The treatment of non-Hodgkin’s lymphoma (NHL) continues to be imperfect. With incidence increasing and the chance of cure at less than 50%, an improved understanding of NHL is needed, including which patients will benefit most from various treatments. The American Cancer Society estimates that 53,900 new cases of NHL will be diagnosed in 2002, and 24,400 related deaths will occur. Both the incidence and mortality of NHL have been rising since the 1970s. Overall, survival rates are suboptimal, with 1-year survivals of 70% and 5-year survivals of only 51%.[2,3]
The ongoing effort to better understand NHL is reflected by the multiple modifications made to NHL classification systems over the past 2 decades. The World Health Organization (WHO) classification system is the most recently developed and is in line to replace the existing Working Formulation and Kiel classification systems.[4,5] The WHO classification reflects improvements in the understanding of the immune system, and is based on several factors, including histology, immune phenotype, genetic abnormalities, and clinical features.
Mitoxantrone (Novantrone) is a cytotoxic anthracenedione, similar in structure to anthracyclines such as doxorubicin(Drug information on doxorubicin). It inhibits topoisomerase II, interferes with RNA, and intercalates with DNA (resulting in strand breaks and cross-links)all of which lead to cell death. Mitoxantrone(Drug information on mitoxantrone) is not cell-cycle specific.[6,7] It was developed in the 1970s as a more tolerable alternative to anthracyclines. Early research established its activity alone and in combination with other chemotherapy agents against breast cancer, leukemia, and lymphoma. More recent studies have demonstrated its activity in the treatment of prostate cancer and in slowing the progression of multiple sclerosis.[7,8]
Specifically, the activity of mitoxantrone has been established against both follicular lymphomas and aggressive lymphomas, including diffuse large-cell lymphomas. In preliminary studies of follicular lymphoma, mitoxantrone at 14 to 18 mg/m² every 3 to 4 weeks yielded responses in previously treated patients (including those who had received doxorubicin), with complete response rates ranging from 6% to 16% and partial response rates from 38% to 56%.[9-11] Previously untreated patients with follicular lymphoma had slightly higher response rates, with a complete response rate of 29% and a partial response rate of 67%.
Patients with relapsed or refractory aggressive lymphoma responded to lower doses of mitoxantrone (12 to 14 mg/m² every 3 to 4 weeks). The complete response rate ranged from 0% to 30% and the partial response rate, from 12% to 63%. Some of these patients had received previous treatment with doxorubicin.[9,10,13-16] This review will evaluate the current use of mitoxantrone in NHL, paying special attention to dose as it relates to outcome.
Determining the optimal dose of mitoxantrone in NHL leads to a related question: What is the comparable dose of mitoxantrone and doxorubicin for use in NHL? The relevance of the question stems from the widespread use of doxorubicin in combination therapy for NHL, the high level of activity of both doxorubicin and mitoxantrone in NHL, and the fact that mitoxantrone is closely related to the anthracyclines pharmacologically.
Posner et al reported that in early comparative trials of mitoxantrone and doxorubicin in breast cancer, a 5:1 ratio of doxorubicin to mitoxantrone was chosen based on data suggesting that this ratio would yield equally myelosuppressive doses of the drugs. Thus, when comparing CNF (cyclophosphamide [Cytoxan, Neosar], mitoxantrone [Novantrone], fluorouracil(Drug information on fluorouracil) [5-FU]) to CAF (cyclophosphamide, doxorubicin [Adriamycin], 5-FU) in breast cancer, 10 mg/m² of mitoxantrone was compared to 50 mg/m² of doxorubicin. Single-agent comparisons used 12 to 14 mg/m² of mitoxantrone and 60 to 75 mg/m² of doxorubicin administered every 3 to 4 weeks.
As described later in this review, the doses of mitoxantrone in combination therapy for NHL have ranged from 10 to 12 mg/m². Given that 12 mg/m² represents a 20% increase in dose intensity over the lower dose, an increase of 2 mg/m² could be an extremely important difference if there is a significant dose-response curve at this dose range.
Moderate reductions in the dose intensity of doxorubicin have produced a striking decrease in treatment outcome for breast cancer patients. In the treatment of aggressive NHL, two studies found that 50 mg/m² of doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin HCl, vincristine, prednisone(Drug information on prednisone)) was superior to 10 mg/m² of mitoxantrone in CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisone),[19,20] and one study found the two regimens to be comparable.
In a fourth trial, CNOP was found to be comparable to CHOP when the dose of mitoxantrone was increased to 12 mg/m² and compared to 50 mg/m² doxorubicin. Similar results were observed in other regimens that substituted mitoxantrone, 12 mg/m², for doxorubicin, 50 mg/m², or mitoxantrone, 10 mg/m², for doxorubicin, 45 mg/m².[24,25] Therefore, the CNOP regimen should include mitoxantrone at 12 mg/m² if the goal is to achieve a therapeutic outcome comparable to that of CHOP with doxorubicin at 50 mg/m².
Patients receiving mitoxantrone experience less nonhematologic toxicity (alopecia, nausea, vomiting) than those receiving doxorubicin. This advantage may be particularly beneficial to patients such as the elderly, who may not tolerate full-dose doxorubicin therapy.
In early trials comparing mitoxantrone to doxorubicin (or CAF to CNF) in breast cancer, significantly lower rates of alopecia, nausea, vomiting, and stomatitis were reported in the mitoxantrone arm. In later trials in lymphoma patients, in which a mitoxantrone-containing regimen was compared to a doxorubicin-containing regimen, the severity of alopecia was significantly reduced in many studies[19,20,22-26] or reported to occur less frequently.[21,27] Similarly, nausea and vomiting were significantly reduced in trials comparing a mitoxantrone regimen to a doxorubicin regimen,[19,20] with one trial reporting significantly less mucositis in the mitoxantrone arm.
Studies have shown that the cardiotoxicity associated with mitoxantrone is qualitatively similar to that associated with the anthracyclines, and is more likely to appear after cumulative mitoxantrone doses of 160 mg/m², or 100 mg/m² if the patient has received previous anthracycline therapy. Although mitoxantrone may be less cardiotoxic than doxorubicin at comparable cumulative doses, caution is necessary because cardiotoxicity can also occur at low doses of mitoxantrone. Patients who have previously received doxorubicin or mediastinal irradiation, or who have underlying cardiac disease, will be at greater risk for mitoxantrone-associated cardiotoxicity.[6,7]