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© 2001 American Society for Clinical Oncology Image-Aided Estimate of Tumor Burden in Hodgkin’s Disease: Evidence of Its Primary Prognostic ImportanceFrom Medicina Interna e Oncologia Medica and Istituto di Radiologia, Università di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia; Servizio di Ematologia, Arcispedale "S. Maria Nuova," Reggio Emilia; Cattedra di Ematologia, Università di Verona, Policlinico di Borgo Roma, Verona; Sezione di Ematologia, Ospedale Civile di Piacenza; Ia Radiodiagnostica, Ospedale "S. Giovanni Battista," Torino; and Divisione di Ematologia, Ospedale "SS. Antonio e Biagio," Alessandria, Italy. Address reprint requests to Paolo G. Gobbi, MD, Medicina Interna e Oncologia Medica, Università di Pavia, Policlinico S. Matteo, P.le Golgi no. 2, 27100 Pavia, Italy; email: gobbipg{at}smatteo.pv.it
PURPOSE: To explore a more direct method for evaluating tumor burden (TB) in Hodgkin’s disease (HD) and to verify its prognostic importance. PATIENTS AND METHODS: The volume of TB at diagnosis was directly and retrospectively measured in 121 HD patients through images of the lesions recorded by computed tomographic (CT) scan of the thorax, abdomen, and pelvis for all deep sites of involvement and many superficial ones, and by ultrasonography (US) for the remaining superficial lesions. RESULTS: The TB, which was obtained from the sum of the volumes of all the lesions measured on CT scans and US and normalized to body-surface area (relative TB [rTB]), showed a median value of 102.6 cm3/m2 (range, 2.2 to 582.8). At multivariate analysis for prognostic value, rTB was the parameter that statistically correlated best with time to treatment failure (P = 2.2 x 10-6), followed by erythrocyte sedimentation rate (ESR) (P = .0003), and serum fibrinogen (P = .0112). The prognostic discrimination allowed by rTB alone proved to be clearly superior to that obtained with the score of the International Prognostic Factor Project. The rTB was found to be correlated with many clinical staging parameters (bulky disease, number of involved lymph node regions, serum lactate dehydrogenase, ESR, hemoglobin, Karnofsky index), but its predictability from these variables was low (R2 = .668). CONCLUSION: Relative TB is emerging as a strong prognostic factor in HD, more powerful than and largely independent of those hitherto known and used. Further studies are needed to confirm these results and exploit their clinical value, particularly the relationship among rTB, drug doses, and response.
THE CONCEPT THAT a small tumor can be treated more easily and more successfully than a large one is derived from a huge amount of age-old experience and clinical evidence. It represents an undisputed cornerstone of clinical practice for surgeons, oncologists, and radiotherapists. The concept also seems to be valid when the tumoral mass is not localized, but diffuse or disseminated, so that further aspects concerning the mechanisms and evolution of the metastatic process are involved. Generally, the total amount of tumor mass present in a patient, the so-called tumor burden (TB), cannot be easily and accurately measured with commonly available techniques. However, in nearly all tumors in which even a rough estimate of TB had been attempted and applied, it invariably showed great clinical and prognostic importance. The tumor-node-metastasis classification system1 by itself can be considered a semiquantitative evaluation of TB, albeit with decreasing accuracy in tumor measurement when moving from the evaluation of tumors (which is truly dimensional) to that of nodes (numerical) and metastasis (simply qualitative). In multiple myeloma, Durie and Salmon’s2 indirect evaluation of the number of tumoral plasma cells is still the basis for the most commonly used staging system in myeloma patients. An indirect and semiquantitative evaluation of TB significantly improved the prognostic estimate in non-Hodgkin’s lymphomas,3,4 despite the fact that it only has two or three possible levels. The total tumor mass score of Jaksic and Vitale5 for chronic lymphocytic leukemia adds further significant information to the Rai and Binet staging classifications.6 In stage III and IV head and neck cancers, the total tumor volume of the primary lesion and involved lymph nodes—measured from computed tomographic (CT) scan data—proved to be the most significant prognostic factor together with nodal CT scan density and patient age.7 In Hodgkin’s disease (HD), the superiority of TB over all other prognostic factors was demonstrated by Specht8 more than 10 years ago; however, the complexity of the method, the need for abdominal lymphangiography (an imaging technique that has become less popular in recent years), and the element of subjectivity connected with Specht’s technique made this semiquantitative TB evaluation difficult to reproduce, so that it was not considered by other investigators. Here we present the results of a retrospective study in which TB was measured through direct CT and ultrasonographic images with a technique that can be considered simple and widely reproducible. TB calculated in this way, and evaluated mainly in relation to disease control, confirms its superiority over all other prognostic factors currently being used and opens some new prospects to clinical investigation.
