Susan Loong

Randomized Trial of Radiotherapy Versus Concurrent Chemoradiotherapy Followed by Adjuvant Chemotherapy in Patients With American Joint Committee on Cancer/International Union Against Cancer Stage III and IV Nasopharyngeal Cancer of the Endemic Variety

PURPOSEnThe Intergroup 00-99 Trial for nasopharyngeal cancer (NPC) showed a benefit of adding chemotherapy to radiotherapy. However, there were controversies regarding the applicability of the results to patients in endemic regions. This study aims to confirm the findings of the 00-99 Trial and its applicability to patients with endemic NPC.nnnPATIENTS AND METHODSnBetween September 1997 and May 2003, 221 patients were randomly assigned to receive radiotherapy (RT) alone (n = 110) or chemoradiotherapy (CRT; n = 111). Patients in both arms received 70 Gy in 7 weeks using standard RT portals and techniques. Patients on CRT received concurrent cisplatin (25 mg/m2 on days 1 to 4) on weeks 1, 4, and 7 of RT and adjuvant cisplatin (20 mg/m2 on days 1 to 4) and fluorouracil (1,000 mg/m2 on days 1 to 4) every 4 weeks (weeks 11, 15, and 19) for three cycles after completion of RT. All patients were analyzed by intent-to-treat analysis. The median follow-up time was 3.2 years.nnnRESULTSnDistant metastasis occurred in 38 patients on RT alone and 18 patients on CRT. The difference in 2-year cumulative incidence was 17% (95% CI, 14% to 20%; P = .0029). The hazard ratio (HR) for disease-free survival was 0.57 (95% CI, 0.38 to 0.87; P = .0093). The 2- and 3-year overall survival (OS) rates were 78% and 85% and 65% and 80% for RT alone and CRT, respectively. The HR for OS was 0.51 (95% CI, 0.31 to 0.81; P = .0061).nnnCONCLUSIONnThis report confirms the findings of the Intergroup 00-99 Trial and demonstrates its applicability to endemic NPC. This study also confirms that chemotherapy improves the distant metastasis control rate in NPC.

The relationship of hepatitis B virus infection and non‐Hodgkin’s lymphoma and its impact on clinical characteristics and prognosis

Aim of the study:u2002 This study aims to evaluate the association between hepatitis B virus (HBV) and lymphoma and to characterize HBV‐related lymphomas. The efficacy of prophylactic lamivudine on HBV reactivation was also evaluated.

Outcome of patients with nasal natural killer (NK)/T-cell lymphoma treated with radiotherapy, with or without chemotherapy†

This study reviews the outcome of patients with nasal natural killer (NK)/T‐cell lymphoma treated at the Therapeutic Radiology Department, National Cancer Centre, Singapore, from 1997 to 2003.

Why are East Asians more susceptible to several infection-associated cancers (carcinomas of the nasopharynx, stomach, liver, adenocarcinoma of the lung, nasal NK/T-cell lymphomas)?

There are at least five cancers with uniquely high incidence amongst East and Southeast Asian ethnic groups - namely nasopharyngeal carcinoma (NPC); gastric carcinoma; hepatocellular carcinoma (HCC); adeno-carcinoma of the lung in female non-smokers and nasal NK/T-cell lymphomas. They all appear to be related to an infective cause (Epstein Barr Virus, Helicobacter pylori, hepatitis B virus). We hypothesize that a genetic bottleneck 30,000years ago at the Last Glacial Maximum could have resulted in unique genetic polymorphisms in Toll-like receptor 8, making East Asians more vulnerable to these infective associated cancers. This bottleneck could have been caused by the presence of malaria in the southern Himalayan conduit between central and East Asia; and only those with an attenuated innate immune response to the malarial parasite (perhaps reflected by the TLR8 polymorphism) were spared the ravages of cerebral malaria; allowing these people to cross into east Asia, but then rendering them susceptible to later endemic infections and their associated cancers.

Weak expression of cyclooxygenase-2 is associated with poorer outcome in endemic nasopharyngeal carcinoma: analysis of data from randomized trial between radiation alone versus concurrent chemo-radiation (SQNP-01)

BackgroundOver-expression of cyclooxygenase-2 (COX-2) enzyme has been reported in nasopharyngeal carcinoma (NPC). However, the prognostic significance of this has yet to be conclusively determined. Thus, from our randomized trial of radiation versus concurrent chemoradiation in endemic NPC, we analyzed a cohort of tumour samples collected from participants from one referral hospital.Methods58 out of 88 patients from this institution had samples available for analysis. COX-2 expression levels were stratified by immunohistochemistry, into negligible, weak, moderate and strong, and correlated with overall and disease specific survivals.Results58% had negligible or weak COX-2 expression, while 14% and 28% had moderate and strong expression respectively. Weak COX-2 expression conferred a poorer median overall survival, 1.3 years for weak versus 6.3 years for negligible, 7.8 years, strong and not reached for moderate. There was a similar trend for disease specific survival.ConclusionContrary to literature published on other malignancies, our findings seemed to indicate that over-expression of COX-2 confer a better prognosis in patients with endemic NPC. Larger studies are required to conclusively determine the significance of COX-2 expression in these patients.

