Hodgkin Lymphoma: Protecting the Victims of Our Success

They strapped the fair young maiden to the table as needles painfully pierced the soft flesh between her tender young toes. As if vivisection were not punishment enough for sins unknown, her spleen is stolen, her liver is assaulted, she is impaled, her skin is repeatedly burned, and her body is filled with poison while she is left to await an uncertain fate. Sounds like something from H.P. Lovecraft, does it not? But indeed, that was the ghost of Hodgkin past. Hodgkin lymphoma (HL) is considered one of the major success stories of modern oncology. Up to 80% of patients with advancedstage disease and more than 90% with limited disease achieve longterm disease-free survival with standard therapies, and most of those patients are cured. But the road to cure has been tortuous and torturing. Before the availability of computed tomography (CT) scans and now positron emission tomography (PET) –CT scans, clinical staging included a lymphangiogram, during which needles were inserted between the patient’s toes through which a blue dye was injected to visualize the lymphatic system. The discoloration of the feet was a near permanent reminder of the procedure. Radiation therapy was the primary therapeutic modality, with chemotherapy reserved for palliation of only the most advanced cases. The most potent of the drugs was nitrogen mustard, a derivative of the poisonous mustard gas from World War I and II, which, when used as chemical warfare, would result in skin ulceration, mucositis, blindness, and bone marrow aplasia. When lower doses of radiation failed to cure enough patients, the dose was increased to the point at which patients suffered from horrendous toxicity and, subsequently, a high frequency of acute leukemia despite being cured of HL. Because of inadequate imaging techniques, all but those without obviously advanced disease were subjected to staging laparotomy with splenectomy, the latter resulting in a life-long risk of fatal sepsis from encapsulated organisms. The first curative chemotherapy regimen included mechlorethamine mustard, vincristine, prednisone, and procarbazine, a regimen that was also associated with acute toxicities of profound nausea and vomiting (in the era before ondansetron), a substantial risk of leukemia and solid tumors, as well as almost universal sterility. Despite these aggressive measures, many patients still experienced relapse, whereas others succumbed to the long-term sequelae of therapy. In few instances in oncology has progress been so methodical. Total nodal irradiation became subtotal, then extended field, and then involved field. Randomized trials demonstrated that regimens such as doxorubicin, bleomycin, vinblastine, and dacarbazine were more effective than the mechlorethamine mustard, vincristine, prednisone, and procarbazine regimen, and without the secondary cancers and infertility. Recently, the German Hodgkin’s Lymphoma Study Group demonstrated that two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus only 20 Gy of radiotherapy (RT) may be adequate for 93% freedom from treatment failure in patients with earlystage disease. Data suggest comparable efficacy for involved nodal RT with, hopefully, a reduction in late effects. Recently, the availability of the exquisitely active brentuximab vedotin, a monoclonal antibodydrug conjugate, has generated hope that we may be able to reduce the amount of chemotherapy further, even in the front-line setting, and this possibility is the subject of planned clinical trials. Lymphangiograms have been supplanted by CT scans, and gallium scans by CTPET scans, negating the need for unnecessary and hazardous surgical exploration. Even the routine chest x-ray, one of the holdovers from the Ann Arbor staging system, is no longer needed because of the increased sensitivity of CT scans. For decades, patients have been treated with an arbitrary number of six to eight cycles of chemotherapy. Instead, the high negative predictive value of the CT-PET is being evaluated as a surrogate marker in risk-adapted clinical trials in an attempt to improve outcome by altering therapy in patients considered to be poor risk, and reducing the amount of therapy in those with lower-risk disease. Yet there is one last bit of torture that has persisted—the dreaded bone marrow biopsy. To adequately stage patients to deliver optimal therapy, assessment for potential bone marrow involvement has been considered mandatory for nearly all patients. The trephine is feared by patients who at one time were subjected to bilateral sampling, yet more recently to only a one-sided procedure. Over the years, a number of smaller studies and a meta-analysis have suggested that the use of PET-CT may obviate the need for a bone marrow biopsy in initial staging of HL. Nevertheless, the procedure may still be needed for non-Hodgkin lymphoma, in which there is a risk of involvement of the bone marrow with a histology discordant from the diagnostic lymph node biopsy. However, such is not the case in HL. A finding consistent among these studies is that no patients with advanced-stage disease have bone marrow involvement without other evidence of being stage IV or in the absence of disease-related JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 36 DECEMBER 2