Treatment of the patient with diffuse large B-cell lymphoma with medical co-morbidities: Newer therapies needed

Recent improvements in the treatment of diffuse large B-cell lymphoma (DLBCL) have been achieved, thanks to the addition of the monoclonal antibody rituximab to chemotherapy [1-4]. In three different studies, rituximab-chemotherapy combinations improved the overall response, failure-free survival, and overall survival rates for patients younger than 60 years with good prognostic features by the Age-Adjusted International Prognostic Factors Index (IPI), and in older patients with any risk factors. However, these prospective randomized studies included only patients who had no other co-morbid conditions. Although investigators performing these trials demonstrated improvement in the outcome for patients who receive treatment with curative intent, they did not provide information about how many patients actually did not qualify for such therapy and received only palliative treatment or no treatment at all for this potentially curable disease.

In their study Hasselblom and colleagues identified 535 patients with DLBCL from the population-based Regional Lymphoma Registry of the Western Sweden Health Care Region who were enrolled from January 1995 to December 2000 [5]. Complete casebook data was available in 525 (98%) of these patients. Patients were separated into two groups: in one, patients received curative intent therapy, and in the other, patients received only palliative care. Those in the first group were treated with various anthracycline-containing combination chemotherapy regimens. If the disease relapsed, they received standard salvage regimens, with high-dose chemotherapy, and stem cell transplant was offered when indicated.

After careful evaluation of their data, the authors concluded that male gender was an adverse prognostic factor. There was no significant difference in the number of male patients in the palliative care group (48%) compared with the curative intent group (55%). The authors found lower response and progression-free survival rates in male patients when compared with females. These results contradict those reported for aggressive lymphomas according to the International Non-Hodgkin's Lymphoma Prognostic Factors Project Model where no differences were found in complete response (p = 0.849), relapse-free survival (p = 0.112), and overall survival rates (p = 0.455) for males compared with females [6]. The reasons for the differences between these two studies are unclear. Males may not tolerate therapy as well as females. Males may have more serious co-morbidities. Also, males may have other adverse features not recognized because of the inherent problems associated with collection of data in this retrospective review.

More importantly, curative intent therapy was offered to only 376 (70%) of all patients; 30% received only palliative care or no treatment at all, representing a very high number of patients who died with disease. Also, only 88% of the patients who received curative intent therapy actually completed their intended treatment. These two groups of patients, those who undergo little treatment and those who discontinue therapy early, represent a substantial number of patients who were considered undertreated.

Incidence of undertreatment varies among different publications. In the Eindhoven Cancer Registry in the Netherlands, investigators found that only 89% of patients younger than 60 years and 77% of patients older than 60 received anthracycline-containing regimens [7]. In another study from the Comprehensive Cancer West registry in the Netherlands, investigators collected data from 1981 to 1989; only 63% of patients in this study received systemic therapy, 41% with anthracycline-containing regimens, and 22% without this drug [8]. The low percentage of patients receiving systemic treatment in these two studies may be related to current practices at the time of the studies and other unknown factors.

In the current study, only 9% of the patients in the palliative care group were alive after 5 years. Interestingly, 118 (22%) of the patients in this study were 80 years or older, 26 of whom were in the curative intent group, representing 7% of this population. However, 92 patients, or 58% of those in the palliative care group, were 80 years or older. Co-morbid illnesses are more frequent in these older patients, and clinicians may have decided to withhold curative intent therapy based upon factors that are still unclear. In the United States, many “unfit” patients also never seek medical attention from physicians at tertiary centers and may be treated by primary care providers, often precluding evaluation for enrollment on clinical trials. For this reason, the real number of patients who would not qualify for curative intent treatment remains unknown [9]. Patients older than 80 years were excluded from the GELA study, and this group of patients represented only 8% of those in the ECOG 4494 study [2],[4]. Data from the latter group of patients have not been reported.

Further studies are needed to define strategies for the patient who is deemed incapable of tolerating effective therapy for DLBCL. Such studies should investigate the use of various supportive care strategies, including growth factors, replacement of anthracycline by less cardiotoxic medications, consolidation with radioimmunotherapy, or other new targeted therapy drugs to improve the outcome of these patients.