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Oligoprogression
ARTICLE IN PRESS
Perspective
Oligoprogression: What Radiologists Need to Know About This Emerging Concept in Cancer Therapeutic Decision-making Steven P. Rowe, MD, PhD, Phuoc T. Tran, MD, PhD, Elliot K. Fishman, MD, Pamela T. Johnson, MD Key Words: Cancer imaging; oligoprogression; oligoprogressive; focal therapy. © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.
INTRODUCTION AND BACKGROUND
I
t has been recognized for some time that human cancers demonstrate remarkable heterogeneity, not only between patients and tissues of origin but even between subpopulations of different cells within a single primary neoplasm or among the metastatic lesions within a single individual (1,2). As overall cancer survivorship continues to increase (3), and patients are exposed to more and more lines of therapy, it is inevitable that selection for aggressive phenotypes among cancer cells will occur and this can lead to seemingly contradictory progression of one or a few sites of disease in spite of an overall tumor burden response to therapy (ie, “oligoprogression”). We have previously discussed the important role of the radiologist in defining the oligometastatic state of cancer, in which patients can harbor a small number (generally less than five) of metastases and yet may still be candidates for targeted therapy (surgical resection, ablation, cryotherapy, or radiation) and potential cure (4,5). In a similar vein, radiologists must be aware of oligoprogression as an emerging concept in modern oncology. The key distinction from oligometastases is that a patient with oligoprogression can have any number of systemic metastases, but only one or a small number are progressing, whereas the remainder are stable or responding to systemic therapy (6). Acad Radiol 2017; ■:■■–■■ From The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287 (S.P.R., E.K.F., P.T.J.); Departments of Radiation Oncology and Molecular Radiation Sciences, Oncology, and The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.T.T.). Received December 12, 2016; accepted December 29, 2016. Address correspondence to: S.P.R. e-mail: [email protected] © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.acra.2016.12.018
Multiple recent publications reviewed in this manuscript have studied the role of focal therapy for oligoprogressive lesions. Ablative radiation is the most commonly employed method in the literature for focal therapy in oligoprogression. Stereotactic radiosurgery refers to the process of using multiple radiation beams at different angles relative to an intracranial site to be treated and delivering large doses of conformal radiation in one or a few fractions (7). Stereotactic ablative radiotherapy (SABR) and stereotactic body radiation therapy (SBRT) both refer to a similar process that is carried out with extracranial sites of disease (6,8). The use of multiple beams generally allows the radiation oncologist to avoid undue toxicity to nearby normal tissues, although if SABR or SBRT is being considered the radiologist may wish to emphasize in the report the degree of nearness or contact between a metastatic deposit and any radiosensitive organs such as the spinal cord or bowel. Outside of ablative radiation, other modalities such as traditional fractionated radiation, radiofrequency ablation, cryotherapy, and surgery may have roles in certain circumstances.
LUNG CANCER The malignancy for which the role of focal therapy for oligoprogression has been most extensively studied is non– small cell lung cancer (NSCLC). An overarching goal of many of the studies in NSCLC has been to continue patients on otherwise effective systemic therapies, reserving later line therapies for more widespread progression (9). The radiologist should carefully examine NSCLC patients on systemic therapy for evidence of new, enlarging, or morphologically more suspicious sites of disease, with particular attention paid to the common areas of disease involvement such as locoregional lymph nodes, ipsilateral or contralateral lung parenchyma, 1
ROWE ET AL
adrenal glands, liver, skeletal structures, and central nervous system. Just as important as identifying the sites of progression in these patients is assuring that the progression is truly limited to one or a few sites. Cheung has recently provided an outstanding review of oligoprogression with an emphasis on NSCLC (6) given the preponderance of the literature. Herein are highlighted some of the findings of a subset of the studies that were also included in his review. For example, an important study involving 65 patients with anaplastic lymphoma kinase-positive or epidermal growth factor receptor (EGFR)-mutant NSCLC found that 25 of 51 patients who progressed on systemic therapy (crizotinib or erlotinib) were oligoprogressive and suitable for focal therapy with stereotactic radiosurgery, whole brain radiation therapy, SABR or SBRT, or surgery (9). An additional progression-free survival period of 6.2 months was achieved in a subset of patients, although those patients again progressed after focal therapy. Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), a set of criteria that is certainly familiar to many oncology imagers, was one of the metrics by which progression could be determined. Yu et al also looked at the role of focal therapy in oligoprogression of EGFR-mutant metastatic NSCLCs that were progressing through treatment with EGFR tyrosine kinase inhibitors (10). The authors excluded patients with oligoprogression confined to the brain. The determination of oligoprogression was based on routine or symptom-based imaging evaluation. The median time to further progression after focal therapy was 10 months, with a median time of 22 months before a change in systemic therapy, suggesting that the treatments targeted to the oligoprogressive sites provided substantive local control of the disease. A recent study was carried out by Gan et al and included 33 patients with anaplastic lymphoma kinase-positive NSCLC who were being treated systemically with crizotinib (11). Fourteen of the 33 patients experienced oligoprogression that did not involve the central nervous system, and they were treated with SABR or SBRT to the oligoprogressive sites of disease. Progression was again determined in part by RECIST 1.1, once more underscoring the important role of radiology in selecting patients to undergo focal therapy. Local control rates at the treated sites were 100% and 86% at 6 months and 12 months, respectively. No significant toxicities related to the radiation therapies were reported. The treated patients were able to maintain therapy with crizotinib longer than those who did not receive SABR or SBRT, with an associated statistically significant increase in 2-year overall survival among those patients taking crizotinib for a longer period of time. OTHER MALIGNANCIES Although the most thorough understanding of the role of targeted therapy with ablative radiation in oligoprogression is in NSCLC, a small but growing volume of data suggest that the same principles may be applicable to other malignancies 2
Academic Radiology, Vol ■, No ■■, ■■ 2017
(12). For example, a recently published case report from Straka et al presented a patient with metastatic clear cell renal cell carcinoma with metastases to lymph nodes, bone, and the right adrenal gland (13). Following initiation of systemic therapy with the tyrosine kinase inhibitor sunitinib, which the patient tolerated well, he had an excellent response in all lymph node and bone lesions, but eventually developed progression in only the right adrenal gland metastasis. SABR or SBRT during a pause in sunitinib therapy caused regression of the adrenal metastasis without any detectable toxicity to the patient. This response allowed the patient to continue to be treated with sunitinib for another 8 months before widespread progression occurred. The role of imaging is underscored in this case, as the decision-making was based on the increasing size of the right adrenal metastatic lesion on serial computed tomography examinations, with subsequent decrease in size following SABR or SBRT. A prospective phase II trial specifically addressing the potential role for SABR or SBRT in keeping metastatic clear cell renal cell carcinoma patients on sunitinib for longer periods of time is currently recruiting participants (ClinicalTrials.gov identifier: NCT02019576). A recent multi-institutional series of men with hormonenaïve oligoprogressive prostate cancer suggested SABR or SBRT can delay initiation of androgen deprivation therapy (ADT) up to an average of 28 months (14). At our own institution, oligoprogressive metastatic castration-resistant prostate cancer is being increasingly treated with SABR or SBRT as a means of providing patients with local control of their progressing sites of disease so that (1) they can be maintained on their current systemic treatment that is controlling their disease, save for oligoprogressive sites; and (2) they can limit or delay initiation of additional hormonal therapy or aggressive chemotherapy regimens. We present an illustrative example of a 72-year-old gentleman with metastatic castration-resistant prostate cancer who had been treated with ADT, docetaxel, abiraterone, and most recently cabazitaxel with almost complete response (serum prostate-specific antigen [PSA] level of 1.0 ng/dL), except for a persistent right adrenal metastasis. The patient demonstrated oligoprogressive disease of the right adrenal metastasis over a period of 6 months, with the lesion growing to 4.0 cm in largest diameter and a raise in PSA to 79 ng/dL. The patient elected to be treated with SABR and SBRT resulting in a PSA nadir to undetectable levels 6.5 months later. The patient is now almost 2 years from any systemic therapy other than ADT and has a PSA of 2.8 ng/dL. CONCLUSIONS Oncology paradigms are evolving with respect to management of oligometastatic disease and oligoprogression. Accordingly, radiologists must be meticulous in detecting all sites of metastatic disease for patients with five or fewer lesions and in identifying metastases that progress despite an otherwise positive treatment response to systemic treatments. The interval growth or suspicious morphologic change of a solitary or small number of lesions should be recognized as
Academic Radiology, Vol ■, No ■■, ■■ 2017
OLIGOPROGRESSION: WHAT RADIOLOGISTS NEED TO KNOW
oligoprogression and emphasized in the impression of the radiology report. A general understanding of the treatment potential of ablative radiotherapy in this context, as outlined in this article, may be a useful tool for the radiologist in the role of consultant to the referring oncologist. As definitions of oligoprogression evolve and patients with malignancies other than NSCLC are studied, prospective trials will hopefully provide definitive evidence of benefit from focal therapy to oligoprogressive sites for increasing survival. REFERENCES 1. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366:883–892. 2. Spremulli EN, Dexter DL. Human tumor cell heterogeneity and metastasis. J Clin Oncol 1983; 1:496–509. 3. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 2016; 66:271–289. 4. Reyes DK, Pienta KJ. The biology and treatment of oligometastatic cancer. Oncotarget 2015; 6:8491–8524. 5. Rowe SP, Hawasli H, Fishman EK, et al. Advances in the treatment of oligometastatic disease: what the radiologist needs to know to guide patient management. Acad Radiol 2016; 23:326–328.
