Published Ahead of Print on July 14, 2014 as 10.1200/JCO.2013.50.1643 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.50.1643
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
cytokeratin CAM 5.2–positive necrotic cells. Given the history of HCC and elevated ␣-fetoprotein, these findings were consistent with metastatic HCC. Sorafenib was started, but development of a total-body rash required discontinuation. Because of neutropenia, the patient was not considered a candidate for chemotherapy. The immunosuppression was then changed to the mTOR inhibitor sirolimus at a dose of 1 mg orally once per day and 2 mg orally once every other day to take advantage of its antineoplastic benefits. However, repeat imaging demonstrated progressive mediastinal disease with mass effect on the left brachiocephalic vein. Given the concern with respect to superior vena cava syndrome, the patient elected to proceed with a course of aggressive palliative RT. Sixty Gy in 2-Gy fractions using three-dimensional conformal RT with 6 megavoltage (MV) photon beams was prescribed. Segments and wedges were used to spare critical structures. To adequately cover the target volume, the esophagus (shown in medium blue in Fig 1A) was included in the planning target volume (red color wash) and the 100% isodose line (red). The esophageal mean dose was 19.2 Gy, maximum dose was 62.8 Gy, and volume receiving ⱖ 60 Gy (V60) was 4.7% (1.1 cm3). After receiving 6 Gy, the patient reported symptoms of heartburn. Famotidine 20 mg orally was increased to twice per day. At 16 Gy, the patient reported mild odynophagia, which was consistent with acute grade 1 esophageal toxicity.1 He was prescribed 10 mL of sucralfate suspension (100 mg/mL) 1 hour before meals and before bedtime, 10 mL of 1:1:1 viscous lidocaine 2%/liquid Maalox (Novartis, Summit, NJ)/diphenhydramine elixir every 6 hours as needed, and pantoprazole 40 mg orally once per day. After receiving 22 Gy, the patient developed severe retrosternal chest pain when swallowing that was consistent with acute grade 3 esophagitis. He was prescribed oxycodone 5 mg orally as needed every 4 to 6 hours and 10 mL of nystatin swish and swallow (100,000 U/mL) four times per day. His symptoms
Early and Severe Radiation Esophagitis Associated With Concurrent Sirolimus Introduction Here we report a case of severe radiation-induced esophageal toxicity at an early stage of radiation therapy (RT), likely a result of concurrent use of the mammalian target of rapamycin (mTOR) inhibitor sirolimus. This case supports the role of sirolimus as a radiosensitizer by demonstrating its potential to cause early and severe normal tissue toxicity. Case Report A 30-year-old man presented with a history of progressive shortness of breath for 3 months and fevers and right-sided chest pain for 2 weeks. The patient’s oncologic history was significant for a neuroblastoma at age 6 years that was treated with right nephrectomy, high-dose chemotherapy, 12 Gy total-body irradiation, and autologous stem-cell transplantation. Five years later, he was diagnosed with hepatitis C that was attributed to blood transfusions. Despite treatment with several interferon-based therapies, the hepatitis C persisted and progressed to cirrhosis. This was later complicated by hepatocellular carcinoma (HCC) and end-stage liver disease, for which the patient underwent an orthotopic liver transplantation. He began receiving tacrolimus, a calcineurin inhibitor, for immunosuppression, and surveillance abdominal imaging for the next 5 years was negative for HCC recurrence. The patient subsequently presented with shortness of breath, fevers, and right-sided chest pain. Computed tomography demonstrated a new mediastinal mass and large right-sided pleural effusion. Bronchoscopy with transbronchial fine-needle aspiration of a right paratracheal lymph node showed necrotic cells that were consistent with carcinoma. Sternotomy revealed a retrocaval mass adherent to the superior vena cava, precluding curative resection. Biopsy yielded
A
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C
Fig 1. Journal of Clinical Oncology, Vol 32, 2014
© 2014 by American Society of Clinical Oncology
Copyright 2014 by American Society of Clinical Oncology
1
Akthar et al
