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Pulmonary Toxicity After Bevacizumab and Concurrent Thoracic Radiotherapy Observed in a Phase I Study for Inoperable Stage III Non–Small-Cell Lung Cancer Introduction Bevacizumab, a recombinant humanized monocloncal antibody against vascular endothelial growth factor, has been approved in combination with chemotherapy for the treatment of advanced non–small-cell lung cancer (NSCLC).1,2 The safety profile of bevacizumab in combination with chemotherapy is generally acceptable.3 Preclinical and early clinical studies have demonstrated enhanced radiation-induced cell kill when antiangiogenic therapy is combined with radiotherapy.4,5 However, tracheoesophageal fistulae have been reported in patients treated with bevacizumab during concurrent chemoradiotherapy for small-cell and non–smallcell lung cancer,6,7 a complication not reported with single-agent bevacizumab. We observed enhanced pulmonary parenchymal toxicity during treatment with bevacizumab concurrent with radiation, a finding that, to the best of our knowledge, has not been previously reported. We performed a phase I trial in patients with inoperable stage III NSCLC, during which induction chemotherapy was followed by radiotherapy concurrent with escalating doses of bevacizumab (NCT00531076). The study was terminated early because of high rates of radiation pneumonitis. Eligible patients with recurrent or newly diagnosed histologically proven, stage III nonsquamous NSCLC suitable for chemoradiotherapy were enrolled between December 2006 and February 2008. Patients underwent involved-field thoracic radiotherapy to a dose of 66 Gy (in 33 once-daily fractions of 2 Gy) and concurrent bevacizumab, starting 3 weeks after completing two cycles of induction cisplatin-based doublet combination chemotherapy. Risks of radiation-induced pulmonary toxicity were limited by restricting eligibility to plans with a V20 ⱕ 36%.8 Five consecutive cohorts of three patients were planned. Cohorts 1 and 2 received bevacizumab at 7.5 mg/kg and cohorts 3 to 5 received a dose of 15 mg/kg. Toxicity was scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Chest computed tomography (CT) scans were scheduled after completing radiotherapy and every 3 months thereafter. After a total of six patients had been enrolled (Table 1), inclusion was stopped when two consecutive patients developed grade 2 late radiation pneumonitis during follow-up. Two additional patients developed grade 3 radiation pneumonitis during subsequent follow-up, at which point the study was terminated. The four cases of grade ⱖ 2 radiation pneumonitis are reviewed below. Case Report 1 A 69-year-old current smoker presented with recurrent largecell carcinoma in the right middle lobe and paratracheal node 4R e104

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D I A G N O S I S

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Table 1. Patient Characteristics Characteristic

No. of Patients

Age, years Median Range Sex Male Female Ethnicity White Smoking history Nonsmoker Former Current Tumor histology Adenocarcinoma Large cell Tumor stage IIIA IIIB Tumor location Right-upper lobe Right-middle lobe Left-upper lobe Subcarinal

% 66 52-73

5 1

83 17

6

100

0 4 2

0 67 33

2 4

33 67

3 3

50 50

2 1 2 1

33 17 33 17

after a previous sleeve resection and nodal dissection for stage IIIA (T1N2M0) of the right upper lobe (forced expiratory volume in 1 second [FEV1], 34% of predicted; forced vital capacity [FVC], 87% of predicted). Protocol radiotherapy doses were delivered with a V20 of 25%. A complete radiologic response was achieved (Fig 1A). Eight months after treatment, the patient developed new extensive reticular shadowing, with areas of consolidation and small cavities in the dorsal aspect of the right middle lobe and marked loss of volume of the right hemithorax (Fig 1B, arrows). The patient was febrile, with worsening nonproductive cough and shortness of breath. A diagnosis of pneumonia with grade 2 late radiation pneumonitis was made. Treatment with antibiotics and corticosteroids resulted in clinical improvement, but the patient died 9 months after completing study treatment. Postmortem revealed Enterobacter cloacae pneumonia in the lower lobes bilaterally as the cause of death. Multiple small cavities ranging from 1 to 2 cm, diffuse fibrosis, granulation tissue, and necrotic tissue were observed in the irradiated right middle lobe. No evidence of residual intrathoracic tumor was found. Case Report 2 A 63-year-old current smoker with stage IIIA (T2N2M0) adenocarcinoma of the right upper lobe was treated with bevacizumab and radiotherapy to the tumor and nodes at stations 4R and 7 (V20, 29%; FEV1, 78% of predicted; FVC, 90% of predicted). A CT scan 4.5 Journal of Clinical Oncology, Vol 30, No 8 (March 10), 2012: pp e104-e108

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Fig 1.

