Modern PET-Guided Radiotherapy Planning and Treatment for Malignant Lymphoma.

Malignant lymphoma comprises a broad spectrum of diverse entities originating from different types of lymphocytes. In the last century, successive improvements of treatment possibilities have led to an continuous amelioration of patient prognosis from lethal outcome to high rates of disease control and long-term survivors. PET/CT-based imaging plays a key role in stratification of stage and treatment response. Especially for radiotherapy, an essential treatment modality for lymphoma patients, functional imaging and the reevaluation of disease activity after frontline chemotherapy has led to major improvements regarding size of treatment fields and toxicity. International expert groups like the International Lymphoma Radiation Oncology Group (ILROG) develop guidelines for the optimal use of imaging for treatment planning. The shift from uniform large-field treatment volumes to complex individual setups taking into account biological response-assessments based on functional imaging resulted in a further de-escalation of side effects and modernization of lymphoma treatment. This paper aims to summarize the use of FDG-PET-imaging for radiation therapy planning in malignant lymphoma in the context of historic and future developments, as well as associated limitations and challenges ahead. We will discuss the contemporary standard of care as recommended by international expert guidelines like the ILROG, the national comprehensive cancer network (NCCN), as well as the newly updated German S3-guidelines.

Efficacy of Boron Neutron Capture Therapy in Primary Central Nervous System Lymphoma: In Vitro and In Vivo Evaluation.

BACKGROUND: Boron neutron capture therapy (BNCT) is a nuclear reaction-based tumor cell-selective particle irradiation method. High-dose methotrexate and whole-brain radiation therapy (WBRT) are the recommended treatments for primary central nervous system lymphoma (PCNSL). This tumor responds well to initial treatment but relapses even after successful treatment, and the prognosis is poor as there is no safe and effective treatment for relapse. In this study, we aimed to conduct basic research to explore the possibility of using BNCT as a treatment for PCNSL. METHODS: The boron concentration in human lymphoma cells was measured. Subsequently, neutron irradiation experiments on lymphoma cells were conducted. A mouse central nervous system (CNS) lymphoma model was created to evaluate the biodistribution of boron after the administration of borono-phenylalanine as a capture agent. In the neutron irradiation study of a mouse PCNSL model, the therapeutic effect of BNCT on PCNSL was evaluated in terms of survival. RESULTS: The boron uptake capability of human lymphoma cells was sufficiently high both in vitro and in vivo. In the neutron irradiation study, the BNCT group showed a higher cell killing effect and prolonged survival compared with the control group. CONCLUSIONS: A new therapeutic approach for PCNSL is urgently required, and BNCT may be a promising treatment for PCNSL. The results of this study, including those of neutron irradiation, suggest success in the conduct of future clinical trials to explore the possibility of BNCT as a new treatment option for PCNSL.

Fibrotic aortic valve disease after radiotherapy: an immunohistochemical study in breast cancer and lymphoma patients.

BACKGROUND: Radiation-associated aortic valve (AV) stenosis is frequently seen as a late sequela after thoracic radiotherapy (RT). Although the clinical relationship between thoracic radiotherapy and valvular dysfunction has been established, the process leading to accelerated aortic valve stenosis remains unclear. The aim of this study was to determine whether increased inflammatory cell infiltration, fibrosis, and calcification is present in aortic valves after radiotherapy at the time of aortic valve replacement. METHODS: Stenotic aortic valve specimens from 43 patients were obtained after surgical aortic valve replacement. A total 28 patients had previously undergone radiotherapy for breast cancer or malignant lymphoma. A total 15 patients were included as control. The valve leaflets were assessed by (immuno)histochemistry for inflammatory cell composition (CD3, CD20, CD68, and CD163) and extracellular matrix changes (collagen and calcification). RESULTS: Aortic valve cell density after radiotherapy for lymphoma was markedly decreased when compared with other groups. Irradiated aortic valve show similar (low) degrees of late T and B lymphocyte infiltration as control valves, whereas macrophage marker CD68 was decreased after radiotherapy for breast cancer. Collagen content was increased following radiotherapy. Aortic valves of patients with lymphoma contained significantly less calcified tissue when compared with the other groups. CONCLUSION: High-dose radiation at a young age (patients with lymphoma) results in cell loss and premature fibrotic aortic valve stenosis as opposed to the degenerative calcific stenosis observed in patients with breast cancer. Our findings suggest a possible dose-dependent effect of radiotherapy on aortic valve fibrosis. The active presence of inflammatory cells may be limited to the acute phase after radiotherapy.