persisted and he was admitted for further work-up and intravenous hydration. A 5-day break from RT was required. Esophagogastroduodenoscopy revealed a cratered esophageal ulcer 25 to 29 cm from the incisors (Fig 1B). Biopsy of the ulcer demonstrated squamous mucosa with significant reactive cytologic atypia, which was consistent with radiation effect (Fig 1C). White arrows depict small arteries with hyalinization of the vessel wall, black arrows depict atypical endothelial cells, and double blue arrows depict large, atypical, hyperchromatic cells representing radiation fibroblasts. These findings were compatible with acute grade 4 radiation esophagitis. Given the early presentation for radiation esophagitis, it was believed that radiosensitization may have occurred from sirolimus. The esophageal ulcer was managed medically, and the patient was transitioned from sirolimus back to tacrolimus during the treatment break. RT was subsequently resumed, and the patient tolerated the remainder of his treatment well, with considerable improvement of esophageal symptoms. Unfortunately, the patient presented with seizures 1 month after completion of thoracic radiation. Imaging demonstrated multiple brain metastases. He received palliative whole-brain RT and subsequently died 3 weeks later. Discussion Radiation-induced esophagitis is a well-recognized complication of thoracic radiation. One group reported that 23 of 254 patients (9%) developed acute grade 3 to 5 esophagitis while undergoing RT for non–small-cell lung cancer with a median dose of 66 Gy from 1992 to 2001.2 Studies have identified several dosimetric predictors of acute radiation-induced esophagitis. These include a maximal point dose of ⱖ 58 Gy, a mean dose to the entire esophagus of ⬎ 34 Gy, the esophageal surface area receiving ⱖ 55 Gy (A55), and V60.3,4 Conflicting data exist on length of irradiated esophagus.5,6 Regarding clinical predictors, multiple studies demonstrate the use of concurrent chemotherapy to be a predictor of acute grade 3 or greater esophageal toxicity.4,7,8 The use of accelerated twice-per-day RT has also been shown to be a predictor of acute esophageal toxicity.2,7 A third predictor is the presence of dysphagia before RT, which may be a surrogate for the extent of mediastinal tumor involvement and thereby a measure of the expected irradiated esophageal volume.2 The patient described here experienced acute grade 4 esophageal toxicity at dosimetric parameters lower than those described in the previously mentioned studies. The patient received a dose of 22 Gy to the mediastinal mass before requiring a treatment break. Furthermore, our patient was not treated with chemotherapy or hyperfractionated radiotherapy, both of which are clinical predictors for an increased risk of esophagitis. The patient did experience dyspepsia before treatment, for which he took 20 mg famotidine orally every day. However, this was from chronic acid reflux rather than from the extent of his mediastinal tumor involvement. Finally, our patient’s progression from acute grade 1 to grade 4 esophageal toxicity within 2 weeks occurred much faster than expected from our institutional experience. There are individual case reports of patients with lung cancer and HIV/AIDS who show increased esophageal toxicity with RT, indicating that immunosuppression may cause increased toxicity.9,10 However, our patient was transitioned from sirolimus, an mTOR inhibitor, 2
© 2014 by American Society of Clinical Oncology
to tacrolimus, a calcineurin inhibitor, and had resolution of the severe toxicity. This suggests an additional mechanism of radiosensitization beyond immunosuppression that is related to sirolimus. A review of sirolimus and its effects on cellular signaling provides an explanation for these clinical findings. Many tumors demonstrate hyperactivation of receptor tyrosine kinases, which in turn causes increased phosphatidyl-inositol 3 kinase signaling.11,12 Phosphatidylinositol 3 kinase signaling has been shown to activate many downstream molecules, including mTOR.13-15 Activated mTOR promotes cellular proliferation16; therefore, efforts to inhibit mTOR may improve tumor control. Several investigations focused on the use of mTOR inhibitors as radiosensitizers