Herpes Simplex Encephalitis as a Complication of Whole-Brain Radiotherapy: A Case Report and Review of the Literature

A 55-year-old male recently diagnosed with stage IV lung adenocarcinoma presented with altered mental status approximately 1 week after the completion of 14 fractions of whole-brain radiotherapy (WBRT) for brain metastases. On admission, he was somnolent but oriented and without focal neurological deficits. Brain imaging revealed marked regression of his brain metastases. Laboratory values were only significant for hyponatremia with urine hyperosmolality consistent with syndrome of inappropriate antidiuretic hormone secretion. The patient developed seizures 3 days after admission, at which time cerebrospinal fluid was significant for positive herpes simplex virus (HSV)-1 PCR but with a negative cell count, and acyclovir was started for HSV encephalitis (HSE). After 3 weeks of acyclovir 10 mg/dl i.v. 3 times per day, he had significant neurological recovery and was discharged. Although HSE is a relatively rare condition, it is the most common cause of sporadic encephalitis in Western countries. Since the pathogenesis is believed to be due to the reactivation of latent HSV, it is possible that patients who are immunosuppressed are at higher risk for HSE. In addition, patients who are immunosuppressed or immunocompromised often present atypically, which may delay time to diagnosis and treatment, thus significantly worsening prognosis. This case report intends to raise awareness of this severe condition in the context of patients who have received WBRT and immunosuppressive therapy. In addition, important considerations of diagnosis and treatment of HSE in this patient population are discussed.Key words: Herpes simplex encephalitis, Cranial irradiation, Brain metastasis, Lung adenocarcinoma, Immunosuppression     

A Herpes simplex virus-1 fatal encephalitis following chemo-radiotherapy, steroids and prophylactic cranial irradiation in a small cell lung cancer patient

Approximately 20-25% of patients with limited small cell lung cancer (SCLC) can be cured with an aggressive approach (chest radiation concomitant with chemotherapy) followed by prophylactic cranial irradiation (PCI) to a total dose of 30-36Gy with 3-2Gy per fraction, five fractions per week. Steroid prophylactic therapy with dexamethasone is usually prescribed during PCI to minimize acute radiation induced brain oedema. This approach may induce an immunosuppressive condition leading to a reactivation of an endogenous latent Herpes simplex virus and severe or fatal acute encephalitis may occur as our report will show. A 55-year-old man affected by locally advanced SCLC was referred to our institution after four cycles of chemotherapy with a good partial remission. Chest radiation started concomitantly with two cycles of chemotherapy followed by PCI 36Gy total dose and dexamethasone 8mg i.m. daily. Fifteen days after PCI completion the patient developed acute neurological symptoms of confusion, cognitive impairment, fever with shaking requiring severe sedation therapy. Twenty-five days later MRI T1 weighted images showed haemorrhagic streaked lines on cortical convolutions of the right cerebral hemisphere and diffuse oedema suggestive of herpetic encephalitis. The DNA consensus test on cerebrospinal fluid (CSF) was positive for Herpes simplex virus 1 infection (HSV-1). A diagnosis of herpetic encephalitis HSV-1 was made. Antiviral therapy with high doses of acyclovir was prescribed but symptoms did not ameliorate leading to a comatose state. The patient died 55 days after the end of PCI. In eligible SCLC patients, PCI is an important part of an aggressive therapeutic approach that improves overall and disease free survival decreasing the risk of relapse in the brain. A primary infection or a reactivation of an endogenous latent HSV in brain parenchyma under steroid therapy concomitant to brain irradiation may compromise these benefits.     

Herpes simplex encephalitis following spinal ependymoma resection: case report and literature review

Herpes simplex encephalitis (HSE) is a rare complication of neurosurgical procedures but must be considered in early deterioration of the postoperative patient. This is the first report of HSE following spinal cord tumor resection. A 65-year-old woman had C2–C5 laminectomy for subtotal resection of intramedullary ependymoma. Six days postoperatively she developed fever, vomiting and rapid decline in mental status. Brain MRI revealed enhancement of left insular cortex. Polymerase chain reaction on cerebrospinal fluid (CSF) identified herpes simplex virus type 1 (HSV-1) as the causal agent. Twenty-one days of acyclovir led to improvement. Three subsequent admissions to neurological intensive care unit were required for deterioration in mental status, including pneumonia, hydrocephalus and deep vein thromboses. Ventriculoperitoneal shunt (VPS), tracheotomy, percutaneous intravenous central catheter (PICC) line and percutaneous endoscopic gastrostomy (PEG) were placed. She was discharged to skilled nursing home care. Acyclovir is effective therapy against HSV, though outcomes may be poor even in optimally treated cases. Empiric treatment must be started even in the absence of serologic evidence of HSV infection if suspicion for HSE is high.     

