Interim-treatment quantitative PET parameters predict progression and death among patients with hodgkin's disease
- Diane Tseng†1,
- Leelanand P Rachakonda†1,
- Zheng Su2,
- Ranjana Advani3,
- Sandra Horning3,
- Richard T Hoppe1,
- Andrew Quon4,
- Edward E Graves1,
- Billy W LooJr1Email author and
- Phuoc T Tran5, 6Email author
© Tseng et al; licensee BioMed Central Ltd. 2012
Received: 24 November 2011
Accepted: 19 January 2012
Published: 19 January 2012
We hypothesized that quantitative PET parameters may have predictive value beyond that of traditional clinical factors such as the International Prognostic Score (IPS) among Hodgkin's disease (HD) patients.
Thirty HD patients treated at presentation or relapse had staging and interim-treatment PET-CT scans. The majority of patients (53%) had stage III-IV disease and 67% had IPS ≥ 2. Interim-treatment scans were performed at a median of 55 days from the staging PET-CT. Chemotherapy regimens used: Stanford V (67%), ABVD (17%), VAMP (10%), or BEACOPP (7%). Hypermetabolic tumor regions were segmented semiautomatically and the metabolic tumor volume (MTV), mean standardized uptake value (SUVmean), maximum SUV (SUVmax) and integrated SUV (iSUV) were recorded. We analyzed whether IPS, absolute value PET parameters or the calculated ratio of interim- to pre-treatment PET parameters were associated with progression free survival (PFS) or overall survival (OS).
Median follow-up of the study group was 50 months. Six of the 30 patients progressed clinically. Absolute value PET parameters from pre-treatment scans were not significant. Absolute value SUVmax from interim-treatment scans was associated with OS as determined by univariate analysis (p < 0.01). All four calculated PET parameters (interim/pre-treatment values) were associated with OS: MTVint/pre (p < 0.01), SUVmeanint/pre (p < 0.05), SUVmaxint/pre (p = 0.01), and iSUVint/pre (p < 0.01). Absolute value SUVmax from interim-treatment scans was associated with PFS (p = 0.01). Three calculated PET parameters (int/pre-treatment values) were associated with PFS: MTVint/pre (p = 0.01), SUVmaxint/pre (p = 0.02) and iSUVint/pre (p = 0.01). IPS was associated with PFS (p < 0.05) and OS (p < 0.01).
Calculated PET metrics may provide predictive information beyond that of traditional clinical factors and may identify patients at high risk of treatment failure early for treatment intensification.
Positron emission tomography  imaging using [18F]fluorodeoxyglucose serves as a valuable functional imaging modality in patients with lymphoma [2–4]. The ability of PET to distinguish between viable tumor and necrosis or fibrosis in residual masses provides an advantage over conventional imaging using computed tomography  or magnetic resonance imaging [6–8]. The high sensitivity and specificity of [18F]FDG-PET imaging for lymphoma staging has been demonstrated in previous studies [9–12]. Fused FDG-PET and CT imaging combines functional with anatomic information about the tumor and is now routinely used in radiation treatment planning. PET-CT is now strongly recommended by the International Harmonization Project in Lymphoma for staging and reassessment of FDG-avid, potentially curable lymphomas such as Hodgkin's disease and diffuse large B-cell lymphoma .
In Hodgkin's disease, long-term disease control is high and late treatment toxicity and secondary cancers are emerging as new challenges. It is therefore increasingly important to develop individualized risk-adapted treatment approaches for this disease. Several recent studies have demonstrated the role of [18F]FDG-PET in predicting clinical outcome for patients with Hodgkin's disease. Advani et al showed that a positive [18F]FDG-PET scan following completion of Stanford V chemotherapy was predictive of freedom from progression, even after controlling for bulky disease and International Prognostic Score (IPS) greater than 2 . The potential clinical utility of [18F]FDG-PET scan may be extended even further. Although the optimal timing for evaluating early response to treatment is yet to be defined, a recent joint Italian-Danish study has prospectively shown that [18F]FDG-PET scan following two cycles of AVBD chemotherapy is superior than IPS in predicting progression-free survival in patients with Hodgkin's disease .