when used concurrently with fractionated RT. One group looked at the use of mTOR inhibition on U87 malignant glioma xenografts with fractionated RT and found significantly enhanced treatment efficacy.17 Radiosensitization with mTOR inhibitors is being investigated in other cancer cell lines as well, including tumor endothelial cells and breast cancer.18,19 Although radiosensitization with mTOR inhibition has the potential to improve tumor control, the clinical relevance of these in vitro findings on normal tissue toxicity is still being characterized. A recent phase I trial was initiated on the basis of mTOR inhibitor radiosensitization.20 This trial enrolled seven patients with stage IIIA non–smallcell lung cancer who received definitive three-dimensional conformal RT to 60 Gy with weekly cisplatin and escalating doses of sirolimus up to 5 mg per day. Three of seven patients in this study reported pain with swallowing that interfered with eating. These symptoms resolved by 4 weeks after RT completion, and the authors concluded that acute toxicity of chemoradiotherapy was not enhanced by mTOR inhibition.20 However, this study did not report esophageal dosimetric constraints. In addition, one patient experienced a dose-limiting toxicity of grade 3 esophagitis in the treatment group receiving 5 mg per day, indicating that the esophagus may be particularly sensitive to the combination of mTOR inhibition and RT. Others have reported individual cases of increased normal tissue toxicity from the concurrent use of RT and sirolimus. One report described a patient with T2N0M0 squamous cell carcinoma of the larynx who had a complete clinical response after 7 fractions of radiation.21 This patient developed worsening odynophagia after approximately 2 weeks of treatment to a dose of 22 Gy and required a 3-day break from radiation. Similarly, our patient required a 5-day break from RT at 22 Gy. The multiple reports of radiation-induced esophagitis associated with sirolimus suggest that the use of concurrent sirolimus with RT may cause early and severe normal tissue toxicity. Caution should be used when considering radiation to be administered concurrently with sirolimus or other novel biologic agents. This case report should prompt other investigators to carefully observe the timing and severity of RT toxicity in association with sirolimus. This will add to our understanding of mTOR inhibitor radiosensitization and thereby allow clinicians to safely exploit the associated radiosensitizing properties.
Adil S. Akthar, Daniel W. Golden, Rita Nanda, Manish R. Sharma, Helen S. Te, K. Gautham Reddy, Xuefeng Zhang, and Renuka Malik Pritzker School of Medicine, University of Chicago, Chicago, IL JOURNAL OF CLINICAL ONCOLOGY
Diagnosis in Oncology
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341-1346, 1995 2. Ahn SJ, Kahn D, Zhou S, et al: Dosimetric and clinical predictors for radiation-induced esophageal injury. Int J Radiat Oncol Biol Phys 61:335-347, 2005 3. Bradley J, Deasy JO, Bentzen S, et al: Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma. Int J Radiat Oncol Biol Phys 58:1106-1113, 2004 4. Singh AK, Lockett MA, Bradley JD: Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with threedimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 55:337-341, 2003 5. Rosenman JG, Halle JS, Socinski MA, et al: High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: Technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys 54:348-356, 2002 6. Werner-Wasik M, Pequignot E, Leeper D, et al: Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: A multivariate analysis of patients with lung cancer treated with nonoperative therapy. Int J Radiat Oncol Biol Phys 48:689-696, 2000 7. Komaki R, Seiferheld W, Ettinger D, et al: Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non-small-cell lung cancer: Long-term follow-up of RTOG 92-04. Int J Radiat Oncol Biol Phys 53:548-557, 2002 8. Maguire PD, Sibley GS, Zhou SM, et al: Clinical and dosimetric predictors of radiation-induced esophageal toxicity. Int J Radiat Oncol Biol Phys 45:97-103, 1999 9. Costleigh BJ, Miyamoto CT, Micaily B, et al: Heightened sensitivity of the esophagus to radiation in a patient with AIDS. Am J Gastroenterol 90:812-814, 1995
