Oscar S.H. Chan

Clinical Outcomes and Patterns of Failure After Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma

PURPOSE To study and report the clinical outcomes and patterns of failure after intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS The treatment outcomes of NPC patients treated with IMRT at Pamela Youde Nethersole Eastern Hospital between 2005 and 2007 were reviewed. The location and extent of locoregional failures were transferred to the pretreatment planning computed tomography for dosimetry analysis. Statistical analyses were performed on dose coverage and locoregional failures. RESULTS A total of 193 NPC patients were analyzed; 93% had Stage III/IV disease. Median follow-up was 30 months. Overall disease failure (at any site) developed in 35 patients. Among these, there were 23 distant metastases, 16 local failures, and 9 regional failures. Four of the locoregional failures were marginal. Dose conformity with IMRT was excellent. Patients with at least 66.5 Gy to their target volumes had significantly less locoregional failure. The 2-year local progression-free, regional progression-free, distant metastasis-free, and overall survival rates were 95%, 96%, 90%, and 92%, respectively. CONCLUSIONS Intensity-modulated radiotherapy provides excellent locoregional control for NPC. Distant metastasis remains the most difficult challenge, and more effective systemic agents should be explored for patients presenting with advanced locoregional diseases.

Evolution of treatment for nasopharyngeal cancer – Success and setback in the intensity-modulated radiotherapy era

BACKGROUND AND PURPOSE To assess the therapeutic gains and setbacks as we evolved from the 2-dimensional radiotherapy (2DRT) to conformal 3-dimensional (3DRT) and to intensity-modulated (IMRT) era. MATERIALS AND METHODS 1593 consecutive patients from 1994 to 2010 were retrospectively analyzed. Evolving changes in the different era included advances in staging investigation, radiotherapy technique, dose escalation, and use of chemotherapy. RESULTS The 3DRT era achieved significant improvement in local failure-free rate (L-FFR), disease-specific survival (DSS) and overall survival (OS). Neurological damage and bone/soft tissue necrosis were significantly reduced. However, the improvement in distant failure-free rate (D-FFR) was insignificant, and more hearing impairment occurred due to chemotherapy. Significantly higher D-FFR was achieved in the IMRT era, but L-FFR did not show further improvement. 5-Year DSS increased from 78% in the 2DRT, to 81% in the 3DRT, and 85% in the IMRT era, while the corresponding neurological toxicity rate decreased from 7.4% to 3.5% and 1.8%. CONCLUSIONS Significant improvement in survival and reduction of serious toxicity was achieved as we evolved from 2DRT to 3DRT and IMRT era; the therapeutic ratio for all T-categories improved with more conformal techniques. Improvements in tumor control were attributed not only to advances in RT technique, but also to better imaging and increasing use of potent chemotherapy. However, it should also be noted that hearing impairment significantly increased due to chemotherapy, L-FFR reached a plateau in the 3DRT era, and it is worrisome that the result for T4 remained unsatisfactory. Besides exploring for more potent chemotherapy and innovative methods, the guideline on dose constraint should be re-visited to optimize the therapeutic ratio.

Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma

A current recommendation for locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy with concurrent cisplatin plus adjuvant cisplatin and fluorouracil (PF). In this randomized trial, the authors evaluated the potential therapeutic benefit from changing to an induction‐concurrent chemotherapy sequence, replacing fluorouracil with oral capecitabine, and/or using accelerated rather than conventional radiotherapy fractionation.

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.

The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer – A planning study

PURPOSE To compare the dosimetric performance of three different treatment techniques - conformal radiotherapy (CRT), double arcs volumetric modulated arc therapy (RapidArc, RA) and Hybrid-RapidArc (H-RA) for locally-advanced non-small cell lung cancer (NSCLC). MATERIAL AND METHODS CRT, RA and H-RA plans were optimized for 24 stage III NSCLC patients. The target prescription dose was 60Gy. CRT consisted of 5-7 coplanar fields, while RA comprised of two 204(o) arcs. H-RA referred to two 204(o) arcs plus 2 static fields, which accounted for approximately half of the total dose. The plans were optimized to fulfill the departmental plan acceptance criteria. RESULTS RA and H-RA yielded a 20% better conformity compared with CRT. Lung volume receiving >20Gy (V20) and mean lung dose (MLD) were the lowest in H-RA (V20 1.7% and 2.1% lower, MLD 0.59Gy and 0.41Gy lower than CRT & RA respectively) without jeopardizing the low-dose lung volume (V5). H-RA plans gave the lowest mean maximum spinal cord dose (34.4Gy, 3.9Gy<CRT and 2.2Gy<RA plans) and NTCP of lung. Higher average MU per fraction (addition 52.4MU) was observed with a reduced treatment time compared with CRT plans. CONCLUSION The H-RA technique was superior in dosimetric outcomes for treating locally-advanced NSCLC compared to CRT and RA.

