Khai Mun Lee

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

PURPOSE The 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. PATIENTS AND METHODS Between 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. RESULTS Distant 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). CONCLUSION This 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.

Randomized Double-Blind Trial of Combined Modality Treatment With or Without Amifostine in Unresectable Stage III Non–Small-Cell Lung Cancer

PURPOSE Greater toxicities have been recognized to be a consequence of combined chemotherapy and radiotherapy in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This study was designed to determine if the use of amifostine could reduce treatment-related toxicities associated with the use of paclitaxel plus carboplatin and thoracic radiotherapy. PATIENTS AND METHODS Sixty patients with unresectable stage III NSCLC were treated with two cycles of paclitaxel 175 mg/m2 and carboplatin (area under the time-concentration curve = 6), followed by thoracic radiotherapy (64 Gy) with concurrent weekly paclitaxel 60 mg/m2. Patients were randomly assigned to receive 740 mg/m2 of amifostine (arm A) or placebo (arm B) before each dose of paclitaxel and carboplatin. Treatment-related toxicities were evaluated at each visit and nerve conduction tests were performed before and after treatment for the objective assessment of neurotoxicity. RESULTS There was no significant difference between arms A and B in grade 3 to 4 neutropenia. In all 72 neurophysiological parameters measured, there was no significant difference between the two treatment arms, although there was a trend toward fewer patients showing deterioration in arm A for six of the parameters. Grade 2 to 3 esophagitis occurred in 43% of patients in arm A and in 70% of patients in arm B. The difference of -27% (95% confidence limit = -50%, 0.4%) was not statistically significant. Response rates and survival were also not significantly different between the two arms. CONCLUSION Pretreatment with amifostine showed a trend toward reducing the severity of esophagitis associated with concurrent chemoradiotherapy, but it did not reach statistical significance. There was no significant protective effect on hematologic or neurologic toxicities induced by paclitaxel and carboplatin.

Concurrent chemoradiotherapy followed by adjuvant chemotherapy in Asian patients with nasopharyngeal carcinoma: toxicities and preliminary results.

PURPOSE Nasopharyngeal carcinoma (NPC) is endemic in Singapore. Nearly 60% of the patients diagnosed with NPC will present with locally advanced disease. The North American Intergroup study 0099 reported improved survival outcome in patients with locally advanced NPC who received combined chemoradiotherapy when compared to radiotherapy alone. Hence we explored the feasibility and efficacy of a similar protocol in our patients. METHODS AND MATERIALS Between June 1996 and December 1997, 57 patients were treated with the following schedule as described. Radical radiotherapy (RT) of 66-70 Gy to the primary and neck with cisplatin (CDDP) 25 mg/m2 on days 1-4 given by infusion over 6-8 hours daily on weeks 1, 4, and 7 of the RT. This is followed by a further 3 cycles of adjuvant chemotherapy starting from week 11 from the first dose of radiation (CDDP 20 mg/m2/d and 5-fluorouracil [5-FU] 1 gm/m2/d on days 1-4 every 28 days). RESULTS The majority of patients (68%) had Stage IV disease. About 54% of patients received all the intended treatment; 75% received all 3 cycles of CDDP during the RT phase and 63% received all three cycles of adjuvant chemotherapy. The received dose intensity of CDDP and 5-FU of greater than 0.8 was achieved in 58% and 60% of the patients respectively. Two treatment-related deaths due to reactivation of hepatitis B and neutropenic sepsis respectively, were encountered. At median follow-up of 16 months, 14 patients had relapsed, 12 systemically and 2 loco-regionally. CONCLUSION Due to the acceptable tolerability of such a protocol in our cohort of patients, we have embarked on a Phase III study to confirm the results of the 0099 Intergroup study in the Asian context.

Management of endometrial cancer in Asia: consensus statement from the Asian Oncology Summit 2009

Endometrial cancer is one of the gynaecological cancers that carries good overall prognosis because it is often detected at early stages of disease. The International Federation of Gynecology and Obstetrics replaced clinical staging with surgical staging in 1988 and updated the system in 2009. Controversies remain regarding the recommended screening protocol for women with a high risk of endometrial cancer, the role and benefit of retroperitoneal lymph-node dissection, the necessity of ovarian resection, the benefit and type of adjuvant radiation therapy, and the safety of hormone-replacement therapy after treatment. This article reviews the available evidence for optimum management of endometrial cancer and how management strategies can be applied in Asian countries with different levels of health-care resource availability and economic development. An overview of the literature for endometrial-cancer screening, diagnosis, and management is discussed. Consensus statements are formulated on the basis of basic, limited, enhanced, and maximum health-care resource availability, using the framework provided by the Breast Health Global Initiative.

