Rituximab Plus Dose–Reduced Cyclophosphamide,Mitoxantrone,Vincristine,and Prednisolone Are Effective in Elderly Patients with Diffuse Large B-Cell Lymphoma of the Thyroid

Introduction

P rimary thyroid lymphoma is a relatively rare disease, and is thought to comprise 1%–5% of all thyroid malignancies, with the incidence being in the range of 0.5 per 100.000 (1,2). In terms of histology, two subtypes are predominately encountered: mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL). A study on 53 patients with thyroid lymphoma (3) has further suggested a subdivision of DLBCL into pure DLBCL as opposed to DLCBL plus MALT lymphoma (in this series also termed high-grade MALT-type lymphoma), with the latter being thought to have a worse prognosis (3 –6).

There is a female predominance in patients with thyroid lymphoma, and all histological subtypes have been shown to be associated with the presence of chronic autoimmune (Hashimoto's) thyroiditis (4). In the largest series to date reported by Derringer et al., lymphocytic thyroiditis was documented in 94% of 108 cases (4), suggesting a potential evolution from chronic antigenic stimulation.

According to the rarity of the disease, only few large series exist on the optimal management. Derringer et al. have reported on 108 patients with various histologies, all of who underwent surgery followed by chemotherapy in 15%, radiotherapy in 18%, or combined radiochemotherapy in 42% (4). This is also in keeping with a series from Korea, in which 63% of 44 patients studied had undergone thyroidectomy as a part of the management (5). In a recent series including 26 patients with primary thyroid lymphoma, Thieblemont and coworkers (6) have reported a more histology-oriented approach, with patients found to have DLBCL being given CHOP-like chemotherapy without extensive surgery. However, data on chemotherapy alone are still scarce in the literature, and little information on the combined use of the anti-CD20 antibody rituximab (R) plus chemotherapy has been published to date.

In this article, we present our experience with three elderly patients judged either inoperable or unfit for surgery, who underwent therapy with R plus dose–reduced chemotherapy with cyclophosphamide, mitoxantrone, vincristine, and prednisolone (R-CNOP).

Patients and Methods

Three consecutive elderly patients aged 86, 88, and 93 years with DLBCL of the thyroid underwent systemic therapy with R plus dose–reduced CNOP. All three patients were women, and presented either with a rapidly enlarging cervical mass (patients 1 and 2) or with dyspnea, slight stridor, and dysphagia (patient 3). Cervical ultrasonography disclosed a tumor arising from the thyroid in all cases, and additional computed tomography scan of the cervical region performed in one patient (patient 3) also suggested the presence of involved local lymph nodes along with impression of trachea and esophagus. As patients 1 and 2 were deemed unfit for surgery due to poor general condition along with impaired cardiac function in one patient, a needle biopsy was performed for diagnosis. In the third case (patient 3), a fine-needle biopsy had only suggested the diagnosis of lymphoma, and open surgical biopsy was performed, though the tumor was rated inoperable. The latter patient also disclosed a long-standing history of autoimmune thyroiditis and had been on medication with L-thyroxine for 11 years. Both other patients had normal thyroid function and normal antibody titers. An unequivocal diagnosis of DLBCL without a MALT lymphoma component was established in all three cases, and patients were referred for further therapy at our department. Apart from cervical ultrasonography, staging consisted of computed tomography scan of thorax and abdomen, whichdisclosed no lesions suggestive of additional sites of involvement. No 18F-fluorodeoxy-glucose-positron emisssion tomography (FDG-PET) scan was done in any of the patients, and none of the patients underwent a bone marrow biopsy.

Treatment consisted of R 375 mg/m² intravenously (i.v.) on day 1, cyclophosphamide 750 mg total i.v. on day 2, mitoxantrone 8 mg total i.v. on day 2, vincristine 1 mg total i.v. on day 2, and 100 mg oral prednisolone on days 1–5 (R-CHOP). Premedication consisted of 1000 mg oral paracetamol and intravenous antihistamines on day 1 and a 5HT3-receptor antagonist before administration of chemotherapy on day 2.