6. Cheung P. Stereotactic body radiotherapy for oligoprogressive cancer. Br J Radiol 2016; 89:20160251. 7. Phillips MH, Stelzer KJ, Griffin TW, et al. Stereotactic radiosurgery: a review and comparison of methods. J Clin Oncol 1994; 12:1085–1099. 8. Timmerman RD, Forster KM, Chinsoo Cho L. Extracranial stereotactic radiation delivery. Semin Radiat Oncol 2005; 15:202–207. 9. Simone CB, 2nd, Burri SH, Heinzerling JH. Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies. Transl Lung Cancer Res 2015; 4:545–552. 10. Yu HA, Sima CS, Huang J, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013; 8:346–351. 11. Gan GN, Weickhardt AJ, Scheier B, et al. Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib. Int J Radiat Oncol Biol Phys 2014; 88:892–898. 12. Cheung P, Thibault I, Bjarnason GA. The emerging roles of stereotactic ablative radiotherapy for metastatic renal cell carcinoma. Curr Opin Support Palliat Care 2014; 8:258–264. 13. Straka C, Kim DW, Timmerman RD, et al. Ablation of a site of progression with stereotactic body radiation therapy extends sunitinib treatment from 14 to 22 months. J Clin Oncol 2013; 31:e401–e403. 14. Ost P, Jereczek-Fossa BA, As NV, et al. Progression-free survival following stereotactic body radiotherapy for oligometastatic prostate cancer treatment-naive recurrence: a multi-institutional analysis. Eur Urol 2016; 69:9–12.
3
Perspective
Oligoprogression: What Radiologists Need to Know About This Emerging Concept in Cancer Therapeutic Decision-making Steven P. Rowe, MD, PhD, Phuoc T. Tran, MD, PhD, Elliot K. Fishman, MD, Pamela T. Johnson, MD Key Words: Cancer imaging; oligoprogression; oligoprogressive; focal therapy. © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.
INTRODUCTION AND BACKGROUND
I
t has been recognized for some time that human cancers demonstrate remarkable heterogeneity, not only between patients and tissues of origin but even between subpopulations of different cells within a single primary neoplasm or among the metastatic lesions within a single individual (1,2). As overall cancer survivorship continues to increase (3), and patients are exposed to more and more lines of therapy, it is inevitable that selection for aggressive phenotypes among cancer cells will occur and this can lead to seemingly contradictory progression of one or a few sites of disease in spite of an overall tumor burden response to therapy (ie, “oligoprogression”). We have previously discussed the important role of the radiologist in defining the oligometastatic state of cancer, in which patients can harbor a small number (generally less than five) of metastases and yet may still be candidates for targeted therapy (surgical resection, ablation, cryotherapy, or radiation) and potential cure (4,5). In a similar vein, radiologists must be aware of oligoprogression as an emerging concept in modern oncology. The key distinction from oligometastases is that a patient with oligoprogression can have any number of systemic metastases, but only one or a small number are progressing, whereas the remainder are stable or responding to systemic therapy (6). Acad Radiol 2017; ■:■■–■■ From The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287 (S.P.R., E.K.F., P.T.J.); Departments of Radiation Oncology and Molecular Radiation Sciences, Oncology, and The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland (P.T.T.). Received December 12, 2016; accepted December 29, 2016. Address correspondence to: S.P.R. e-mail: [email protected] © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.acra.2016.12.018
Multiple recent publications reviewed in this manuscript have studied the role of focal therapy for oligoprogressive lesions. Ablative radiation is the most commonly employed method in the literature for focal therapy in oligoprogression. Stereotactic radiosurgery refers to the process of using multiple radiation beams at different angles relative to an intracranial site to be treated and delivering large doses of conformal radiation in one or a few fractions (7). Stereotactic ablative radiotherapy (SABR) and stereotactic body radiation therapy (SBRT) both refer to a similar process that is carried out with extracranial sites of disease (6,8). The use of multiple beams generally allows the radiation oncologist to avoid undue toxicity to nearby normal tissues, although if SABR or SBRT is being considered the radiologist may wish to emphasize in the report the degree of nearness or contact between a metastatic deposit and any radiosensitive organs such as the spinal cord or bowel. Outside of ablative radiation, other modalities such as traditional fractionated radiation, radiofrequency ablation, cryotherapy, and surgery may have roles in certain circumstances.
