Originally published as JCO Early Release 10.1200/JCO.2007.11.9867 on July 30 2007

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Impact of Positive Positron Emission Tomography on Prediction of Freedom From Progression After Stanford V Chemotherapy in Hodgkin's Disease

Ranjana Advani, Lauren Maeda, Philip Lavori, Andrew Quon, Richard Hoppe, Sheila Breslin, Saul A. Rosenberg, Sandra J. Horning

From the Stanford University Comprehensive Cancer Center, Stanford, CA

Address reprint requests to Ranjana Advani, MD, Stanford University Medical Center, 875 Blake Wilbur Dr, Stanford, CA 94305; e-mail: radvani{at}stanford.edu

	ABSTRACT

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Purpose: To correlate [¹⁸F]fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) status after chemotherapy, but before radiation, with outcome in patients treated with the Stanford V regimen.

Patients and Methods: We analyzed retrospectively 81 patients with Hodgkin's disease who had serial [¹⁸F]FDG-PET scans performed at baseline and again at the completion of Stanford V chemotherapy, before planned radiotherapy. Patients with favorable stage I/II (nonbulky mediastinal disease) and those with bulky mediastinal disease or stage III/IV were scanned after 8 and 12 weeks of chemotherapy, respectively. Radiotherapy fields were determined before starting chemotherapy based on baseline computed tomography scans.

Results: After chemotherapy, six of 81 patients had residual [¹⁸F]FDG-PET–positive sites, all in sites for which radiotherapy was planned. Four of the six patients with positive [¹⁸F]FDG-PET scans after chemotherapy experienced relapse compared with just three of 75 patients with negative [¹⁸F]FDG-PET scans. At a median follow-up of 4 years, the freedom from progression (FFP) was 96% in postchemotherapy [¹⁸F]FDG-PET–negative patients versus 33% in [¹⁸F]FDG-PET–positive patients (P < .0003). In a bivariate Cox model, [¹⁸F]FDG-PET positivity after chemotherapy remained a highly significant predictor of progression-free survival even after controlling for bulky disease and International Prognostic Score more than 2.

Conclusion: These data indicate that PET status after chemotherapy is strongly predictive of FFP with the Stanford V regimen despite the use of consolidative radiotherapy. These results have implications for the design of clinical trials adapted to functional imaging.

	INTRODUCTION

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Positron emission tomography (PET) has emerged as an important tool in the management of patients with lymphoma. The majority of studies conducted using PET have included a mix of patients with both Hodgkin's disease (HD) and non-Hodgkin's lymphoma. Current clinical PET uses the radiolabeled glucose analog [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) to evaluate glycolytic activity, which is greater in malignant tissue. [¹⁸F]FDG-PET better discriminates viable tumor from necrotic tissue and has a higher diagnostic sensitivity than other staging procedures such as gallium scintigraphy and computed tomography (CT). The high sensitivity and specificity of [¹⁸F]FDG-PET imaging for staging of lymphoma has been established in multiple studies.^1-4 Mid-chemotherapy [¹⁸F]FDG-PET status has also been reported to be a strong predictor of progression-free survival (PFS).⁵ More recent studies have largely corroborated these results and also suggest that [¹⁸F]FDG-PET may have a high predictive value as early as after two cycles of chemotherapy.^6,7

Although a handful of recent studies have suggested similar results for [¹⁸F]FDG-PET in HD,^8-10 the prognostic value of monitoring HD with [¹⁸F]FDG-PET and the optimal time for evaluating early response to treatment remains unclear. HD studies thus far are limited by small numbers, different treatment regimens, variable timing of scans during the course of treatment, and short follow-up. A recent study has evaluated prospectively the role of [¹⁸F]FDG-PET imaging after two cycles and at completion of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy for HD. At a median follow-up of 23 months, interim [¹⁸F]FDG-PET status after two cycles of chemotherapy was as accurate as [¹⁸F]FDG-PET status after the completion of chemotherapy with ABVD in predicting PFS.¹¹

Since 1988, we have the used the Stanford V regimen, a combined-modality approach in the management of patients with HD. At 12 years, for all stages of disease, the freedom from progression (FFP) and overall survival (OS) were 89% and 95%, respectively.^12,13 For combined-modality treatment regimens, such as Stanford V, for which radiation therapy (RT) is an integral part of the therapy, the optimal timing for [¹⁸F]FDG-PET scanning is unknown.

The objectives of these retrospective analyses were to correlate [¹⁸F]FDG-PET status after chemotherapy, but before radiation, with outcome in patients treated with the Stanford V regimen at a single institution; and to evaluate patterns of failure as related to [¹⁸F]FDG-PET status and use of RT.