Patients’ preference for radiotherapy fractionation schedule in the palliation of symptomatic unresectable lung cancer†

The palliative radiotherapeutic management of unresectable non‐small‐cell lung cancer is controversial, with various fractionation (Fx) schedules available. We aimed to determine patient’s choice of Fx schedule after involvement in a decision‐making process using a decision board. A decision board outlining the various advantages and disadvantages apparent in the Medical Research Council study of Fx schedules (17 Gy in two fractions vs 39 Gy in 13 fractions) was discussed with patients who met Medical Research Council eligibility criteria. Patients were then asked to indicate their preferred Fx schedules, reasons and their level of satisfaction with being involved in the decision‐making process. Radiation oncologists (RO) could prescribe radiotherapy schedules irrespective of patients’ preferences. Of 92 patients enrolled, 55% chose the longer schedule. English‐speaking patients were significantly more likely to choose the longer schedule (P = 0.02, 95% confidence interval: 1.2–7.6). Longer Fx was chosen because of longer survival (90%) and better local control (12%). Shorter Fx was chosen for shorter overall treatment duration (80%), cost (61%) and better symptom control (20%). In all, 56% of patients choosing the shorter schedule had their treatment altered by the treating RO, whereas only 4% of patients choosing longer Fx had their treatment altered (P < 0.001). Despite this, all (100%) patients were satisfied with being involved in the decision‐making process. The decision board was useful in aiding decision‐making, with both Fx schedules being acceptable to patients. Interestingly, despite the longer average survival associated with longer Fx, nearly half of the patients believed that this was not as important as a shorter duration of treatment and lower cost. Despite patients’ preferences, there were significant alterations of preferred schedules because of RO’s own biases.

Outcomes of Adjuvant Chemoradiotherapy After a Radical Gastrectomy and a D2 Node Dissection for Gastric Adenocarcinoma

Purpose:Intergroup 0116 (INT-0116) established adjuvant chemoradiation as the standard of care for resected high-risk adenocarcinoma of the stomach in the United States. However, adjuvant chemoradiation remains controversial in many parts of Asia and Europe, where patients tend to undergo a more thorough D2 dissection. In INT-0116, 90% of patients had a limited or inadequate node dissection (D0 or D1). Also, 17% of patients in the chemoradiation arm had to discontinue treatment because of toxicities. The objectives of this retrospective study are to report the clinical outcomes of a cohort of patients who were mostly treated with a D2 node dissection and received adjuvant chemoradiation as per INT-0116, and the toxicities of chemoradiation in the context of more aggressive surgery. Methods:After the results of INT-0116 became apparent, we adopted an institutional policy whereby patients who would otherwise fit the inclusion criteria of INT-0116 received adjuvant chemoradiation. Between March 1999 and November 2004, 70 consecutive patients with pathologic stage T3, T4, or node-positive disease were treated according to the chemoradiation arm of INT-0116. Patients received intravenous 5-fluorouracil 425 mg/m2 and leucovorin 20 mg/m2 in cycles 1, 3, and 4. Concurrent chemoradiation was given in cycle 2 and consisted of bolus 5-fluorouracil and leucovorin and radiotherapy (45 Gy over 25 fractions in 5 weeks). All patients were operated on by dedicated Japan-trained Surgical Oncologists. Results:Sixty-seven patients (96%) had a D2 nodal dissection. Sixty-five patients (93%) had negative pathologic margins (R0 resection) and 5 (7%) had microscopically involved margins (R1 resection). The median follow-up was 27 months (range, 10.1–60.3). The 3-year overall survival, disease-free survival, and local control were 60.6%, 54.1%, and 84.3%, respectively. Of the 30 patients who relapsed, 5 (17%) had isolated locoregional recurrences only. The National Cancer Institute – Common Terminology Criteria version 3.0 acute grade 3 or 4 gastrointestinal and hematological toxicity rates were 15.7% and 4.3%, respectively. Toxicities led to chemotherapy dose-reductions in 18 patients and dose-delay in 19 patients. Including chemotherapy dose-reductions and delays, 66 patients (94%) completed the entire chemoradiation regimen. There were no toxicity-related deaths. Conclusion:In our cohort of 70 patients who had a more thorough D2 node dissection, adjuvant chemoradiation was well tolerated with acceptable toxicities and reasonable tumor control.

Complementary and alternative medicine practices among Asian radiotherapy patients.

Aim:  To describe the prevalence, expectations and factors associated with the use of complementary and alternative medicine (CAM) in Asian radiotherapy patients.

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.

