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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 4  |  Page : 134-138

Using interim positron emission tomography as a predictor for relapse-free survival in hodgkin lymphoma: Experience from a single Institution


Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

Date of Submission03-Mar-2021
Date of Decision01-Jun-2021
Date of Acceptance07-Jun-2021
Date of Web Publication3-Dec-2021

Correspondence Address:
Dr. Ming- Chung Wang
Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No.123, DAPI Rd., Niaosong Dist., Kaohsiung City 83301
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCRP.JCRP_14_21

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  Abstract 


Background: Since the emergence of 18F-fluoro-2-deoxyglucose positron emission tomography (PET), PET has been widely implemented for the initial staging and evaluation of treatment response of classical Hodgkin lymphoma (cHL). Interim PET after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has been proven to be a reliable tool to predict clinical outcomes in patients with cHL, and response-adapted therapies based on interim PET results have become the standard method of treatment. The aim of this study was to report our experience of using interim PET in our institution and determine whether it is a predictive marker for cHL. In addition, we also analyze associations between other patient characteristics and interim PET results at initial diagnosis. Materials and Methods: This retrospective study enrolled patients verified to have newly diagnosed cHL and who received ABVD as frontline treatment between 2008 and 2019 in our hospital. Interim PET was arranged after 2-3 cycles of ABVD, and we used Deauville 5-point score to evaluate the response. Subgroup analysis was performed to assess correlations between interim PET and patient characteristics. Results: Sixty patients underwent interim PET examinations. The age ranged from 14 to 74 years with a medium follow-up of 18.3 months (range: 4–113 months). The patients who had negative interim PET results (n = 36, 60%) had significantly longer relapse-free survival than those with positive results (P < 0.001). Patients with bulky disease, B-symptoms, or neutrophil to lymphocyte ratio (NLR) >6 were more likely to have positive interim PET-computed tomography results (P < 0.001, 0.023, and 0.037, respectively). Conclusion: Interim PET plays an important role in predicting relapse free survival for patients with Hodgkin lymphoma at our institution. A high NLR was correlated with interim PET results in this study.

Keywords: Hodgkin lymphoma, interim positron emission tomography, neutrophil to lymphocyte ratio


How to cite this article:
Liu HL, Wang MC, Kuo CY, Ma MC, Liao CK. Using interim positron emission tomography as a predictor for relapse-free survival in hodgkin lymphoma: Experience from a single Institution. J Cancer Res Pract 2021;8:134-8

How to cite this URL:
Liu HL, Wang MC, Kuo CY, Ma MC, Liao CK. Using interim positron emission tomography as a predictor for relapse-free survival in hodgkin lymphoma: Experience from a single Institution. J Cancer Res Pract [serial online] 2021 [cited 2022 Jan 25];8:134-8. Available from: https://www.ejcrp.org/text.asp?2021/8/4/134/331647




  Introduction Top


Classical Hodgkin lymphoma (cHL) is a type of B-cell lymphoma derived from germinal centers at the stage of differentiation. Doxorubicin-containing regimens with or without radiotherapy are currently the treatment of choice for cHL. In the past decade, interim positron emission tomography (PET) using 18F-fluoro-2-deoxyglucose (FDG) after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has been proven to be a reliable tool to predict the clinical outcomes of patients with Hodgkin lymphoma (HL).[1] Interim PET has greatly changed treatment strategies such as omitting bleomycin after negative interim PET results to avoid the pulmonary toxic effect or escalating to more intensive treatments such as escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for those with positive findings on the interim scan response.[2],[3] Response-adapted therapies based on interim PET results have become the mainstream of treatment and have been incorporated into the current treatment guidelines.