LUNG CANCER The malignancy for which the role of focal therapy for oligoprogression has been most extensively studied is non– small cell lung cancer (NSCLC). An overarching goal of many of the studies in NSCLC has been to continue patients on otherwise effective systemic therapies, reserving later line therapies for more widespread progression (9). The radiologist should carefully examine NSCLC patients on systemic therapy for evidence of new, enlarging, or morphologically more suspicious sites of disease, with particular attention paid to the common areas of disease involvement such as locoregional lymph nodes, ipsilateral or contralateral lung parenchyma, 1
ROWE ET AL
adrenal glands, liver, skeletal structures, and central nervous system. Just as important as identifying the sites of progression in these patients is assuring that the progression is truly limited to one or a few sites. Cheung has recently provided an outstanding review of oligoprogression with an emphasis on NSCLC (6) given the preponderance of the literature. Herein are highlighted some of the findings of a subset of the studies that were also included in his review. For example, an important study involving 65 patients with anaplastic lymphoma kinase-positive or epidermal growth factor receptor (EGFR)-mutant NSCLC found that 25 of 51 patients who progressed on systemic therapy (crizotinib or erlotinib) were oligoprogressive and suitable for focal therapy with stereotactic radiosurgery, whole brain radiation therapy, SABR or SBRT, or surgery (9). An additional progression-free survival period of 6.2 months was achieved in a subset of patients, although those patients again progressed after focal therapy. Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), a set of criteria that is certainly familiar to many oncology imagers, was one of the metrics by which progression could be determined. Yu et al also looked at the role of focal therapy in oligoprogression of EGFR-mutant metastatic NSCLCs that were progressing through treatment with EGFR tyrosine kinase inhibitors (10). The authors excluded patients with oligoprogression confined to the brain. The determination of oligoprogression was based on routine or symptom-based imaging evaluation. The median time to further progression after focal therapy was 10 months, with a median time of 22 months before a change in systemic therapy, suggesting that the treatments targeted to the oligoprogressive sites provided substantive local control of the disease. A recent study was carried out by Gan et al and included 33 patients with anaplastic lymphoma kinase-positive NSCLC who were being treated systemically with crizotinib (11). Fourteen of the 33 patients experienced oligoprogression that did not involve the central nervous system, and they were treated with SABR or SBRT to the oligoprogressive sites of disease. Progression was again determined in part by RECIST 1.1, once more underscoring the important role of radiology in selecting patients to undergo focal therapy. Local control rates at the treated sites were 100% and 86% at 6 months and 12 months, respectively. No significant toxicities related to the radiation therapies were reported. The treated patients were able to maintain therapy with crizotinib longer than those who did not receive SABR or SBRT, with an associated statistically significant increase in 2-year overall survival among those patients taking crizotinib for a longer period of time. OTHER MALIGNANCIES Although the most thorough understanding of the role of targeted therapy with ablative radiation in oligoprogression is in NSCLC, a small but growing volume of data suggest that the same principles may be applicable to other malignancies 2
Academic Radiology, Vol ■, No ■■, ■■ 2017
(12). For example, a recently published case report from Straka et al presented a patient with metastatic clear cell renal cell carcinoma with metastases to lymph nodes, bone, and the right adrenal gland (13). Following initiation of systemic therapy with the tyrosine kinase inhibitor sunitinib, which the patient tolerated well, he had an excellent response in all lymph node and bone lesions, but eventually developed progression in only the right adrenal gland metastasis. SABR or SBRT during a pause in sunitinib therapy caused regression of the adrenal metastasis without any detectable toxicity to the patient. This response allowed the patient to continue to be treated with sunitinib for another 8 months before widespread progression occurred. The role of imaging is underscored in this case, as the decision-making was based on the increasing size of the right adrenal metastatic lesion on serial computed tomography examinations, with subsequent decrease in size following SABR or SBRT. A prospective phase