3 + 3 design phase 1 study (Table 2). Toxicity was evaluated weekly during treatment. During follow-up, toxicity was evaluated 1 month after completing RT and every 3 months subsequently for 2 years. If 0 of 3 patients had dose limiting toxicities (DLT), subsequently enrolled patients were treated at the next radiotherapy or sunitinib dose level (see Table 3). If ≥2 of 3 patients have DLTs, dose escalation was terminated and the next lowest dose level was declared the maximal tolerated dose (MTD) for phase 2 evaluation. If 1 of 3 patients had a DLT, then 3 more patients were treated at the same dose level, and if the incidence of DLT among 6 patients is <2 of 6, then the dose was escalated to the next level. Acute and available late toxicities were included in consideration of dose escalation. After the MTD was identified, an expanded cohort totaling 10 patients was treated at that dose level to confirm safety.
|Dose Level||Radiation Dose||Sunitinib Dose*|
|1||40 Gy in 10 fractions||25 mg PO QD|
|2||40 Gy in 10 fractions||37.5 mg PO QD|
|3||50 Gy in 10 fractions||37.5 mg PO QD|
|4||50 Gy in 10 fractions||50 mg PO QD|
|5||60 Gy in 10 fractions||50 mg PO QD|
|Adverse Event||All Grades||Grade 3||Grade 4|
|Metabolic abnormalities||5||2 (phosphorus)||0|
Toxicity was in assessed in patients at regular intervals by using the Common Terminology Criteria for Adverse Events criteria (version 3.0). Dose limiting events were defined as any grade 4 or 5 toxicity and unexpected grade 3 toxicity. Expected grade 3 toxicities from radiation include mucositis or esophagitis lasting ≤7 days. Grade 3 metabolic and hematologic toxicities are considered expected events with sunitinib and therefore were not considered DLTs.23
Follow-up visits, including complete history and physical examination, were planned 1 month after completing RT and every 3 months subsequently for 2 years. Patients underwent diagnostic imaging studies before all follow-up visits after the initial 1-month visit. During follow-up, the following diagnostic imaging studies were required: CT scan of chest, abdomen, and pelvis or whole body 18-FDG PET/CT. Other imaging, including bone scan, plain x-ray, or MRI, could be ordered as clinically indicated. Tumor response for each metastatic lesion and patient was assessed using Response Evaluation and Criteria in Solid Tumors (RECIST) of the most recent imaging study. The RECIST definition of complete response was modified to include disappearance of the target tumor radiographically or metabolically (standardized uptake value = 0 when the pretreatment PET was metabolically active).24 Local in-field recurrence was defined as progression or recurrence within the high-dose region (> 80% isodose volume). Actuarial overall and progression-free survival rates were evaluated by the Kaplan-Meier method. Patients considered to have disease-free survival had either a partial response or a complete response locally without distant progression.
Patient characteristics for the 21 patients and 36 metastatic lesions are shown in Table 4. The median tumor size was 3.2 cm (range 0.9 to 6 cm).
|Variable||No. of Patients|
|Median age, y||65 (range, 47-82)|
|ECOG performance status|
|No. of metastases|
|No. of involved organs|
|Primary sites (histology)|
|Head and neck squamous cell carcinoma||4|
|Nonsmall cell lung cancer||2|
|Renal cell carcinoma||2|
Ninety-7 percent of the prescribed radiotherapy was delivered and 5 patients had treatment delays for flu-like symptoms (n = 2), myelosuppression (n = 2) and patient noncompliance (n = 1). Compliance with concurrent sunitinib was excellent in dose levels 1, 2, and 3. At dose level 4, all 5 patients required either a dose reduction, drug holiday, or treatment discontinuation due to acute toxicity. Ten patients continued on maintenance sunitinib. Reasons for not receiving sunitinib include patient refusal (n = 4), receiving alternative systemic therapy (n = 2), toxicity (n = 2), early progression (n = 2), and patient noncompliance (n = 1).
