The objective was to determine the prognostic value of functional imaging (FI) in predicting outcome of patients with recurrent/refractory Hodgkin lymphoma (HL) before undergoing high-dose chemotherapy with autologous stem cell transplantation (ASCT).
Clinical and imaging data were retrospectively reviewed in 211 consecutive patients treated with ASCT from February 1993 to May 2004. The FI results were correlated with progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier survival analysis.
Responses were assessed by conventional criteria and evaluated by positron emission tomography (PET) (n = 68) and gallium scans (n = 144) before ASCT. A complete response (CR) or unconfirmed CR (CRu) was seen in 51% of patients, a partial response (PR) in 41% of patients, and stable or progressive disease in 7% of patients. FI was positive in only 6 of 110 (5%) of CR/CRu patients, in 48 of 86 (56%) of PR patients, and in all 3 patients with progressive disease. The 3-year PFS was 69% for patients with negative FI versus 23% for patients with positive FI (P < .0001). The 3-year OS rates were 87% and 58%, respectively (P < .0001). The 3-year PFS for patients in PR with negative FI was 51% comparable to patients in CR (76%) versus 27% for patients in PR with positive FI (P < .0001). In a multivariate model, positive FI was found to be independently prognostic of PFS.
Hodgkin lymphoma (HL) is a malignant neoplasm with high cure rates. With 8000 new cases annually diagnosed in the U.S., greater than 75% of these patients will survive disease-free for more than 5 years, with most cured.1–3 Patients not achieving complete remission (CR) at first-line treatment or who experience recurrence after CR are often salvaged with cytoreductive chemotherapy followed by high-dose chemotherapy supported by autologous stem cell transplantation (ASCT), inducing long-term disease-free survival in chemosensitive patients assessed on clinical, radiologic, and pathologic criteria.4–9
Most patients who develop a recurrence after ASCT will die of their disease. Therefore, it is important to identify higher-risk patients so new treatment strategies can be developed. Investigators studied several prognostic factors predicting the outcome of patients with recurrent/refractory HL with discrepant results. Features that are considered important survival determinants include first response duration, age, anemia, presence of extranodal disease, B-symptoms at recurrence, stage, and chemosensitivity before ASCT.5, 10–12
Chemosensitivity and response to treatment are assessed using clinical, radiologic, and pathologic criteria. Computed tomography (CT) remains the standard for lymph node disease evaluation. Defining response criteria using conventional radiographic characteristics remains difficult however because HL patients treated with chemotherapy often exhibit persistent residual masses of uncertain significance, which may contain fibrotic tissue or viable tumor.13 Functional imaging (FI) studies such as 18F-fluoro-deoxyglucose (FDG) positron emission tomography (PET) and gallium (67Ga) scans performed partway through conventional chemotherapy or after completion are more sensitive and specific than conventional radiographic techniques for restaging postchemotherapy and reportedly better predict outcome in both HL and non-Hodgkin lymphoma (NHL).14 However, the value of PET and 67Ga scans in patients with recurrent/refractory HL in predicting recurrence after ASCT has not been adequately studied. Published reports usually contain small numbers or a mix of HL and NHL patients.15, 16
In this study we assessed the prognostic value of pretransplantation PET and 67Ga scans in recurrent/refractory HL patients treated with high-dose chemotherapy (HDCT) followed by ASCT.
MATERIALS AND METHODS
Between February 1993 and May 2004, 317 consecutive patients with recurrent/refractory HL received HDCT followed with ASCT at The University of Texas M. D. Anderson Cancer Center. Of these individuals, 211 had PET or 67Ga scans before ASCT and were study-eligible based on the following inclusion criteria: histologic-proven HL with induction failure or first/subsequent recurrence and at least a PET or 67Ga scan performed after salvage chemotherapy and before ASCT, unless 1 negative evaluation occurred during treatment. All patients signed an Institutional Review Board-approved informed consent document.
Sixty-three percent received the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD regimen); 47% of patients with stage I and II disease received adjuvant radiation therapy. After documented progression or recurrence, 171 (81%) patients received ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) or ASHAP (doxorubicin, methylprednisolone, cytarabine, and cisplatin) as salvage therapy. The conditioning regimen for most patients (69%) was BEAM (carmustine, etoposide, cytarabine, and melphalan). The remaining patients received CBV (cyclophosphamide, carmustine, and etoposide) or BuCY (busulfan and cyclophosphamide) conditioning. All underwent HDCT followed by ASCT independent of results from chemotherapy as determined by CT or FI.
