Coping With Knife: Postoperative Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma

Coping With Knife: Postoperative Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma

Accepted Manuscript Gray Zone Coping with Knife: Post-operative Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma Shushan Rana, MD, John H...

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Accepted Manuscript Gray Zone Coping with Knife: Post-operative Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma Shushan Rana, MD, John Holland, MD, Carol Marquez, MD, Avyakta Kallam, MD, James O. Armitage, MD, Parag Sanghvi, MD, MSPH PII:

S0360-3016(17)34056-7

DOI:

10.1016/j.ijrobp.2017.10.043

Reference:

ROB 24572

To appear in:

International Journal of Radiation Oncology • Biology • Physics

Received Date: 5 September 2017 Revised Date:

25 October 2017

Accepted Date: 27 October 2017

Please cite this article as: Rana S, Holland J, Marquez C, Kallam A, Armitage JO, Sanghvi P, Gray Zone Coping with Knife: Post-operative Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/ j.ijrobp.2017.10.043. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Coping with Knife: Post-operative Management of Nodular Lymphocyte Predominant Hodgkin Lymphoma Shushan Rana, MDa, John Holland, MDa a

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Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon

Commentary

Resected Nodular Lymphocyte Predominant Hodgkin lymphoma: What Next?

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Carol Marquez, MDb b

Department of Radiation Oncology, Stanford School of Medicine, Stanford, CA

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Management of Resected Nodular Lymphocyte Predominant Hodgkin Lymphoma: A Medical Oncology Perspective Avyakta Kallam, MDc, James O. Armitage, MDc c

Division of Oncology/Hematology, University of Nebraska Medical Center, Omaha, Nebraska

Post-Operative Nodular Lymphocyte Predominant Hodgkin Lymphoma: Watch and Wait or Radiate?

Corresponding Author:

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Shushan Rana, MD KPV4 3181 SW Sam Jackson Rd Portland, OR 97239 Phone: 503-494-8756 Fax: 503-346-0237 [email protected]

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Parag Sanghvi, MD, MSPHd d Department of Radiation Medicine and Applied Sciences, University of California San Diego School of Medicine, San Diego, California

Conflicts of Interest Notification No actual or potential conflicts of interest exist

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Coping with Knife: Post-operative management of Nodular Lymphocyte Predominant Hodgkin Lymphoma

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A 47-year-old woman presented to her primary care physician with right arm pain and paresthesias prompting cervical MRI. Imaging revealed C6-7 spinal stenosis and an incidental T2 hyperintense left thyroid nodule measuring 1.9 cm (Figure 1). A neck ultrasound revealed a 3.2 x 2.8 spongiform left thyroid nodule and a 0.7 x 0.6 mm inferior right isthmus nodule. FNA of the left thyroid nodule demonstrated abundant mixed lymphoid cells. The patient underwent left hemithyroidectomy with pathology showing a 2.2 x 2.0 cm nodular lymphocyte predominant Hodgkin lymphoma (NLPHD) (Figure 2). The posterior and inferior surgical margins were negative but less than 0.1 mm from the inked margin. Postoperative PET-CT demonstrated no evidence of residual locoregional or distant disease.

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1. Would you recommend observation or further therapy with either radiation or chemotherapy? 2. If you recommend post-operative radiation, what dose and fractionation would you use and what volume would you treat? 3. How would you counsel this patient on weighing her risk of recurrence versus risk of secondary malignancy or long term radiation side effects?

Resected Nodular Lymphocyte Predominant Hodgkin lymphoma: What Next?

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In this case of an adult with completely resected disease, the choices for therapy are observation or radiation therapy alone. Extrapolating from a pediatric population with residual disease per Children’s Oncology Group (COG) study AHOD03P1, chemotherapy (AV-PC) would be supported as it confers an excellent 5-year event free survival (EFS) of 88.1% [1]. Additionally, those patients with resected disease who were observed had a 5-year EFS of 77%. However, in adults, chemotherapy is usually reserved for those patients with advanced disease. Rituximab alone would not be recommended because it has been associated with an increased risk of relapse in the recent report from the German Hodgkin Study Group (4-year progression free survival of 81%) [2]. Given these data, I recommend this particular patient be closely observed. While this approach will require her to be monitored for both local and distant relapse, she will not face the potential longterm toxicities of hypothyroidism and second malignancy from radiation and she will still have an excellent 5-year progression free survival. If she were to fail, there is good evidence that chemotherapy can provide effective salvage, as evidenced again by the COG study where the observed patients who relapsed were successfully treated with AV-PC. With observation, she has a low risk of relapse at ~2025%, an excellent overall survival of 88% at 5 years per a recent NCDB analysis, and no toxicity, a very reasonable set of outcomes[3]. Carol Marquez, MD Department of Radiation Oncology Stanford University School of Medicine Stanford, California

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Appel, B.E., et al., Minimal Treatment of Low-Risk, Pediatric Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children's Oncology Group. J Clin Oncol, 2016. 34(20): p. 2372-9. Eichenauer, D.A., et al., Long-Term Course of Patients With Stage IA Nodular LymphocytePredominant Hodgkin Lymphoma: A Report From the German Hodgkin Study Group. J Clin Oncol, 2015. 33(26): p. 2857-62. Parikh, R.R., et al., Early-Stage Classic Hodgkin Lymphoma: The Utilization of Radiation Therapy and Its Impact on Overall Survival. Int J Radiat Oncol Biol Phys, 2015. 93(3): p. 684-93.