Active breathing control for patients receiving mediastinal radiation therapy for lymphoma: Impact on normal tissue dose.

PURPOSE: Active breathing control (ABC) is emerging as a tool to reduce heart and lung dose for lymphoma patients receiving mediastinal radiation therapy (RT). The objective of this study was to report our early institutional experience with this technique, with emphasis on quantifying the changes in normal tissue dose and exploring factors that could be used to select patients with the greatest benefit. METHODS AND MATERIALS: Patients receiving mediastinal involved-field RT (IFRT) for lymphoma were eligible. The ABC was performed using a moderate deep-inspiration breath-hold (mDIBH) technique. All patients were replanned with free-breathing (FB) computed tomographic data sets and comparisons of lung, cardiac, and female breast tissue doses were made between mDIBH and FB plans. Logistic regression models were used to identify factors associated with improvement in mean lung and heart dose with mDIBH. RESULTS: Forty-seven patients were analyzed; the majority (87.2%) had Hodgkin lymphoma. Median prescribed dose was 30 Gy (range, 20-36 Gy), with 78.7% of cases being treated with parallel-opposed beams. The use of mDIBH significantly improved average mean lung dose (FB: 11.0 Gy; mDIBH: 9.5 Gy; P < .0001), lung V20 (28% vs 22%; P < .0001), and mean heart dose (14.3 Gy vs 11.8 Gy; P = .003), but increased the mean breast dose (FB: 3.0 Gy; mDIBH 3.6 Gy; P = .0005). The magnitude of diaphragmatic excursion on the inhale scan was significantly associated with dosimetric improvement in both heart and lung dose with mDIBH. CONCLUSIONS: Mediastinal IFRT for lymphoma delivered with mDIBH can significantly reduce lung and heart dose compared with FB, although not for all patients, and may increase breast dose in females. Its implementation is achievable in both adult and pediatric populations. Further work is necessary to better predict which patients benefit from this technique.

Application of metabolic PET imaging in radiation oncology.

Positron emission tomography (PET) is a noninvasive imaging technique that provides functional or metabolic assessment of normal tissue or disease conditions and is playing an increasing role in cancer radiotherapy planning. (18)F-Fluorodeoxyglucose PET imaging (FDG-PET) is widely used in the clinic for tumor imaging due to increased glucose metabolism in most types of tumors; its role in radiotherapy management of various cancers is reviewed. In addition, other metabolic PET imaging agents at various stages of preclinical and clinical development are reviewed. These agents include radiolabeled amino acids such as methionine for detecting increased protein synthesis, radiolabeled choline for detecting increased membrane lipid synthesis, and radiolabeled acetate for detecting increased cytoplasmic lipid synthesis. The amino acid analogs choline and acetate are often more specific to tumor cells than FDG, so they may play an important role in differentiating cancers from benign conditions and in the diagnosis of cancers with either low FDG uptake or high background FDG uptake. PET imaging with FDG and other metabolic PET imaging agents is playing an increasing role in complementary radiotherapy planning.

Berberine inhibits acute radiation intestinal syndrome in human with abdomen radiotherapy.