An Epstein-Barr virus positive natural killer lymphoma xenograft derived for drug testing

Natural killer (NK) lymphomas occurring more frequently in the Far East and South America respond poorly to anthracycline-based regimens. Here we report an in vivo NK lymphoma xenograft (NK-S1) derived from the testicular metastasis of a patient with an extranodal NK lymphoma (nasal type). The NK-S1 xenograft, established in severe combined immune deficient (SCID) mice retained the same imunophenotypic features as the original tumor. NK-S1 disseminated intra-abdominally to the testis, intestine and liver. Although doxorubicin, rapamycin, bevacizumab, rapamycin-doxorubicin, and bevacizumab-doxorubicin had no effects on the growth of subcutaneous NK-S1 xenografts, intraperitoneal (IP) delivery of cyclophosphamide caused complete tumor regression; this tumor regression was associated with apoptosis, upregulation of activated caspase-3, and cleaved Poly(ADP-ribose) polymerase (PARP). In an IP model of NK lymphoma, cyclophosphamide also prolonged the survival of mice and potently inhibited tumor dissemination and ascites formation. Our data suggest that the NK-S1 xenograft is a useful tool for screening preclinical drugs, and cyclophosphamide may be a useful drug for the treatment of this disease.

Presence of a high-grade component in gastric mucosa-associated lymphoid tissue (MALT) lymphoma is not associated with an adverse prognosis.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B cell lymphoma (DLBCL) show a spectrum of disease characterized by varying proportions of low-grade and high-grade components. While the natural history and optimum treatment for low-grade gastric MALT lymphoma and DLBCL is well established, the prognosis and optimal treatment of patients with both low- and high-grade components is not well established. The purpose of our study was to evaluate the clinical characteristics, survival outcomes, and prognostic factors of patients with gastric MALT lymphoma and gastric DLBCL. A retrospective review of patients with gastric MALT lymphoma, gastric DLBCL, or MALT lymphoma with a high-grade component treated at our centers from 1994 to 2006 was performed. Patients were divided into three categories: “pure MALT lymphoma,” “MALT lymphoma with high-grade component” (mixed), and “pure DLBCL.” Seventy-six patients were included in our study—26 with pure MALT, 22 with MALT with high-grade component (“mixed”), and 28 with pure DLBCL. Pure MALT lymphoma and mixed lymphoma patients had similar clinical characteristics, whereas pure DLBCL patients had less favorable disease characteristics with significantly poorer performance status, higher number of extranodal sites of disease, higher stage, and larger proportion of bone marrow involvement and international prognostic index (IPI) scores compared with mixed lymphoma. The majority of mixed lymphoma (72.7%) and DLBCL patients (71.4%) were treated with chemotherapy. Of patients receiving chemotherapy, a higher proportion of mixed lymphoma and DLBCL patients received anthracycline-based combination chemotherapy regimens compared with MALT lymphoma (73% vs 71% vs 8%) whereas the proportion of mixed lymphoma and DLBCL patients was similar (pu2009=u20090.919). At a median follow-up of 37xa0months, the 5-year overall survival was 66.9%. The 5-year overall survival was 78% for MALT lymphoma, 84% for mixed lymphoma, and 45% for DLBCL. On univariate analysis, DLBCL histology, age, performance status, serum albumin, lactate dehydrogenase, bone marrow, number of extranodal sites, stage, and IPI score were prognostic for inferior survival. On multivariate analysis, DLBCL histology remained significantly prognostic for inferior survival, independent of chemotherapy regimen (hazard ratio (HR) 6.66, 95% confidence interval (CI) 2.01–21.41, pu2009=u20090.001). Mixed histology was not prognostic for inferior survival (HR 1.13, 95% CI 0.28–4.54, pu2009=u20090.868). Other factors prognostic for inferior survival were serum albumin <37xa0g/L (HR 3.22, 95% CI 1.11–13.22, pu2009=u20090.034) and treatment with non-cyclophosphamide, doxorubicin, vincristine, and prednisolone chemotherapy (HR 4.89, 95% CI 1.67–14.36, pu2009=u20090.004). In conclusion, the clinical characteristics of mixed histology MALT lymphoma are similar to low-grade MALT lymphoma and significantly different from pure DLBCL. The prognosis of mixed histology MALT lymphoma is significantly better than pure DLBCL, independent of IPI and chemotherapy regimen, and pure DLBCL histology is independently prognostic of inferior survival outcome.

