Early-Stage Hodgkin Lymphoma
Genetic alterations and amplifications in the 9p24.1 locus have recently been found to be a defining genetic feature of cHL. Amplification of 9p24.1 has been associated with unfavorable outcomes. Amplification of 9p24.1 (which includes the loci encoding the PD-L1 and PD-L2 genes) is more common in patients with advanced stage disease and is associated with shorter PFS.23
A recent study attempted to integrate several different prognostic factors in cHL patients who were treated with ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) and underwent an interim PET (iPET) scan after 2 cycles of ABVD. Focusing on those with a negative iPET scan, it was found that expression of CD68 and PD-1 in microenvironment cells, and STAT1 negativity in HRS cells identified a subset of PET-2 negative patients with a 3-year PFS significantly lower than that of the remaining PET-2 negative population (64% versus 95%). The algorithm correctly predicted the response to treatment in more than half of the patients who had relapse or disease progression despite a negative PET-2 scan. It therefore appears feasible, using tissue biomarkers at diagnosis, to identify patients at increased risk for poor outcome, even if the iPET scan is negative.53
ROLE OF PET/CT IN ASSESSMENT OF RESPONSE TO THERAPY
PET/CT has been increasingly used for response assessment at various stages in lymphoma in recent years. Almost all types of lymphomas are fluorodeoxyglucose (FDG) avid; however, Hodgkin lymphoma is FDG avid in 97% to 100% of cases. In 2009, a 5-point scale was developed to score PET images with regard to treatment response, either partway through treatment (iPET) or at the end of therapy.54 It was recommended as the standard reporting tool at the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, and is thus now referred to as the Deauville score. A score of 1 is given if there is no uptake, 2 if the uptake ≤ mediastinum, 3 if > mediastinum but ≤ liver, 4 if uptake moderately higher than liver, 5 if uptake is markedly higher than liver and/or new lesions. X designates new areas of uptake unlikely to be related to lymphoma. In most trials, a score of 1 or 2 is considered a complete response and a score of 4 or 5 is considered a treatment failure. A score of 3 is sometimes considered a complete response, depending on the study. The Deauville criteria have been widely used in newer clinical trials utilizing response-adapted treatment as defined by PET response. PET/CT is recommended for staging and restaging at the end of therapy, in clinical practice, and clinical trials. Interim PET/CT scan, while commonly performed in clinical practice, is only recommended if the results will alter therapy (eg, if that information will result in the clinician omitting radiation therapy [RT] or altering the chemotherapy plan).
,Early studies of iPET showed that achieving PET negativity early in the course of treatment was strongly associated with PFS and overall survival.55 Subsequent studies confirmed the importance of achieving a negative iPET. As a result, considerable efforts have been put into designing response-adapted treatment approaches using iPET (see Treatment section), with some of these approaches now being listed in the National Comprehensive Cancer Network (NCCN) guidelines and being used in standard practice.
TREATMENT
EVOLUTION OF TREATMENT
The treatment of Hodgkin lymphoma has evolved over the past century, starting with the discovery of RT as effective treatment in the early 20th century. Long-term survival of patients with Hodgkin lymphoma treated with involved-field radiation therapy (IFRT) was first reported in the 1960s.56,57 Outcomes improved further with the introduction of combined modality treatment (CMT) using chemotherapy and RT, with the overall 5-year relative survival for patients with Hodgkin lymphoma (all stages) treated in 2006–2012 being 85.4% to 87.3%.3 Since the majority of patients are now cured with modern therapy, treatment-related complications have become an important competing cause of mortality. Recent studies have therefore focused on maintaining efficacy while reducing toxicities, and refining the process of selecting patients who might benefit from more aggressive therapy. While RT was the first treatment modality shown to be curative for Hodgkin lymphoma,56,57 multiple subsequent studies showed that CMT is superior to RT alone in terms of relapse-free survival.58–63 In the GHSG H8-F trial, the estimated 5-year event-free survival and overall survival rates were significantly higher after 3 cycles of MOPP-ABV (mechlorethamine, vincristine, procarbazine, and prednisone combined with doxorubicin, bleomycin, and vinblastine) plus IFRT than after subtotal nodal radiotherapy alone. The 10-year overall survival estimates were 97% and 92%, respectively (P = 0.001).64 As a result, CMT replaced RT alone as the standard of care for limited-stage Hodgkin lymphoma. However, for elderly or infirm patients, or those with other comorbidities making them poor chemotherapy candidates, RT alone may be a very reasonable option.65 More recently, an increasing body of evidence has accumulated to support the use of chemotherapy alone in early stage cHL. This literature has consistently shown that omission of RT is associated with a modest increase in relapse, without a clear compromise in long-term overall survival. For some patients, the trade-off in terms of avoiding radiation (and the associated late effects) may be worth the small increase in relapse risk, since long-term survival does not appear to be substantially worse with chemo-therapy alone. Table 3 and Table 4 provide a summary of recent key studies which have defined treatment options for early-stage cHL.48,66–71