Before salvage chemotherapy, disease was assessed by conventional diagnostic methods (CDM): clinical examination; laboratory screening; chest X-ray; CT scan of the neck, chest, abdomen, and pelvis; bone marrow biopsy, and, if indicated, magnetic resonance imaging (MRI). Restaging was performed after salvage therapy and ASCT. Conventional and functional diagnostic test and follow-up results were obtained from patient records. Remission status was evaluated using reported standardized guidelines.17 CR was defined as complete disappearance of detectable clinical/radiographic evidence of disease and disease-related symptoms (present before therapy) and normalization of biochemical abnormalities. CR/unconfirmed (CRu) was defined by a residual lymph node presence greater than 1.5 cm in greatest transverse dimension that regressed 75% or more. Previously confluent individual lymph nodes must have regressed by more than 75% compared with original mass. CRu also includes patients with indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural atypia). Partial response (PR) was defined as a 50% or greater reduction in the product sum of the dimensions of all measured lesions. Progressive disease was defined as a greater than 25% increase in the product sum of the 2 longest dimensions of any measurable lesion or appearance of new lesion(s). Refractory disease was defined as progression during initial therapy or recurrence within 8 weeks of completion.
Sixty-eight patients had at least 1 PET scan between salvage chemotherapy and before ASCT. Body PET scans were performed in 64 patients, who fasted 6 hours before the procedure. Each patient was injected with 555 MBq (15 mCi) of [18F]FDG after ensuring blood sugar did not exceed 200 mg/dL and was placed in a quiet room. Imaging began 1 hour later. Scans were obtained from the base of skull to mid-thigh using an ECAT EXACT HR + (Siemens/CTI, Knoxville, Tenn). Transmission/emission images were acquired over 3 to 5 minutes per position using 2-dimensional mode (with septa) and 67Ga source. For study interpretation, images were reconstructed using iterative reconstruction with segmented attenuation correction.
Four patients had hybrid PET/CT scans (Discovery ST-8; GE Medical Systems, Milwaukee, Wis) acquired in 2-dimensional mode for 3 minutes per bed position. Emission data were corrected for scatter, random events, and dead-time losses using the manufacturer's software. Images were reconstructed both with and without attenuation correction using CT. Nonenhanced CT images were acquired with helical mode (speed, 13.5 mm per rotation) from the base of skull to upper thigh. PET images were reconstructed using standard vendor-provided algorithms with ordered subset expected maximization and scored as either positive or negative. A negative PET scan was defined as having no evidence of disease, with positive being any focal or diffuse area of increased activity in location incompatible with normal anatomy and suspect for residual disease.
One hundred forty-four patients had at least 1 67Ga scan between salvage chemotherapy and before ASCT. 67Ga scans were performed with intravenous injection of 8 to 10 mCi of gallium citrate Ga 67 with imaging 48 to 120 hours later. Scans were performed before and 3 weeks after 2 or more cycles of chemotherapy. Patients received 8 to 10 mCi of gallium citrate Ga 67 as a bolus injection. With a dual detector gamma camera, body images were performed at 10 cm/min speed and 48-hour minimum. The 93-KeV, 184-KeV, and 296-KeV peaks were used with 20% and 10% windows. Images typically had 2 to 4 m counts. SPECT imaging was performed at 48 to 72 hours, depending on the patient's clinical status, and displayed in transaxial, sagittal, and coronal views. Interpretation of the results was performed from hardcopy transparencies and interactive console display, volume-rendered 3-dimensional images with full knowledge of clinical, laboratory, and other imaging findings.
All scans were scored either positive or negative. A negative FI study was defined as having no evidence of activity from the 67Ga, PET, or the PET/CT images. A positive FI study was defined as any focal or diffuse area of increase 67Ga or [18F]FDG activity above background levels not representing physiological increased 67Ga or [18F]FDG uptake.
Our primary aim was to determine the prognostic value of functional studies before ASCT to predict progression-free (PFS) and overall survival (OS) rates. PFS was defined as the interval from ASCT to the date of objective evidence of recurrence/progression or death for any reason. OS was calculated from ASCT date until lymphoma-related death or death from any reason. Patients without progression or death were censored at last follow-up date. Categorical patient characteristics and outcomes were summarized in frequency tables; comparisons were made using the chi-square or Fisher exact test, as appropriate. Continuous variables were summarized using median and range. Comparison by important patient subgroups was made using the Wilcoxon rank sum test. Survival outcomes (PFS and OS) were estimated using the Kaplan-Meier method, and survival distribution comparisons among patient groups were performed using the log-rank test. Several factors were evaluated as possible PFS and OS prognostic indicators, which included: age, gender, histology, stage B-symptoms at baseline and recurrence, extranodal disease (defined as direct extension to an adjacent organ from a lymph node mass and noncontiguous extranodal site involvement), prior radiotherapy, duration of first remission (greater than vs less than 1 year), Moscowitz score10 (a combination of duration of first remission, extranodal disease, and B-symptoms present at recurrence), type of salvage therapy and conditioning, status before ASCT, and FI and conventional studies. Prognostic impact, measured in terms of patient hazard ratio characteristics, was estimated alone and in multivariable Cox (proportional hazards) regression models. No variable selection procedures were used. Statistical analyses were conducted using SAS software (SAS Institute Inc, Cary NC). Graphics were produced using SPlus (Mathsoft, Seattle, Wash).
