Risk profile and outcome in Hodgkin's lymphoma: is obesity beneficial?

O. Landgren1,*, H. Andrén1, B. Nilsson2, A. Ekbom3 and M. Björkholm1

1 Department of Medicine, Division of Hematology, and 2 Units of Cancer Epidemiology and 3 Clinical Epidemiology, Karolinska Hospital and Institutet, Stockholm, Sweden

* Email: landgreo{at}mail.nih.gov

Great advances have been made in oncology with regard to diagnostics, prognostics and therapeutics. However, dosing of chemotherapy in most cancers is still being based on the estimation of body surface area (BSA) [log (body surface in m2)=0.425 log (weight in kg) + 0.725 log (length in cm)+ 1.8564]. BSA fails, however, to standardize the marked inter-patient variation in pharmacokinetics for most cytotoxic drugs [1Go]. If not adjusted for, overweight and obese individuals receive higher relative (to tumor burden) doses of chemotherapy compared with normal or underweight individuals.

Obesity has been identified as a significant risk factor for many cancers and, after tobacco use, may be the single strongest modifiable cancer risk factor. Despite detailed evaluation of prognostic factors in different cancers, our knowledge of the effects of adiposity (which is becoming a more common patient characteristic) in cancer diagnosis, treatment and survival, is limited. In studies of breast and colorectal cancer and of non-Hodgkin's lymphoma (HL), however, a high body mass index (BMI) has been associated with a worse prognosis and a greater risk for disease recurrence [2Go–4Go]. The present study was designed to assess the impact of BMI on prognosis in a well-characterized cohort of chemotherapy treated patients with HL with a long follow-up.

We retrieved clinical and biological data from patients diagnosed with HL >16 years of age and treated with chemotherapy within the framework of the Stockholm HL Study Group 1973–1994 with follow-up until 1 January 2001 or death (n=301; corresponding to 53% of the entire number of HL patients diagnosed in the same population-based catchment area during the study period). Included in the study were all HL patients treated with chemotherapy whose weight and length data at diagnosis were available [n=246 (82%); median age 37 years, range 16–86] [5Go]. Clinical characteristics of included patients were virtually the same as of those who were excluded because of lack of information. Univariate tests (Wilcoxon–Gehan) were conducted for the following variables: age, gender, clinical stage, BMI at start of chemotherapy, the independent seven International Prognostic Score (IPS) factors, histopathology, type of chemotherapy, relative dose intensity (RDI), and presence or not of B-symptoms and bulky disease at diagnosis. RDI was categorized according to a three-graded arbitrary scale. BMI was categorized as follows: obese (BMI > 30), overweight (25 < BMI < 30), normal weight (18 < BMI < 25), and underweight (BMI < 18); significant factors were then included in the multivariate Cox regression model. Cause-specific survival (CSS) was calculated from the time of diagnosis until the day of death from HL or treatment-related death. Overall survival (OS) was counted from the time of diagnosis until the day of death, irrespective of cause. The study was approved by the Karolinska ethics committee.

Fifty-four (22%) patients were classified as obese or overweight. The prognostic profile varied significantly (P <0.05) between the BMI groups, with a better prognostic profile among obese and overweight patients (Table 1). The RDI distribution did not differ between the BMI groups (data not shown). The 5-year CSS for the BMI groups was 100% (obese), 88% (overweight) and 75% (normal and underweight; normal and underweight patients did not differ with regard to CSS why they were analyzed together), respectively (Figure 1). The corresponding 5-year OS for the BMI groups was 100%, 79% and 70%, respectively. In the uni- and multivariate regression analyses, BMI was independently and significantly associated with CSS (Table 2).


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Table 1. Patient characteristics (n=246)

 


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Figure 1. Cause-specific survival in Hodgkin's lymphoma patient treated with chemotherapy with reference to body mass index (BMI) at diagnosis.

 

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Table 2. Multivariate analyses of clinical variables in relation to cause-specific survival

 
In the current series of HL patients treated with chemotherapy, adiposity was thus associated with both a significantly better prognostic risk profile, and an improved CSS in multivariate analysis. These results were somewhat unexpected, and appear to be in contrast to the limited number of reports on obesity in relation to outcome in breast cancer, colon cancer and non-HL patients treated with chemotherapy [2Go–4Go].

We have no clear explanation to the present findings. It may be, given the association between received drug dose and tumor response in HL [5Go], that BSA-based chemotherapy results in a relative ‘under-treatment’ of normal and underweight individuals. Other explanations for the improved survival among obese patients include residual confounding from other (and systematically more favorable, as indicated in Table 1) set-up of prognostic markers in HL. It may also be that our weight measurement did not accurately reflect pre-disease weight, but was influenced by (prognostically unfavorable) disease-related factors such as B-symptoms.

Notwithstanding our present inability to explain potential mechanisms underlying the association between adiposity and improved prognosis following chemotherapy in HL, we believe that the role of adiposity should be explored in prospective cohorts.


    Acknowledgements
 
We thank Dr Johan Askling for critical review of the manuscript. This study was supported by grants from the Swedish Cancer Society, the Stockholm County Council and Karolinska Institutet Foundations.


    References
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1. Gurney H. Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative. J Clin Oncol 1996; 14: 2590–2611.[Abstract]

2. Berclaz G, Li S, Price KN et al. Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience. Ann Oncol 2004; 15: 875–884.[Abstract/Free Full Text]

3. Tarella C, Caracciolo D, Gavarotti P et al. Overweight as an adverse prognostic factor for non-Hodgkin's lymphoma patients receiving high-dose chemotherapy and autograft. Bone Marrow Transplant 2000; 26: 1185–1191.[CrossRef][ISI][Medline]

4. Meyerhardt JA, Catalano PJ, Haller DG et al. Influence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma. Cancer 2003; 98: 484–495.[CrossRef][ISI][Medline]

5. Landgren O, Algernon C, Axdorph U et al. Hodgkin's lymphoma in the elderly with special reference to type and intensity of chemotherapy in relation to prognosis. Haematologica 2003; 88: 438–444.[ISI][Medline]





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