Although the benefits of using interim PET as a predictive marker are evident, there are still some obstacles between the current guidelines and physicians in Taiwan. Since parenteral and oral procarbazine is unavailable in Taiwan, escalation to a more intensive treatment after positive PET results is not an option, and there are currently no other substitutions due to a lack of clinical evidence. On the other hand, frequent PET scans in short intervals may increase the cost of health insurance. As a consequence, interim PET is not routinely arranged for treatment response evaluation in our country. Therefore, some simple assessment tools such as neutrophil to lymphocyte ratio (NLR) have been proposed for risk stratification in patients with newly diagnosed cHL, and they have been shown to be correlated with interim PET scan results.[4],[5],[6]

In this study, we report our experiences of using interim PET in our institution and examined whether it can serve as a predictive marker for all stages of HL during frontline treatment. Furthermore, we analyzed other patient characteristics to investigate whether they were correlated with interim PET results and whether they could be used for risk stratification.


  Materials and Methods Top


This retrospective study was approved by Chang Gung Medical Foundation Institutional Review Board, which waived the requirement to obtain informed consent (IRB No. 202100224B0). A total of 127 patients who were diagnosed with cHL were included. The age of the patients ranged from 11 to 85 years and they received ABVD chemotherapy with or without radiotherapy. The stage of disease was based on the Ann Arbor classification and was further classified into early stage, intermediate stage, and advanced stage according to the German Hodgkin Study Group (GHSG) risk classification system.[7] Of the 127 patients, 60 who underwent interim PET, which was defined as PET after 2 or 3 cycles of ABVD chemotherapy, were included for analysis. To evaluate the interim PET response, we used Deauville 5-point scale criteria.[8] A Deauville score of 1-2 point was defined as a negative interim PET result and Deauville score of 3-5 point was defined as a positive interim PET result. Relapse-free survival (RFS) was calculated from the date of first cycle of ABVD chemotherapy to the day of relapse or event-related death. The patients without relapse were censored on the last follow-up visit at clinics. Subgroup analysis was then performed to evaluate the correlations of interim PET results and other patient characteristics at diagnosis, and the NLR was recorded before the first course of chemotherapy. We used SPSS 19.0 software (SPSS Inc., Chicago, II, USA) for statistical analyses, and the Kaplan–Meier method to construct survival curves.


  Results Top


Of the 127 included patients, sixty had interim PET data for response analysis. The baseline characteristics of the sixty patients are shown in [Table 1]. The median age was 29 years (range: 14–74 years) at initial diagnosis with a medium follow-up of 18.3 months (range: 4–113 months). Most of them received interim PET after 2 cycles of ABVD chemotherapy (n = 55, 91.7%). According to the GHSG risk group classification systems, most of the patients were advanced stage (n = 30, 50%). The patients who had negative interim PET-computed tomography (CT) results (n = 36, 60%) had a longer RFS than those with positive results (P < 0.001, log-rank test). The median RFS was not reached in the patients with negative interim PET results and was 13.83 months (95% confidence interval [CI]: 4.08–23.58 months) in the patients with positive interim PET results [Figure 1]. Only two patients had relapsed disease with a medium follow-up of 18.5 months (range: 5.2–70.2 months). All of the patients with early-stage cHL had negative interim PET results, and the median survival was not reached. For the intermediate stage group, the patients with negative interim PET results had a longer RFS (P = 0.004, log-rank test), and the median survival was not reached. The median survival was 5.75 months (95% CI: 4.94–15.43 months, n = 7) for those with positive results [Figure 2]. As for the advanced stage group, the patients with negative interim PET results also had a longer RFS (P = 0.035, log-rank test), and the median survival was not reached for those with negative interim PET results. For those with positive results, the median survival was 13.83 months (95% CI: 4.12–23.55 months, n = 14) [Figure 3]. Further analysis of correlations between patient characteristics and interim PET results is shown in [Table 2]. In our cohort, patients with bulky disease or B-symptoms at initial presentation were more likely to have positive interim PET results (P < 0.001 and 0.023, respectively). Two patients had no available lab data at initial diagnosis. For the other 58 patients, a high NLR at initial diagnosis seemed to be correlated with interim PET-CT results. The patients with an NLR >6 at initial diagnosis had a higher incidence of positive interim PET results (P = 0.037).
Figure 1: Kaplan–Meier curves showing different relapse-free survival curves based on interim positron emission tomography results in all stages of classical Hodgkin lymphoma (median survival: Not reached in the interim positron emission tomography negative group, n = 39; 13.83 months in the interim positron emission tomography positive group, n = 21; P < 0.001 by the log rank test)

