NPC-0501 trial on the value of changing chemoradiotherapy sequence, replacing 5-fluorouracil with capecitabine, and altering fractionation for patients with advanced nasopharyngeal carcinoma.

BACKGROUND: A current recommendation for the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy (RT) with concurrent cisplatin followed by adjuvant cisplatin and 5-fluorouracil (PF). This randomized NPC-0501 trial evaluated the therapeutic effect of changing to an induction-concurrent sequence or accelerated-fractionation sequence, and/or replacing 5-fluorouracil with capecitabine (X). METHODS: Patients with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC initially were randomly allocated to 1 of 6 treatment arms (6-arm full-randomization cohort). The protocol was amended in 2009 to permit centers to opt out of randomization regarding fractionation (3-arm chemotherapy cohort). RESULTS: A total of 803 patients were accrued (1 of whom was nonevaluable) from 2006 to 2012. Based on the overall comparisons, neither changing the chemotherapy sequence nor accelerated fractionation improved treatment outcome. However, secondary analyses demonstrated that when adjusted for RT parameters and other significant factors, the induction-concurrent sequence, especially the induction-PX regimen, achieved significant improvements in progression-free survival (PFS) and overall survival. Efficacy varied among different RT groups: although no impact was observed in the accelerated-fractionation group and the 3-arm chemotherapy cohort, a comparison of the induction-concurrent versus concurrent-adjuvant sequence in the conventional-fractionation group demonstrated a significant benefit in PFS (78% vs 62% at 5 years; P = .015) and a marginal benefit in overall survival (84% vs 72%; P = .042) after adjusting for multiple comparisons. Comparison of the induction-PX versus the adjuvant-PF regimen demonstrated better PFS (78% vs 62%; P = .027) without an increase in overall late toxicity. CONCLUSIONS: For patients irradiated using conventional fractionation, changing the chemotherapy sequence from a concurrent-adjuvant to an induction-concurrent sequence, particularly using induction cisplatin and capecitabine, potentially could improve efficacy without an adverse impact on late toxicity. However, further validation is needed for confirmation of these findings.

Proposal for the 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy.

BACKGROUND: An accurate staging system is crucial for cancer management. Evaluations for continual suitability and improvement are needed as staging and treatment methods evolve. METHODS: This was a retrospective study of 1609 patients with nasopharyngeal carcinoma investigated by magnetic resonance imaging, staged with the 7th edition of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system, and irradiated by intensity-modulated radiotherapy at 2 centers in Hong Kong and mainland China. RESULTS: Among the patients without other T3/T4 involvement, there were no significant differences in overall survival (OS) between medial pterygoid muscle (MP) ± lateral pterygoid muscle (LP), prevertebral muscle, and parapharyngeal space involvement. Patients with extensive soft tissue involvement beyond the aforementioned structures had poor OS similar to that of patients with intracranial extension and/or cranial nerve palsy. Only 2% of the patients had lymph nodes > 6 cm above the supraclavicular fossa (SCF), and their outcomes resembled the outcomes of those with low extension. Replacing SCF with the lower neck (extension below the caudal border of the cricoid cartilage) did not affect the hazard distinction between different N categories. With the proposed T and N categories, there were no significant differences in outcome between T4N0-2 and T1-4N3 disease. CONCLUSIONS: After a review by AJCC/UICC preparatory committees, the changes recommended for the 8th edition include changing MP/LP involvement from T4 to T2, adding prevertebral muscle involvement as T2, replacing SCF with the lower neck and merging this with a maximum nodal diameter > 6 cm as N3, and merging T4 and N3 as stage IVA criteria. These changes will lead not only to a better distinction of hazards between adjacent stages/categories but also to optimal balance in clinical practicability and global applicability.

Prognostic nomogram for refining the prognostication of the proposed 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy.

BACKGROUND: The objective of this study was to develop a nomogram for refining prognostication for patients with nondisseminated nasopharyngeal cancer (NPC) staged with the proposed 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system. METHODS: Consecutive patients who had been investigated with magnetic resonance imaging, staged with the proposed 8th edition of the AJCC/UICC staging system, and irradiated with intensity-modulated radiotherapy from June 2005 to December 2010 were analyzed. A cohort of 1197 patients treated at Fujian Provincial Cancer Hospital was used as the training set, and the results were validated with 412 patients from Pamela Youde Nethersole Eastern Hospital. Cox regression analyses were performed to identify significant prognostic factors for developing a nomogram to predict overall survival (OS). The discriminative ability was assessed with the concordance index (c-index). A recursive partitioning algorithm was applied to the survival scores of the combined set to categorize the patients into 3 risk groups. RESULTS: A multivariate analysis showed that age, gross primary tumor volume, and lactate dehydrogenase were independent prognostic factors for OS in addition to the stage group. The OS nomogram based on all these factors had a statistically higher bias-corrected c-index than prognostication based on the stage group alone (0.712 vs 0.622, P <.01). These results were consistent for both the training cohort and the validation cohort. Patients with <135 points were categorized as low-risk, patients with 135 to <160 points were categorized as intermediate-risk, and patients with ≥160 points were categorized as high-risk. Their 5-year OS rates were 92%, 84%, and 58%, respectively. CONCLUSIONS: The proposed nomogram could improve prognostication in comparison with the TNM stage group. This could aid in risk stratification for individual NPC patients. Cancer 2016;122:3307-3315. © 2016 American Cancer Society.