Radiation-induced acute intestinal symptoms (RIAISs) are the most relevant complication of abdominal or pelvic radiation. Considering the negative impact of RIAIS on patients' daily activities, the preventive effects of berberine on RIAIS in patients were investigated. Thirty-six patients with seminoma or lymphomas were randomized to receive berberine oral (n = 18) or not (n = 18). Forty-two patients with cervical cancer were randomized to a trial group (n = 21) and control group (n = 21). Radiotherapy used a parallel opposed anterior and posterior. 300-mg berberine was administered orally three times daily in trial groups. Eight patients with RIAIS were treated with 300-mg berberine three times daily from the third to the fifth week. Toxicities, such as fatigue, anorexia/nausea, etc., were graded weekly according to CTC version 2.0. Patients with abdominal/pelvic radiation in the control group showed grade 1 fatigue, anorexia/nausea, colitis, vomiting, proctitis, weight loss, diarrhea and grade 2 anorexia/nausea, fatigue. Only grade 1 colitis, anorexia/nausea, and fatigue were seen in patients of abdominal radiation treated with berberine. Grade 1 fatigue, colitis, anorexia/nausea, and proctitis occurred in patients of pelvic radiotherapy treated with berberine. Pretreatment with berberine significantly decreased the incidence and severity of RIAIS in patients with abdominal/pelvic radiotherapy when compared with the patients of the control group (P < 0.05). RIAIS were reduced in patients with abdominal radiotherapy/pelvic radiation after receiving berberine treatment. Berberine significantly reduced the incidence and severity of RIAIS and postponed the occurrence of RIAIS in patients with abdominal or whole pelvic radiation.

Clinical review: treatment of vitreoretinal lymphoma.

Vitreoretinal lymphoma is the most common type of intraocular lymphoma. It is mostly a high-grade B-cell malignancy with a poor prognosis, and is often associated with primary central nervous system lymphoma. Since intraocular lymphoma was first recognized almost 60 years ago, its treatment has gradually evolved. In the early years enucleation was often performed. Since that time, radiation therapy alone, systemic chemotherapy alone, or a combination of the two have been used extensively Because of the limited intraocular penetration of drugs administered systemically, the systemic and local toxicity of chemotherapy and radiation therapy and the high rate of recurrence, intravitreous chemotherapy, mainly using methotrexate, has become popular in the last decade, with encouraging results. More recently, biological treatment with intravitreal injections of rituximab has been investigated, with good results and minimal side effects. This review summarizes the present knowledge on vitreoretinal lymphoma therapy, with an eye to future molecular approaches.

Effect of Yangyin Humo Decoction on oral mucomembranous reaction to radiotherapy.

OBJECTIVE: To observe the effect of Yangyin Humo Decoction (YHD) on oral mucomembranous reaction in patients with head-neck tumor undergoing radiotherapy. METHODS: Forty-Forty-two patients with head-neck tumor undergoing radiotherapy were randomized equally into two groups. The two conventional Western medical treatment was administered to all, including intravenous dripping of 2% lidocaine 20 mL, dexamethasone 5 mg, gentamycin 80,000 units, vitamin B(12) 5 mg, dissolved in saline 250 mL, and 5% sodium bicarbonate solution for gargling, but to the patients in the tested group, YHD was given additionally. The medication was started simultaneously all through the whole course of the radiotherapy. Patients were examined every day to observe and compare the degree, initiating time, and repairing time of their oral lesions; the dosage of radiation they received was recorded as well. RESULTS: The degree of mucomembranous reaction that appeared in most patients in the test group was of grade 1-2, while in the control group, it was grade 2-3. The average time for oral lesion of 1, 2, 3 grades to be initiated in the test group was 12.0+/-1.1, 11.0+/-1.3 and 10.0+/-0.8 days, respectively, after radiation started, which was later than that in the control group (P<0.01). Moreover, the average repairing time for the lesions of grades 1, 2, and 3 in the test group was 3.0+/-0.7, 10.0+/-1.3 and 19.0+/-0.8 days, which were shorter than those in the control group respectively (P<0.01). The radiation applied on the primary tumor of patients with oral lesion of grade 1-3 in the test group was 24.2+/-2.2, 42.0+/-2.6 and 58.0+/-1.6 Gy on the average, respectively, which were higher than that applied on patients in the control group (P<0.05 or P<0.01). CONCLUSION: The Chinese herbal preparation YHD could alleviate oral mucomembranous reaction to radiation applied in patients with head-neck tumor.

Results of treatment of 112 cases of primary CNS lymphoma.