	PATIENTS AND METHODS

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Patient Selection
Patients treated between 1995 and 2004 (a time period in which [¹⁸F]FDG-PET was first introduced) were identified from the lymphoma database at Stanford University based on the following criteria: [¹⁸F]FDG-PET scans performed pretreatment and at the completion of chemotherapy but before the planned RT, and a minimum follow-up of 2 years after the completion of combined-modality therapy. Decisions to image after chemotherapy presumably were based on access to the [¹⁸F]FDG-PET scanner and patient convenience. Consent to use the database information was obtained from the Stanford University Institutional Review Board.

Classical HD was confirmed histologically according to the WHO classification in all patients, with pathology review at Stanford University Medical Center (Stanford, CA).¹⁴ Patients were staged according to the Ann Arbor classification.¹⁵ The International Prognostic Score (IPS) was calculated for all patients using the seven risk factors described.¹⁶ Bulky mediastinal disease was defined as a mediastinal mass greater than one third of the maximum intrathoracic diameter on a standing posteroanterior chest radiograph. All patients had baseline staging CT scans, as well as [¹⁸F]FDG-PET scans performed pretreatment and 1 to 2 weeks after the completion of chemotherapy but before the initiation of RT. Post-RT repeat imaging was done at least 2 months after completion of RT.

The [¹⁸F]FDG-PET scans were performed at either the Palo Alto Veterans Administration Hospital (Palo Alto, CA) or Stanford University Medical Center. All scans at the Palo Alto Veterans Administration Hospital were performed on either an ECAT or ECAT HR+ [¹⁸F]FDG-PET scanner (Siemens Medical Systems, Erlangen, Germany). All scans at Stanford were performed on a Discovery LS [¹⁸F]FDG-PET/CT scanner (GE Medical Systems, Waukesha, WI). Patients were injected with 10 to 15 mCi of [¹⁸F]FDG and a standard 45- to 60-minute tracer uptake period was used. Scans at both centers were reviewed by a board-certified nuclear medicine physician experienced in [¹⁸F]FDG-PET interpretation and were scored as positive or negative for residual disease based on visual analysis.

Treatment
Patients with favorable stage I/II asymptomatic (nonbulky mediastinal disease) and those with bulky mediastinal disease or stage III/IV were treated with 8 or 12 weeks of chemotherapy, respectively, as described previously.^12,13 RT fields were determined before starting chemotherapy based on baseline CT scans. Specifically results of [¹⁸F]FDG-PET scans performed after chemotherapy did not influence RT decisions, and patients were treated according to the assigned protocol. RT at 30 Gy was delivered to involved sites in favorable stage I/II patients, and at 36 Gy to sites 5 cm and macroscopic splenic disease for all others as described previously.^12,13 Six patients with favorable stage I/II received a lower radiation dose of 20 Gy to involved sites as part of a study initiated in 2003. RT for all patients was performed at Stanford University Medical Center and commenced within 2 weeks of completion of chemotherapy. After completion of RT, patients were observed with a chest radiograph and routine laboratory data every 3 months during years 1 to 2, every 6 months during years 3 to 5, and annually thereafter. CT scans were performed at 6 months, and 1 and 2 years after completion of therapy. Suspected relapses were confirmed in all cases with histologic diagnosis and, if confirmed, patients were treated with high-dose therapy with autologous stem-cell support.

Statistical Design
FFP was defined as time from the start of treatment to documented progression of disease. There were no deaths on follow-up, so there is no competing risk. A postchemotherapy bivariate Cox model analysis was performed to determine if [¹⁸F]FDG-PET positivity after chemotherapy was associated significantly with FFP after adjusting for pretreatment IPS or the presence of bulky disease, separately. These models were run two ways, including IPS or bulky disease as covariates or as stratifiers of the base hazard. Both methods came to the same conclusion, so we report results only for the covariate method. All analyses were done in the language R, using Harrell's Design package. Because of the small number of relapses observed (n = 7), we used Fisher's exact test to verify the results of log-rank tests; for the same reason, the multivariate analyses are intended only to check if the effects of [¹⁸F]FDG-PET positivity after chemotherapy could be explained by either bulky disease or IPS.