There were no dose limiting events in dose levels 1, 2, or 3 during the dose escalation phase. Among 5 patients treated on dose level 4, there were 3 DLTs in 2 patients, which comprised transient grade 4 thrombocytopenia, transient grade 4 lymphopenia, and grade 3 nausea lasting ≥7 days. During the expanded cohort of dose level 3, there were 3 dose limiting toxicities occurring in 1 patient, which comprised transient grade 4 anemia, lymphopenia, and thrombocytopenia. In aggregate, 1 of 10 patients treated on dose level 3 experienced a DLT. The 3 patients experiencing DLTs were all treated on dose level 3 or 4, received prior chemotherapy, and required large volume liver radiation with concurrent sunitinib. In 2 of these cases, DLTs resulted in premature discontinuation of radiation.
Other grade 3 adverse events included 9 patients with grade 3 lymphopenia, 4 patients with grade 3 neutropenia, 2 patients with grade 3 elevated GGT, 1 patient with grade 3 elevated bilirubin, 2 patients with hypophosphatemia, and 1 patient with grade 3 thrombocytopenia. One patient with hepatitis C experienced hemorrhoidal bleeding during therapy. The patient received liver radiation, which may have affected sunitinib metabolism and exacerbated her baseline rectal bleeding from liver dysfunction. Although not attributed to protocol therapy, 1 patient, who received radiation therapy to the L4 vertebral body and was previously treated with 2 courses of head and neck radiotherapy (cumulative dose of 100 Gy) outside the context of protocol therapy, subsequently developed grade 5 tracheal necrosis. There are no significant late radiation toxicities occurring ≥6 months after therapy among the 13 patients with adequate follow-up (see Table 4).
At last follow-up, of 36 treated lesions, we noted a complete local response in 15 lesions (42%), partial response in 6 lesions (17%), stable disease in 10 lesions (28%), and progressive disease in 5 lesions (14%). Eight patients had available pretreatment tumor markers and 6 had a reduction of >50% after treatment. Complete responses in all irradiated sites with no evidence of new lesions on imaging were achieved in 9 patients (43%). At a median follow-up of 10 months for surviving patients (range 2.4 to 17.8 months), 8 (38%) patients are alive without evidence of disease. Nine patients had isolated distant failures (43%), 3 patients had both local and distant failures (14%), and 1 patient with no evidence of progression died of comorbid illness (5%). Thirteen patients have experienced disease progression at a median of 58 days (range 2 to 386 days). Patterns of failure analysis reveals 5 patients that failed elsewhere in the irradiated organ only, 2 patients who failed only in an unirradiated organ, 5 patients that failed in both irradiated and unirradiated organs, and 1 comorbid death. Among treatment failures, 3 patients had isolated recurrences that were amenable to additional local therapy.
The 1-year actuarial local control, progression-free survival, and overall survival were 85%, 44%, and 75%, respectively (Fig. 1). Examples of unexpected complete responses in patients with pancreatic adenocarcinoma and head and neck squamous cell carcinoma are shown in Figures 2 and 3, respectively.
Radiation therapy for metastatic disease is given primarily with the goal of palliation.19 Therefore, low dose-intensity radiation is used to avoid treatment-related complications with standard low-precision large field radiation. However, when radiation is used to eradicate gross disease, higher doses are needed. There is now an expanding experience with image-guided extracranial stereotactic radiotherapy as effective local therapy for metastatic lesions. This technique requires secure patient immobilization, accurate patient repositioning, accounting for internal organ motion, use of highly conformal dose distributions, registration of patient anatomy to fiducial markers, and use of dose intense fractionation schemes.25 Local control ranging from 60 to 90% has been reported for metastatic tumors of the spine, lung and liver, which is significantly higher than standard palliative radiation.20, 21, 24 Toxicity has been acceptable in multiple US, European, and Japanese trials of extracranial stereotactic radiotherapy to carefully selected lung, liver, spine, pelvic, and abdominal tumors despite the use very high biological equivalent doses.20, 24, 26, 27 With this approach, long-term data suggesting durable remissions have been reported.21, 24 However, because systemic failures predominate, it is logical to integrate systemic therapy with this new approach.21, 24 Although many practitioners of stereotactic body radiotherapy are using 1 to 5 fractions with daily fraction sizes exceeding 10 Gy, the hypofractionated radiation regimen of 40 to 50 Gy in 10 fractions described by Uematsu in 2001 and extensively tested as treatment for oligometastases at University of Rochester remains an effective and well tolerated regimen.21 With the goal of safely incorporating radiosensitizing systemic therapy for a variety of treatment sites, we elected to use the 10 fraction regimen.