BACKGROUND: Chemotherapy with or without radiotherapy is the mainstay of treatment for primary central nervous system lymphoma (PCNSL). High-dose methotrexate (MTX) is the most effective drug available to treat these lesions, either as a single agent or in combination with other drugs. Due to the lack of well-conducted randomized trials, the optimal treatment remains controversial. Available retrospective studies are difficult to discuss, however, some common themes can be found. METHODS: One hundred and twelve patients with PCNSL were treated with four different regimens over a period of 24 years. Treatment regimens were: whole-brain irradiation (WBI) alone, MVP (MTX, vincristine, and predonisolone), ProMACE-MOPP hybrid (cyclophosphamide, pirarubicin, etoposide, vincristine, procarbazine, prednisone, and MTX) and R-MTX (rituximab, MTX, pirarubicin, procarbazine, and prednisone) combined-modality therapy. RESULTS: The median failure-free survival was 16 months, and the median overall survival (OS) was 24 months. The 2- and 5-year actuarial probability of survival was 52.4 +/- 4.8% [95% confidence intervals (CI)] and 30.2 +/- 4.8% (95% CI), respectively. The ProMACE-MOPP protocol, Karnofsky performance status (KPS), MTX dose and WBI were associated with good OS by univariate models. By multivariate analysis, MTX dose, WBI dose, and its square dose were significantly associated with good OS. 20-30 Gy WB, and 500 mg/m(2) of MTX dose appeared important determinants of OS. CONCLUSIONS: A modest dose of MTX (500 mg/m(2)) followed by reduced-dose WBI for patients who respond appears a feasible treatment approach that minimizes serious toxicity.

Initial evaluation of (227)Th-p-benzyl-DOTA-rituximab for low-dose rate alpha-particle radioimmunotherapy.

Radioimmunotherapy has proven clinically effective in patients with non-Hodgkin's lymphoma. Radioimmunotherapy trials have so far been performed with beta-emitting isotopes. In contrast to beta-emitters, the shorter range and high linear energy transfer (LET) of alpha particles allow for more efficient and selective killing of individually targeted tumor cells. However, there are several obstacles to the use of alpha-particle immunotherapy, including problems with chelation chemistry and nontarget tissue toxicity. The alpha-emitting radioimmunoconjugate (227)Th-DOTA-p-benzyl-rituximab is a new potential anti-lymphoma agent that might overcome some of these difficulties. The present study explores the immunoreactivity, in vivo stability and biodistribution, as well as the effect on in vitro cell growth, of this novel radioimmunoconjugate. To evaluate in vivo stability, uptake in balb/c mice of the alpha-particle-emitting nuclide (227)Th alone, the chelated form, (227)Th-p-nitrobenzyl-DOTA and the radioimmunoconjugate (227)Th-DOTA-p-benzyl-rituximab was compared in a range of organs at increasing time points after injection. The immunoreactive fraction of (227)Th-DOTA-p-benzyl-rituximab was 56-65%. During the 28 days after injection of radioimmunoconjugate only, very modest amounts of the (227)Th had detached from DOTA-p-benzyl-rituximab, indicating a relevant stability in vivo. The half-life of (227)Th-DOTA-p-benzyl-rituximab in blood was 7.4 days. Incubation of lymphoma cells with (227)Th-DOTA-p-benzyl-rituximab resulted in a significant antigen-dependent inhibition of cell growth. The data presented here warrant further studies of (227)Th-DOTA-p-benzyl-rituximab.

Erupción de pápulas foliculares y comedones localizados en el abdomen y en el labio superior / Eruption of follicular papules and comedones localizad on the abdomen and upper lip

No disponible

An analysis of the long-term therapeutic effect of the integrated therapy of traditional Chinese medicine and radiotherapy on abdominal malignant tumor.

To observe the long-term therapeutic effect of the integrated therapy of radiotherapy and Chinese herbal drugs for treatment of abdominal malignant tumor and explore the applied value of differential treatment during radiotherapy. Sixty cases of abdominal malignant tumor with hyperactivity of fire due to yin deficiency or deficiency of both qi and blood were randomly divided into an integrated treatment group of 30 cases and a control group of 30 cases. The integrated treatment group was treated by combination of radiotherapy and Chinese herbal drugs and the control group by simple radiotherapy. The results shows that in the integrated treatment group, the score of physical state was 23.17 +/- 7.18, score of psychological quality 21.23 +/- 4.53 and total score of living quality 44.40 +/- 11.22, and survival rate for three years was 67.55%, which were significantly superior to those of the control group (P < 0.01). It is then concluded that differential treatment of TCM could play a valuable role in treating abdominal malignant tumor during radiotherapy, which can improve the long-term living quality and prolong the survival time of the patients.

