Impact of Time from Diagnosis to Initiation of Curative-Intent Chemotherapy on Clinical Outcomes in Patients with Hodgkin Lymphoma
Authors: Brooks Edward G. , Connors Joseph M. , Sehn Laurie H. , Gascoyne Randy D. , Savage Kerry J. , Shenkier Tamara , Klasa Richard , Gerrie Alina S. , Skinnider Brian , Slack Graham , Villa Diego 
Published: October 2019

Abstract

Introduction
Hodgkin lymphoma is a highly curable lymphoid malignancy when treated with multi-agent chemotherapy regimens such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The optimal timing of curative intent chemotherapy and the impact of treatment delay on clinical outcomes in Hodgkin lymphoma are currently unknown.

Patients and Methods
Adult patients diagnosed with Hodgkin lymphoma in British Columbia (BC) between January 1999 and December 2010 were identified in the BC Cancer Agency Centre for Lymphoid Cancer Database. Patients were included if they received at least one cycle of ABVD with curative intent. Patients treated with regimens other than ABVD and those treated with palliative intent were excluded. Additional demographic data were obtained from the BC Cancer Registry. Chemotherapy administration data, including drugs, dates administered, and treatment center, were obtained from the BC Cancer Agency provincial pharmacy database. Time to treatment initiation was defined as the time between the date of definitive histological confirmation of Hodgkin lymphoma and date of the first dose of ABVD. We then evaluated the effect of time to treatment initiation on overall survival (OS) and progression-free survival (PFS) at 5 years.

Results
A total of 879 patients were identified: 110 (13%) received ABVD within 2 weeks of diagnosis, 260 (30%) within 3 – 4 weeks, 405 (46%) within 5 – 8 weeks, and 104 (12%) beyond 8 weeks. Inpatient chemotherapy, elevated LDH, poor performance status, advanced stage, B symptoms, and bulky disease were all associated with treatment initiation within 2 weeks (p<0.01 for all factors). Age >45 and nodular lymphocyte predominant histology were significantly associated with treatment initiation >8 weeks (p<0.01 for all factors). Residence in a rural location at the time of diagnosis or the need to travel more than 200 km in order to receive initial chemotherapy were not associated with time to treatment (P = 0.26 and P = 0.90, respectively). Reasons for treatment initiation >8 weeks included systematic delays in the process of referral, staging, and scheduling of treatment (n=66), uncontrolled comorbidities (n=13), patient refusal of earlier treatment (n=9), pregnancy (n=5), revised pathological diagnosis (n=4), unknown cause of delay (n=4), and social or substance abuse factors (n=3).
With a median follow-up of 5.6 years (range 1 month – 14 years) in living patients, the 5-year OS estimates were 90% (standard error (SE) 3%) for time to treatment<2 weeks, 93% (SE 2%) for 3-4 weeks, 92% (SE 1%) for 5-8 weeks, and 84% (SE 4%) for >8 weeks (P = 0.012). Five-year PFS estimates were 82% (SE 4%) for time to treatment<2 weeks, 79% (SE 3%) for 3-4 weeks, 86% (SE 2%) for 5-8 weeks, and 84% (SE 4%) for >8 weeks (P = 0.198). In multivariate analysis, age, gender, performance status, stage, and time to treatment were significantly associated with OS, while only age and stage were significantly associated with PFS.

Conclusions
In a publicly funded healthcare system with universal access to cancer treatment and standardized diagnostic review, initiation of ABVD beyond 8 weeks appears to be associated with worse OS but not PFS. Reasons for treatment delay in this group are heterogeneous and may be responsible for the detrimental effect on OS. Nonetheless, clinicians should make every effort possible to initiate curative-intent chemotherapy as soon as a diagnosis of Hodgkin lymphoma is established.

Disclosures:
No relevant conflicts of interest to declare.