	RESULTS

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Eighty one patients who met the criteria stated above were identified. The characteristics of these patients are listed in Table 1. The median age was 29 years (range, 18 to 47 years) with 39 males and 42 females. Eighteen patients had "B" symptoms and 60 had sites of disease 5 cm. Of the 81 patients, 43 patients were classified as stage I or II favorable; 16 had stage II with bulky mediastinal disease. The remaining 22 patients had stage III or IV disease, of whom eight had bulky mediastinal presentation. Thirty-five patients were treated with 8 weeks of Stanford V chemotherapy. Of these, 29 patients received 30 Gy, and six patients received 20 Gy irradiation to involved sites. Forty-six patients were treated with 12 weeks of Stanford V chemotherapy followed by 36 Gy RT to sites 5 cm and macroscopic splenic disease as described.^12,13 Forty-four patients had an IPS of 0 or 1, 34 patients had an IPS of 2 or 3, and three patients had an IPS 4. The median follow-up was 4 years.

All 81 patients had [¹⁸F]FDG-PET–positive sites of disease at the time of diagnosis. After the completion of chemotherapy, six patients had residual disease that was [¹⁸F]FDG-PET positive and 75 patients had negative [¹⁸F]FDG-PET scans (Fig 1). We found no association between initial bulky mediastinal disease and postchemotherapy residual [¹⁸F]FDG-PET–positive disease. Three (12.5%) of the 24 patients with bulky mediastinal disease had residual [¹⁸F]FDG-PET–positive disease, versus three (5.2%) of 57 patients without bulky mediastinal disease (P = 1 for association, Fisher's exact test). Similarly, no association was found between the pretreatment IPS and a positive postchemotherapy [¹⁸F]FDG-PET scan. Of the 44 patients with IPS 0 to 1, three (6.8%) had residual [¹⁸F]FDG-PET–positive disease versus three (8%) of 37 patients with IPS 2 (P = 1 for association, Fisher's exact test).

View larger version (29K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Outcome based on postchemotherapy [18F]fluorodeoxyglucose positron emission tomography (PET) scan results. XRT, x-ray therapy; +, positive; –, negative.

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Freedom from progression in patients with positive [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) scans after chemotherapy (– – –) versus negative [18F]FDG-PET scans (——).

Given that these patients represented only 35% of the total 233 patients with HD treated during the study period, we compared the outcome of the study group with patients who had not had a [¹⁸F]FDG-PET scan. The FFP was similar (90%) in both groups irrespective of whether [¹⁸F]FDG-PET scans were done or not (Fig 3).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Freedom from progression (FFP) study group versus overall patients treated. There was no difference in the FFP when the study group (– – –) was compared with the group that did not have [18F]fluorodeoxyglucose positron emission tomography scans (——).

	DISCUSSION

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All the postchemotherapy [¹⁸F]FDG-PET–positive sites were in the mediastinum and all of these patients received subsequent irradiation based on prechemotherapy-defined RT fields. Notably, all relapses occurred in the radiated mediastinum or at its margin (Table 2). Two patients had additional synchronous distant sites of failure (infradiaphragmatic and osseous). Three of the six patients who were [¹⁸F]FDG-PET positive after chemotherapy had bulky mediastinal disease and all three eventually experienced relapse. Thus, in our patient population, the addition of RT delivered according to the Stanford V protocol did not overcome the adverse prognostic significance of [¹⁸F]FDG-PET positivity. These patients were resistant to RT in the doses that were used. In addition, on multivariate analysis, [¹⁸F]FDG-PET–positive status conferred additional risk even after stratifying for bulky disease.

Although these numbers are too small to make definitive conclusions, they do raise the issue of whether there may be biologic differences between mediastinal and nonmediastinal HD. Interestingly, these patients all received successful salvage therapy with high-dose therapy and autologous stem-cell support, with OS at 4 years of 100%. It is provocative to consider that patients who are [¹⁸F]FDG-PET positive after chemotherapy may benefit more from high-dose therapy with stem-cell support rather than consolidative RT.

Our study group represents 35% of the total 233 patients with HD treated with combination Stanford V and RT at Stanford University Medical Center during the study period. More scanned patients had bulky mediastinal disease (30%) compared with the larger group treated in that time period (15%). This observation suggests that there may have been a bias in the referral pattern for [¹⁸F]FDG-PET imaging in this setting. Despite this difference, the FFP of the study group was similar to the total set of patients treated in the same era (Fig 3).