Results

Treatment was performed as scheduled in all patients; two patients received six courses of therapy, and one patient was given eight cycles due to the presence of lesions suggestive of residual lymphoma after six courses of therapy. Tolerance of treatment was excellent, with side effects being mostly mild and not interfering with application of therapy as planned. One patient had leukocytopenia grade III after the second cycle of therapy, and thus was put on prophylactic granulocyte colony stimulating factor (G-CSF) for the following therapies. Another patient developed anemia WHO grade II after cycle number 6 and was given darbepoietein once weekly for the further two cycles. Two patients developed mild nausea/emesis, and two patients showed infectious episodes not related to leukocytopenia. One patient had upper urinary tract infection, which required application of parenteral antibiotics, whereas another patient was found to have bronchitis and treated with an oral quionolone.

Symptomatic improvement of dyspnea and dysphagia was seen in patient 3 after two cycles of therapy, and all three patients developed a complete remission (CR) of their lymphoma as judged by radiological restaging after three courses in all cases. Treatment was discontinued after six courses in two patients, whereas one had to be given eight courses for radiological CR. All three patients were alive and without signs of recurrence 16, 19, and 25 months after finalization of therapy.

Discussion

Thyroid lymphoma is a relatively rare disease, which has been reported to be associated with chronic autoimmune thyroiditis/Hashimoto's thyroiditis. The most common histological subtypes are marginal zone B-cell lymphoma of the MALT (MALT lymphoma) and DLBCL, which is characterized by rapid growth and an aggressive clinical course. Accordingly, Thieblemont and coworkers (6) have reported a probability of 5-year overall survival of 44% for patients with DLBCL as opposed to 100% for other subtypes of lymphoma arising in the thyroid. Similar findings have been documented in a series from Korea, as only 53% of patients with DLBCL were reported to achieve a CR following various forms of therapy, whereas 100% of patients with MALT lymphoma showed CR after treatment (5).

Little prospective data exist on the management of primary thyroidal DLBCL, and most authors have advocated an aggressive multimodal approach including debulking surgery, anthracycline-containing chemotherapy, and sometimes radiotherapy. In recent years, however, Meyer-Rochow and coworkers have found a change in the role of surgery, with a shift from radical surgery to open biopsy as a diagnostic procedure in a substantial percentage of patients (7). However, limited information on the activity of systemic treatment without prior thyroidectomy exists. An analysis of the subgroup of 13 patients with thyroid DLBCL presented by Thieblemont and coworkers (6), nevertheless, shows that only 8/13 patients developed a CR after CHOP-like chemotherapy, whereas 5 achieved only a partial response (PR). In addition, one out of eight patients in CR relapsed 1 year after completion of therapy. One of these patients underwent therapy with CHOP plus the monoclonal antibody R in this series, as did two patients with DLBCL of the thyroid in a recent report (8). Apart from this, no data have been reported to date on the combined use of R plus chemotherapy in DLBCL of the thyroid although R plus chemotherapy has become standard treatment in almost any subtype of B-cell lymphoma.

In keeping with the current literature reporting a marked predilection for thyroid lymphoma in female patients, our three patients were women, and one had a long-standing history of chronic autoimmune thyroiditis. No features of MALT lymphoma were detected in any of our patients. In view of the advanced age and the comorbidity, however, two patients were judged unfit for surgery and the disease was diagnosed by needle biopsy, whereas the lymphoma was deemed unresectable in the third patient, in whom the disease had been diagnosed by excisional biopsy.

All three patients undergoing treatment with dose-reduced R-CNOP at our institution obtained a CR, and all three patients are alive without disease recurrence 16–25 months after completion of therapy. These results are encouraging, as all three patients tolerated treatment well without relevant side effects in spite of their advanced age and decreased performance status. Toxicities were mainly hematological, and consisted of leukocytopenia grade III (which could be prevented by prophylactic administration of G-CSF for the following cycles) and anemia grade II in one patient each, along with mild nausea/emesis in two cases. One patient was hospitalized for parenteral antibiotics due to an upper urinary tract infection, which was not related to an episode of leukocytopenia.

These data further contribute to the scarce body of evidence that R plus chemotherapy (even at a reduced dose) might be highly effective in patients with DLBCL of the thyroid and is a good treatment option for elderly and unfit patients. In view of the relatively sobering results obtained with chemotherapy alone, this approach appears to promising in this subgroup of patients with DLBCL.