Evaluation criteria of [18F]FDG-PET scans were qualitative in these studies. Variability in interpretation of PET-CT scans, particularly in cases with faint residual uptake or "intermediate-positive" scans, limits the broad clinical utility of this tool. Whether quantitative PET parameters is a predictive factor for disease progression in Hodgkin's disease is not well established. Metabolic tumor volume (MTV) has been described in a previous study incorporating patients with Hodgkin's disease and non-Hodgkin's lymphoma to be an independent prognostic factor, but this study had a short follow-up period of 12.7 months and it did not examine the prognostic value of interim-treatment PET parameters . We hypothesize that pre- and interim-treatment quantitative PET parameters may provide increased predictive strength beyond traditional clinical factors such as the International Prognostic Score (IPS).
No. of patients (%)
9 - 75
> = 45 yo
0 - 2
> = 3
PET Imaging protocol
PET images were acquired on a GE Discovery LS PET-CT scanner (GE Medical Systems, Milwaukee, WI) as previously described . In brief, each patient received 12 to 18 mCi of FDG 45 to 60 min before PET/CT imaging. PET data were acquired using about seven bed positions, with 3 to 5 min of acquisition time per position. Patients were injected between 12-18 miCi of FDG based on patient weight. The amount of FDG injected for individual patients did not vary significantly provided that their weights did not change significantly between the scans.
Measurement of quantitative PET parameters
Interim-treatment scans were performed at a median of 55 days from the staging PET-CT, corresponding to 2 cycles of Stanford V chemotherapy which was the most commonly used regimen in this cohort of patients. Interim-treatment scans were then registered to the corresponding pre-treatment scans and the identical regions interrogated. The ratio of interim- to pre-treatment PET parameters was calculated, for instance, as follows: interim-treatment SUVmax/pre-treatment SUVmax. We herein refer to these values as calculated PET parameters.
Clinical relapse was defined as death, biopsy-proven recurrence or radiographic findings leading to a change in management based on clinical judgment. The Cox proportional hazards model was used for univariate analysis to assess the effect of patient variables and treatment factors on the end points described above. Survival graphs were generated by the product limit method of Kaplan and Meier and log-rank analysis was utilized for differences between proportions. Analysis was facilitated using R freeware by the GNU project(5) and Prism v4.0 by GraphPad .
Of the 30 patients in this cohort, the majority (53%) had stage III-IV disease, 67% had an IPS of 2 or greater, and 30% had an IPS of 3 or greater. Patient characteristics, including patient age, gender, stage, bulky disease, extranodal disease, IPS score, and chemotherapy received, are summarized in Table 1.
Characteristics of patients who have relapsed
mid/pre tx MTV
mid/pre tx iSUV
Progressed at completion of chemo and RT
Progressed at completion of chemo and RT
Dyspnea & fluid overload after cycle 4 of ABVD, h/o orthotopic heart transplant
Expanding large axillary mass, chemo suspended for surgical excision
Died unexpectedly after 2 cycles chemo
Evidence of disease recurrence on PET-CT but asymptomatic
The average MTV for the pre-treatment PET-CT scans was 344 mL (range 8 - 1496 mL). The average value for maximum SUV in pre-treatment PET-CT scans was 15.9 (range 5 - 44), for mean SUV 5.3 (range 3 - 10), and for iSUV 1841.6 (range 24 - 8907). The average MTV for the interim-treatment PET-CT scans was 44 mL (range 0 - 515 mL). The average value for maximum SUV in interim-treatment PET-CT scans was 4.0 (range 0 - 19.3), for mean SUV 2.1 (range 0 - 7), and for iSUV 223.5 (range 0 - 2983).
Summary of Cox proportional hazards analysis of quantitative PET parameters
Pre-treatment PET Metrics
Interim PET Metrics
Calculated PET Metrics
In our study, we have demonstrated that the absolute value SUVmax from interim-treatment scans were significantly associated with OS and PFS on univariate analysis. In addition, the calculated PET parameters from interim-treatment/pre-treatment PET-CT scans, MTVmid/pre, SUVmaxmid/pre, and iSUVmid/pre, were predictive for PFS and OS. Calculated SUVmean from interim-treatment/pre-treatment PET-CT scans is also predictive of OS. This is consistent with the hypothesis that the chemosensitivity of the tumor as measured by PET-CT early during treatment is predictive of clinical outcome.