Herpes simplex encephalitis in patients with cancer

Case reports and animal models suggest that chemotherapy, corticosteroids and radiotherapy (RT) may increase the risk of herpes simplex encephalitis (HSE). We retrospectively examined cases of HSE at an academic hospital devoted to cancer care. Patients were identified by positive herpes simplex virus (HSV) polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) or by brain pathology. There were seven patients with HSE over a 12 year period, four of whom had received cranial RT. During this time, a total of 997 patients were treated with cranial RT, suggesting a greater incidence than the expected risk of two to four cases per million people per year in the general population. Five patients had recently received chemotherapy and three were on dexamethasone. MRI findings were typical; four patients had bilateral anterior temporal lesions and three had unilateral-temporal lesions. Four patients had a normal CSF white blood cell count, three of whom had prior RT and dexamethasone. Four patients were positive for HSV-1, and two for HSV-2. One patient had a negative CSF PCR for HSV, but autopsy confirmed active HSE. Though still rare, the risk of HSE may be increased in patients with cancer, especially in those receiving cranial RT. MRI findings were typical, but CSF white blood cell count was normal in four patients and one had negative CSF testing, suggesting that CSF results may be misleading in this population.     

The role of herpes simplex virus in the development of oral mucositis in bone marrow transplant recipients

Herpes simplex virus (HSV) has been implicated as a major etiologic factor in the development of ulcerative mucositis in bone marrow transplant (BMT) recipients. In this study, 60 patients who received BMTs were evaluated for at least 30 days post-transplant for ulcerative mucositis and the presence of culturable HSV. Fifty-nine patients received prophylactic acyclovir. Forty-six patients developed ulcerative lesions and 45 of these were culture negative for HSV. Neither the source of transplant (autologous versus allogenic) nor the HSV antibody status of the patient affected the frequency of mucositis. The conditioning regimen appeared to be the most significant factor contributing to the severity of ulcerative mucositis. While the majority of ulcers occurred on movable nonkeratinized mucosa in BMT recipients, the usual sites of reactivation of intraoral HSV are nonmovable, keratinized mucosa. We conclude that HSV is probably not a major etiologic agent of mucositis in BMT recipients and that acyclovir is an effective agent in preventing HSV reactivation.     

Efficacy of Herpes Vaccine and Acyclovir (ACV) in a Rabbit Model Following Intraocular Inoculation of Herpes Simplex Virus

Abstract

It has been shown that injection of herpes simplex virus (HSV) type I into the vitreous body of the eye in 18-day-old albino rabbits consistently induced encephalitis. In the untreated group the lesions followed a defined anatomical pathway in the central nervous system and produced a chronic progressive disease with 95% survival. Detailed observations in the spread of HSV along the optic pathway determined the extent of damage at any given day. Some of the old rabbits developed typical her-petic lesions on nose and lips. HSV was demonstrated from these lesions by electron microscopy and also by tissue culture isolation. The combined efficacy of heat-killed herpes vaccine prepared from the same isolate and acyclovir (ACV) in this animal model was studied by starting treatment four days before or four days after the challenge. Ten animals immunised before the challenge were protected. However, immunisation after the challenge not only did not confer protection, but surprisingly, appeared to enhance the primary disease. All 10 rabbits immunised after the challenge developed weakness of the hind legs and progressed very rapidly to paralysis. ACV treatment alone did not completely abrogate the HSV infection, there appears to be reactivation of HSV which produced fresh small lesions. However, a combination of immunisation and treatment with ACV after the challenge of the 10 rabbits in the group prevented the development of weakness of the hind legs or paralysis. Detailed observations on the spread of HSV along the optic pathway revealed that pathological lesions and damage were limited in the ACV and combined treatment with ACV and vaccine group.     

Herpes lymphadenitis in association with chronic lymphocytic leukemia.

BACKGROUND: Herpes simplex virus (HSV) infections range in severity from common cutaneous outbreaks to life-threatening central nervous system and deep organ involvement. HSV lymphadenitis is extremely rare but occurs both as a component of widely disseminated disease and as a localized, mild illness. METHODS: Five patients with chronic lymphocytic leukemia (CLL) underwent lymph node biopsy and were found to have histologic and immunophenotypic evidence of HSV infection in association with CLL. RESULTS: The patients were 3 males and 2 females ranging in age from 50 to 86 years. Only 1 patient had clinical evidence of cutaneous herpes at any time; in that patient, herpes lymphadenitis preceded the cutaneous herpes by 3 years. Four patients received no therapy for herpes at any time, whereas one was treated with intravenous and oral acyclovir. One patient died of CLL approximately 20 months after herpes lymphadenitis was diagnosed. The remaining four patients are alive with CLL. No patient had a fulminant clinical course related to HSV or developed disseminated infection. CONCLUSIONS: Herpes lymphadenitis may not have a fulminant course even in immunosuppressed CLL patients, even if they receive no antiviral therapy.     

Combined hepatic artery 5-fluorouracil and irradiation of liver metastases. A randomized study

The effect of hepatic irradiation (RT) after intraarterial 5-fluorouracil (5-FU) was evaluated in 37 randomized patients with colorectal adenocarcinoma hepatic metastases. Patients underwent percutaneous transbrachial artery catheterization of the hepatic artery followed by 21-day continuous 5-FU infusion (CT). Hepatic irradiation of 25.5 Gy was delivered to 19 patients 14 days after completion of infusion (CT + RT). All patients received subsequent weekly maintenance 5-FU. A 37% (seven of 19) response rate was observed in CT + RT, and a 50% response rate (nine of 18) in CT: median survival was 6 months for CT + RT, and 8 months for CT, (P = 0.106). Improved survival was observed in two subsets of patients. Tumor vascularity was graded angiographically from 0 to 4+; those patients with highest vascularity (4+) had a 20-month median survival (P = 0.0009). Patients with Grade 1, well-differentiated, histologic type had a median survival of 20 months (P = 0.0001). Four patients with both 4+ vascularity and Grade 1 histologic type had 27.5 months' median survival (P = 0.0019). Age, performance status, elevated liver function tests, previous systemic therapy, and time interval between diagnosis and entry on this study did not impact on survival (P greater than 0.05), nor did these variables eliminate the significance of vascularity and grade (P less than 0.05). Survival after intraarterial 5-FU infusion was not improved by this regimen of sequential external irradiation. Regional therapy may benefit those patients with 4+ vascular tumors and/or well-differentiated tumor grade. Future trials are needed to explore the interaction of halogenated pyrimidines with irradiation and determine whether these prognostic factors can aid in patient selection for regional therapy of hepatic metastases.     

Herpes simplex infection in acute myelogenous leukemia and other hematologic malignancies: a prospective study

To better define the frequency and clinical characteristics of herpes simplex virus (HSV) infection in adult patients with acute myelogenous leukemia (AML), the authors prospectively studied 29 patients undergoing remission induction chemotherapy with twice weekly throat wash cultures for an average of 25.3 days. Ten seropositive patients (34.5%) shed HSV at least once. Eight patients were asymptomatic. Two episodes of herpes labialis were severe and persistent, but no visceral dissemination was observed. Reactivation of HSV infections in AML patients presumably with marked immunosuppression occurs, but less frequently and more benignly than has been suggested. Daunomycin and cytosine arabinoside, which can inhibit HSV replication, may have accounted for this lower frequency of reactivation.     

Filgrastim and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia.

Alemtuzumab (anti-CD52; Campath-1H) is effective in fludarabine-refractory chronic lymphocytic leukemia (CLL), but is associated with infection and early onset neutropenia. To reduce toxicity, filgrastim (G-CSF) was administered concurrently with alemtuzumab. In total, 14 CLL patients (median age 59) with a median of 3.5 prior regimens (range 1--12) received i.v. alemtuzumab, stepped up from 3 to 30 mg the first week, then 30 mg thrice weekly for 12 weeks. Filgrastim 5 microg/kg was administered daily 5 days before and throughout alemtuzumab therapy. Six patients developed cytomegalovirus (CMV) reactivation 3--6 weeks into treatment; six patients developed fever, three neutropenia, and one pneumonia. The patient with CMV pneumonia died; ganciclovir cleared CMV in the other patients. Five patients developed early neutropenia (weeks 2--5). Four patients developed delayed neutropenia (weeks 10--13) unassociated with CMV reactivation. Nine patients ceased therapy because of infectious and hematologic toxicity. Five partial responses were noted, all in patients with lymph nodes>cm, lasting a median of 6.5 months (range 5--13). Filgrastim and alemtuzumab were given concurrently with manageable infusion toxicity and clinical activity, but the efficacy of this regimen was limited by delayed neutropenia of unclear etiology and CMV reactivation. Filgrastrim should not be administered prophylactically during alemtuzumab therapy outside clinical trials.     

