2007 ANNUAL SITE STUDY HODGKIN S LYMPHOMA

Transcription

1 2007 ANNUAL SITE STUDY HODGKIN S LYMPHOMA SUSQUEHANNA HEALTH David B. Nagel, M.D. April 11, 2008

2 Hodgkin s lymphoma was first described by Thomas Hodgkin in It remained an incurable malignancy until the early 1960 s when the concept of extended field radiotherapy encompassing nodal regions above and below the diaphragm, in addition to the spleen and in some cases even the liver and lungs, was used with success in curing a percentage of patients stage I through III Hodgkin s disease. The development of systemic chemotherapy by DeVita and colleagues in the mid-1960 s with the development of MOPP chemotherapy enabled a percentage of patients with advanced Hodgkin s disease to be cured. By the 1980 s, MOPP had given way to ABVD chemotherapy and a number of patients were being treated with combined modality therapy utilizing various combinations of chemotherapy and radiation therapy in an attempt to increase the cure rate over what had been seen with single modality therapy. Success has been seen with combined modality therapy to the point that it has become the accepted treatment for both favorable and unfavorable stages I and II Hodgkin s disease and various subsets of stage III Hodgkin s disease, i.e. bulky mediastinum involvement. Staging of Hodgkin s disease is based on the Ann Arbor staging system with the Cotswolds modification. 1 In addition to this, a number of prognostic factors have been identified that are not a part of this staging system. These include: the number of involved regions, size of tumor mass (primarily mediastinal), B symptoms, age greater than 50 years, male gender, elevated ESR, cytology (mixed cellularity), anemia and low serum albumin. 2,3 These risk factors have been used in various combinations to separate patients into the following 3 groups: early stage favorable, early stage unfavorable, and advanced stage by the cooperative groups investigating treatment of Hodgkin s disease. 2,3 2

3 Our study encompasses the dates from January 1, 1990 through December 31, During the early part of this trial, stages I and II Hodgkin s disease were commonly treated with subtotal nodal radiotherapy alone. At the end of this period the same stages were treated either with chemotherapy alone or combined modality therapy usually involving initial chemotherapy followed by radiotherapy to involved sites of disease. The treatment for stages III and IV Hodgkin s disease during this period saw less change and remained either chemotherapy alone or combined modality therapy on a case-by-case basis. Controversies remain in the optimal treatment of the various stages of Hodgkin s disease, however, combined modality therapy has emerged as the standard preferred treatment for favorable and unfavorable early stage Hodgkin s lymphoma. 2,6,9,11 There is less agreement as to the optimum treatment strategy for those patients with advanced stage Hodgkin s lymphoma. 9 Our 63 analytic patients over 11 years at Susquehanna Health give us an average of approximately 6 new patients with Hodgkin s disease per year. We analyzed various aspects of the patient group including additional malignancies: those occurring prior to presentation of Hodgkin s disease and those that occurred after Hodgkin s disease treatment. The latter have frequently been termed secondary malignancies some of which may be attributed to the treatment, some of which may have developed irrespective of the treatment. Because of our small number of patients, we are not able to perform statistical analysis of this data, however, table 2 does show disposition of the malignancies occurring after the treatment of Hodgkin s disease in each patient. 3

4 Table 2 Second Primary Status Large Cell Lymphoma, Colon Alive and disease-free Larynx, Melanoma Alive and disease-free Colon Deceased from Colon CA Penis Deceased from ESRD Nerve Sheath Tumor Alive with disease Wilms, Kidney Deceased from other causes Tables 3 through 6 detail various attributes of our patient cohort. Table 3 shows the age at diagnosis exhibiting the bimodal peaks in age distribution characteristic of Hodgkin s disease. Table 4 shows that approximately two-thirds of our patients presented with multiple nodal regions involved with Hodgkin s disease. Table 5 shows nodular sclerosing is the dominant histology occurring in almost two-thirds of our patients with mixed cellularity found in the majority of the remaining patients. Indeed, lymphocyte predominance and lymphocyte depletion are uncommon pathologic entities. An additional 4 patients were found to have nodular lymphocyte predominant Hodgkin s disease (NLPHD), but these patients were not included in this analysis since NLPHD follows a distinctly different natural history and is excluded in most analyses of treatment of Hodgkin s disease. Table 6 shows the distribution of symptoms at presentation with stage II predominating in 46% of our patient cohort followed by stage III and IV, each representing approximately 20% of the cohort. 4