We reviewed treatment results for 317 consecutive recurrent/refractory HL patients who underwent ASCT at The University of Texas M. D. Anderson Cancer Center between 1993 and 2004; 211 experienced FI before ASCT, 68 had PET scans, 144 had 67Ga scans, and 1 patient had both (Fig. 1).
One hundred twenty-four patients were male. The median age at transplantation was 30 years (range, 11–77 years) (Table 1). Treatment varied according to stage and date of diagnosis. The most common chemotherapy regimen administered was ABVD (78% of patients); 100 received radiotherapy as part of the initial treatment. Sixty-six patients had disease considered refractory to initial therapy and 143 entered CR with primary therapy. Remission lasted for more than 12 months in 111 patients. All underwent staging at progression or recurrence. Eighty-one percent received ASHAP or ESHAP chemotherapy, ASCT conditioning regimen was BEAM in 69%.
Table 1. Patient Characteristics, Treatment, and Outcomes Before ASCT
Of the 211 FIs performed before ASCT, 68 (32%) were reported positive for residual lymphoma; 25 of 68 PET scans (37%) were reported positive, as were 43 (30%) of the 144 67Ga scans. Correlation between response assessed by CDM and FI is delineated in Table 2. Six (5%) of the 110 patients in CR/CRu had a positive FI. In contrast, 56% of patients who achieved a PR and 14 (93%) with stable or progressive disease had positive FI studies.
Table 2. Correlation Between Computed Tomography and Functional Imaging
With a median follow-up of 2.8 years among patients without progression after ASCT, 96 (45%) developed recurrence and 64 (30%) died. Of these, 54 (86%) died of progressive disease. Three-year PFS and OS rates were 78% (95% confidence interval [95% CI], 72–84%) and 54% (95% CI, 48–62%), respectively (Fig. 2). Of the 68 patients with positive FI studies, 50 (74%) developed recurrence and 33 (48%) died, with a 6-month median time to progression (95% CI, 5–10 months). However, only 46 of the 143 (32%) patients with negative studies recurred, and 31 (22%) died. The 3-year PFS rates for patients with positive and negative FI studies were 23% (95% CI, 15–37%) and 69% (95% CI, 61–77%), respectively (P < .0001) (Fig. 3A). The 3-year OS rates were 58% (95% CI, 46–73%) and 87% (95% CI, 81–94%) for patients with positive and negative studies, respectively (P < .0001) (Fig. 3B). When evaluated separately, 68% of PET-positive and 74% of the 67Ga-positive patients recurred. Recurrences were seen in 23% and 27% of the PET-negative and 67Ga-negative patients, respectively; a small difference between the PET and 67Ga groups may be related to the longer follow-up on the 67Ga patients.
Correlation of Outcomes by Conventional Diagnostic Methods and FI Studies
Of the 110 patients in CR or CRU, only 6 (5%) patients had a positive FI. Three-year PFS for patients in CR/CRu positive and negative studies were 67% and 77%, respectively (P = .979). However, FI studies were especially predictive of outcome for patients who achieved PR after salvage chemotherapy for recurrence by conventional criteria. Of the 86 (41%) patients in PR before ASCT, 48 (56%) had positive FI. Thirty-four (71%) patients with positive FI tests developed recurrence compared with 17 (43%) with negative studies (P < .0001). The 3-year PFS for patients in CR, PR with negative studies, and PR with positive studies were 76%, 52%, and 27%, respectively (P < .0001) (Fig. 4A). The OS for patients in PR was also affected by results of the FI studies. Patients in PR with negative FI studies had outcomes similar to patients in CR; in contrast, patients with positive FI studies had worse outcomes. The 3-year OS for patients in CR, PR with negative studies and PR with positive ones were 90%, 80%, and 65%, respectively (P = .003) (Fig. 4B).