These data suggest that absolute value and calculated PET metrics taken from quantitative analysis of PET imaging may augment the IPS for predicting PFS or OS. IPS is utilized for prognostication of patients with advanced Hodgkin's disease and not early stage disease. The development of prognostic and predictive tools for patients beyond standard clinical staging could be an important advancement for adaptive treatment approaches. Relapses in this study occurred only in patients with advanced stage disease, so we could not determine if quantitative PET parameters were predictive for early stage disease. For the patients in this study, PFS and OS are 100% for early stage, non-bulky disease (n = 9). In a larger group of 101 patients with favorable early stage disease treated with Stanford V chemotherapy followed by radiation therapy (20 or 30 Gy) according to established protocols at Stanford, FFP was 94% and OS was 97% . In our study, four-year PFS for advanced disease (stage III and IV or early stage bulky disease) is 70% and OS is 85% (n = 21). In a larger group of 142 patients with advanced disease treated with Stanford V chemotherapy followed by 36 Gy to involved sites at Stanford, 5-year PFS was 89% and OS was 96%. The small sample size in our study limits our ability to directly compare clinical outcomes between the patients in our study and the larger group of patients with Hodgkin's disease treated at Stanford.
We showed that absolute value interim-treatment SUVmax was predictive for OS using the average SUVmax of 4.0 as the threshold value. This threshold level was chosen for illustrative purposes to demonstrate that differences in clinical outcomes can be separated based upon quantitative PET metrics. This analysis points to the potential utility of a quantitative approach for cases that may be difficult to assess following chemotherapy. However, the optimal cut-off values to be used in Hodgkin's disease still needs to be further evaluated in prospective clinical studies. The optimal technique and threshold values for segmenting hypermetabolic tumor foci also warrants further examination.
We describe several quantitative PET parameters that may be potentially applicable for predicting clinical outcome in patients with Hodgkin's disease. In our study, PET parameters from pre-treatment scans were not significant. This may be due to the small sample size of our study. Alternatively, it may be that the chemosensitivity of the tumor is more important for predicting clinical outcome than the magnitude of metabolically active tumor burden at diagnosis. It is interesting to note that both interim-treatment absolute value and calculated (interim-treatment/pre-treatment) SUVmax were predictive for overall survival and progression free survival. We hypothesize that tumor chemosensitivity may be reflected in interim-treatment PET scan parameters. Absolute value interim-treatment MTV has the advantage of being more directly measured than calculated MTV, although calculated MTV has the advantage of reflecting the change in metabolic activity from baseline. The absolute value PET parameters were used to determine the calculated PET parameters (for instance, absolute value interim-treatment SUVmax/pre-treatment SUVmax). In our dataset, absolute value SUVmax and calculated SUVmax were highly correlated (Spearman R = 0.94 and p = 0.0001). It is also notable that 16 patients had interim-treatment SUVmax of 0, and as a result, calculated SUVmax also shared the same value 0 for 16 of the 30 patients. The best approach for applying quantitative PET data in the treatment of patients with Hodgkin's disease warrants further study in a prospective manner.
Our results although preliminary, are consistent with the joint Italian-Danish study showing that [18F]FDG-PET scan following two cycles of AVBD chemotherapy predicts progression-free survival in Hodgkin's disease patients. The interpretation of the PET-CT scans differs in our study in that we employ quantitative analysis rather than qualitative assessment. The establishment of quantitative methods of assessing PET-CT scans may aid in the interpretation of scans with minimal residual uptake or with "intermediate-positive" disease. It also has the potential for standardizing the interpretation of scans to reduce the variability in technique among clinical trials and across different institutions. Since a PET-CT is generally performed to assess the extent of disease before and during treatment for patients with Hodgkin's disease, quantitative analysis would be a practical and cost-effective strategy for incorporating these data into clinical practice.