10. Leigh BR, Lau DH: Severe esophageal toxicity after thoracic radiation therapy for lung cancer associated with the human immunodeficiency virus: A case report and review of the literature. Am J Clin Oncol 21:479-481, 1998 11. Arcaro A, Zvelebil MJ, Wallasch C, et al: Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol Cell Biol 20:3817-3830, 2000 12. Paez J, Sellers WR: PI3K/PTEN/AKT pathway: A critical mediator of oncogenic signaling. Cancer Treat Res 115:145-167, 2003 13. Haas-Kogan D, Shalev N, Wong M, et al: Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol 8:1195-1198, 1998 14. Mills GB, Lu Y, Kohn EC: Linking molecular therapeutics to molecular diagnostics: Inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo. Proc Natl Acad Sci U S A 98:10031-10033, 2001 15. Neshat MS, Mellinghoff IK, Tran C, et al: Enhanced sensitivity of PTENdeficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 98:10314-10319, 2001 16. Hay N, Sonenberg N: Upstream and downstream of mTOR. Genes Dev 18:1926-1945, 2004 17. Eshleman JS, Carlson BL, Mladek AC, et al: Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 62:7291-7297, 2002 18. Albert JM, Kim KW, Cao C, et al: Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther 5:1183-1189, 2006 19. Shinohara ET, Cao C, Niermann K, et al: Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 24:5414-5422, 2005 20. Sarkaria JN, Schwingler P, Schild SE, et al: Phase I trial of sirolimus combined with radiation and cisplatin in non-small cell lung cancer. J Thorac Oncol 2:751-757, 2007 21. Shinohara ET, Maity A, Jha N, et al: Sirolimus as a potential radiosensitizer in squamous cell cancer of the head and neck. Head Neck 31:406-411, 2009
DOI: 10.1200/JCO.2013.50.1643; published online ahead of print at www.jco.org on July 14, 2014
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www.jco.org
© 2014 by American Society of Clinical Oncology
3
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
cytokeratin CAM 5.2–positive necrotic cells. Given the history of HCC and elevated ␣-fetoprotein, these findings were consistent with metastatic HCC. Sorafenib was started, but development of a total-body rash required discontinuation. Because of neutropenia, the patient was not considered a candidate for chemotherapy. The immunosuppression was then changed to the mTOR inhibitor sirolimus at a dose of 1 mg orally once per day and 2 mg orally once every other day to take advantage of its antineoplastic benefits. However, repeat imaging demonstrated progressive mediastinal disease with mass effect on the left brachiocephalic vein. Given the concern with respect to superior vena cava syndrome, the patient elected to proceed with a course of aggressive palliative RT. Sixty Gy in 2-Gy fractions using three-dimensional conformal RT with 6 megavoltage (MV) photon beams was prescribed. Segments and wedges were used to spare critical structures. To adequately cover the target volume, the esophagus (shown in medium blue in Fig 1A) was included in the planning target volume (red color wash) and the 100% isodose line (red). The esophageal mean dose was 19.2 Gy, maximum dose was 62.8 Gy, and volume receiving ⱖ 60 Gy (V60) was 4.7% (1.1 cm3). After receiving 6 Gy, the patient reported symptoms of heartburn. Famotidine 20 mg orally was increased to twice per day. At 16 Gy, the patient reported mild odynophagia, which was consistent with acute grade 1 esophageal toxicity.1 He was prescribed 10 mL of sucralfate suspension (100 mg/mL) 1 hour before meals and before bedtime, 10 mL of 1:1:1 viscous lidocaine 2%/liquid Maalox (Novartis, Summit, NJ)/diphenhydramine elixir every 6 hours as needed, and pantoprazole 40 mg orally once per day. After receiving 22 Gy, the patient developed severe retrosternal chest pain when swallowing that was consistent with acute grade 3 esophagitis. He was prescribed oxycodone 5 mg orally as needed every 4 to 6 hours and 10 mL of nystatin swish and swallow (100,000 U/mL) four times per day. His symptoms