months after completing treatment showed a partial tumor response, mild reticular changes with air bronchograms in the right upper lobe, and fibrotic changes in the apex consistent with grade 2 late radiation pneumonitis (Fig 2, arrow). The radiologic abnormalities progressed over time with an increase in consolidation and reticular changes and a loss of volume in the right-upper and middle lobes (Fig 2, arrows). Two years and 4 months after completion of treatment, a cavity appeared in the area of radiation damage in the right-upper lobe (Fig 2, arrows). The cavity enlarged on follow-up scans (Fig 2, arrows) and the patient developed a purulent cough, fetor, intermittent fever, and weight loss. A diagnosis of an abscess in a postradiation pulmonary cavity was made. The patient underwent a thoracic wall fenestration but died as a result of postoperative septic shock 2 years and 9 months after completing study treatment. Case Report 3 A 74-year-old former smoker with stage IIIB (T2N3M0) adenocarcinoma of the right-upper lobe underwent concurrent bevacizumab and irradiation (V20, 35%; FEV1, 92% of predicted; FVC, 107% of predicted). He developed symptoms consistent with mild radiation pneumonitis without radiologic changes (Figs 3A and 3B) in the last week of study treatment, but his symptoms did not require treatment. A follow-up CT scan at 3 months revealed a partial tumor response, with new ground-glass attenuation in the upper lobes bilaterally, as well as in the left-lower lobe (Figs 3C and 3D, arrows). All infiltrative lung changes were restricted to the radiation fields. At this point, the patient complained of progressive shortness of breath, a nonproductive cough, and fatigue with alternating episodes of feeling cold and warm. On examination, he was hypoxic (oxygen saturation, 83%), hypothermic (temperature, 34.7°C) and dyspnoeic. Plasma inflammatory markers were mildly raised. A diagnosis of grade 3 radiation pneumonitis was made and the patient was hospitalized and started on supplemental oxygen, prednisolone, and antibiotics. After an initial mild improvement, several attempts to wean the patient off the corticosteroids and oxygen failed. He continued on long-term oral prednisolone and home oxygen without any further clinical improvement. The patient died of distant disease progression 7 months later. www.jco.org

Case Report 4 A 47-year-old former smoker with a stage IIIA (T2N2M0) large-cell carcinoma of the left-upper lobe underwent bevacizumab and radiotherapy (V20, 29%; FEV1, 107% of predicted; FVC, 110% of predicted). A follow-up CT scan performed 3.4 months after radiotherapy showed a partial tumor response with multiple areas of extensive atelectasis/consolidation and airbronchograms, with a small left-sided pleural effusion. All changes were confined to the radiotherapy field. The patient complained of progressive fatigue, nausea, general malaise, and a nonproductive cough. On examination, she was afebrile with bilateral lung crepitations. A diagnosis of grade 3 radiation pneumonitis was made. She was started on oral prednisolone. A CT scan after 1 month showed persistent but mildly reduced left-sided consolidation and atelectasis. She developed progressive disease with liver and bone metastases 2 months after the onset of the pneumonitis and died of extrapulmonary disease 4 months later. Discussion Radiation-induced lung injury is a well-recognized adverse effect of radiotherapy, and severe (grade 2-3) radiation fibrosis has been reported in 8.3% of patients after conformal radiotherapy for NSCLC.9 In patients undergoing definitive chemoradiotherapy for stage III NSCLC, grade ⱖ 2 and grade ⱖ 3 radiation pneumonitis has been reported in 25% and 16% of patients, respectively, and increased rates have been reported in patients with high V20 values.10,11 The pathogenesis of radiation pneumonitis is unclear but emerging data suggest a potential role of the profibrogenic cytokine transforming growth factor ␤, although results are inconsistent.12-14 Despite the sample size of our study of radiation with concurrent bevacizumab for stage III NSCLC, the observed rate of 67% grade ⱖ 2 radiation-induced lung injury is alarming, particularly as study inclusion was limited to patients with low V20 values and as no concurrent chemotherapy was administered, which was the case in other reported trials.6 Besides the high incidence, the observed toxicity was characterized by changes that were largely restricted to radiation fields and was associated with the development of cavities in two of four patients. Bevacizumab likely played a central role in these events, which raises © 2012 by American Society of Clinical Oncology

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4.5 months after RT

22 months after RT

28 months after RT

31 months after RT

33 months after RT

Fig 2.

questions about the safety of combining bevacizumab with concurrent thoracic radiation in NSCLC. The mechanism of enhanced radiation-induced lung injury with bevacizumab and concurrent thoracic radiation is unclear. In preclinical studies, angiogenesis inhibitors have demonstrated enhanced e106

radiation-induced cell kill,4,5 and a possible explanation may be the transient normalization of the tumor vasculature, leading to a period of increased oxygenation during which enhanced radiationinduced regression is observed.15-17 Bevacizumab has also been shown to significantly downregulate genes involved in proliferation

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Fig 3.