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6 Staging of Hodgkin s disease during this time period of 1990 to 2001 is represented in table 7. Ninety-eight percent of the patients had CT scans including chest, abdomen and pelvis, 71% of these patients had a gallium scan. Bone marrow biopsies 6

7 (table 8) were done in 86% of the patients. They were positive in 10%, negative in 76%, not performed in 11% and 3% unknown if it was performed. Treatment of Hodgkin s disease can be divided into 3 categories: chemotherapy, radiation therapy and combined modality therapy consisting of a combination of chemotherapy and radiotherapy. Combined modality therapy generally consists of several cycles of chemotherapy followed by different radiotherapy strategies which 7

8 evolved over the time of this study from subtotal nodal radiotherapy to extended field radiotherapy and most recently to involved field radiotherapy treating only the involved site with a small margin around it. Table 9 shows the 63 cases analyzed by treatment and arranged by stage. Three of the 63 patients received no treatment. Of the remaining 60 patients, 31 received chemotherapy, 7 received radiotherapy and 22 received combined modality therapy. Forty-nine patients treated achieved complete remission and 11 patients were never disease free. Twenty-five of 31 patients receiving chemotherapy treatment, 5 of 7 receiving radiation therapy and 19 of 22 receiving combined modality therapy achieved a complete remission. Thirty-four patients of the 49 complete responders remained disease free and 15 failed. Recurrence data is further delineated in the paragraph below table 9. The initial stage of disease for the fifteen patients who failed their first course of therapy was as follows: 3-IA, 3-2A, 1-2B, 2-3B, 1-4A and 5-4B. Fourteen of the 15 8

9 recurred in the same lymph node chain as at diagnosis. Ten of 25 chemotherapy, 2 of 5 radiotherapy and 3 of 19 combined modality therapy complete responders failed their first course of therapy. The average number of months to first failure in this recurrence group was 32 months from initial diagnosis. All of these patients received salvage therapy; either chemotherapy alone, radiotherapy alone or combined chemo/radiation modality. Six patients received therapy with a bone marrow transplant, 2 being still alive. Of these 15; 8 patients are currently disease-free, 6 are deceased from Hodgkin s lymphoma and 1 deceased from other causes. Survival data was examined for the 60 patients receiving treatment and graphed on tables 10, 11 and 12. Tables 10 and 11 show overall 5-year survival and disease-free survival respectively. To date 25 patients are deceased; 17 from this disease and 8 from other causes. Both graphs show superiority of combined modality therapy over either chemotherapy or radiation therapy alone. Table 12, detailing overall survival analyzed by AJCC stage, shows our stage I 5-year survival is lower than that seen for stages II through IV. We feel that this result is anomalous and may be explained by the small number of patients in this group (8) as well as their advanced age. Six of the 8 patients were age 49 or greater with an average age of Age greater than 45 is considered an adverse prognostic factor in the International Prognostic Score (IPS) system for Hodgkin s lymphoma. 3,4 In addition, only 3 of the 7 treated Stage I patients received combined modality therapy. 9

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11 Table 13 breaks down treatment of stage I and II patients by modality. This graph shows superiority in treatment by combined modality therapy over chemotherapy and radiotherapy only patients. 11

12 Analysis: Aside from our overall survival of this small group of stage I patients, comparison of our stage II, III and IV patients with the All NCDB Facilities observed 5- year survival table 14 and All Pennsylvania State Facilities observed 5-year survival Hodgkin s lymphoma table 15 is very similar for stage II patients, and is better than either of the comparison groups for stage III patients and stage IV patients. 12

13 Recent published literature of treatment for early stage Hodgkin s disease clearly favors combined modality therapy over either chemotherapy or radiotherapy alone. The 13

