W.T. Ng

Factors contributing to the efficacy of concurrent–adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma: Combined analyses of NPC-9901 and NPC-9902 Trials

BACKGROUND The current standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) was conventional-fractionation radiotherapy plus concurrent-adjuvant chemotherapy as recommended by the Intergroup-0099 Study. This combined analysis of the NPC-9901 and the NPC-9902 Trials aims to provide more comprehensive data to evaluate the efficacy of the Intergroup-0099 regimen and the contributing factors. METHODS Eligible patients with stage III-IVB non-keratinizing NPC were randomly assigned to radiotherapy-alone (RT(i) group: 218 patients) or chemoradiotherapy (CRT(i) group: 223 patients) using cisplatin (100mg/m(2)) for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg/m(2)/day for 4 days) for three cycles. The median follow-up was 6.1 years. FINDINGS Comparison by intention-to-treat showed that the CRT(i) group achieved significant improvement in overall failure-free rate (FFR), locoregional-FFR and cancer-specific survival (p ≤ 0.019); but the improvements for distant-FFR and overall survival (OS) were statistically insignificant (p ≥ 0.14). Further exploratory studies based on actual treatment showed that an additional improvement achieved was a significant gain in OS (CRT(a) versus RT(a) group: 72% versus 63% at 5-year, p=0.037). Multivariate analyses showed that the dose of cisplatin during the concurrent phase had significant impact on locoregional-FFR and OS, while that of fluorouracil during the adjuvant phase was significant for distant-FFR. The 5-year locoregional-FFR for patients who received 0-1, 2 and 3 concurrent cycles were 79%, 88% and 88%, respectively; the corresponding distant-FFR by adjuvant cycles were 68%, 78% and 77%, respectively. INTERPRETATION Our results support the current practice of adding concurrent cisplatin plus adjuvant cisplatin-fluorouracil to radiotherapy for treating patients with locoregionally advanced NPC. The concurrent phase is important for locoregional control and survival, cisplatin 200mg/m(2) in two concurrent cycles might be adequate. Additional chemotherapy using fluorouracil-containing combination contributed to improving distant control.

The battle against nasopharyngeal cancer

This is a review of the evolving efforts to understand and combat nasopharyngeal carcinoma (NPC), a most peculiar cancer with a distinctly skewed geographic and ethnic distribution. Multifactorial etiology with dynamic interplay of genetic predisposition, Epstein-Barr virus (EBV) infection and environmental carcinogens is suggested. With changing lifestyle in Hong Kong, the age-standardized incidence rate has decreased by more than 50% during the past 30 years. The advent of megavoltage radiotherapy has transformed this once lethal cancer into one that is readily curable. Advances in technology and addition of chemotherapy have led to gratifying improvements. Overall survival exceeding 75% at 5 years could now be achieved; series using advanced technique with intensity-modulation consistently achieved excellent locoregional control. Studies are on-going to develop more potent systemic therapy for distant control. Serious late toxicities remain a serious concern demanding further improvement in radiotherapy technique and optimization of dose fractionation. Translational researches are increasingly important for the ideal goals of prevention, early detection and more accurate prognostication/prediction to work toward personalized medicine. The battle against NPC is one of the most fascinating successes in oncology, it is highly hopeful that with international collaborations and concerted efforts, we can totally conquer this cancer.

MAJOR LATE TOXICITIES AFTER CONFORMAL RADIOTHERAPY FOR NASOPHARYNGEAL CARCINOMA-PATIENT-AND TREATMENT-RELATED RISK FACTORS