Staging of nasopharyngeal carcinoma – The past, the present and the future

This article reviews the evolution of the International Union Against Cancer/American Joint Committee on Cancer staging system for nasopharyngeal carcinoma. With the increasing availability of newer imaging methods, more sophisticated radiotherapy techniques and rapidly evolving molecular assays, we also examine newer clinical features that might have impact on staging. A new version of the staging system taking into account of some of these factors is also proposed.

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.

The impact of dosimetric inadequacy on treatment outcome of nasopharyngeal carcinoma with IMRT

BACKGROUND AND PURPOSE This study aims to address the relationship between tumor size and dosimetric inadequacy in treating nasopharyngeal carcinoma (NPC), and how it subsequently affects the local control. MATERIAL AND METHODS 444 NPC patients treated with IMRT from 2005 to 2010 were included in the study. The planning aim was to deliver at least 66.5 Gy (i.e. 95% of 70 Gy) to 95% of the primary gross tumor volume (GTV_P) while keeping all the critical neurological organs at risk (OAR) within dose tolerance. Treatment outcome were analyzed according to T stage, GTV_P volume and the degree of under-dosing. RESULTS Disease outcome was related to T stage, GTV_P volume and the degree of under-dosing. The 5-year local failure free survival (LFFS), disease free survival (DFS) and overall survival (OS) for T4 disease were 74%, 50.4% and 63.6% respectively. 48 cm(3) was identified as the critical cut-off GTV_P volume, the large volume group (GTV_P ≥ 48 cm(3)) had lower 5-year DFS (50.4% vs. 76.6%) and OS (65.2% vs. 86.3%, p < 0.001). Most T4 diseases (and some T3) were under-dosed (<66.5 Gy) and an under-dosed GTV_P volume of 3.4 cm(3) was found to be prognostically important. Multivariate analyses showed that the effect of GTV_P volume on LFFR and DFS was outweighed by the degree of under-dosing. CONCLUSIONS Treatment outcome of locally advanced NPC was significantly affected by the volume of under-dosed (<66.5 Gy) GTV_P due to the neighboring neurological structures. A new set of OAR dose constraint and specification is proposed.

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.

The prognostic value of histological typing in nasopharyngeal carcinoma.

We analyzed the relation of histological typing in late stage nasopharyngeal carcinoma (NPC) with clinical outcome and excision repair cross complementation group 1 protein (ERCC1) expression. The biopsy specimens of 259 patients with NPC were reviewed by two pathologists for classification according to 2005 WHO subtypes. The patients were of stage III to IVB and treated with radiotherapy (RT) alone or concurrent-adjuvant chemoradiotherapy (CRT). Expression of ERCC1 protein detected by immunohistochemistry on paraffin sections was correlated with the histological subtypes. There were 10 cases (3.9%) of differentiated non-keratinizing carcinoma compared with 249 cases of conventional undifferentiated carcinoma. The former exhibited more advanced squamous differentiation with 3 cases belonging to the papillary variant. The degree of ERCC1 expression was generally high compared with the median of the cohort. Clinically, the differentiated group fared poorly compared with the undifferentiated group with respect to loco-regional failure-free rate, distant failure-free rate, disease-free survival and overall survival (p≤0.05). Treatment modality of the 10 patients (5 RT, 5 CRT) was similar to the whole cohort. Contrary to general acceptance that differentiation of non-keratinizing NPC had little bearing on prognosis, we demonstrated that in endemic area differentiation in fact conferred a worse prognosis in stage III to IVB patients. There was positive correlation of differentiation with ERCC1 expression. We advocate precise histological typing of NPC in pathology report for prognostic purpose and outcome correlation.