The limitations of our study are the relatively small number of patients, relatively small number of clinical events (progression and/or death), and retrospective method. Due to the small number of patients, we were not able to select a more homogenous population of patients receiving identical chemotherapy regimen, e.g. our stage I-II patients. Due to the low numbers of events we were also unable to perform a multivariate analysis to exclude the influence of other clinical and treatment related prognostic factors as compared to our quantitative PET metrics. In spite of these limitations, we present statistically significant data correlating quantitative interim-treatment PET metrics with clinical progression.
In conclusion, quantitative assessment of FDG-PET status after chemotherapy will likely be helpful for identifying patients at high risk of treatment failure at an early time point when treatment intensification could be considered. The preliminary findings of our study supports the quantitative interpretation of FDG-PET images as possibly an important tool guiding the design of prospective clinical trials of functional imaging for Hodgkin's disease.
We would like to thank the Stanford Scholarly Concentration Travel Award for supporting Diane Tseng's presentation of this work at the 2011 American Society of Radiation Oncology annual meeting. We would also like to thank Peter Maxim, PhD, and Edward Mok, PhD, for their assistance.
- Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992, 327: 1478-1484. 10.1056/NEJM199211193272102View ArticlePubMedGoogle Scholar
- Gallamini A, Rigacci L, Merli F, Nassi L, Bosi A, Capodanno I, Luminari S, Vitolo U, Sancetta R, Iannitto E, Trentin L, Stelitano C, Tavera S, Biggi A, Castagnoli A, Versari A, Gregianin M, Pelosi E, Torchio P, Levis A: The predictive value of positron emission tomography scanning performed after two courses of standard therapy on treatment outcome in advanced stage Hodgkin's disease. Haematologica 2006, 91: 475-481.PubMedGoogle Scholar
- Hutchings M, Loft A, Hansen M, Pedersen LM, Buhl T, Jurlander J, Buus S, Keiding S, D'Amore F, Boesen AM, Berthelsen AK, Specht L: FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 2006, 107: 52-59. 10.1182/blood-2005-06-2252View ArticlePubMedGoogle Scholar
- Gallamini A, Hutchings M, Rigacci L, Specht L, Merli F, Hansen M, Patti C, Loft A, Di Raimondo F, D'Amore F, Biggi A, Vitolo U, Stelitano C, Sancetta R, Trentin L, Luminari S, Iannitto E, Viviani S, Pierri I, Levis A: Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 2007, 25: 3746-3752. 10.1200/JCO.2007.11.6525View ArticlePubMedGoogle Scholar
- GNU Project, The Comprhensive R Archive Network. R 2.5.1Institute for Statistics and Mathematics of the WU Wien; [http://cran.r-project.org/]
- Jerusalem G, Beguin Y, Fassotte MF, Najjar F, Paulus P, Rigo P, Fillet G: Whole-body positron emission tomography using 18F-fluorodeoxyglucose for posttreatment evaluation in Hodgkin's disease and non-Hodgkin's lymphoma has higher diagnostic and prognostic value than classical computed tomography scan imaging. Blood 1999, 94: 429-433.PubMedGoogle Scholar
- Jerusalem G, Warland V, Najjar F, Paulus P, Fassotte MF, Fillet G, Rigo P: Whole-body 18F-FDG PET for the evaluation of patients with Hodgkin's disease and non-Hodgkin's lymphoma. Nucl Med Commun 1999, 20: 13-20. 10.1097/00006231-199901000-00004View ArticlePubMedGoogle Scholar
- Stumpe KD, Urbinelli M, Steinert HC, Glanzmann C, Buck A, von Schulthess GK: Whole-body positron emission tomography using fluorodeoxyglucose for staging of lymphoma: effectiveness and comparison with computed tomography. Eur J Nucl Med 1998, 25: 721-728. 10.1007/s002590050275View ArticlePubMedGoogle Scholar
