To improve HL treatments, the recent studies goal is to achieve the best chance of curing well with the least possible long-term risks of chemotherapy. Subsequently, modern approaches have attempted to investigate PET/CT parameters predictive ability to define subgroups of patients who will show early response after start of therapy . The most commonly studied parameter is SUVmax, but unfortunately, it reflects the metabolic activity of the most aggressive tumor cell , while the functional imaging parameters (MTV and TLG) overcome SUVmax limitation as they evaluate the total volume and metabolic activity of tumor cells . In our study, the predictive value of the initial quantitative indices of PET/CT (SUVmax, TLG, MTV) has been evaluated during the management of HL.
As many criteria were developed to assess the tumors therapeutic response, Tawfik et al. reported that PET response criteria in solid tumor (PERCIST) had improved the PET/CT predictive value . So we adopt a new RECIL criteria with a simple approach of estimating PET/CT parameters' values from maximum three largest target lesions rather than the whole-body approach. We have found that the initial SUVmax and TLG showed a good predictive value to distinguish between the patients with CR from those with nCR.
Similarly, the available literature has demonstrated the predictive value of TLG as an effective tool for response evaluation in FDG-avid lymphoma. Wang et al. reported that initial TLG tends to be superior to SUVmax and MTV in predicting survival . Moustafa et al. suggested that TLG is an independent predictor of survival in malignant lymphoma especially in high risk patients and may be an influential predictor of lymphoma outcome .
Pike et al. and Zaucha et al. considered TLG as a very strong prognostic parameter which can improve the predictive value of PET/CT and was associated with interim PET response [22, 23]. El-Galaly et al. and Guo et al. suggested that high initial total TLG predicts significantly worse progression [24, 25].
Our threshold value of TLG is much lower than that of previous work by Pike et al. and Akhtari et al. who reported WBTLG cutoff value of 3318 in advanced HL and 1703 in early-stage HL, respectively. It is clear that this is variation is due to different methods of tumor burden assessment. However, our cutoff value requires more validation [22, 26].
Both initial SUVmax and TLG have similar sensitivity, specificity, accuracy, ROC as a diagnostic tool in distinguishing the CR from the nCR. We deduce that patients with low initial target lesions' TLG will have a better outcome than those with higher values. We suggest that TLG can be used as an alternative to SUVmax because SUVmax provides limited semiquantitative estimate of single voxel activity of a tumor mass and is affected by various factors like image noise, uptake period, body composition and plasma glucose level .
The study by Pike et al. was inconsistent with our results, where they demonstrated the predictive value of MTV as an effective tool for response evaluation. They measured the initial total MTV and MTV of the bulkiest lesion in advanced HL patients to evaluate whether both could predict prognosis and interim PET response. They reported that initial MTV is associated with interim PET response .
Moustafa et al. suggested that MTV is an independent predictor of malignant lymphoma survival and outcome .
Also El-Galaly et al., Guo et al. and Kanoun et al. studies were different with our results as they reported that tumor burden quantification by initial WBMTV may enhance prognostication and proved that lymphoma patients with a low initial MTV had a better prognosis than those with a high MTV [24, 25, 27].
Zaucha et al. and Cottereau et al. considered MTV as a very strong prognostic parameter being superior to the available parameters [23, 28].
On the contrary, our results show that the initial MTV does not have significant difference between patients with CR and nCR. This difference may be attributed to the methodological differences regarding tumor burden assessment. We adopted quantitative assessment of only maximum three largest target lesions, while other investigators measured total MTV.
Unlike the three target lesion approach, the whole-body approach may more reliably reflect the patient’s tumor status and treatment response in terms of MTV assessment. Son et al. and Pellegrino et al. stated that using the sum of PET/CT parameter of all patient's lesions was more expressive of the metabolically active tumor volume than measuring it at one site [29, 30].
Elevated LDH is associated with high tumor burden as cancer cells are dependent on anaerobic metabolism with subsequent production of lactate from glucose (Warburg effect) .
Subsequently, LDH can be used to monitor response to chemotherapy for certain types of cancers like lymphoma by assessing it at diagnosis, after treatment, and during follow-up . Although there are few studies correlating LDH to SUVmax , to the best of our knowledge, there are no reports investigating the correlation of LDH with TLG or MTV in HL.
We have found a significant correlation between the initial LDH and initial SUVmax, MTV and TLG. A possible explanation for this correlation is attributed to the major role of nicotinamide adenine dinucleotide reduced/ nicotinamide adenine dinucleotide oxidized (NADH/NAD+) homeostasis in various metabolic reactions including glucose metabolism whereas NADH/NAD+ are up regulated in tumor cells in order to maintain its survival reduction of pyruvate to lactate (the Warburg effect) by LDH to produce NAD+ .
This increased glucose metabolism accounts for FDG accumulation into cancer cells and subsequently all quantitative parameters especially TLG which is theoretically superior to other measurements because it incorporates both parameters by taking into account the level of glucose accumulation within the total volume of all the regions of all ROIs .
Our finding regarding SUVmax correlation with LDH is consistent with Ucar et al. who found in 34 patients -13 patients had HL- that end of treatment (EOT) SUVmax are related to the EOT laboratory parameters such as LDH  and inconsistent with Li et al. who found in 103 patients -19 had HL- that SUVmax at biopsy site was not significantly correlated with LDH .
This study was limited by few limitations. First, its short duration including only interim PET/CT studies with unavailability of EOT. Functional parameters of EOT would have given more comprehensive evaluation of the quantitative indices. However, the retrieved quantitative indices of initial scans could give insights into prognosis and the effectiveness of therapy. Second, the heterogeneous patient population in terms of the pathological subtypes and chemotherapy regimen. More prospective studies dedicated to specific pathological subtypes and treatment regimen will be more appropriate for proper functional indices assessment.