[Cutaneous neoplasms]. / Neoplasien der Haut.

The skin is the organ most commonly affected by malignancies. Various cancers of the skin show a dramatic increase in incidence over the last decades. Epithelial skin tumors are most frequently, e.g., basal cell carcinoma and the squamous cell carcinoma with its precursors, the actinic keratoses. Melanoma, which is extremely difficult to treat in advanced tumor stages, is dreaded. Besides that, there are other epithelial malignant diseases, e.g. Morbus Bowen and adnexal tumors originating from the skin appendices. Mesenchymal malignant neoplasias such as Morbus Kaposi, angiosarcomas and other dermal sarcomas, are rare. Since the majority of malignant neoplasms is removable and curable by a simple surgical intervention, the knowledge of the different skin tumors is essential for non-dermatologist.

Coping of cancer patients during and after radiotherapy--a follow-up of 2 years.

AIM: We wanted to understand coping strategies specific to different phases up to two years after radiotherapy, to identify patients who are at higher risk of mood disturbances and to characterise the association between coping strategies and psychosocial adaptation. PATIENTS AND METHODS: From 1997 to 2001, 2,169 patients with different diagnoses were screened (27.8% refused to participate). Data of 276 patients from the beginning of radiotherapy (ti1) and 5 follow-up investigations (ti6/2 years) could be analysed. With the FKV (Freiburg Questionnaire Coping with Disease) cancer-specific coping aspects were assessed. The association between coping styles and psychosocial adaptation was evaluated using the Questionnaire on Stress in Cancer Patients (QSC) and the questionnaire on Functional Assessment of Cancer Treatment (FACT-G). RESULTS: 'Active problem-orientated' coping and 'distractions' are the most important coping strategies. Only 'active problem-orientated' and 'depressive' coping showed a significant decrease. We observed higher means on the scales of the FKV in women. Marital status (single, married, divorced/widowed) had a significant influence on active problem-orientated coping and spirituality. Age, children, education, T/M status and curative/ palliative intention of treatment had no influence on coping styles. Breast cancer patients and lymphoma patients demonstrated the highest use of coping strategies after radiotherapy with a significant decrease of 'active problem-orientated coping'. Depressive coping and minimizing importance at ti1 were associated with high psychosocial distress and low quality of life (QoL) at ti6. CONCLUSION: The correlation of coping mechanisms at the beginning of radiotherapy with low QoL and high psychosocial stress at 2 years could help to identify patients at risk for low psychosocial adaptation. Psycho-oncologically trained teams of physicians would best correspond to this profile of needs and would contribute significantly to an ameliorated adaptation of patients to cancer which could lead to higher life satisfaction.

Choosing an optimal radioimmunotherapy dose for clinical response.