14 German Hodgkin s Study Group HD-10 study for patients with favorable Hodgkin s disease receiving 2 to 4 cycles of ABVD combined with involved field radiation therapy showed an overall survival of 97% and freedom from treatment failure of 94% at a median follow up of 4 years. 5 Another recent study was the EORTC-GELA H-8 trial, which treated early stage favorable and unfavorable patients with 3 cycles of MOPP- ABVD plus involved field radiation therapy. This showed a 5-year event free survival rate of 98%. The recommendation from this paper dated December 5, 2007 was for patients with early stage Hodgkin s disease to be treated with chemotherapy plus involved field radiation therapy as standard treatment. 6 The current NCCN guidelines also recommend combined modality therapy for early stage Hodgkin s disease. Future Directions: FDG-PET scanning has emerged as a powerful imaging tool for the staging of lymphomas and PET is now strongly recommended before treatment of Hodgkin s disease. It is now also being used for post treatment assessment since a complete response is required for cure of this disease. 7 Nearly all-ongoing trials of early stage Hodgkin s disease incorporate FDG-PET/CT for assessment of the response to treatment after 1 or 2 cycles of ABVD. 8 It is hoped that this information will lead to adaptive treatment strategies according to response by PET scan. Since our study preceded the general use of PET scanning for Hodgkin s lymphoma, none of the 63 patients in this study received PET scan during their initial workup and treatment. Future studies will continue to try to resolve various controversies in the treatment of Hodgkin s disease: 1. What is the optimal chemotherapy regimen and number of cycles in early and advanced Hodgkin s disease? 14

15 2. What is the optimal radiation therapy dose and extent of coverage in involved field radiation therapy? 3. What is the role of radiation therapy in advanced Hodgkin s disease? 9 4. Are there subsegments of favorable Hodgkin s disease that can be treated with chemotherapy only? How can adaptive therapy strategies be used with FDG-PET CT scanning after 1 to 2 cycles of chemotherapy? 8 6. What is the risk of second malignancy with the current radiation therapy utilizing involved field with the current dose recommendations of 20 to 30 Gy? 11 A recent article from February 1, 2006 in the JCO shows no second cancers observed in the CMT group with median follow up of 8.1 years, but longer term follow up is still needed to assess the risk of second malignancy in this group of patients. 11 Conclusions: Excluding our small group of stage I patients, the treatment of Hodgkin s disease at Susquehanna Health for stages II through IV compared very favorably with all Pennsylvania State facilities data and all NCDB facilities data for years 1998 through Due to the small number of our stage I patients and the fact that their average age at 54 placed them in a negative prognostic category, a comparison of our stage I patients with the larger databases is not valid. Although our number of patients in any one-treatment group is small, it is interesting to note the superiority in terms of local recurrence and overall survival and disease free survival of our combined modality group compared to chemotherapy or radiotherapy alone. FDG-PET/CT scanning should now be a standard part of the work-up of any patient presenting with Hodgkin s disease, and 15

16 should also be used as a follow up test to assure complete response to therapy. Mature data is still not available as to how PET scanning should be used during treatment to form adaptive treatment strategies. Until these data are available we should refrain from the use of PET scan for this purpose. Our own data is in agreement with the current recommendations by the NCCN 2 and recent literature showing a superiority of combined modality therapy in the treatment of early stage Hodgkin s disease. 5,6 16

17 References 1 Hodgkin s disease: Cotwolds meeting. The Journal of Medical Oncology. 1989; 7: Yahalom, J. Favorable early stage Hodgkin s lymphoma. NCCN March; 4 (3): International prognostic factors project in advanced Hodgkin s disease. New England Journal of Medicine. 1998; 339: Hodgkin s lymphoma in the elderly: A different disease in patients over 60. References Oncology. 21 (8): Diehl, V et al. Hodgkin s disease from pathology specimen to cure. Journal of Clinical Oncology. 2005; 21 (sup 1): abst Ferme, C et al. Chemotherapy plus involved-field radiation in early stage Hodgkin s disease. New England Journal of Medicine. 2007; 357: Revised response criteria for malignant lymphoma. Journal of Clinical Oncology. 25 (5): Hodgkin s disease from pathology specimen to cure. New England Journal of Medicine Nov 8; 357 (19): Yahalom, J. Don t throw out the baby with the bathwater: On optimizing cure and reducing toxicity in Hodgkin s lymphoma. Journal of Clinical Oncology Feb 1; 24 (4): Chemotherapy plus involved-field radiation in early stage Hodgkin s disease, letters to the editors. New England Journal of Medicine; 358 (7): Combined-Modality therapy versus radiotherapy alone for treatment of early-stage Hodgkin s disease: Cure balanced against complications. Journal of Clinical Oncology Feb 1; 24: