Journal of Neuro-Oncology 14: 271-275, 1992. O 1992 Kluwer Academic Publishers. Printed in the Netherlands.

Clinical Study

Primary central nervous system lymphoma: a role for adjuvant chemotherapy

Marc C. Chamberlain 1 and Victor A. Levin2 Brain Tumor Research Center, Department of Neurological Surgery, University of California School of Medicine, San Francisco, San Francisco, California 94143, USA; 1Present address: University of California, San Diego, Department of Neurosciences, San Diego, CA 92103, USA; 2Present addres: University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA

Key words: adjuvant chemotherapy, CNS, lymphoma, primary Summary

Sixteen immunocompetent patients, 10 of whom were previously reported, with primary non-Hodgkins lymphoma of the central nervous system (PCNSL) were treated and followed longitudinally by the Neurooncology Service at the University of California, San Francisco (UCSF) and the University of California, San Diego (UCSD). After undergoing surgery (biopsy or resection), these patients received radiation therapy (RT) with hydroxyurea (HU) followed by adjuvant chemotherapy with the combination of procarbazine, CCNU, and vincristine (PCV) as previously reported. All patients ultimately died of progressive recurrent PCNSL. Toxicity using the HU + RT followed by PCV schedule was tolerable. Median and quartile survival data (41 and 65 months, respectively) suggest efficacy for this chemotherapy schedule and further emphasizes a role for adjuvant chemotherapy in the primary treatment of PCNSL.

Introduction

Methods

We have previously reported on the results of 10 patients with primary CNS lymphoma [1]. These patients were treated following surgery with radiotherapy (RT) and hydroxyurea (HU), both a radiosensitizing and lymphocidal chemotherapeutic agent, followed by procarbazine, CCNU and vincristine (PCV). At the time of initial reporting the majority of patients had not manifested tumor progression. The present report extends our previous experience with the inclusion of 6 additional patients and, in addition, has followed all patients until death due to recurrent PCNSL.

Sixteen consecutive immunocompetent patients (defined as patients without Acquired Immune Deficiency Syndrome [AIDS] or congenital immunodeficiencies or patients requiring immunosuppressant drug therapy) with primary CNS lymphoma and a Karnofsky performance status >60 who were seen by the Neuro-Oncology Service at UCSF (10/16 patients) and UCSD (6/16) were followed from January 1977 through February 1991. Diagnosis was confirmed by surgery in 14 patients and at postmortem examination in 2. All patients had B cell lymphomas, either large cell or immunoblastic subtypes. All patients received 55 to 62 Gy of brain irradiation given (RT) in 25-34 fractions of 1.8 to 2 Gy each within four weeks of diagnosis. Similar to our previous report [1], during RT,

272 hydroxyurea was given orally at a dose of 300 mg/m2 every six hours, every other day (Monday, Wednesday, Friday). PCV chemotherapy was begun 2-4 weeks after the completion of RT. CCNU (110 mg/M 2) was given orally on a day 1, procarbazine (60 mg/M 2) on days 8 through 21 (oral administration), and vincristine (1.4 mg/M 2intravenous administration) on days 8 and 29. This cycle was repeated every 6-8 weeks for one year or until the tumor progressed. Dose modifications were made in patients who had myelotoxicity according to criteria established by the Northern California Oncology Group [2].

Evaluation of response

The evaluation consisted of a neurological examination and a contrast-enhanced magnetic resonance (MR) or computerized tomographic (CT) brain scan as previously reported [1]. The response to treatment was determined on the basis of sequential evaluations performed after completion of RT and before each course of chemotherapy. Steroid (dexamethasone) doses were kept at the lowest value patient neurological signs and symptoms permitted. The response to treatment, was categorized as follows: Complete response (CR) was defined as complete disappearance of tumor; partial response (PR) as -> 50% decrease in tumor volume defined by contrast enhanced cranial MR or CT imaging; stable disease (SD) as < 50% tumor reduction; and progressive disease (PD) as -> 25% increase in tumor volume or the appearance of new areas of tumor.