Impaired in vitro interferon, blastogenic, and natural killer cell responses to viral stimulation in acquired immune deficiency syndrome

The in vitro immune response to herpes simplex virus (HSV), type 1, strain 539, HSV type 2, strain 316D, and cytomegalovirus was studied in 20 patients (14 with acquired immune deficiency syndrome, four with the acquired immune deficiency syndrome-related symptom complex, and two sexually active asymptomatic homosexuals) and 18 heterosexual healthy controls. Peripheral blood mononuclear cells were cultured with 2 X 10(5) plaque-forming units of heat-inactivated viruses, their lymphocyte blastogenic responses were measured after 5 days in culture by [3H]-thymidine incorporation, their interferon production was measured after 24 hr and 5 days, and natural killer (NK) cell activation was measured after 24 hr and 5 days of culture. Blastogenic responses to viruses were significantly low for only HSV, type 1:1.75 X 10(3) cpm in patients' cells compared to 6.36 for controls. Interferon responses to all three viruses were significantly low at both 24 hr and 5 days; e.g., HSV, type 1:139 IU/ml in patients' cells compared to 777 for controls at 24 hr. NK cell responses of patients were lower than those of controls when tested fresh and after 24 hr of incubation: 6.1 versus 11.7% and 9.2 versus 16.8% target cell lysis, respectively. Exposure to viruses boosted NK cell responses of both patients' and controls' cells, but boosting was generally greater among the normal rather than the patients' cells. The abnormalities of response were present in all three patient groups. Addition of interleukin-2 in vitro increased the patient and control blastogenic and NK responses but did not augment the interferon responses. The in vitro responses to both HSV, type 1, and HSV, type 2, correlated significantly with our conventional assays of the percentage and absolute level of T4+-helper lymphocytes in the blood and the blastogenic responses to mitogens, such as phytohemagglutinin, pokeweed mitogen, and concanavalin A. This system should be useful for the study of host defense in acquired immune deficiency syndrome patients and those in high-risk groups, and also for the in vitro evaluation of immunomodulators.     

Fatal adenovirus infection during alemtuzumab (anti-CD52 monoclonal antibody) treatment of a patient with fludarabine-refractory B-cell chronic lymphocytic leukemia

Alemtuzumab (Campath-1H) is a humanized CD52 monoclonal antibody that targets normal as well as malignant B- and T-lymphocytes. Alemtuzumab has significant antitumor activity in chronic lymphocytic leukemia (B-CLL) but also induces immunosuppression. We describe a case of fatal adenovirus infection in a heavily pretreated patient with fludarabine-refractory B-CLL receiving alemtuzumab therapy, drawing attention to the fact that also viruses other than cytomegalovirus (CMV) and herpes simplex (HSV) need to be considered in B-CLL patients with fever of unknown origin while on alemtuzumab treatment.     

Risk factors for hepatitis B virus reactivation after conformal radiotherapy in patients with hepatocellular carcinoma

This study investigated whether conformal radiotherapy affects hepatitis B virus (HBV) reactivation, and the risk factors for HBV reactivation in patients with HBV‐related hepatocellular carcinoma (HCC). Sixty‐nine patients with HCC were included in this retrospective study. Before radiotherapy (RT), all patients underwent imaging examinations and some baseline examinations, including CBC, liver function test, renal function test, α‐fetoprotein level, hepatitis B (HB) surface antigen, HB surface Ab, HB e antigen, HB e Ab, and serum HBV DNA quantification. During the period of RT and at least 16 weeks after the end of RT, CBCs were carried out weekly and the other tests were monitored monthly or more frequently if necessary. The clinical features and dosimetric parameters of RT were recorded. Univariate and multivariate logistic regression algorithms were used to analyze the risk factors of HBV reactivation. The incidence of complications in the study population was as follows: radiation‐induced liver disease, 17.4%; HBV reactivation, 24.6%; and HBV reactivation‐induced hepatitis, 21.7%. The HBV DNA level and dose volume parameters including normal liver volume, V20, and mean dose were associated with HBV reactivation. There was a relatively high incidence of HBV reactivation in HCC patients after the end of conformal RT. The serum HBV DNA level and some dosimetric parameters related to normal liver, including normal liver volume, V20, and mean dose, were the prognosis factors of HBV reactivation and should be carefully considered before conformal RT.     