Clinical trials have documented the single-agent efficacy of radioimmunotherapy (RIT) in lymphoma, and several combination therapy studies are now in progress. RIT agents are currently becoming generally available for clinical use in lymphoma therapy. Solid tumors, which are notoriously less responsive to any single agent, have demonstrated clinically useful responses, albeit temporary, and multimodality studies have been instituted. However, a sincere debate continues regarding the basic parameters to be used to define appropriate therapeutic dosing when using this modality in clinical cancer care. It is a good time to reevaluate relevant dose response information from preclinical and clinical RIT. Preclinical studies have demonstrated abundant evidence of dose response in tumor and normal tissue in homogenous model systems; however, substantive variation occurs between the dose responses of tumors with low and variable (or shed) antigen expression, as well as between histologically different tumor models. Clinical studies of various heavily pretreated patient populations given several very different RIT pharmaceuticals have led to disparate conclusions regarding patient dosing methods and dosimetric predictions of toxicity and efficacy. Single-study data on previously untreated lymphoma patients with similar histology has demonstrated a correlation of imaging dosimetry with toxicity and tumor response. High-dose therapy with bone marrow support has also demonstrated a high tumor response rate and nonmarrow normal organ toxicities that correlate with the calculated dose to those organs from imaging. In iodine-131 ((131)I)--anti-CD20 studies, (131)I was demonstrated to have variable excretion, and estimated total-body radiation dose from tracer study proved a predictive surrogate for marrow toxicity. Yttrium-90 ((90)Y)--anti-CD20, which has little (90)Y excretion from the body, demonstrated the injected dose per body weight to be more predictive of marrow toxicity than indium-111 ((111)In) tracer dosimetry methods in heavily pretreated patients, and showed maximal safety with standard mCi/kg therapy dosing. Variations in clinical RIT choices, dosing methods, and dosimetry methods emphasize the need to review the relevant information to date. Future clinical trial designs, the sophistication of dosimetry, treatment planning, and clinical treatment decisions should all be focused on achieving the best benefit-risk relationship for each patient.

Early radiation effects in highly apoptotic murine lymphoma xenografts monitored by 31P magnetic resonance spectroscopy.

PURPOSE: Phosphorus-31 magnetic resonance spectra (31P-MRS) were obtained from highly apoptotic murine lymphoma xenografts before and up to 24 hr following graded doses of radiation ranging from 2 to 30 Gy. Radiation-induced apoptosis was also estimated up to 24 hr by scoring apoptotic cells in tumor tissue. METHODS AND MATERIALS: Highly apoptotic murine lymphoma cells, EL4, were subcutaneously transplanted into C57/BL mice. At 7 days after transplantation, radiation was given to the tumor with a single dose at 3, 10, and 30 Gy. The beta-ATP/Pi, PME/Pi, and beta-ATP/PME values were calculated from the peak area of each spectrum. Radiation-induced apoptosis was scored with counting apoptotic cells on hematoxylin and eosin stained specimens (% apoptosis). RESULTS: The values of % apoptosis 4, 8, and 24 hr after radiation were 21.8, 19.6, and 4.6% at 3 Gy, 35.1, 25.6, and 14.8% at 10 Gy, 38.4, 38.0, and 30.6% at 30 Gy, respectively (cf. 4.4% in control). There was no correlation between early change in beta-ATP/Pi and % apoptosis at 4 hr after radiation when most of the apoptosis occurred. An early decrease in PME/Pi was observed at 4 hr after radiation dose at 30 Gy. For each dose, the values of beta-ATP/Pi 24 hr after radiation were inversely related to radiation dose. CONCLUSION: The increase in beta-ATP/Pi observed by 31P-MRS was linked to the degree of histological recovery from radiation-induced apoptosis.

Short intensive primary chemotherapy and radiotherapy in sporadic primary CNS lymphoma (PCL).

PURPOSE: To assess the efficacy and toxicity of combined modality therapy with short intensive primary chemotherapy in the treatment of primary CNS lymphoma (PCL). METHODS AND MATERIALS: Prospective study of 31 nonimmunodeficient patients with PCL treated with initial chemotherapy (13 shortened MACOP-B; and 18 modified MACOP with high dose methotrexate) followed by radiotherapy (whole brain and a boost). Patients were aged 18-72 years (median 51 years). Eight patients had positive CSF cytology of which one had spinal meningeal disease; one patient had vitreous involvement. RESULTS: The overall complete response (CR) rate after chemotherapy and radiotherapy was 69% (95% Confidence Interval: 49-84%). At a median follow-up of 24 months (4 months to 10 years) median survival was 23 months and 5-year survival 34%. Age, sex, performance status, number of lesions, CSF cytology, and extent of surgery were not of prognostic significance for survival on univariate analysis. Eleven patients developed mucositis (Grade 3+) and 21 hematological toxicity (Grade 3+) with 22 septicemic episodes in 15 patients. Three patients developed dementia, one assumed to be treatment related, and two due to recurrent disease. CONCLUSION: The survival results of short intensive primary chemotherapy followed by radiotherapy are similar to the results of chemotherapy in Stage IV aggressive systemic non-Hodgkin's lymphoma, although the treatment was associated with high morbidity. The apparently favorable results when compared to radiotherapy alone may at least in part be due to selection of patients with good prognostic factors. To confirm the benefit of combined chemotherapy and radiotherapy over either of the two modalities alone requires evaluation in large prospective and ideally randomized studies.