There have been several recent studies reporting the predictive accuracy of [¹⁸F]FDG-PET scans in the evaluation of post-treatment residual disease in patients with HD. A high negative predictive value of [¹⁸F]FDG-PET (80% to 100%) has been demonstrated in most studies, indicating that [¹⁸F]FDG-PET status accurately identifies patients with a favorable prognosis.^17-22 Our study confirms this finding, given that the postchemotherapy [¹⁸F]FDG-PET–negative patients had an FFP of 96%. Given that the majority of patients in these studies, including our own, received RT after a negative [¹⁸F]FDG-PET scan, the question of the additional benefit of RT in patients with a negative postchemotherapy [¹⁸F]FDG-PET scan is not answered by this study. Our results in [¹⁸F]FDG-PET–positive patients (all of whom were radiated) suggest that ongoing trials in which the design calls for RT in [¹⁸F]FDG-PET–positive patients may not result in a high cure rate using the doses used in our study.

The treatment of HD has evolved during the last two decades; a risk-adapted approach currently is used to minimize long-term toxicities while maintaining excellent outcomes. The utility of consolidative RT is under scrutiny because of potential long-term complications. The recent HD-6 trial reported a superior FFP in a subset of patients with early-stage HD who achieved a complete remission by CT scan after two cycles of ABVD, suggesting that RT may be avoided in a subset of patients if early complete remission is achieved.²³ However, when the Stanford V regimen was administered variably, as in the Italian study, with substantial modifications to the RT (limit on the number of sites treated, a different definition of bulk, and a delay in initiating RT to a median of 6 weeks), inferior results were reported.²⁴ Extrapolation of these results based on CT criteria to functional imaging may be premature and deserve additional study. Furthermore, the definition of risk factors for early-stage disease vary considerably across studies, and interpretation of results need to take into account the patient stratification.²⁵

For patients with advanced HD, the IPS helps identify patients who may benefit from a more aggressive, albeit more toxic treatment approaches.²⁶ However, these factors are all pretreatment and do not take into account response to therapy that may be more predictive of outcome than pretreatment prognostic risk factors. Recent data from the Intergruppo Italiano Linfomi support this concept. In this study, a negative [¹⁸F]FDG-PET scan after two cycles of chemotherapy emerged as the only significant factor in multivariate analysis, which included other variables of tumor burden.²⁷ The 2-year FFS for patients with negative [¹⁸F]FDG-PET scan after two cycles and patients with positive scans was 95% and 6% respectively (P < .01). Even though only approximately 50% of our patients had advanced disease, similar findings were observed. In the multivariate analysis, [¹⁸F]FDG-PET status after chemotherapy had added predictive ability, over and above IPS or bulky disease. These data suggest that treatment decisions may need to be altered based on [¹⁸F]FDG-PET status after first-line chemotherapy rather than stratification based on pretreatment IPS alone. This approach recently has been used in stratification of patients treated with escalated versus standard bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone with excellent results, and may provide a rational way to determine who may benefit from more aggressive therapy.²⁸

Future investigations will likely focus on a prognostic assessment of early treatment response as well as the development of methods to quantify functional tumor burden. [¹⁸F]FDG-PET uses a quantitative approach to analysis, with the standardized uptake value (the ratio of activity per volume unit over injected activity per body mass). Standardized uptake value is a semiquantitative measure of metabolic activity and has been shown to have independent prognostic value. Given that our study was performed in the early days of [¹⁸F]FDG-PET imaging, we were unable to assess this parameter.

In conclusion, as the management of HD becomes more tailored, it will be important to evaluate the role of newer imaging techniques and their interpretation. In the combined-modality setting, [¹⁸F]FDG-PET status after chemotherapy may be useful in identifying a small subset of patients who might not benefit from RT and for whom treatment intensification could be considered. The results of our study may also have implications for the design of clinical trials adapted to functional imaging.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Ranjana Advani, Richard Hoppe, Saul A. Rosenberg, Sandra J. Horning

Provision of study materials or patients: Ranjana Advani, Richard Hoppe, Saul A. Rosenberg, Sandra J. Horning

Collection and assembly of data: Ranjana Advani, Lauren Maeda, Sheila Breslin

Data analysis and interpretation: Ranjana Advani, Philip Lavori, Andrew Quon, Richard Hoppe, Saul A. Rosenberg, Sandra J. Horning

Manuscript writing: Ranjana Advani, Lauren Maeda, Philip Lavori, Andrew Quon, Richard Hoppe, Saul A. Rosenberg, Sandra J. Horning

Final approval of manuscript: Ranjana Advani, Richard Hoppe, Sandra J. Horning

	NOTES

 
published online ahead of print at www.jco.org on July 30, 2007.

Presented in part at the Ninth International Conference on Malignant Lymphoma, June 7-10, 2005, Lugano, Switzerland.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted March 30, 2007; accepted May 17, 2007.

This article has been cited by other articles:

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