Development and application of modern statistical methods for studies of childbearing among lymphoma survivors

Lymphoma is a haematological malignancy commonly originating from B-cells. Each year more than 2,000 new cases are diagnosed in Sweden. Lymphomas are historically categorised into Hodgkin and non-Hodgkin lymphoma. Compared to other cancer forms, Hodgkin lymphoma has a very good prognosis and is especially affecting young adult individuals. Hence, survivors of Hodgkin lymphoma often have a long life ahead after finishing their treatment. But also, many non-Hodgkin lymphoma patients get diagnosed at young ages. Young lymphoma survivors often have not yet finished their family planning, leading to concerns about the impact of treatments and lymphoma on their childbearing. Hence, this thesis aims to investigate childbearing among lymphoma survivors, and develop and apply novel statistical methods to this end where needed.

Study I aimed to compare childbirth patterns between young adult classical Hodgkin lymphoma patients treated with intensive chemotherapy treatment (6-8 BEACOPP) and less intensive chemotherapy treatment (ABVD). We identified a cohort of lymphoma survivors diagnosed in Sweden, Denmark, and Norway to estimate hazard ratios and cause-specific cumulative incidence functions of childbirth in the presence of death as competing event, comparing the different treatment regimens. Our study showed that both childbirth rates and cumulative incidences of childbirths after diagnosis were similar in female classical Hodgkin lymphoma survivors treated with ABVD and 6-8 BEACOPP. However, male survivors treated with 6-8 BEACOPP had an estimated 15.9 percentage points lower chance of having children diagnosis compared to males treated with ABVD.

Study II aimed to investigate childbirth patterns among non-Hodgkin lymphoma survivors by clinical and histological subtypes. To this end, we utilised data from a matched cohort study of lymphoma survivors diagnosed in Sweden, Denmark, and Norway. Each lymphoma survivor was concurrently matched to 10 (Sweden and Denmark) or 5 (Norway) lymphoma-free comparators from the general population on birth year, sex, and country. We used Cox models to report time-varying hazard ratios, and flexible parametric models to estimate the mean number of childbirths in the presence of the competing risk of death. Overall, we found that non-Hodgkin lymphoma survivors had similar long-term childbirth patterns as their matched comparators, except for patients diagnosed with diffuse large B-cell lymphoma who had a slightly decreased mean number of childbirths up to 10 years after diagnosis.

Study III aimed to develop a parametric model for estimating the mean number of events in the presence of competing risks. For this we developed a model that jointly estimates the intensity process of the recurrent and competing event. This model can be used to estimate the mean number of events in the presence of competing risks as well as transformations of the mean number of event function, e.g., difference in the mean number of events and standardised versions thereof. We implemented our model in the R-package JointFPM, which is available on The Comprehensive R Archive Network (CRAN) and tested it under different scenarios in a simulation study. The model showed overall low bias and good coverage in situations in which the intensity function of the recurrent event does not depend on the number of previous events.

Study IV aimed to explore patterns of healthcare utilisation in children born to lymphoma survivors. For this, we identified all children born to lymphoma survivors diagnosed between 2000 and 2018 in Sweden and matched them on maternal age to 5 children born to lymphoma-free parents. We used tree-based scan statistic to identify disease and drug prescription clusters associated with increased healthcare utilisation at the p<0.05 threshold. We found that children born to lymphoma survivors had an overall increased rate of in- and outpatient visits as well as drug dispensations compared to children born to lymphoma-free parents distributed across a broad range of disease and drug groups.

In conclusion, we found that lymphoma survivors have good chances of having children even after treatment with intensive chemotherapy. Receiving intensive chemotherapy treatment is, however, substantially lowering the chance of having children for male classical Hodgkin lymphoma patients. Having children after being diagnosed with and treated for lymphoma is unlikely to negatively impact the offspring's health. Additionally, we developed and implemented a new parametric estimator of the mean number of events in the presence of competing risks, which offers a useful addition to standard time-to-event analysis.

List of scientific papers

I Joshua P. Entrop, Caroline E. Weibull, Karin E. Smedby, Lasse H. Jakobsen, Andreas K. Øvlisen, Daniel Molin, Ingrid Glimelius, Anna Marklund, Harald Holte, Alexander Fosså, Knut B. Smeland, Tarec C. El‐Galaly and Sandra Eloranta. ‘Reproduction Patterns among Classical Hodgkin Lymphoma Survivors Treated with BEACOPP and ABVD in Sweden, Denmark and Norway—A Population‐based Matched Cohort Study’. In: International Journal of Cancer 153.4 (15th Aug. 2023), pp. 723–731. https://doi.org/10.1002/ijc.34552

II Joshua P. Entrop, Caroline E. Weibull, Karin E. Smedby, Lasse H. Jakobsen, Andreas K. Øvlisen, Ingrid Glimelius, Anna Marklund, Thomas S. Larsen, Harald Holte, Alexander Fosså, Knut B. Smeland, Tarec C. El‐Galaly and Sandra Eloranta. ‘Reproduction Patterns among non‐Hodgkin Lymphoma Survivors by Subtype in Sweden, Denmark and Norway: A Population‐based Matched Cohort Study’. In: British Journal of Haematology 202.4 (Aug. 2023), pp. 785–795. https://doi.org/10.1111/bjh.18938

III Joshua P. Entrop, Lasse H. Jakobsen, Michael J. Crowther, Mark Clements, Sandra Eloranta and Caroline E. Dietrich. ‘Parametric Estimation of The Mean Number of Events in The Presence of Competing Risks’. [Manuscript]

IV Joshua P. Entrop, V. Wintzell, Caroline E. Dietrich, Ingrid Glimelius, Tarec C. El-Galaly, Karin E. Smedby and Sandra Eloranta. ‘Utilisation of Healthcare in Children Born to Lymphoma Survivors in Sweden’. [Manuscript]