General Design Since CT scan of the thorax, abdomen, and pelvis has become a routine tool in the initial staging of HD patients, as accepted at the Cotswolds meeting,9 this study aimed to evaluate three-dimensionally the images of all identifiable lesions on CT scans in order to measure them volumetrically. A retrospective preliminary study in a patient population with sufficient follow-up time was initiated for reliable prognostic evaluation. A limitation to this study was that total body CT scan was clearly not available, and enlarged high cervical, submandibular, or crural nodes are outside the routinely scanned CT fields. Nevertheless, although physical examination is considered sufficient for the evaluation of superficial lymphadenopathies,9 ultrasonographic evaluation of clinically involved superficial sites has become nearly customary in many institutions, providing the complementary information on number and size of lymph nodes necessary to complete imaging-aided measurement of TB in many patients.
Patient Population and Clinical Management Staging categorization, systemic symptoms recording, bulky mass evaluation, and count of involved lymph node regions were performed according to the Cotswolds meeting criteria. The Committee recommendations were also followed when evaluating response to therapy in relation to the definition of remission as complete (CR), partial (PR), or null (NR) and to the definition of progressive disease (PD). Therapy was not analytically examined as to drug doses and times of administration but only checked to see that it corresponded to standard and widely accepted protocols with respect to clinical staging data. Since no limitations on clinical stages were fixed to enter the study, therapy differed widely, according to four accepted controlled clinical trials. Stage I and II patients with very favorable prognostic factors (histologic type other than lymphocytic depletion, no symptoms, no bulky mass, no extranodal lesions, low levels of ESR and LDH) were treated with extended-field radiotherapy alone (seven patients); cases with the same stages but the presence of one unfavorable factor (except histologic type and symptoms) received vinblastine, bleomycin, and methotrexate (VBM)11 chemotherapy with involved-field radiotherapy (19 patients); subjects with stage I to II disease, with lymphocyte depletion histology or B symptoms or more than one unfavorable factor were treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)12 chemotherapy followed by extended-field radiotherapy (24 patients). Finally, 71 patients with stages IIB, III, and IV disease received alternated mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/ABVD13 in three centers or mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, melphalan, and vindesine (MOPPEBVCAD)14 chemotherapy in the remaining three centers. In advanced-disease patients, radiotherapy was limited to slowly or incompletely responding sites during drug delivery. Undersigned informed consent was available for each patient. The median follow-up time was 64 months (range, 19 to 124).
TB Assessment In 57 patients, a spiral scan was performed; in the remaining 64, traditional scans were accepted on the condition that the images were contiguous and 10 mm thick. Different CT scan units were used in different diagnostic centers (Siemens Somatom 2, 2DR, Plus, Plus 4, Erlangen, Germany), but none of the CT scanners used a scanning time longer than 5 seconds. The magnetic records of the patients selected were reanalyzed to assess TB. The radiologists were called to carefully outline the borders of each HD lesion they had diagnosed on each CT scan slice: the boundaries of every neoplastic area were marked manually and the exterior limits of the lesions were considered for this evaluation. The volume of each tumor mass was obtained using the software programs contained in the CT scanners (the area of the lesion on the slice and the thickness of the slice). Healthy structures surrounded by or included in HD tissue (eg, vessels, nerves, and so on) were subtracted. On the other hand, necrotic areas were included in the computation because they correspond to a preceding amount of tumor, necessary to the volume of the present mass. The total volume of the tumor detected through CT scan examination was derived from the sum of the volumes of all the lesions identified in all the scanned slices. Visceral lesions—when present—were handled with the same technique used for lymph nodes; no cases with bone marrow involvement were present, for which a semiquantitative estimate would be unavoidable. On average, the reexamination of CT scans, the identification of the involved structures in each slice, and the calculation procedures took the radiologist about 20 to 30 minutes. Superficial lymph nodes outside thoracic and abdominal CT scans had to be measured through ultrasonography (US). When the volume of a pathologic lymph node could not be directly measured through the software resources of the US instruments (Toshiba Sonolayer, with 7-MHz probe, Toshiba America Medical Systems, Irvine, CA), at least two ultrasonographically measured dimensions of the lymph node had to be available. The volume was then estimated by computing the volume of the corresponding ellipsoid (when the diameters showed three different values) or rotational ellipsoid (when two of the three diameters were equal). Because axillary, infraclavicular, pectoral, and inguinal regions are generally included in the thoracic, abdominal, and pelvic CT scans and can be measured on tomographic slices with the above-mentioned technique, the superficial lymph nodes that required US scans for volumetric assessment were the cervical, preauricular, and femoral ones (epitrochlear and popliteal are very rarely involved in HD). Sometimes, CT scans were extended to supraclavicular regions, especially when large lymph node agglomerates were involved, but for the most part the evaluation of supraclavicular nodes had to be ultrasonographic. US evaluation required a variable length of time, according to the number of lymph node areas studied, but took about 10 minutes on average. When making all the CT and US scan measurements, radiologists were blinded to all other clinical information. Thus, the absolute TB (aTB) in cubic centimeters derived from the sum of the volumes of the lesions measured at CT scan and of those evaluated by US. Moreover, since it seems reasonable that an identical aTB may play different roles in patients of different sizes, the TB was normalized to body size. This relative TB (rTB) was computed by dividing the aTB by the patient’s body-surface area, taken as the simplest and most current measure of metabolically active body mass. This rTB, being the result of a volume divided by a surface, should have a linear dimension (such as a "height") and should be properly expressed in millimeters or centimeters; however, here we preferred to measure rTB in cubic centimeters per square meter so as to provide an easier and more familiar unit for clinicians.