Early and Severe Radiation Esophagitis Associated With Concurrent Sirolimus Introduction Here we report a case of severe radiation-induced esophageal toxicity at an early stage of radiation therapy (RT), likely a result of concurrent use of the mammalian target of rapamycin (mTOR) inhibitor sirolimus. This case supports the role of sirolimus as a radiosensitizer by demonstrating its potential to cause early and severe normal tissue toxicity. Case Report A 30-year-old man presented with a history of progressive shortness of breath for 3 months and fevers and right-sided chest pain for 2 weeks. The patient’s oncologic history was significant for a neuroblastoma at age 6 years that was treated with right nephrectomy, high-dose chemotherapy, 12 Gy total-body irradiation, and autologous stem-cell transplantation. Five years later, he was diagnosed with hepatitis C that was attributed to blood transfusions. Despite treatment with several interferon-based therapies, the hepatitis C persisted and progressed to cirrhosis. This was later complicated by hepatocellular carcinoma (HCC) and end-stage liver disease, for which the patient underwent an orthotopic liver transplantation. He began receiving tacrolimus, a calcineurin inhibitor, for immunosuppression, and surveillance abdominal imaging for the next 5 years was negative for HCC recurrence. The patient subsequently presented with shortness of breath, fevers, and right-sided chest pain. Computed tomography demonstrated a new mediastinal mass and large right-sided pleural effusion. Bronchoscopy with transbronchial fine-needle aspiration of a right paratracheal lymph node showed necrotic cells that were consistent with carcinoma. Sternotomy revealed a retrocaval mass adherent to the superior vena cava, precluding curative resection. Biopsy yielded
A
I N
B
C
Fig 1. Journal of Clinical Oncology, Vol 32, 2014
© 2014 by American Society of Clinical Oncology
Copyright 2014 by American Society of Clinical Oncology
1
Akthar et al
persisted and he was admitted for further work-up and intravenous hydration. A 5-day break from RT was required. Esophagogastroduodenoscopy revealed a cratered esophageal ulcer 25 to 29 cm from the incisors (Fig 1B). Biopsy of the ulcer demonstrated squamous mucosa with significant reactive cytologic atypia, which was consistent with radiation effect (Fig 1C). White arrows depict small arteries with hyalinization of the vessel wall, black arrows depict atypical endothelial cells, and double blue arrows depict large, atypical, hyperchromatic cells representing radiation fibroblasts. These findings were compatible with acute grade 4 radiation esophagitis. Given the early presentation for radiation esophagitis, it was believed that radiosensitization may have occurred from sirolimus. The esophageal ulcer was managed medically, and the patient was transitioned from sirolimus back to tacrolimus during the treatment break. RT was subsequently resumed, and the patient tolerated the remainder of his treatment well, with considerable improvement of esophageal symptoms. Unfortunately, the patient presented with seizures 1 month after completion of thoracic radiation. Imaging demonstrated multiple brain metastases. He received palliative whole-brain RT and subsequently died 3 weeks later. Discussion Radiation-induced esophagitis is a well-recognized complication of thoracic radiation. One group reported that 23 of 254 patients (9%) developed acute grade 3 to 5 esophagitis while undergoing RT for non–small-cell lung cancer with a median dose of 66 Gy from 1992 to 2001.2 Studies have identified several dosimetric predictors of acute radiation-induced esophagitis. These include a maximal point dose of ⱖ 58 Gy, a mean dose to the entire esophagus of ⬎ 34 Gy, the esophageal surface area receiving ⱖ 55 Gy (A55), and V60.3,4 Conflicting data exist on length of irradiated esophagus.5,6 Regarding clinical predictors, multiple studies demonstrate the use of concurrent chemotherapy to be a predictor of acute grade 3 or greater esophageal toxicity.4,7,8 The use of accelerated twice-per-day RT has also been shown to be a predictor of acute esophageal toxicity.2,7 A third predictor is the presence of dysphagia before RT, which may be a surrogate for the extent of mediastinal tumor involvement and thereby a measure of the expected irradiated esophageal volume.2 The patient described here experienced acute grade 4 esophageal toxicity at dosimetric parameters lower than those described in the previously mentioned