Results

The clinical data on the 16 immunocompetent patients with PCNSL is summarized in Table 1 (patients 1-10 previously reported). The patients were 11 to 65 years old (median, 52 years) and survived 7 to 81 months (median, 41 months). All patients died of recurrent CNS tumor without evidence of

extraneural lymphoma. There were 10 males and 6 females in the series. Twelve of 16 patients responded to therapy (CT/ MR response) with resolution of contrast-enhancing masses following RT (complete response); however, regions of nonenhancing hypodensity often persisted following therapy (8/16). Four of 16 patients had a partial response following RT. Following radiation therapy, all patients were on stable or decreased steroid doses (mean 4 mg, range 0-16 mg/day). Performance status was maintained in all patients during follow-up except in a single patient who deteriorated during treatment (KPS = 40). Four patients with residual lesions, evaluable by cranial CT/MR, demonstrated a complete response to PCV chemotherapy. No hematologic toxicity was seen with H U however, 3/16 patients complained of nausea without vomiting felt to be attributable to HU. Myelosuppression was modest with PCV chemotherapy (median nadir white blood cell count 2100/mm3; range 1100--4300/mm3: median nadir platelet count 81,000/mm3; range 28156,000/mm3). Dose reduction (decrease in both CCNU and procarbazine dose by 25%) was required in 12 of 73 cycles of therapy. No episodes of neutropenic fever, transfusion or chemotherapyrelated deaths occurred. All patients died of progressive central nervous system disease (12 parenchymal; 3 parenchymal and leptomeningeal; 1 parenchymal and orbital). No patient at time of death had clinical evidence of systemic lymphoma. The median and quartile survival times for the 16 patients were 41 and 65 months respectively.

Discussion

Primary CNS non-Hodgkins lymphomas are rare tumors that represent 0.5% to 1.2% of all CNS tumors and about 2% of all lymphomas [3-6]. Primary CNS lymphomas account for > 90% of all parenchymal CNS lymphomas, whereas the overwhelming majority of leptomeningeal lymphomas arise from metastatic systemic non-Hodgkins lymphomas. Patients with acquired immunodeficiency syndrome, patients taking steroids (especially

273

those with collagen vascular disease), transplant recipients, and patients with primary immunodeficiency syndromes are all at risk for primary CNS lymphoma [3]. Immunosuppression, either acquired or congenital, is a common characteristic of these groups. Primary CNS lymphomas are more common in males than females (1.5 : 1) and occur over a wide age range; the peak occurrence is in the 4th to 6th decades. The average time from the onset of the disease to diagnosis is 2 to 3 months. The presenting symptoms may be compressed into four categories (listed in decreasing frequency of occurrence); 1) Those associated with increased intracranial pressure, such as nausea, vomiting and headaches; 2) those associated with deficits in higher cortical function, including dementia, change of

personality and psychiatric manifestations; 3) focal neurologic deficits; and 4) new onset of seizures. Characteristic brain CT findings include: isodense to slightly hyperdense lesions on the unenhanced scan; a variable amount edema and associated mass affect that is typically less than expected for the size of the lesion; homogeneous enhancement; ill defined or blurred tumor margins not respecting the anatomic boundaries; frequent crossing of the midline; bilaterally and often symmetric lesions; and a predilection for basal ganglia, thalami, corpus callosum and periventricular white matter [4]. Reports in the literature suggest that magnetic resonance imaging with gadolinium-enhancement is more sensitive in evaluating patients with primary CNS lymphoma compared to brain CT imaging [8]. The role of staging myelography is not clear from the available literature, and present

Table 1. Patient characteristics, treatment, and outcome

Patient 1o 2°

Age

Surgery

R T (WB/T/SC)