- Kostakoglu L, Goldsmith SJ: Fluorine-18 fluorodeoxyglucose positron emission tomography in the staging and follow-up of lymphoma: is it time to shift gears? Eur J Nucl Med 2000, 27: 1564-1578. 10.1007/s002590000340View ArticlePubMedGoogle Scholar
- O'Doherty MJ, Macdonald EA, Barrington SF, Mikhaeel NG, Schey S: Positron emission tomography in the management of lymphomas. Clin Oncol (R Coll Radiol) 2002, 14: 415-426. 10.1053/clon.2002.0118View ArticleGoogle Scholar
- Schiepers C, Filmont JE, Czernin J: PET for staging of Hodgkin's disease and non-Hodgkin's lymphoma. Eur J Nucl Med Mol Imaging 2003,30(Suppl 1):S82-88.View ArticlePubMedGoogle Scholar
- Naumann R, Beuthien-Baumann B, Reiss A, Schulze J, Hänel A, Bredow J, Kühnel G, Kropp J, Hänel M, Laniado M, Kotzerke J, Ehninger G: Substantial impact of FDG PET imaging on the therapy decision in patients with early-stage Hodgkin's lymphoma. Br J Cancer 2004, 90: 620-625. 10.1038/sj.bjc.6601561PubMed CentralView ArticlePubMedGoogle Scholar
- Cheson BD: The International Harmonization Project for response criteria in lymphoma clinical trials. Hematol Oncol Clin North Am 2007, 21: 841-54. 10.1016/j.hoc.2007.06.011View ArticlePubMedGoogle Scholar
- Advani R, Maeda L, Lavori P, Quon A, Hoppe R, Breslin S, Rosenberg SA, Horning SJ: Impact of positive positron emission tomography on prediction of freedom from progression after Stanford V chemotherapy in Hodgkin's disease. J Clin Oncol 2007, 25: 3902-3907. 10.1200/JCO.2007.11.9867View ArticlePubMedGoogle Scholar
- Grow AQE, Loo BW Jr: Metabolic tumor volume as an independent prognostic factor in lymphoma [Abstract 6594]. Journal of Clinical Oncology 2005, 23: 583S.Google Scholar
- Horning SJ, Hoppe RT, Breslin S, Bartlett NL, Brown BW, Rosenberg SA: Stanford V and radiotherapy for locally extensive and advanced Hodgkin's disease: mature results of a prospective clinical trial. J Clin Oncol 2002, 20: 630-637. 10.1200/JCO.20.3.630View ArticlePubMedGoogle Scholar
- Donaldson SS, Hudson MM, Lamborn KR, Link MP, Kun L, Billett AL, Marcus KC, Hurwitz CA, Young JA, Tarbell NJ, Weinstein HJ: VAMP and low-dose, involved-field radiation for children and adolescents with favorable, early-stage Hodgkin's disease: results of a prospective clinical trial. J Clin Oncol 2002, 20: 3081-3087. 10.1200/JCO.2002.12.101View ArticlePubMedGoogle Scholar
- Diehl V, Franklin J, Hasenclever D, Tesch H, Pfreundschuh M, Lathan B, Paulus U, Sieber M, Rüffer JU, Sextro M, Engert A, Wolf J, Hermann R, Holmer L, Stappert-Jahn U, Winnerlein-Trump E, Wulf G, Krause S, Glunz A, von Kalle K, Bischoff H, Haedicke C, Dühmke E, Georgii A, Loeffler M: BEACOPP: a new regimen for advanced Hodgkin's disease. German Hodgkin's Lymphoma Study Group. Ann Oncol 1998,9(Suppl 5):S67-71.View ArticlePubMedGoogle Scholar
- Lee PWD, Lavori P, Quon A, Hara W, Maxim P, Le QT, Wakelee H, Donington J, Graves E, Loo BW: Metabolic tumor burden predicts for disease progression and death in lung cancer. Int J Radiation Oncology Biol Phys 2007, 69: 328-333. 10.1016/j.ijrobp.2007.04.036View ArticleGoogle Scholar
- GraphPad: Kaplan-Meier Analysis. In GraphPad Prism version 4.0a for Macintosh ed. San Diego, California; 2003.Google Scholar
- Advani RH, Hoppe RT, Maeda LS, Baer DM, Mason J, Rosenberg SA, Horning SJ: Stage I-IIA Non-bulky Hodgkin's Lymphoma. Is Further Distinction Based on Prognostic Factors Useful? The Stanford Experience. Int J Radiat Oncol Biol Phys 2010.Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.