studies. The patient received a dose of 22 Gy to the mediastinal mass before requiring a treatment break. Furthermore, our patient was not treated with chemotherapy or hyperfractionated radiotherapy, both of which are clinical predictors for an increased risk of esophagitis. The patient did experience dyspepsia before treatment, for which he took 20 mg famotidine orally every day. However, this was from chronic acid reflux rather than from the extent of his mediastinal tumor involvement. Finally, our patient’s progression from acute grade 1 to grade 4 esophageal toxicity within 2 weeks occurred much faster than expected from our institutional experience. There are individual case reports of patients with lung cancer and HIV/AIDS who show increased esophageal toxicity with RT, indicating that immunosuppression may cause increased toxicity.9,10 However, our patient was transitioned from sirolimus, an mTOR inhibitor, 2
© 2014 by American Society of Clinical Oncology
to tacrolimus, a calcineurin inhibitor, and had resolution of the severe toxicity. This suggests an additional mechanism of radiosensitization beyond immunosuppression that is related to sirolimus. A review of sirolimus and its effects on cellular signaling provides an explanation for these clinical findings. Many tumors demonstrate hyperactivation of receptor tyrosine kinases, which in turn causes increased phosphatidyl-inositol 3 kinase signaling.11,12 Phosphatidylinositol 3 kinase signaling has been shown to activate many downstream molecules, including mTOR.13-15 Activated mTOR promotes cellular proliferation16; therefore, efforts to inhibit mTOR may improve tumor control. Several investigations focused on the use of mTOR inhibitors as radiosensitizers when used concurrently with fractionated RT. One group looked at the use of mTOR inhibition on U87 malignant glioma xenografts with fractionated RT and found significantly enhanced treatment efficacy.17 Radiosensitization with mTOR inhibitors is being investigated in other cancer cell lines as well, including tumor endothelial cells and breast cancer.18,19 Although radiosensitization with mTOR inhibition has the potential to improve tumor control, the clinical relevance of these in vitro findings on normal tissue toxicity is still being characterized. A recent phase I trial was initiated on the basis of mTOR inhibitor radiosensitization.20 This trial enrolled seven patients with stage IIIA non–smallcell lung cancer who received definitive three-dimensional conformal RT to 60 Gy with weekly cisplatin and escalating doses of sirolimus up to 5 mg per day. Three of seven patients in this study reported pain with swallowing that interfered with eating. These symptoms resolved by 4 weeks after RT completion, and the authors concluded that acute toxicity of chemoradiotherapy was not enhanced by mTOR inhibition.20 However, this study did not report esophageal dosimetric constraints. In addition, one patient experienced a dose-limiting toxicity of grade 3 esophagitis in the treatment group receiving 5 mg per day, indicating that the esophagus may be particularly sensitive to the combination of mTOR inhibition and RT. Others have reported individual cases of increased normal tissue toxicity from the concurrent use of RT and sirolimus. One report described a patient with T2N0M0 squamous cell carcinoma of the larynx who had a complete clinical response after 7 fractions of radiation.21 This patient developed worsening odynophagia after approximately 2 weeks of treatment to a dose of 22 Gy and required a 3-day break from radiation. Similarly, our patient required a 5-day break from RT at 22 Gy. The multiple reports of radiation-induced esophagitis associated with sirolimus suggest that the use of concurrent sirolimus with RT may cause early and severe normal tissue toxicity. Caution should be used when considering radiation to be administered concurrently with sirolimus or other novel biologic agents. This case report should prompt other investigators to carefully observe the timing and severity of RT toxicity in association with sirolimus. This will add to our understanding of mTOR inhibitor radiosensitization and thereby allow clinicians to safely exploit the associated radiosensitizing properties.