Sunitinib (SU11248) is a small molecule receptor tyrosine kinase inhibitor that targets multiple pathways including PDGFRα, c-kit, VEGFR1, VEGFR2, VEGFR3, FLT3, and RET. These receptor tyrosine kinases are implicated in tumor proliferation, angiogenesis, and metastasis. Overall, sunitinib has a favorable toxicity profile with adverse events that have been manageable and generally reversible. Sunitinib significantly prolonged time to progression (27 vs 6 weeks, P < .001) and improved overall survival (hazard ratio [HR] .49, P = .007) in a phase 3 trial of metastatic GIST after failure of imitanib.28 In addition sunitinib had an encouraging 31% objective response rate and more than doubled disease-free survival in a phase 3 trial of metastatic renal cell carcinoma.23 There are now multiple published phase 1 and 2 studies documenting activity as a single agent in several types of advanced cancers.29, 30 Recently, sunitinib has been shown to have the most promiscuous binding activity among the 7 tyrosine kinase inhibitors approved for human use.31 On the basis of these data, its novel mechanism of action and evidence of activity in historically treatment refractory histologies, we hypothesized that sunitinib would be a useful and well-tolerated adjunct to intensive focal radiation in a variety of tumor types.
To the author's knowledge, this is the first report demonstrating the safety and efficacy of concurrent sunitinib and radiotherapy. Sunitinib can be safely integrated into dose-intense protocols of image-guided radiotherapy at doses up to 37.5 mg. In contrast to a larger published experience with bevacizumab and radiotherapy, which suggests an increase in necrosis and fistula formation, there is no evidence of potentiation of radiation toxicity in this study. Conversely, concurrent radiotherapy appears to limit the tolerability of full dose sunitinib. Five dose-limiting toxicities occurred in 3 heavily pretreated patients who received liver radiotherapy. Grade 4 thrombocytopenia, grade 4 lymphopenia, grade 4 anemia, and protracted grade 3 nausea are uncommon with full dose sunitinib alone. Taking into account volume of bone marrow irradiated, combined sunitinib appears to decrease white blood cells, platelets, neutrophils, and monocytes compared with radiation alone (unpublished data). Although the specific mechanism for these physiological changes is not currently known, large volume liver irradiation may decrease metabolism of sunitinib. Therefore, the recommended phase 2 dose of sunitinib with concurrent radiotherapy is 37.5 mg. Patients with liver PTVs measuring >6 cm will be ineligible for a phase 2 trial. This study provides proof of principle that patients with oligometastases may an appropriate population to study the interaction between radiation and promising biological therapies, particularly agents with efficacy across various histologies.
Although not the primary endpoint, this trial provides evidence of significant clinical activity of combined sunitinib and radiotherapy. At the very least, the response rates seem favorable compared with systemic therapy alone, even when factoring in progression outside of the high dose radiation field. Durable complete responses were noted in historically treatment refractory histologies including pancreatic adenocarcinoma, malignant melanoma, hepatocellular carcinoma, and head and neck squamous cell carcinoma, suggesting possible clinical benefit. Furthermore, this regimen resulted in complete responses in patients with prostate adenocarcinoma and colorectal adenocarcinoma and local complete responses in leiomyosarcoma, nonsmall cell lung cancer, and renal cell carcinoma. These major responses in a variety of histologies lend support to continuing this study as a multi-institutional phase 2 trial.
Supported in part by the Mount Sinai School of Medicine Department of Radiation Oncology and Pfizer. The study was investigator-initiated and partly supported by Pfizer through a grant covering data management, administrative support and regulatory costs.