II trial specifically addressing the potential role for SABR or SBRT in keeping metastatic clear cell renal cell carcinoma patients on sunitinib for longer periods of time is currently recruiting participants (ClinicalTrials.gov identifier: NCT02019576). A recent multi-institutional series of men with hormonenaïve oligoprogressive prostate cancer suggested SABR or SBRT can delay initiation of androgen deprivation therapy (ADT) up to an average of 28 months (14). At our own institution, oligoprogressive metastatic castration-resistant prostate cancer is being increasingly treated with SABR or SBRT as a means of providing patients with local control of their progressing sites of disease so that (1) they can be maintained on their current systemic treatment that is controlling their disease, save for oligoprogressive sites; and (2) they can limit or delay initiation of additional hormonal therapy or aggressive chemotherapy regimens. We present an illustrative example of a 72-year-old gentleman with metastatic castration-resistant prostate cancer who had been treated with ADT, docetaxel, abiraterone, and most recently cabazitaxel with almost complete response (serum prostate-specific antigen [PSA] level of 1.0 ng/dL), except for a persistent right adrenal metastasis. The patient demonstrated oligoprogressive disease of the right adrenal metastasis over a period of 6 months, with the lesion growing to 4.0 cm in largest diameter and a raise in PSA to 79 ng/dL. The patient elected to be treated with SABR and SBRT resulting in a PSA nadir to undetectable levels 6.5 months later. The patient is now almost 2 years from any systemic therapy other than ADT and has a PSA of 2.8 ng/dL. CONCLUSIONS Oncology paradigms are evolving with respect to management of oligometastatic disease and oligoprogression. Accordingly, radiologists must be meticulous in detecting all sites of metastatic disease for patients with five or fewer lesions and in identifying metastases that progress despite an otherwise positive treatment response to systemic treatments. The interval growth or suspicious morphologic change of a solitary or small number of lesions should be recognized as
Academic Radiology, Vol ■, No ■■, ■■ 2017
OLIGOPROGRESSION: WHAT RADIOLOGISTS NEED TO KNOW
oligoprogression and emphasized in the impression of the radiology report. A general understanding of the treatment potential of ablative radiotherapy in this context, as outlined in this article, may be a useful tool for the radiologist in the role of consultant to the referring oncologist. As definitions of oligoprogression evolve and patients with malignancies other than NSCLC are studied, prospective trials will hopefully provide definitive evidence of benefit from focal therapy to oligoprogressive sites for increasing survival. REFERENCES 1. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366:883–892. 2. Spremulli EN, Dexter DL. Human tumor cell heterogeneity and metastasis. J Clin Oncol 1983; 1:496–509. 3. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 2016; 66:271–289. 4. Reyes DK, Pienta KJ. The biology and treatment of oligometastatic cancer. Oncotarget 2015; 6:8491–8524. 5. Rowe SP, Hawasli H, Fishman EK, et al. Advances in the treatment of oligometastatic disease: what the radiologist needs to know to guide patient management. Acad Radiol 2016; 23:326–328.
6. Cheung P. Stereotactic body radiotherapy for oligoprogressive cancer. Br J Radiol 2016; 89:20160251. 7. Phillips MH, Stelzer KJ, Griffin TW, et al. Stereotactic radiosurgery: a review and comparison of methods. J Clin Oncol 1994; 12:1085–1099. 8. Timmerman RD, Forster KM, Chinsoo Cho L. Extracranial stereotactic radiation delivery. Semin Radiat Oncol 2005; 15:202–207. 9. Simone CB, 2nd, Burri SH, Heinzerling JH. Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies. Transl Lung Cancer Res 2015; 4:545–552. 10. Yu HA, Sima CS, Huang J, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013; 8:346–351. 11. Gan GN, Weickhardt AJ, Scheier B, et al. Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib. Int J Radiat Oncol Biol Phys 2014; 88:892–898. 12. Cheung P, Thibault I, Bjarnason GA. The emerging roles of stereotactic ablative radiotherapy for metastatic renal cell carcinoma. Curr Opin Support Palliat Care 2014; 8:258–264. 13. Straka C, Kim DW, Timmerman RD, et al. Ablation of a site of progression with stereotactic body radiation therapy extends sunitinib treatment from 14 to 22 months. J Clin Oncol 2013; 31:e401–e403. 14. Ost P, Jereczek-Fossa BA, As NV, et al. Progression-free survival following stereotactic body radiotherapy for oligometastatic prostate cancer treatment-naive recurrence: a multi-institutional analysis. Eur Urol 2016; 69:9–12.
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