Statistics
The prognostic value of rTB was investigated through regressions applied to the proportional-hazards model.16 A number of univariate and multivariate regressions were performed using no more than four to five factors each time, according to the most suitable proportion between number of recorded events and number of factors tested.17 In particular, the variables with a clear individual prognostic value at univariate analysis (actually, all those examined) were then grouped for separate steps of multivariate regression according to similarity and/or probable interrelationship as follows: general data (age, sex, performance status, general symptoms, and histology); data regarding tumor amount and distribution (stage, number of involved lymph node areas, bulky mass, and rTB); hematic prognosticators (ESR, Hb, LDH, and Cu); and serum proteins (Alb, To test the prognostic ability of rTB, multivariate comparisons were made not only with a number of currently used prognostic factors but also with the most recent (and probably the most powerful) composite index elaborated by the International Prognostic Factor Project (IPFP) for advanced HD.24 This index is known to give acceptable results even in early-stage patients,25,26 who constitute, however, no more than 40% of the present series. In the multivariate analyses, the fact that ß2-m was available in only 64 of the 121 cases led us to perform separate sets of calculations, either including or excluding this variable.
The median values of aTB and rTB in the 121 HD patients studied were, respectively, 175.1 cm3 (range, 4 to 985) and 102.6 cm3/m2 (range, 2.2 to 582.2). Figure 1, which shows the scattergram of aTB in relation to body-surface area, demonstrates that there is no relationship between aTB and patient body type. Table 1 lists the values of rTB recorded in relation to the main clinical characteristics presented at pretreatment staging. A relationship clearly exists between rTB and each of the clinical factors listed, but the most impressive ones are with systemic symptoms and bulky mass: rTB volumes are nearly two and four times higher, respectively, in patients who present B symptoms and bulky tumor.
In the multivariate analysis of prognostic value in relation to TTF, rTB surpassed every other currently used prognostic factor: age, sex, stage, histologic type, systemic symptoms, number of involved lymph node areas, Hb, Alb,  2, Cu, LDH, and KI. As listed in Table 2, only ESR and Fb level retained statistically significant prognostic values after consideration of rTB when ß2-m was excluded from the analysis. When ß2-m was included in the analysis, thus reducing the number of patients studied, the only other important factor besides rTB and ESR were ß2-m and KI, though with lower levels of statistical significance. Considering the administered treatments in the analysis (radiotherapy alone or chemotherapy alone or combinations of both) did not impair the value of rTB as the first prognosticator. Such a pivotal role was confirmed also in two distinct subsets of patients, either presenting or not presenting large mediastinal masses, respectively, thus demonstrating that rTB has an overwhelming prognostic effect on tumor bulk itself.
This leading prognostic importance of rTB was analyzed in comparison with the IPFP score, which has been demonstrated to integrate the seven clinical variables with the best predictive power in HD. Table 3 shows that rTB has a predictive power definitely higher than that of IPFP, which ceases to be statistically adequate when compared with rTB. Figure 2 graphically illustrates the superior prognostic discrimination allowed on the same population by rTB, categorized in three classes around two empirical threshold values (90 and 280 cm3/m2, respectively), as compared with the IPFP score.
The predictability of rTB from other simple and current clinical and laboratory data was rather unsatisfactory. Table 4 lists bulky mass, LDH level, and ESR as the parameters best related to rTB. Unfortunately, the R2 value, which expresses the amount of rTB variability explained in terms of the independent variables considered, is low and demonstrates that only an insufficient part of rTB (67%) can be predicted by bulky mass, LDH, and ESR. Therefore, at present, direct measurement of rTB seems to be unavoidable.