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Figure 2: Kaplan–Meier curves showing different relapse-free survival curves based on interim positron emission tomography results in intermediate stage classical Hodgkin lymphoma (median survival: Not reached in the interim positron emission tomography negative group, n = 13; 5.75 months in the interim positron emission tomography positive group, n = 7; P = 0.004 by the log rank test)

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Figure 3: Kaplan–Meier curves showing different relapse-free survival curves based on interim positron emission tomography results in advance stage classical Hodgkin lymphoma (median survival: Not reached in the interim positron emission tomography negative group, n = 16; 13.83 months in the interim positron emission tomography positive group, n = 14; P = 0.037 by the log rank test)

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Table 1: Patient characteristics

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Table 2: Results of interim PET in subgroup

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  Discussion Top


Traditionally, cHL was divided into four subtypes according to histological features including nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted until 1999, when nodular lymphocyte-predominant HL was identified as another subgroup.[9] HL was originally considered to be a curable neoplasm owing to the application of high-dose extended field radiotherapy. However, due to late toxicity and tissue damage, chemotherapy was introduced for further disease control. The first highly effective regimen of chemotherapy for HL was the combination of mechlorethamine, vincristine, procarbazine, and prednisone which was first proposed by Devita, et al.[10] This regimen was then replaced by other combinations of chemotherapy due to its unfavorable toxicity profile, and ABVD subsequently became the major treatment strategy.[11] Interim PET has greatly changed the situation again, and response-adapted therapies based on interim PET results have become the standard treatment. In a meta-analysis which pooled 14 studies with 2079 patients, the unadjusted hazard ratio was 4.90 (95% CI 3.47–6.90).[12] Interim PET following two cycles of ABVD had high negative predictive value and was superior to the international prognostic score (IPS) in predicting outcome. In a retrospective, international, multicenter study involving 260 patients with newly diagnosed cHL of all stages who receiving 4-8 cycles of ABVD with or without involved-field radiotherapy, the 3-year progression-free survival (PFS) rates for patients with negative and positive interim PET results were 95% and 28%, respectively, which were independent of the IPS.[13] Under the concept of using interim PET results as a predictive marker for risk stratification, numerous clinical trials have been conducted for all stages of HL. In our study, interim PET results were strongly correlated with RFS in all different stages of cHL according to the GHSG criteria. In ten patients with early-stage cHL, eight had no disease relapse after negative interim PET results. For the patients with intermediate or advanced stage disease, interim PET results also showed a significant prognostic value, and the predictive value was more evident in the patients with intermediate-stage disease. These findings are consistent with modern world practice which suggests that response-adapted treatment protocols may be implemented in clinical practice. In the modern era, PET-adapted treatment strategies are aimed at reducing the toxicity of chemotherapy or late side effects of radiotherapy in patients with negative interim PET results, such as omitting radiotherapy after 3-4 cycles of ABVD or reducing ABVD to 2 cycles while keeping radiotherapy in early stage cHL.[3],[14],[15] On the other hand, escalating treatment to more intensified chemotherapy after positive interim PET results will increase the disease control rate. The eBEACOPP regimen has played a major role in subsequent chemotherapy to achieve a better outcome.[3] However, to use more intensified chemotherapy in our country, a substitute for procarbazine must be found. Since dacarbazine and procarbazine have the same pharmacological efficacy and are both used to treat cHL, there is an emerging treatment protocol known as escalated BEACOPDac, in which procarbazine is replaced with dacarbazine. In a retrospective study including a total of 141 patients with advanced-stage cHL, 89 received escalated BEACOPDac, and the efficacy was not compromised compared to the other 52 patients who receiving eBEACOPP.[16] However, more real-world data are required.