Phase III randomized trial of radiotherapy versus concurrent chemo-radiotherapy followed by adjuvant chemotherapy in patients with AJCC/UICC (1997) stage 3 and 4 nasopharyngeal cancer of the endemic variety

5500 Background: Intergroup 00-99 study for Nasopharyngeal Cancer (NPC) showed a benefit of adding chemotherapy to radiotherapy (RT). This study aimed to confirm the findings of 00-99 in patients from an endemic region. Specific objectives were to compare the rates of distant metastases, disease free (DFS) and overall survival (OS). METHODS 221 patients were randomized between 9/1997 to 5/2003. 220 are included in this analysis. 109 received radiotherapy (R) alone and 111 had chemo-radiotherapy (C). Patients were all staged by CT / MR, CXR, liver and bone imaging. All had AJCC(1997) Stage 3 or 4 disease as well as WHO Type II or III histology. All patients (C & R) received 70Gy in 7 wks using standard RT portals and techniques. Those on (C) received concurrently cisplatin (25mg/m2 D1-4) on wks 1,4 and 7 of RT and adjuvant cisplatin (20mg/m2 D1-4) and 5FU (1000mg/m2 D1-4) every 4 wks (wk 11, 15, 19) for 3 cycles following completion of RT. RESULTS All patients were followed up for a minimum of 6 mths. 45% had Stage III and 54% Stage IV disease. 2 patients were non-compliant in the R arm. In the C arm, 40% had dose reduction / reduced cycles of chemo during the concurrent phase; 31% did not receive any adjuvant chemotherapy; and another 27% had dose reduction / reduced or delayed cycles of chemo. 6 patients had their RT dose reduced. To date, 59 patients (37 R, 22 C) have died. Cause of death was disease-related for 51 (32 R, 19 C) . Median survival time for R was 49.9 months, but this has not been reached for those on C. 2-year DFS rates were 62% for R and 76% for C. Hazard ratio (HR) was 0.67 (95% CI: 0.42 to 1.08, p = 0.10). 2-year cumulative incidence rate for distant metastasis was 28% (95% CI 18% to 37%) for R and 14% (95% CI 7% to 21%) for C. (p = 0.034). 2-year OS rates were 77% for R and 85% for C respectively. The HR estimate was 0.54 (95% CI: 0.32 to 0.89, p = 0.02). CONCLUSIONS This trial confirms the results of Intergroup 0099 and the results are shown to be applicable to the endemic type of NPC. This study also confirms that chemotherapy improves distant control in NPC. No significant financial relationships to disclose.

Hepatitis B reactivation in a patient receiving radiolabeled rituximab

Following the establishment of the chimeric anti-CD20 antibody, rituximab, for the treatment of CD20-positive non-Hodgkin’s lymphoma (NHL), it has now been shown that the radiolabeled monoclonal antibody results in higher complete and overall response rates than the non-labeled counterpart [1]. There are two approved radioimmunotherapy (RIT) agents for treatment of relapsed or refractory indolent NHL. The role of RIT earlier in the disease course, in different disease settings and in conjunction with other forms of therapy is being tested [2]. Hence, an increasing role of RIT as part of standard NHL treatment regimes is likely. We now present a patient who developed hepatitis B reactivation after receiving RIT. A 48-year-old Chinese female with chronic hepatitis B virus (HBV) infection was diagnosed with stage IV follicular lymphoma in May 1996 and treated with six cycles of cyclophosphamide, vincristine and prednisolone (CVP). She relapsed in June 1999 and progressed despite multiple lines of chemotherapy, including rituximab in June 2000 and three cycles of cyclophosphamide, doxorubicin and prednisolone (CHP) (March to May 2001). The latter was complicated by hepatitis B reactivation for which she received lamivudine (June 2001 to March 2002). On further progression, she was treated with iodine 131-labeled rituximab in May 2002, receiving 75 cGy total body dose. Table 1 shows the blood count trend before and after infusion of radiolabeled rituximab. Her pre-RIT transaminases were normal, HbsAg positive, HBeAg negative, anti-HBeAb positive and HBV DNA <0.7 MEq/ml serum (Bayer). She attained good partial remission of lymphoma with radiolabeled rituximab. Her HBV DNA remained undetectable on serial monthly assays up till and including August 2002. In September 2002, she developed hepatitis B reactivation-raised alanine transaminase (75 U/l) and aspartate transaminase (42 U/l), HBV DNA 40.6 MEq/ml, HBeAg negative and antiHBeAb positive. Lamivudine was started upon reactivation resulting in full recovery. The lymphoma, however, progressed 5 months post-RIT. Hepatitis B is endemic in South East Asia. Although the frequency of hepatitis B reactivation with use of rituximab is unknown, there have been several reported cases of fatal fulminant hepatic failure in patients who received rituximab concurrently with chemotherapy [3, 4]. This report shows that the use of radiolabeled monoclonal antibody as a single agent is sufficient to induce hepatitis B virus reactivation, albeit in a heavily pretreated patient. Interestingly, our patient developed hepatitis reactivation only with RIT and not with rituximab alone. This was likely due to the prolonged period of lymphopaenia and immune suppression (see Table 1). Detection and monitoring of chronic HBV infection is important in the use of RIT. Y. L. Soong . K. M. Lee . S. Li Er Loong (*) Department of Radiation Oncology, National Cancer Centre, 11 Hospital Drive, Singapore, Singapore, 169610 e-mail: trdlle@nccs.com.sg Tel.: +65-63214204 Fax: +65-62228675