Chemotherapy

59 11

STR STR

6000/ -- / -- + H U 6000/-- /-- + HU

PCV+ PCVx

2 1

Survival (mos) 7, D R

BCNU x 1

3° 4°

43 62

5°

56

STR PM

4500/6120/ -- + H U 4500/6120/ -- + H U

M G B G × 6* Thiotepa × 6 IO* PCV x 1 PCV x 4

STR

4700/5600/ -- + H U

BCNU × 1

52, D R

STR PM STR STR

6000/-6000/-5044/5040/ --

PCVx PCVx PCV× PCV ×

ll, ll, 60, 70,

STR GTR

3500/5500/2500 + H U 6 0 0 0 / - - / -- + H U

PCV x 6 PCV× 4

38, D R 44, D R

BX

6000/-- /-

PCV×

48, D R

46, D R 8, D R

IMP* 6°

65

7° 8° 9°

52 54 58

10 ° 11 • 12 •

23 24 48

/-- + /-- + /-- + /3060 +

HU HU HU HU

+ HU

1 4 7 2

6

DR DR DR DR

13 •

52

BX

6 0 0 0 / - - / -- + H U

H D MTX* PCVx 3

14 • 15 •

54 49

BX BX

6000/-- /--

+ HU

PCVx

6

30, D R

6200/ -- / - -

+ HU

PCV× 6 H D MTX

38, D R

16 •

52

BX

6100/-

+ HU

PCV×

47, D R

/--

6

24, D R

H D MTX

Legend: o = Patients treated as UCSF; STR = Subtotal; G T R = Gross total resection; BX = Biopsy; PM = Postmortem diagnosis; I M P = 1-125 implant; D R = Death, disease related; M G B G = Methyl G A G ; * = Salvage therapy; WB = Whole brain irradiation; T = Tumor irradiation; SC = Spinal cord irradiation; PCV = Procarbazine, C C N U , Vincristine; H D MTX = High-dose methotrexate; H U = H y d r o x y u r e a ; • = patients treated at U C S D ; IO = Intra-Ommaya.

274 indications for its use would be dictated by evidence of clinical involvement [9]. Although histopathological analysis of tumor tissue is the standard method of diagnosis, several other criteria can be used to diagnose primary CNS lymphoma. These criteria include: evidence of concurrent ocular lymphoma [4, 6, 10]; the presence of malignant cells in vitreous fluid or CSF [6, 11]; multifocal, deep subcortical nuclear, or corpus callosum lesions on CT/MR brain scan [6-8]; hyperdense lesion(s) with dense homogenous contract enhancement on CT/MR brain scan; and responsiveness to the administration of steroid or radiation therapy [13-16]. Neuroradiographic appearance and responsiveness to steroids may suggest a diagnosis of PCNSL however, except for positive cytological findings, these criteria in isolation are nonspecific and alternate diagnoses cannot be confidently excluded. Given the low operative mortality associated with computer-assisted stereotactic biopsy, we advocate precise pathologic diagnosis to facilitate the choice of appropriate therapy. A number of chemotherapeutic regimens have been evaluated in the treatment of immunocompetent patients with primary CNS lymphoma both in the adjuvant and recurrent setting [1, 3-6, 12-17]. Given the large number of drugs active against extraneural non-Hodgkins lymphoma, it is not surprising to find a variety of drugs employed against primary CNS lymphoma. In that there are no phase III studies comparing chemotherapeutic regimens in primary CNS lymphoma, single arm studies are best compared by evaluating time to tumor progression and patient survival. In this regard, radiation therapy plus hydroxyurea followed by sequential PCV chemotherapy compares favorably to other regimens using differeing chemotherapies and more favorably than radiation therapy alone ]4-6, 13-17]. Until recently, radiotherapy, either whole brain or crainospinal irradiation, was considered the standard adjuvant therapy for patients with PCNSL. This statement remains true for immunocompromised patients (i.e. AIDS-related PCNSL) however, numerous authors have demonstrated a survival advantage for immunocompetent patients with PCNSL treated with both systemic chemotherapy and radiotherapy [1, 12-17]. At pre-

sent it is unclear whether chemotherapy alone may be sufficient to treat primary CNS lymphoma, thereby obviating the need for radiation therapy, or alternatively, radiation therapy may be delayed and used as consolidative therapy at potentially a reduced dose. Both approaches have been utilized though never in a comparison study [16, 17]. In conclusion, adjuvant chemotherapy in the treatment of primary CNS lymphoma in immunocompetent patients given following radiation therapy appears to meaningfully prolong patient survival. Unfortunately, even when utilizing this combined modality therapy, therapy appears to be palliative and not curative.

Acknowledgements This research was supported in part by HEW Grant CA-13525 and the American Cancer Society Regular Clinical Fellowship. I would like to especially thank Sarah Sepulveda for her secretarial and editorial assistance.

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