The primary importance of TB estimation in HD has already been demonstrated very clearly by Specht and Nissen in a few studies between 1986 and 1992.8,27-30 In this sense, the present data are a confirmation of their work, probably the first outside the Danish experience; however, two original points have been added here: first, the feasibility of direct TB evaluation through the imaging material now available from current staging procedures; and second, the considerable prognostic role of TB in comparison with not only every other commonly used factor but even the most recently devised multiple prognostic score. Some comments are needed to better clarify certain aspects. It must be clear that what we have tried to measure is the entire tumor, not just the strictly neoplastic component. It is well known that in HD tissue neoplastic cells are a variable but generally minor component of the tumoral lesion compared with the heterogeneous inflammatory portion. Specht8 was able to devise a scoring system for TB estimate, count the percent of neoplastic cells present in the diagnostic lymph node biopsy, and from these data extrapolate four ranks of truly neoplastic cell burden. We believe that such a calculation may be unnecessary for several reasons: the questionable reliability of the assumption that the percent of neoplastic cells found in the diagnostic lymph node is constant in every other involved site; the complexity and laboriousness of microscopic evaluation of the neoplastic component in the initial biopsy in order to ensure acceptable accuracy; the possibility of multiplying the inaccuracy of the TB estimate by that of the neoplastic cell concentration; and, above all, the actual dependence of the volume of an HD lesion on both the quantity of neoplastic cells and their specific functional ability to attract, stimulate, and accumulate the reactive cell component. As is well known, this reactive polymorphous cell population can be related more to the type and number of cytokines directly secreted or triggered by the Reed-Sternberg and HD cells rather than to the true number of these cells. There is evidence that many of the clinical manifestations we have learned to evaluate for therapeutic choice (ie, B symptoms, acute-phase laboratory tests) are also related to the complex cytokine milieu evoked by the neoplastic cells. Moreover, in everyday practice, all the clinical evaluations performed on involved sites necessary for management and follow-up are usually made on the basis of the volume of the lesions that can be recorded either through direct palpation or instrumental images, irrespective of the variable quota of the underlying neoplastic cells. Thus, when we measure the volume of a lesion, we are evaluating not only what is currently considered necessary and sufficient for clinical management, but also what is related to both the amount itself and the interactive functional property of the neoplastic cell component. Possible sources of inaccuracy in estimating TB volume, as it was performed in this study, may include the following:
We are fully aware of these possible sources of error that generally lead to an underestimation of TB, but the strongest arguments in favor of this measurement, inaccurate though it may be, are the confirmation of its excellent, dramatic prognostic power and the fact that the simplicity of the method can be improved further and easily standardized. First, we believe our method offers a relatively more direct, more easily reproducible, and better approximating technique for evaluating TB than the roughly semiquantitative estimate proposed by Specht.8 Second, we must emphasize that possible and even admittedly present evaluation inaccuracies cannot limit the primary prognostic value of TB assessment, which makes every other important prognostic factor hitherto known seem secondary. Indeed, even the most recent multiple prognostic index, the IPFP score, which integrates the significance of the seven best clinical parameters selected from more than 4,000 patients, becomes secondary in this patient series when compared directly with TB. Obviously, confirmation of this result is needed on larger patient populations. Much can be done to improve the accuracy of the TB estimate in the future. Many of the above-mentioned sources of inaccuracy (especially those in points 2, 3, and 4) seem to be easily correctable in a future prospective study by using a spiral CT scan, which includes the whole neck and bilateral inguinal area as well as the thorax, abdomen, and pelvis. This would represent a limited extension of the routine staging procedures but would avoid separate ultrasonographic evaluation of superficial lymph nodes. US might occasionally be retained—at the discretion of the radiologist—for a complementary evaluation of infradiaphragmatic organs, where it might offer some occasional advantage over CT scan. As to the limited sensitivity of CT scan (point 1), this problem might be overcome by single-photon emission computed tomography, which offers the same possibility of spatial reconstruction and measurement and would guarantee a more sensitive measurement of the patient’s TB if necessary. Moreover, the relationship between rTB and ß2-m must be explored more extensively. In conclusion, the very interesting prognostic value of TB in HD has been fully confirmed. A direct quantitative method for its estimation has been studied, one that is simpler and more easily reproducible than that described by Specht et al.8,27-30 From a prospective point of view, spiral CT scan from the neck to the groin, evaluated for TB assessment by a conscientious radiologist, can offer the clinician what is probably the most powerful prognostic tool available. Moreover, in the future, the knowledge of a patient’s TB might offer the possibility of evaluating re- sponse to therapy in terms of not only the adequacy of the drug doses given in relation to patient size, as is currently done, but also in relation to the size of the tumor he or she is carrying.
Supported in part by a grant from the Ministero dell’Università, Rome, and by the Fondazione "Adolfo Ferrata e Edoardo Storti," Pavia, Italy.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
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