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Management of Resected Nodular Lymphocyte Predominant Hodgkin Lymphoma: A Medical Oncology Perspective

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For this patient with localized resected nodular lymphocyte predominant Hodgkin lymphoma, we favor a “watch and wait” approach or radiotherapy alone after a frank discussion of the pros and cons of each approach [1]. Observation following complete resection in early stage disease has been studied predominantly in the pediatric population with one study showing an overall progression free survival of 67% at 26 months [2]. In adults, there is little data of observation alone. In one study, the addition of radiotherapy improved progression free survival. However, the 10 year overall survival was 91% for patients who were observed versus 93% in patients treated with radiotherapy [3]. Since patients can relapse following treatment of localized nodular lymphocyte predominant Hodgkin lymphoma whether or not they receive adjutant radiotherapy, close follow-up is necessary. In this indolent lymphoma, relapses have been reported greater than 10 years after treatment. However, if patients do relapse, they almost always respond to salvage therapy and still are likely to be cured. A small proportion of patients with nodular lymphocyte predominant Hodgkin lymphoma will transform to diffuse large B-cell lymphoma (DLBCL) [3, 4]. Prompt recognition of this phenomenon and appropriate therapy for DLBCL can still lead to long term survival. Since radiotherapy is limited to involved sites only, and the disease does not usually involve the mediastinum, there is less radiotherapy to the heart and breasts, limiting long-term side effects [5].

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James O. Armitage, MD Division of Oncology/Hematology, University of Nebraska Medical Center Omaha, Nebraska

Filippi, A.R., et al., Involved-site image-guided intensity modulated versus 3D conformal radiation therapy in early stage supradiaphragmatic Hodgkin lymphoma. Int J Radiat Oncol Biol Phys, 2014. 89(2): p. 370-5. Mauz-Korholz, C., et al., Resection alone in 58 children with limited stage, lymphocytepredominant Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma. Cancer, 2007. 110(1): p. 179-85. Biasoli, I., et al., Nodular, lymphocyte-predominant Hodgkin lymphoma: a long-term study and analysis of transformation to diffuse large B-cell lymphoma in a cohort of 164 patients from the Adult Lymphoma Study Group. Cancer, 2010. 116(3): p. 631-9. Farrell, K., P. McKay, and M. Leach, Nodular lymphocyte predominant Hodgkin lymphoma behaves as a distinct clinical entity with good outcome: evidence from 14-year follow-up in the West of Scotland Cancer Network. Leuk Lymphoma, 2011. 52(10): p. 1920-8. Hawkes, E.A., A. Wotherspoon, and D. Cunningham, The unique entity of nodular lymphocytepredominant Hodgkin lymphoma: current approaches to diagnosis and management. Leuk Lymphoma, 2012. 53(3): p. 354-61.

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Avyakta Kallam, MD Division of Oncology/Hematology, University of Nebraska Medical Center Omaha, Nebraska

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Post-Operative Nodular Lymphocyte Predominant Hodgkin Lymphoma: Watch and Wait or Radiate?

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In adults, the German Hodgkin Study Group has published their long-term outcomes in nodular lymphocyte predominant patients with Stage IA disease [1]. In their experience, long term progression free survival (PFS) was equivalent in patients who were treated with combined modality therapy, extended field radiotherapy or involved field radiotherapy with an 8-year PFS of 84.3 – 91.9%. In this patient, the site of disease is extra-nodal involving the thyroid gland and the margin of resection is < 0.1 mm. I would discuss the pros and cons of immediate therapy vs. observation. Involved site radiotherapy (ISRT) is very appropriate in this setting and will provide excellent disease-free control and the best opportunity to mitigate the likelihood of requiring chemotherapy in the future [2]. The clinical treatment volume (CTV) would include the post-operative bed, the residual thyroid gland, level IV and VI nodal basins in the vicinity of the thyroid bed. I would prescribe 30 Gy in 15 - 17 fractions with appropriate PTV margins based on treatment planning technique and image guidance capabilities. I would counsel the patient regarding the long-term risk of hypothyroidism and 2nd malignancy. A recent dosimetric analysis in patients with Hodgkin lymphoma who received chemotherapy and radiation showed that patients with thyroid V30Gy > 62.5% had a 70.8% incidence of hypothyroidism at a median follow-up of 3 years [3]. A recent large multi-institutional retrospective series in women who received radiation after age 35 years had an extremely low likelihood of developing a 2nd malignancy [4]. Parag Sanghvi, MD MSPH Department of Radiation Medicine and Applied Sciences University of California San Diego School of Medicine San Diego, California

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Eichenauer, D.A., et al., Long-Term Course of Patients With Stage IA Nodular LymphocytePredominant Hodgkin Lymphoma: A Report From the German Hodgkin Study Group. J Clin Oncol, 2015. 33(26): p. 2857-62. Yahalom, J., et al., Modern radiation therapy for extranodal lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys, 2015. 92(1): p. 11-31. Cella, L., et al., Thyroid V30 predicts radiation-induced hypothyroidism in patients treated with sequential chemo-radiotherapy for Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys, 2012. 82(5): p. 1802-8. Michaelson, E.M., et al., Thyroid malignancies in survivors of Hodgkin lymphoma. Int J Radiat Oncol Biol Phys, 2014. 88(3): p. 636-41.

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Fig 1. T2 weighted axial image of the left thyroid nodule

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Figure 2. A) Pathology demonstrating thyroid follicles surrounded by a dense infiltrate of lymphocytes. B) High magnification demonstrating popcorn cells (arrow), pathognomonic for NLPHD, and Reed-Sternberg cells (arrowhead).