Breast-conserving therapy after previous irradiation for lymphoma

There is an increased risk of breast cancer in patients who have undergone radiation treatment for lymphoma. While this usually precludes further radiotherapy (RT), we report five women who received irradiation for lymphoma and who subsequently received breast-conserving therapy between 1995 and 2007 for early-stage breast cancer. There was an overlap between the two treatment fields in all patients. RT for lymphoma ranged between 29.8 and 40 grays (Gy). The interval between lymphoma and the diagnosis of breast cancer was 11–24 years. All five patients had lumpectomy and received subsequent RT (45 Gy in four patients, 50 Gy in the other). All tolerated breast RT well, and toxicity was limited to grade 1 events. All five patients were alive at last follow-up, and there was no local recurrence in the irradiated breast in any patient. We conclude that previous RT for lymphoma is not necessarily an absolute contraindication to breast-conserving therapy.     

18F-FDG PET early after radiotherapy in lymphoma patients

OBJECTIVE: The aim of this study was to evaluate the rate of postactinic inflammatory alterations that could lead to false-positive results in FDG-PET images, in a group of lymphoma patients studied with positron emission tomography (PET) early after the end of radiation therapy. MATERIALS AND METHODS: Sixteen (16) consecutive patients were referred to our center for malignant lymphoma; 14 of 16 patients had a mediastinal bulky mass at diagnosis. Each patient underwent chemotherapy and then radiotherapy (RT): for clinical reasons, shortly after RT (range, 25-56 days; mean, 38.7 days) a FDG PET scan was required to evaluate the effect of therapy. We intravenously injected 370 MBq of 18F-FDG, and after 60-90 minutes we recorded images. RESULTS: Despite a relatively short time after RT, there was no pathological tracer uptake in 13 of 16 patients. In 3 cases, a mild increase in FDG uptake was observed, but no findings which would lead to a false-positive diagnosis. In 2 of 3 cases, postactinic pneumopathy was diagnosed (PET scan performed 51 and 52 days after RT); while in 1 patient, soft-tissue inflammation was present (PET scan performed 42 days after RT). CONCLUSION: Our data indicates that the rate of postactinic PET inflammatory alterations in lymphoma patients is not very high and appear to be not strictly linked to the elapsed time since the end of RT treatment.     

Increased risk of cancer after Bell’s palsy: a 5-year follow-up study

Reactivation of latent herpes simplex virus (HSV) type I or varicella-zoster virus (VZV) has been recognized as the most common pathomechanism underlying Bell??s palsy. There is also increased reactivation of HSV or VZV in patients with immunosuppressed states and in cancer patients. The purpose of this study was to investigate the risk for cancer during a 5-year follow-up period after diagnosis of Bell??s palsy by using a population-based dataset in Taiwan. We used data from the ??Longitudinal Health Insurance Database??. We identified 2,618 patients with Bell??s palsy as the study cohort and randomly selected 13,090 patients to be used as a comparison cohort. Cox proportional hazards regression was performed to compare the 5-year risk of subsequent cancer between the study and comparison cohorts. We found that the incidence of cancer was 1.55 (95?% CI 1.35?C1.78) per 100 person-years for patients with Bell??s palsy and 1.09 (95?% CI 1.02?C1.18) per 100 person-years for comparison patients. After censoring cases that died from non-cancer causes during the follow-up period and adjusting for urbanization, monthly income, geographic region, and diabetes, the hazard ratio (HR) for cancer during the 5-year follow-up period for patients with Bell??s palsy was 1.43 times that for comparison patients (95?% CI 1.22?C1.73). There was a particularly increased risk of oral cancer (HR?=?2.49; 95?% CI 1.54?C4.03) for patients with Bell??s palsy compared with the other patients. We conclude that patients with Bell??s palsy were at significant risk of cancer during a 5-year follow-up period after diagnosis.     