[Use of antibodies or their fragments for the treatment of tumors]. / L'utilisation des anticorps ou de leurs fragments pour le traitement des tumeurs.

During the last 15 years, various antibodies specific for antigens associated with determined types of cancer have been used therapeutically, including some in unlabeled forms as immune effectors. The results of clinical studies have been unpromising for patients with colorectal cancer at the advanced metastatic stage but much more favorable in terms of increased survival for the adjuvant situation of residual microscopic disease. Antibodies have also been used as carriers for cytotoxic substances, but with rather disappointing clinical results when they were labeled with toxins or antimitotic agents. The results have been variable for labeling with radionuclides (mainly iodine-131), some-times proving quite favorable for refractory forms of non-hodgkin's lymphomas or acute leukemias. In this last indication, radioimmunotherapy has been associated with chemotherapy to enhance action before a bone-marrow graft. However, the clinical results have been disappointing in the treatment of solid tumors, showing responses only in the case of small targets. In the future, treatment with antibodies will focus on microscopic tumors, in association with other therapeutic modalities especially, chemotherapy and biotherapy.

Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD).

Prior studies have suggested that pre-irradiation methotrexate (MTX)-based chemotherapy improves duration of response and survival in primary central nervous system lymphoma (PCNSL). To circumvent the potential emergence of drug resistance, we combined high-dose MTX with agents highly active against systemic lymphoma. Patients received three week cycles of CHOD (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [2 mg maximum] on day 1; dexamethasone 10 mg/m2 days 1-5), and MTX (3.5 gm/m2) with leucovorin rescue on day 8 (or on recovery from the CHOD nadir). Whole brain irradiation (WBRT) was planned after at least three cycles. Eighteen patients were treated. Complete responses were seen in eleven patients, and partial responses in three. Four progressed during therapy, three succumbing to progressive disease and one subsequently responding to WBRT. Response duration was 37.5 months in those responding to therapy. The time to progression for all eighteen patients was 19.5 months. Medial survival was 25.5 months. Disease-free survival was 50% at 38 months in MCHOD responders. Grade 3 or 4 myelotoxicity was seen in 19 of 50 cycles. There were three instances of neutropenic fever, three of azotemia, two of deep vein thrombosis, and one each of community-acquired pneumonia, intracranial hemorrhage, superior vena cava syndrome, and hepatotoxicity. Late radiation-related toxicities were seen in two patients. Pre-irradiation MCHOD has activity against PCNSL, but appears to be no better than MTX monotherapy and has greater toxicity.

Radioimmunotherapy: recent results and future directions.

PURPOSE: To review antibody structure, function, and production; suitable radioisotopes for radioimmunotherapy; challenges facing the field; recent clinical results; toxicity; and future directions. DESIGN: The radioimmunotherapy literature was reviewed, with an emphasis on clinical results and future directions. RESULTS: The highest complete response rates (overall, approximately 50%) have been achieved in patients with B-cell non-Hodgkin's lymphoma. Challenges that currently face radioimmunotherapy include circulating free antigen, binding of antibodies to nonspecific Fc receptors, insufficient tumor penetration, antigenic heterogeneity and insufficient antigen expression, antigenic modulation, and development of human antimouse antibodies. Possible approaches to these challenges, including high-dose radioimmunotherapy and chemotherapy followed by autologous bone marrow transplantation, the use of radionuclides such as yttrium 90 (90Y) and copper 67 (67Cu), and the development of humanized and bifunctional antibodies, are under investigation. CONCLUSION: Although radioimmunotherapy is a relatively new field, substantial progress has been made. Additional research will ultimately resolve many of the challenges that currently face radioimmunotherapy and hopefully lead to the cure of some currently incurable malignancies.