PURPOSE To retrospectively analyze the factors affecting late toxicity for nasopharyngeal carcinoma. METHODS AND MATERIALS Between 1998 and 2003, 422 patients were treated with a conformal technique with 2-Gy daily fractions to a total dose of 70 Gy. Conventional fractionation (5 fractions weekly) was used in 232 patients and accelerated fractionation (6 fractions weekly) in 190 patients. One hundred seventy-one patients were treated with the basic radiotherapy course alone (Group 1), 55 patients had an additional boost of 5 Gy in 2 fractions (Group 2), and 196 patients underwent concurrent cisplatin-based chemotherapy (Group 3). RESULTS The 5-year overall toxicity rate was significantly greater in Group 3 than in Group 1 (37% vs. 27%, p = 0.009). Although the overall rate in Group 2 was not elevated (28% vs. 27%, p = 0.697), a significant increase in temporal lobe necrosis was observed (4.8% vs. 0%, p = 0.015). Multivariate analyses showed that age and concurrent chemotherapy were significant factors. The hazard ratio of overall toxicity attributed to chemotherapy was 1.99 (95% confidence interval, 1.32-2.99, p = 0.001). The mean radiation dose to the cochlea was another significant factor affecting deafness, with a hazard ratio of 1.03 (95% confidence interval, 1.01-1.05, p = 0.005) per 1-Gy increase. The cochlea that received >50 Gy had a significantly greater deaf rate (Group 1, 18% vs. 7%; and Group 3, 22% vs. 14%). CONCLUSION The therapeutic margin for nasopharyngeal carcinoma is extremely narrow, and a significant increase in brain necrosis could result from dose escalation. The significant factors affecting the risk of deafness included age, concurrent chemoradiotherapy, and greater radiation dose to the cochlea.

Sensorineural Hearing Loss After Treatment of Nasopharyngeal Carcinoma: A Longitudinal Analysis

PURPOSE To analyze the effects of radiotherapy (RT) and chemotherapy in relation to sensorineural hearing loss (SNHL) after contemporary treatment of nasopharyngeal carcinoma. METHODS AND MATERIALS A total of 87 nasopharyngeal carcinoma patients were treated with RT or chemoradiotherapy using either three-dimensional conformal RT or intensity-modulated RT between 2004 and 2005. Tympanometry and pure-tone audiogram assessments were performed before treatment and then serially at 6-month intervals. The dose-volume data of the cochlea were analyzed. The effects of cisplatin administered in concurrent and nonconcurrent phases was explored. RESULTS Of the 170 eligible ears, RT (n = 30) and chemoradiotherapy (n = 140) resulted in 40% (n = 12) and 56.4% (n = 79) persistent SNHL (> or = 15 dB loss), respectively, after a median follow-up of 2 years. SNHL at a high frequency was more frequent statistically in the chemoradiotherapy group than in the RT-alone group (55% vs. 33.3%, p < 0.01), but not at a low frequency (7.9% vs. 16.7%, p = 0.14). Within the chemoradiotherapy group, the mean cochlea dose and concurrent cisplatin dose were important determinants of high-frequency SNHL, with an odds ratio of 1.07/Gy increase (p = 0.01) and an odds ratio of 1.008/mg/m(2) increase (p < 0.01), respectively. Age, gender, and nonconcurrent cisplatin dose were not statistically significant factors. A mean radiation dose to the cochlea of <47 Gy would result in <15% of patients developing severe (> or = 30 dB) high-frequency SNHL. CONCLUSION The results of our study have shown that high-frequency SNHL is significantly related to the mean cochlea dose and the concurrent cisplatin dose. A mean dose constraint of 47 Gy to the cochlea is recommended to minimize SNHL after chemoradiotherapy.

Screening for family members of patients with nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is well known for its peculiarly skewed distribution with highest incidence in Southern Chinese population. Familial aggregation is evident, hence screening for early detection is offered by oncology centers in Hong Kong to first‐degree relatives of patients with NPC. During the period 1994–2001, 929 family members were screened in our center. The screenees were advised to attend an annual examination that includes serological test against Epstein Barr Virus (EBV), physical examination to exclude cervical lymphadenopathy and cranial nerve palsy, and endoscopic examination of the nasopharyngeal region. Two different methods were used for the serology test: indirect immuno‐fluorescent (IF) test for IgA against viral capsid antigen; and starting in 1997 enzyme‐linked immunosorbent assay (ELIZA) against nuclear antigen and viral capsid antigen. Twelve cases of nasopharyngeal carcinoma were diagnosed, giving a detection rate of 5/1,155 (433/100,000) person‐year for male and 7/1,404 (499/100,000) person‐year for female participants observed. The corresponding average annual incidence in Hong Kong during this period was 24.1 and 9.6 per 100,000, respectively. Forty‐one percent of these detected cases had Stage I disease, whereas only 2% of patients referred to the department for primary treatment presented with such early disease. Six cases were detected at first visit, and all were EBV‐positive. Another 78 screenees with positive serology at first visit were followed up for 204 person years, and thus far NPC was detected in 3 after an interval of 6–32 months. Of the 845 initially EBV‐negative screenees followed up for 2,337 person‐years, NPC was detected in 3 after an interval of 12–45 months. One showed sero‐conversion at the time of diagnosis. We conclude that family members of known patients do show a substantially higher risk of developing NPC, and regular screening by current method improves the chance of early detection.