Two cases of bronchiolitis obliterans organizing pneumonia (BOOP) induced radiotherapy after surgery of breast cancer

We report two cases of bronchiolitis obliterans organizing pneumonia (BOOP) induced radiotherapy after surgery of breast cancer. One of the patients was a 58-year-old woman. She underwent a conserving surgery for bilateral breast cancers, and received radiation therapy to the remaining part of bilateral breasts. Two months after the termination of irradiation, cough, fever and general fatigue developed. We clinically diagnosed this case as BOOP after radiation therapy. After initiation of oral steroid therapy, the clinical symptoms and radiographic findings disappeared. Another patient was a 57-year-old woman. She underwent radical mastectomy for right breast cancer. A month after the operation, she suffered from local recurrence, so radiation therapy to the thoracic wall was performed. After irradiation, resection of the thoracic wall lesion was performed because of malignancy from local skin biopsy specimen. Two months after the termination of irradiation, cough, dyspnea and fever developed. We clinically diagnosed this case as radiation-induced BOOP by BAL and TBLB findings. After an initiation of steroid therapy, the clinical symptoms and radiographic findings disappeared. It is important to be aware of BOOP as a complication in the patient who was given radiation after surgery of breast cancer.     

Enhancement of host cell reactivation of ultraviolet-irradiated Herpes simplex virus by caffeine, hydroxyurea and 5-bromodeoxyuridine.

Enhancement of host cell reactivation (HCR) of ultraviolet (UV)-irradiated herpes simplex virus (HSV) was demonstrated in cell cultures pretreated with caffeine, hydroxyurea, or 5-bromodeoxyuridine (BrdUrd). The effect of caffeine on HCR was shown to depend on the time of drug treatment with respect to infection. In cultures treated with caffeine during the course of virus replication, the infectivity of irradiated HSV was reduced about nine-fold, while cultures pretreated with the drug before infection showed an increase in infectivity. The extent of HCR enhancement depended on the time interval between treatment with caffeine and infection, drug concentration, and the UV irradiation dose to which HSV was exposed. Magnitude of enhancement of HCR by caffeine differed in various cell species. The results suggest that enhanced HCR of UV-irradiated HSV by DNA antimetabolities is associated with DNA repair activated in consequence of cell DNA damage.     

Late radiation side-effects in three patients undergoing parotid irradiation for benign disease

We report three patients in whom standard radiation therapy was given and serious late radiation damage was seen.The first patient suffered recurrent parotiditis and a parotid fistula. He was treated initially with 20 Gy in ten fractions via a 300 kV field. Further irradiation was required 1 year later and 40 Gy was given in 2 Gy fractions by an oblique anterior and posterior wedged photon pair. Ten years later he developed localized temporal bone necrosis. The second patient, with pleomorphic salivary adenoma, developed localized temporal bone necrosis 6 years after 60 Gy had been given using standard fractionation and technique. The third patient received 55 Gy in 25 fractions for a pleomorphic salivary adenoma and after 3 years developed temporal bone necrosis. Sixteen years later the same patient developed cerebellar and brainstem necrosis.All patients developed chronic persistent infection during or shortly after the radiation therapy, which increased local tissue sensitivity to late radiation damage. As a result, severe bone, cerebellar and brainstem necrosis was observed at doses that are normally considered safe. We therefore strongly recommend that any infection in a proposed irradiated area should be treated aggressively, with surgical debridement if necessary, before radiotherapy is administered, or that infection developing during or after irradiation is treated promptly.     

Improved five year survival after combined radiotherapy-chemotherapy for stage I-II non-hodgkin's lymphoma

In order to improve the prognosis of patients with localized non-Hodgkin's lymphomas (NHL) who are treated with radiotherapy (RT), a prospective controlled study utilizing a combined modality approach was carried out in patients with pathologic Stage 1[-II NHL. After treatment with regional RT, patients in complete remission were randomized to receive either no further therapy or 6 cycles of cyclophosphamide, vincristine and prednisolone (CVP). At 5 years from completion of irradiation, the relapse-free survival was 46.3% after RT and 72.1% after RT plus CVP (P = 0.005). The corresponding findings for the overall survival calculated from the beginning of irradiation were 55.8 and 82.8% respectively (P = 0.03). The favorable effects of adjuvant chemotherapy on relapse-free survival were statistically significant only in the subgroup with diffuse histology. In patients who relapsed after RT alone, the salvage therapy failed to induce a high incidence of second durable remission. Adjuvant chemotherapy is indicated to improve the cure rate in pathologic stage I-II NHL with diffuse histology when regional RT is utilized.