Prognostic Factors Analyses for PFS and OS
Prognostic factors associated with PFS and OS, based on demonstrated historical clinical value, were entered into univariate and multivariable logistic regression models. In a univariate model, negative FI studies, remission status, and the Moscowitz score significantly affected PFS and OS results (Table 3). In a multivariate model, independent prognostic factors for PFS included presence of B-symptoms at the time of recurrence (P = .031), achievement of a CR/CRu before ASCT (P = .001), use of BEAM as a conditioning regimen for ASCT (P = .003), and pre-ASCT positive FI studies (P = .0005) with a hazard ratio of 2.3 (95% CI: 1.44–3.68). For OS, CR/CRu before ASCT, use of adjuvant radiation therapy as initial treatment (P = .025), and use of BEAM regimen at the time of ASCT (0.007) were independent prognostic factors (Table 4).
Table 3. Univariate Analysis for Progression-Free Survival and Overall Survival
Our study suggests an important role for FI studies in evaluation of patients with recurring HL scheduled for HDCT followed by ASCT. FI, performed after salvage chemotherapy was initiated and before ASCT, had independent prognostic value for predicting PFS and OS of HL patients. Salvage cytoreductive chemotherapy followed by HDCT/ASCT resulted in 3-year event-free survival (EFS) rates of 50% or greater4–9 in patients with recurrent/refractory HL, with various factors influencing outcome, including length of initial remission, presence of extranodal disease, and B-symptoms.10–12 The most important prognostic factor may be patient remission status before ASCT.
Recently, investigators demonstrated that results of FI studies are better predictors of outcomes than are CT scans in the initial therapy of HL and NHL.18, 19 Jerusalem et al.20 analyzed the results for 54 HL/NHL patients and found a positive predictive value for 100% recurrence for PET versus 42% for CT. The recurrence rate was only 10% when both PET and CT scans were negative for disease. FI studies early in the course of therapy are also potential tools for determining which patients will remain disease-free after therapy completion.21, 22 In another study, investigators suggested that FI can identify patients with high-risk lymphoma who might benefit from HDCT/ASCT as front-line therapy, considering that sustained biologic response is an important feature before transplantation.23 Other studies assessed the value of FI before ASCT; however, many studies included low numbers and did not distinguish between NHL and HL patients.15, 16
To our knowledge, the current study, although retrospective, is the first large series of HL patients where FI before ASCT was shown to play an important prognostic role. In this study, although negative FI could not completely exclude minimal residual disease, patients with negative FI had a favorable PFS and OS compared with those with positive FI, particularly for patients considered to be in PR by CDM. However, only a prospective study evaluating FI in a randomized setting can fully evaluate its prognostic importance before ASCT. Nonetheless, patients with residual uptake in this setting experience a high risk of recurrence and poor prognosis. Such patients with positive uptake may need more innovative approaches.24
Moscowitz et al.10 identified 3 factors before initiating cytoreductive chemotherapy that can predict outcome, including presence of B-symptoms, extranodal disease, and complete remission duration of less than 1 year. In our study, the presence of B-symptoms and lack of CR/CRu at ASCT were independently predictive of PFS along with BEAM as the conditioning choice and FI results, whereas CR/CRu, radiation therapy, and BEAM were independently predictive for OS. Our data also suggest improvement in OS among FI-negative patients (P = .059).
The current study has possible limitations. First, this is a retrospective study; however, we tried to minimize this problem by using strict inclusion criteria for all patients. The 3-year PFS and OS of 54% and 77%, respectively, are consistent with those reported in the literature,25, 26 suggesting that this population represents a typical group of patients with recurrent/refractory HL. Second, PET and 67Ga scan results were considered equivalent. An attempt was made to separately assess predictive value of each type; although a higher accuracy of PET was confirmed by direct comparison of the 2 modalities,27 recurrence rates were similar between them, without statistically significant differences. Third, written reports were used to establish predictive CT value and FI; however, all clearly stated whether findings were positive or negative for residual/recurrent disease.
In conclusion, the results of the current study support the concept that FI after salvage chemotherapy for patients with recurrent/refractory HL scheduled for ASCT should be a standard assessment tool, defining pre-ASCT chemosensitivity. A negative pre-ASCT FI is associated with a favorable outcome, although patients with positive pre-ASCT FI are more likely to have viable disease and a higher recurrence risk. These patients may benefit from more innovative treatment options; however, prospective studies in randomized treatment settings are needed before change of therapy can be tested in this patient group based on FI alone.
We thank Jorge Romaguera, Uday Popat, Peter McLaughlin, Alma Rodriguez, Fernando Cabanillas, and Richard Champlin for review of the article, and Ms. Jottalyn Campbell, Ms. Cindy Cabrera, and Ms. Alison Woo for editorial support, and Mr. Mark Brandt for data analysis.