The strength/weakness of the AJCC/UICC staging system (7th edition) for nasopharyngeal cancer and suggestions for future improvement

BACKGROUND AND PURPOSE To evaluate the current AJCC/UICC staging system (7th edition) for nasopharyngeal carcinoma and to explore for future improvement. MATERIALS AND METHODS A total of 985 patients, initially staged with preceding 5-6th edition, were retrospectively re-staged with the 7th edition. All were assessed by magnetic resonance imaging, and all 945 non-disseminated patients were irradiated with conformal/intensity-modulated technique. RESULTS Staging factors by both the 5-6th edition and the 7th edition were strongly significance for important endpoints (p<0.001). Down-staging of the previous T2a to T1 and, stages IIA to I in the 7th edition was appropriate. However, the impacts on overall stage distribution and prognostication were minimal. Further down-staging of the current T2 to T1, N2 to N1, stages II to I, and merging of N3a and N3b, stages IVA and IVB were suggested. With the 7th edition, the 5-year disease-specific survival (DSS) was 100% for stage I, 95% for II, 90% for III, 67% for IVA, 68% for IVB and 18% for IVC. The corresponding DSS for the proposed stages I, II, III and IV were 95%, 86%, 67% and 18%, respectively. CONCLUSIONS The changes introduced in the 7th edition were appropriate, but the magnitude of improvement was minimal. With improving results by modern management, further simplification of the staging system is suggested. The proposed system could lead to more accurate prognostication, further validation is warranted.

Radical radiotherapy for nasopharyngeal carcinoma in elderly patients: The importance of co-morbidity assessment

Elderly patients represent a unique challenge for radical treatment in nasopharyngeal carcinoma (NPC) because of age and co-morbid conditions. We sought to evaluate the outcome of this particular group of patients and to identify key factors affecting treatment outcome. From 1998 to 2008, 990 consecutive NPC patients without distant metastasis were treated with radical radiotherapy with planned total dose >66 Gy. Among them, 103 (10.4%) patients were elderly aged >70 (group A). Their clinical characteristics and outcome were compared with those aged <70 (group B). Mortality at 90 days was used as a proxy of early deaths related to treatment. Co-morbidities were measured by the Adult Co-morbidity Evaluation 27 (ACE-27). Group A presented more commonly with poorer performance status. They showed higher rates of acute reaction, radiotherapy incompletion and mortality at 90 days (7.8% vs. 1.2%, p<0.001). The 5-year overall survival rates were 43.9% and 78.1% for groups A and B, respectively (p<0.001). No difference in failure free survival rates was noted. For group A, ACE-27 was the only predicting factor for mortality at 90 days [ACE-27 2-3 vs. 0-1: HR 15.86 (2.68-93.95), p=0.002], and the most important prognostic factors for overall survival included age, presenting stage and ACE-27 (p<0.05). Elderly NPC patients had poorer tolerance to radiotherapy. Early deaths related to treatment were not uncommon. A reasonable disease control can still be attained after radical radiotherapy for those who were able to survive through the peri-radiotherapy period. Patient selection and treatment approach with reference to ACE-27 should be considered.

If concurrent–adjuvant chemoradiotherapy is beneficial for locoregionally advanced nasopharyngeal carcinoma, would changing the sequence to induction–concurrent achieve better outcome?