A promising new regimen for the treatment of advanced extranodal NK/T cell lymphoma

Extranodal NK/T cell lymphoma (ENKTL) is a distinct entity in the World Health Organization (WHO) classifi cation that is almost always associated with Epstein-Barr virus (EBV) infection and is more common among Asians. Although local radiotherapy is fairly effective in controlling early stage ENKTL, prognosis is dismal for patients with advanced stage ENKTL [1]. Currently, there is no standard fi rst line therapy for the treatment of advanced ENKTL. Anthracyclinebased regimens such as CHOP (cyclophosphamide, doxorubicin, vinciristine and prednisolone) yield dismal response rates ( 15%), partly because the neoplastic NK cells over-express p-glycoprotein, a mediator of the multidrug resistance (MDR) phenotype [2]. Other novel regimens incorporating L-asparaginase have reported better results [3] but await further confi rmation. We present a 30-year-old lady with advanced ENKTL who achieved complete response with a novel treatment regimen after progressing through L-asparaginase based chemotherapy. Our patient presented with a fi ve month history of fever, left eye redness and neck swelling. Computed tomography (CT) revealed generalized lymphadenopathy involving cervical, axillary, paratracheal, para-aortic, iliac and inguinal nodes as well as massive hepatosplenomegaly with splenic infarcts. Magnetic resonance imaging (MRI) brain/orbits showed no intracranial disease. The EBV DNA titre at diagnosis was 11 297 copies/ml. Biopsies taken from the nasopharyngeal soft tissue mass and the left submandibular lymph node revealed a neoplastic lymphoid population that expressed the pan-T cell markers CD2 and CD3, the NK cell marker CD56 and the cytotoxic molecule TIA1, with in situ hybridization for EBV encoded RNA (EBER) strongly positive. Bone marrow trephine biopsy revealed similar histological fi ndings. The patient thus had Stage IV nasal ENKTL, with an international prognostic index (IPI) score of 3 (elevated lactate dehydrogenase, advanced Ann Arbor Stage and multiple extranodal disease sites). She was started on an L-aspariginase based regimen that comprised dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide (SMILE), a combination that had previously shown promising results in Phase I studies for patients with advanced or refractory ENKTL [2]. The chemotherapy was given over 14 days with growth factor support, and repeated every 28 days. Disease response was evaluated clinically, radiologically with positron emission tomography (PET)-CT, and with serial EBV DNA titres. Despite initial response, there was disease progression following cycle 3 of SMILE, with rising EBV DNA titres. Her treatment was also complicated by methotrexate retention and prolonged neutropenia. Treatment was then switched to a novel regimen comprising bortezomib, gemcitabine, ifosfamide and oxalipaltin (B-GIFOX) given over four days with growth factor support, repeated every two weeks. PET CT after two cycles revealed near complete response, with EBV titres rendered undetectable for two consecutive readings (see Figure 1). The chemotherapy was well tolerated with no signifi cant hematologic or extra-hematologic toxicities. The patient received a total of four cycles of chemotherapy with a progression free survival of two months.

High incidence of nasopharyngeal cancer： similarity for 60% of mitochondrial DNA signatures between the Bidayuhs of Borneo and the Bai-yue of Southern China

Populations in Southern China (Bai-yue) and Borneo (Bidayuh) with high incidence of nasopharyngeal cancer (NPC) share similar mitochondrial DNA signatures, supporting the hypothesis that these two populations may share the same genetic predisposition for NPC, which may have first appeared in a common ancestral reference population before the sea levels rose after the last ice age.

Abstract 1824: Sun exposure and the risk of malignant lymphoma in an Asian population: The Singapore Lymphoma Study

INTRODUCTION Recent epidemiological studies have reported an inverse association between sun exposure and Non-Hodgkin lymphoma (NHL) which may be related to vitamin D or other factors, but these studies have been conducted almost exclusively in the Western countries, and in temperate locations. METHODS The Singapore Lymphoma Study is a hospital-based, case-control study conducted in Singapore between Feb 2005 and Dec 2008. Singapore residents (men and women, ethnic Chinese/Malays/Indians) aged 18 to 90 formed the study population. Detailed information on outdoor activities under sun (for recreational or occupational purposes) during childhood and in adulthood, skin colour and sun sensitivity, and other information on other possible risk factors were collected in personal interviews. A total of 543 incident malignant lymphomas including 74 Hodgkin9s lymphoma (HL), 403 B-cell and 61 T and NK-cell NHL and 5 others, and 830 controls were recruited. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression analysis, adjusted for age, gender, ethnicity, and housing types as surrogate for social economic status. RESULTS Skin colour and sun sensitivity did not show any association with risk of malignant lymphoma, after adjusting for ethnicity. We observed a reduced overall risk of NHL (but not HL) among subjects who reported spending time outdoors regularly, especially on weekends/rest days. A lower risk of NHL was associated with recreational sun exposure in childhood non-school days (OR 0.7, 95% CI 0.5-0.9) and in adulthood weekends/rest days (OR 0.8, 95%CI 0.6-1.0), and the observed association was significant in females when stratified by gender. In addition, occupational sun exposure in males was inversely associated with the risk of NHL (OR 0.7, 95%CI 0.5-1.0). Cumulative working time outside under sun appeared unrelated to NHL overall. The associations were more consistently observed in B-cell NHL subtypes (OR 0.6, 95%CI 0.5-0.8), in diffuse large B-cell lymphoma (OR 0.6, 95%CI 0.5-0.9) and mucosal-associated lymphoid tissue lymphoma (OR 0.5, 95%CI 0.2-1.0), than in T-cell NHL. CONCLUSION As the first case-control lymphoma study in Asia, our data are consistent with an inverse association between intermittent sun exposure and NHL in this study population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1824.