and DNA repair.5 Whether the mechanisms of tumor radiosensitization are also responsible for the enhanced radiation-induced lung injury needs to be investigated. Another related study evaluating acute locoregional toxicity in patients with breast cancer who were treated with adjuvant radiotherapy combined with bevacizumab did not report a higher rate of radiation pneumonitis or fibrosis compared with radiotherapy alone.18 In conclusion, despite the small sample size and promising response rate, we observed a high incidence of pulmonary toxicity when radiotherapy and concurrent bevacizumab were administered in patients with stage III NSCLC after two cycles of induction chemotherapy. Given the tracheoesophageal fistulae reported after concurrent chemoradiotherapy with bevacizumab, a risk-benefit analysis would not appear to favor this combination treatment. Concurrent bevacizumab with thoracic radiotherapy is therefore unlikely to be further developed as a treatment option for stage III NSCLC. In addition, as antiangiogenic therapies play an increasing role in the systemic treatment of selected tumors, well-designed trials to study toxicity of similar agents using other schedules (eg, maintenance as opposed to concurrent administration) are required to establish safe and optimal strategies.

Joline S.W. Lind, Suresh Senan, and Egbert F. Smit Vrije Universiteit University Medical Center, Amsterdam, the Netherlands

ACKNOWLEDGMENT

The study was financially supported by Roche Netherlands. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those www.jco.org

relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Suresh Senan, Roche Netherlands (C), Eli Lilly (U) Stock Ownership: None Honoraria: Suresh Senan, Roche Research Funding: Suresh Senan, Roche Expert Testimony: None Other Remuneration: None REFERENCES 1. Cohen MH, Gootenberg J, Keegan P, et al: FDA drug approval summary: Bevacizumab (Avastin) plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist 12:713-718, 2007 2. Cohen MH, Gootenberg J, Keegan P, et al: FDA drug approval summary: Bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer. Oncologist 12:356-361, 2007 3. Crino` L, Dansin E, Garrido P, et al: Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): A phase 4 study. Lancet Oncol 11:733-740, 2010 4. Senan S, Smit EF: Design of clinical trials of radiation combined with antiangiogenic therapy. Oncologist 12:465-477, 2007 5. Koukourakis MI, Giatromanolaki A, Sheldon H, et al: Phase I/II trial of bevacizumab and radiotherapy for locally advanced inoperable colorectal cancer: Vasculature-independent radiosensitizing effect of bevacizumab. Clin Cancer Res 15:7069-7076, 2009 6. Spigel DR, Hainsworth JD, Yardley DA, et al: Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol 28:43-48, 2010 7. Gore E, Currey A, Choong N: Tracheoesophageal fistula associated with bevacizumab 21 months after completion of radiation therapy. J Thorac Oncol 4:1590-1591, 2009 8. Senan S, De Ruysscher D, Giraud P, et al: Literature-based recommendations for treatment planning and execution in high-dose radiotherapy for lung cancer. Radiother Oncol 71:139-146, 2004

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9. Mazeron R, Etienne-Mastroianni B, Pe´rol D, et al: Predictive factors of late radiation fibrosis: A prospective study in non-small cell lung cancer. Int J Radiat Oncol Biol Phys 77:38-43, 2010 10. Senan S, Cardenal F, Vansteenkiste J, et al: A randomized phase II study comparing induction or consolidation chemotherapy with cisplatin-docetaxel, plus radical concurrent chemoradiotherapy with cisplatin-docetaxel, in patients with unresectable locally advanced non-small-cell lung cancer. Ann Oncol 22:553-558, 2011 11. Albain KS, Swann RS, Rusch VW, et al: Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: A phase III randomised controlled trial. Lancet 374:379-386, 2009 12. Zhao L, Sheldon K, Chen M, et al: The predictive role of plasma TGF-beta1 during radiation therapy for radiation-induced lung toxicity deserves further study in patients with non-small cell lung cancer. Lung Cancer 59:232-239, 2008 13. Vujaskovic Z, Groen HJ: TGF-beta, radiation-induced pulmonary injury and lung cancer. Int J Radiat Biol 76:511-516, 2000 14. De Jaeger K, Seppenwoolde Y, Kampinga HH, et al: Significance of plasma transforming growth factor-beta levels in radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 58:1378-1387, 2004

15. Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145-147, 2004 16. Jain RK: Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307:58-62, 2005 17. Winkler F, Kozin SV, Tong RT, et al: Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553-563, 2004 18. Goyal S, Rao MS, Khan A, et al: Evaluation of acute locoregional toxicity in patients with breast cancer treated with adjuvant radiotherapy in combination with bevacizumab. Int J Radiat Oncol Biol Phys 79:408-413, 2011 [epub ahead of print on May 6, 2010]

DOI: 10.1200/JCO.2011.38.4552; published online ahead of print at www.jco.org on February 13, 2012

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JOURNAL OF CLINICAL ONCOLOGY