Adil S. Akthar, Daniel W. Golden, Rita Nanda, Manish R. Sharma, Helen S. Te, K. Gautham Reddy, Xuefeng Zhang, and Renuka Malik Pritzker School of Medicine, University of Chicago, Chicago, IL JOURNAL OF CLINICAL ONCOLOGY
Diagnosis in Oncology
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:1341-1346, 1995 2. Ahn SJ, Kahn D, Zhou S, et al: Dosimetric and clinical predictors for radiation-induced esophageal injury. Int J Radiat Oncol Biol Phys 61:335-347, 2005 3. Bradley J, Deasy JO, Bentzen S, et al: Dosimetric correlates for acute esophagitis in patients treated with radiotherapy for lung carcinoma. Int J Radiat Oncol Biol Phys 58:1106-1113, 2004 4. Singh AK, Lockett MA, Bradley JD: Predictors of radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with threedimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 55:337-341, 2003 5. Rosenman JG, Halle JS, Socinski MA, et al: High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: Technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys 54:348-356, 2002 6. Werner-Wasik M, Pequignot E, Leeper D, et al: Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: A multivariate analysis of patients with lung cancer treated with nonoperative therapy. Int J Radiat Oncol Biol Phys 48:689-696, 2000 7. Komaki R, Seiferheld W, Ettinger D, et al: Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non-small-cell lung cancer: Long-term follow-up of RTOG 92-04. Int J Radiat Oncol Biol Phys 53:548-557, 2002 8. Maguire PD, Sibley GS, Zhou SM, et al: Clinical and dosimetric predictors of radiation-induced esophageal toxicity. Int J Radiat Oncol Biol Phys 45:97-103, 1999 9. Costleigh BJ, Miyamoto CT, Micaily B, et al: Heightened sensitivity of the esophagus to radiation in a patient with AIDS. Am J Gastroenterol 90:812-814, 1995
10. Leigh BR, Lau DH: Severe esophageal toxicity after thoracic radiation therapy for lung cancer associated with the human immunodeficiency virus: A case report and review of the literature. Am J Clin Oncol 21:479-481, 1998 11. Arcaro A, Zvelebil MJ, Wallasch C, et al: Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol Cell Biol 20:3817-3830, 2000 12. Paez J, Sellers WR: PI3K/PTEN/AKT pathway: A critical mediator of oncogenic signaling. Cancer Treat Res 115:145-167, 2003 13. Haas-Kogan D, Shalev N, Wong M, et al: Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol 8:1195-1198, 1998 14. Mills GB, Lu Y, Kohn EC: Linking molecular therapeutics to molecular diagnostics: Inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo. Proc Natl Acad Sci U S A 98:10031-10033, 2001 15. Neshat MS, Mellinghoff IK, Tran C, et al: Enhanced sensitivity of PTENdeficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 98:10314-10319, 2001 16. Hay N, Sonenberg N: Upstream and downstream of mTOR. Genes Dev 18:1926-1945, 2004 17. Eshleman JS, Carlson BL, Mladek AC, et al: Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 62:7291-7297, 2002 18. Albert JM, Kim KW, Cao C, et al: Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther 5:1183-1189, 2006 19. Shinohara ET, Cao C, Niermann K, et al: Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 24:5414-5422, 2005 20. Sarkaria JN, Schwingler P, Schild SE, et al: Phase I trial of sirolimus combined with radiation and cisplatin in non-small cell lung cancer. J Thorac Oncol 2:751-757, 2007 21. Shinohara ET, Maity A, Jha N, et al: Sirolimus as a potential radiosensitizer in squamous cell cancer of the head and neck. Head Neck 31:406-411, 2009
DOI: 10.1200/JCO.2013.50.1643; published online ahead of print at www.jco.org on July 14, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
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