IntroductionRadiotherapy (RT) is the primary treatment modality for nasopharyngeal carcinoma, and concurrent–adjuvant chemoradiotherapy (CA-CRT) is regarded as the standard of care for locally advanced disease after survival benefit was demonstrated by randomized clinical trials. However, there remain concerns about the exact magnitude of the benefit and tolerability by such an approach.MethodsThrough an extensive literature review, this paper provides an update on the available data on induction–concurrent chemoradiotherapy (IC-CRT) and a comparison with CA-CRT.ResultsStudies on IC-CRT show that tolerance and compliance to induction chemotherapy are better than adjuvant chemotherapy while the acute toxicity rates are similar. The reported failure-free rates and survival rates are encouraging for IC-CRT. However, part of the improvement might be attributed to better RT techniques, and the exact magnitude of benefit attributed to the induction phase remains uncertain.ConclusionThe strategy with IC-CRT is an appealing option to be considered especially for patients with extensive locoregional disease infiltrating/abutting critical structures. Data from ongoing phase III trials will need to be available before the current standard of CA-CRT is at risk of being replaced.

Trends and patterns of breast conservation treatment in Hong Kong: 1994-2007.

PURPOSE Breast conservation treatment (BCT) was quite unpopular in Hong Kong until the early 1990s, but the trends and patterns of BCT use in the past 14 years have not been studied since. The purpose of this study was to identify the latest trends and patterns. METHODS AND MATERIALS All consecutive cases of female breast cancer referred to a community oncology center in Hong Kong between 1994 and 2007 were retrospectively reviewed. Of the 2,375 women with T1-2 invasive breast cancer who underwent surgery, 1,137 (48%) had T1 (</=2 cm) disease and 1,238 (52%) had T2 (>2 cm-</=5 cm) disease. Median patient age was 51 years (range, 24-95 years); 65% patients had their surgery in public hospitals. RESULTS Of the total patient cohort, 2,153 (91%) patients presented with palpable breast masses and only 104 (4%) with mammographically detected cancers. Overall, 721 (30%) and 1,654 (70%) patients underwent BCT and mastectomy, respectively. There was no significant increase in the BCT rates (31%, SD 5%; p = 0.804) or mammographic detection rates (5%, SD 1%; p = 0.125) in Hong Kong between 1994 and 2007. In multivariate analyses, age </=50 years (OR 2.479; p < 0.001), mammographically detected tumors (OR 1.868; p = 0.007), T1 tumors (OR 3.159; p < 0.001), surgeries in private hospitals (OR 1.288; p = 0.018), and negative nodal status (OR 1.886; p < 0.001) were independent factors predictive of a higher likelihood of a woman having BCT. CONCLUSIONS Our results indicate a satisfactory acceptance of BCT by patients who are young and have small tumors, node-negative disease, or surgery in private hospitals. However, the continuing unpopularity of breast screening is likely a major factor limiting the broad use of BCT.

A phase II study of pemetrexed combined with cisplatin in patients with recurrent or metastatic nanopharyngeal carcinoma

Pemetrexed is a novel chemotherapy agent with good efficacy and toxicity profiles. This phase II study aimed at evaluating its use in combination with cisplatin for recurrent or metastatic nasopharyngeal carcinoma (NPC). All participating patients had metastatic or recurrent NPC with prior treatment by platinum-based chemotherapy. The study regimen comprised of pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2), repeated 3-weekly for 4 cycles. Efficacy evaluation was based on both radiological and biochemical responses. Patients with no progressive disease and good tolerance were given another 2-4 cycles. Fifteen patients were treated for a total of 4-8 cycles (median, 6 cycles); 9 had distant metastases and 6 had loco-regional recurrences only. Reduction of DNA copies of EB virus by ≥50% was observed in 93% accessible patients, with 21% of them being biochemical complete response (CR). Radiologically, 1 (7%) patient achieved CR, 2 (13%) achieved partial response and 8 (53%) had stable diseases. The median time to progression was 30 weeks. Treatment was well tolerated with only 1 (7%) patient developing grade 4 toxicity (of anemia). The most common grade 3 toxicities were neutropenia (27%) and anemia (20%). The baseline mean total QOL scores (as measured with FACT-H&N version 4) was 100.4 and showed no significant change after the fourth cycle (95.6, p=0.20) and sixth cycle (91.9, p=0.15). Pemetrexed in combination with cisplatin is a well tolerated regimen with encouraging efficacy for metastatic and recurrent NPC. Further evaluation of its role in the management of NPC is warranted.