Before interim PET was proven to be an efficient tool for risk stratification, other risk scores were developed to evaluate the prognosis. The presence of bulky mass and B-symptoms has been incorporated into the current risk stratification protocols, both of which were shown to be correlated with interim PET results in our cohort. In addition, one of the most widely accepted scoring systems is the IPS, which was proposed in 1998 and was designed for advanced-stage cHL. The score is comprised seven factors including a serum albumin level of <4 g/dL, a hemoglobin level of <10.5 g/dL, male sex, an age of ≥45 years or older, Stage IV disease by Ann Arbor classification, a white cell count >15,000/mm3, and lymphocyte count of <600/mm3 or 8% of the white cell count.[17] Although IPS score has been replaced by interim PET, it still shares the concept that leukocytosis and lymphopenia are risk factors for advanced HL. Thus, NLR has been used as a cost-effective tool to quickly determine the clinical outcomes of patients with newly diagnosed HL. Some cutoff NLR values have been established including 4.3 for predicting overall survival (OS) of all stages of HL and six for predicting OS and PFS in nodular sclerosis type cHL.[18],[19] In this study, we used NLR >6 as a cutoff and found that NLR had a good correlation with interim PET scan results. The NLR may be an additional predictor for early risk stratification for the frontline treatment of cHL, however, further studies and investigations are needed.

Interim PET plays an important role in predicting outcomes at our hospital after frontline treatment of ABVD. High NLR, bulky mediastinal mass, and presence of B symptoms at initial diagnosis were correlated with interim PET results in this study and may be effective in predicting outcomes.


  Conclusion Top


Interim PET plays an important role in predicting relapse free survival for patients with Hodgkin lymphoma at our institution. A high NLR was correlated with interim PET results in this study.

Acknowledgment

We thank the multidisciplinary team of the hematologic cancer at our hospital for their assistance and cooperation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Gallamini A, Kostakoglu L. Interim FDG-PET in Hodgkin lymphoma: A compass for a safe navigation in clinical trials? Blood 2012;120:4913-20.  Back to cited text no. 8
    
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Diehl V, Sextro M, Franklin J, Hansmann ML, Harris N, Jaffe E, et al. Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: Report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease. J Clin Oncol 1999;17:776-83.  Back to cited text no. 9
    
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Devita VT Jr., Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann Intern Med 1970;73:881-95.  Back to cited text no. 10
    
11.
Duggan DB, Petroni GR, Johnson JL, Glick JH, Fisher RI, Connors JM, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: Report of an intergroup trial. J Clin Oncol 2003;21:607-14.  Back to cited text no. 11
    
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Aldin A, Umlauff L, Estcourt LJ, Collins G, Moons KG, Engert A, et al. Interim PET-results for prognosis in adults with Hodgkin lymphoma: A systematic review and meta-analysis of prognostic factor studies. Cochrane Database Syst Rev 2019;9:CD012643.  Back to cited text no. 12
    
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Gallamini A, Barrington SF, Biggi A, Chauvie S, Kostakoglu L, Gregianin M, et al. The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale. Haematologica 2014;99:1107-13.  Back to cited text no. 13
    
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Radford J, Illidge T, Counsell N, Hancock B, Pettengell R, Johnson P, et al. Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma. N Engl J Med 2015;372:1598-607.  Back to cited text no. 14
    
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Straus DJ, Jung SH, Pitcher B, Kostakoglu L, Grecula JC, Hsi ED, et al. CALGB 50604: Risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET. Blood 2018;132:1013-21.  Back to cited text no. 15
    
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Santarsieri A, Sturgess K, Brice P, Menne T. F, Osborne W, Creasey T, et al. Procarbazine-free escalated beacopdac in frontline therapy of advanced Hodgkin lymphoma reduces red cell transfusion requirements and may shorten time to menstrual period recovery compared to escalated beacopp and appears to be as efficacious. Blood 2019;134 Suppl 1:1564.  Back to cited text no. 16
    
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Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 1998;339:1506-14.  Back to cited text no. 17
    
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Marcheselli R, Bari A, Tadmor T, Marcheselli L, Cox MC, Pozzi S, et al. Neutrophil-lymphocyte ratio at diagnosis is an independent prognostic factor in patients with nodular sclerosis Hodgkin lymphoma: Results of a large multicenter study involving 990 patients. Hematol Oncol 2017;35:561-6.  Back to cited text no. 19
    


    Figures

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    Tables

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