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Recent studies have shown that metabolic tumor volume (MTV) by positron emission tomography/computed tomography (PET/CT) is an important prognostic parameter in patients with non-Hodgkin's lymphoma. However, it is unknown whether doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) alone in early stage Hodgkin's lymphoma would lead to similar disease control as combined modality therapy (CMT) using MTV by PET/CT. One hundred and twenty-seven patients with early stage Hodgkin's lymphoma who underwent PET/CT at diagnosis were enrolled. The MTV was delineated on PET/CT by the area ≥SUVmax, 2.5 (standardized uptake value [SUV]). Sixty-six patients received six cycles of ABVD only. The other 61 patients received CMT (involved-field radiotherapy after 4–6 cycles of ABVD). The calculated MTV cut-off value was 198 cm3. Clinical outcomes were compared according to several prognostic factors (i.e. age ≥50 years, male, performance status ≥2, stage II, B symptoms, ≥4 involved sites, extranodal site, large mediastinal mass, CMT, elevated erythrocyte sedimentation rate and high MTV). Older age (progression-free survival [PFS], P = 0.003; overall survival [OS], P = 0.007), B symptoms (PFS, P = 0.006; OS, P = 0.036) and high MTV (PFS, P = 0.008; OS, P = 0.007) were significant independent prognostic factors. Survival of two high MTV groups treated with ABVD only and CMT were lower than the low MTV groups (PFS, P < 0.012; OS, P < 0.045). ABVD alone was sufficient to control disease in those with low MTV status. However, survival was poor, even if the CMT was assigned a high MTV status. The MTV would be helpful for deciding the therapeutic modality in patients with early stage Hodgkin's lymphoma.
Previously, extensive radiation therapy was the first therapeutic option to treat early stage Hodgkin's lymphoma (HL). However, patients remained at risk of death due to late radiation-induced adverse effects including secondary cancer.[1-4] Several clinical studies have shown that better disease control rates occur in patients with early stage HL treated with combined modality treatment (CMT) compared with radiotherapy alone.[5, 6] These results allowed for reduced numbers of chemotherapy cycles or low-dose involved-field radiotherapy (IFRT) for patients with early stage HL. Several recent studies have shown that chemotherapy alone could be an available treatment option for some populations of patients with early stage HL.[7, 8] However, the massive pathological lesion in early stage HL is still a difficult problem to successfully treat with chemotherapy alone.
18F-Fluoro-deoxyglucose positron emission tomography (18F-FDG-PET) is a valuable functional imaging modality in patients with malignant lymphoma.[9-11] This modality provides useful guidance for managing HL at several points in staging, monitoring or response during and after treatment.[9-15] Recent studies have shown that metabolic tumor volume (MTV) as the tumor burden on positron emission tomography/computed tomography (PET/CT) is a prognostic factor in some subtypes of non-Hodgkin's lymphoma.[16-19] However, it is not well established whether the quantitative tumor burden detected using PET/CT is a predictive factor for clinical outcome or an important indicator for establishing therapeutic planning in early stage HL.
The objective of the present study was to investigate whether MTV by PET/CT is a clinical parameter predicting survival in patients with early stage HL.
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The standard of care for patients with early stage HL is chemotherapy followed by IFRT. The National Comprehensive Cancer Network (NCCN) guideline for favorable early stage HL lists chemotherapy alone as an option only for highly selected patients for whom radiotherapy is contraindicated. However, the detection of serious complications such as cardiopulmonary disease and second malignancy in long-term survivors treated with radiotherapy has prompted reconsideration of the role for CMT. Some investigators have advocated the option of chemotherapy alone and several study groups tested the hypothesis that chemotherapy alone could provide equivalent disease control to that achieved with CMT.[26-29] A clinical study from the Memorial Sloan–Kettering Cancer Center showed similar freedom from progression and overall prognosis between AVBD alone and a CMT group in stages I, II and IIIA without bulky disease. A non-randomized study from Spain also demonstrated similar results between patients with non-bulky early stage HL treated with CT alone and those with CMT. Coincident with these studies, our results showed that survival in the ABVD alone group was not different from that in the CMT group, although a small population with bulky disease was included.
The CMT is still a reasonable standard therapeutic option in patients with early stage HL, particularly those with bulky disease. This means that radiotherapy to bulky disease in combination with chemotherapy would be needed to reduce the risk of recurrence. However, if the overall pathological lesion is not bulky disease and there is a high tumor burden status due to non-bulky multifocal mass lesions, the selection of treatment modality is complicated. Previous studies have demonstrated that total tumor burden measured using a CT scan can be a predictive tool for evaluating the curative potential of a treatment combination.[30, 31] According to those studies, the treatment strategy might be decided dependent on the total tumor burden as well as the presence of bulky disease.
The ability of 18F-FDG PET to distinguish viable tumors and necrosis or fibrosis in residual masses provides an advantage over conventional imaging using CT or magnetic resonance imaging.[32-34] 18F-FDG PET/CT is now strongly recommended by the International Harmonization Project in Lymphoma for staging and reassessment of FDG-avid potentially curable lymphomas. However, almost all evaluations using 18F-FDG PET/CT in HL were qualitative.
Several clinical studies that focused on quantitative tumor burden using 18F-FDG PET/CT found that high tumor burden status regardless of a bulky lesion is an important prognostic factor in patients with non-HL.[16-19] In the present study, a high MTV status by 18F-FDG PET/CT was also associated with poor prognosis in early stage HL. Moreover, compared with unfavorable prognostic factors reflecting the quantitative manifestation of a mass lesion such as large mediastinal disease, high MTV status by 18F-FDG PET/CT had more potent predictive power in the clinical outcome. Therefore, the risk evaluation would be determined according to the assessment of 3-D quantitative burden rather than simple cross-sectional parameters.
The treatment strategy could be determined according to MTV status. No differences in the clinical outcomes of patients with low MTV status and who underwent CMT and ABVD were observed. Therefore, ABVD alone would be available to be performed in low tumor burden status in the early stage, because the standard treatment is clarified as CMT, but radiotherapy-induced complications is still a concern.
However, a high MTV status requires a more intensive treatment strategy and ABVD alone is not a sufficient treatment option for disease control. Furthermore, even if CMT was assigned to patients with high MTV status, the clinical outcome was poorer than that of patients with low MTV status. Because a large radiation dose was identified as one relavant risk factor to secondary malignancy or cardiopulmonary disease, CMT such as ABVD followed by IFRT is recommended as the standard of treatment in patients with early stage HL. However, our results suggest that high MTV status remains an unfavorable prognostic factor and that more higher intensity therapeutic options such as an increasing dose of radiation therapy compared with IFRT or development of more potent chemotherapy regimen compared with ABVD are needed.
In conclusion, assessing the total tumor burden by 18F-FDG PET/CT was valuable for predicting the prognosis in patients with early stage HL. A well-designed prospective study will provide further information regarding confirmation of our results.