Chemotherapy for Nasopharyngeal Cancer: Neoadjuvant, Concomitant, and/or Adjuvant.

Nasopharyngeal cancers are unique among other head and neck cancers, not only in epidemiology and histological characteristics, but also on treatment strategies as well. Radiotherapy is the primary treatment due to its radiosensitivity. In locally advanced stages, concurrent chemoradiation has been established to be effective to eradicate the disease and improve survival, in favor of radiotherapy alone. While increasing studies have explored the potential benefit of adding more chemotherapy to the concurrent regimen, whether adjuvant or neoadjuvant, it is generally agreed that proper patient selection is needed to stratify high-risk groups to intensify treatment and to optimize the disease outcome. Future studies are ongoing, possibly with the addition of biomarkers such as EBV DNA for risk group stratification. Refinement of patient groups that should be selected for combined modality treatment in stage II disease is also warranted.

Treatment outcomes of nasopharyngeal carcinoma in modern era after intensity modulated radiotherapy (IMRT) in Hong Kong: A report of 3328 patients (HKNPCSG 1301 study).

PURPOSE: To evaluate treatment outcomes, failure patterns and late toxicities in patients with nasopharyngeal carcinoma (NPC) treated by intensity modulated radiotherapy (IMRT) in 6 public hospitals in Hong Kong over a 10-year period from 2001 to 2010. MATERIAL AND METHODS: Eligible patients were identified through the Hong Kong Cancer Registry data base. Clinical information was retrieved and verified by oncologists working in the individual centers. Treatment details, survival outcomes and late toxicities were analyzed. RESULTS: A total of 3328 patients were recruited. The median follow-up time was 80.2 months. The 8-year actuarial overall survival (OS), local failure-free survival (LFFS), regional failure-free survival (RFFS), distant failure free survival (DFFS), progression-free survival (PFS) for the whole group was 68.5%, 85.8%, 91.5%, 81.5% and 62.6% respectively. Male gender, older age, advanced T and N stage were adverse prognostic factors for OS, DFFS and PFS, whereas use of chemotherapy in form of concurrent chemo-irradiation (CRT), neoadjuvant + CRT, or CRT + adjuvant chemotherapy were favorable prognostic factors for OS and PFS. The local control was adversely affected by advanced T stage. N stage remained as the single adverse prognostic factor for regional control. Distant metastasis was the commonest site of failure. CONCLUSION: IMRT is an effective treatment for NPC with excellent overall loco-regional control. Distant metastasis is the major site of failure. Concurrent chemotherapy with cisplatin has an established role in NPC patients treated by IMRT.

Prospective, Multicenter, Phase 2 Trial of Induction Chemotherapy Followed by Bio-Chemoradiotherapy for Locally Advanced Recurrent Nasopharyngeal Carcinoma.

PURPOSE: To evaluate, in a phase 2 study, whether induction docetaxel, cisplatin, and fluorouracil (TPF) followed by weekly docetaxel and cetuximab in concurrence with intensity modulated radiation therapy can improve the treatment outcome for patients with advanced locally recurrent nasopharyngeal carcinoma (rNPC). METHODS AND MATERIALS: Thirty-three patients with rNPC (T3-T4, N0-N1, M0) were recruited. Of these, 19 patients (57.6%) had stage rT3 recurrence, and the rest had stage rT4. Eight patients also had rN1 at the time of relapse. Treatment outcomes and safety were evaluated. RESULTS: Among these 33 patients, 1 died after 1 cycle of TPF, 5 patients withdrew from the study during the induction period because of grade ≥3 toxicities; 27 patients completed the whole course of treatment, but 1 died before any assessment could be made. The median follow-up period was 28.5 months. The progression-free survival and overall survival at 3 years for the whole group were 35.7% and 63.8%, respectively. Among the 26 patients who could be assessed after treatment, the complete response rate was 30.8%, and the locoregional control rate at 3 years was 49.2%. Temporal lobe necrosis (TLN) developed in 8 cases. The rates of grade ≥3 hearing loss, soft tissue necrosis, dysphagia, and trismus were 30.8%, 15.4%, 11.5%, and 19.2%, respectively. Overall, 5 patients died owing to acute (1 after cycle 1 TPF and 1 after completion of bio-chemoradiotherapy) or late (2 epistaxis and 1 TLN) treatment-related complications. CONCLUSIONS: The proposed salvage treatment regimen for advanced locally recurrent NPC could achieve a better treatment outcome than seen in previous studies. However, poor tolerability of induction TPF and the high rate of TLN limit its applicability outside clinical trials.

Concurrent-Adjuvant Chemoradiation Therapy for Stage III-IVB Nasopharyngeal Carcinoma-Exploration for Achieving Optimal 10-Year Therapeutic Ratio.

PURPOSE: This is an updated combined analysis of 2 randomized studies (NPC-9901 and NPC-9902 trials) to evaluate the 10-year outcome attributed to the addition of concurrent-adjuvant chemotherapy for advanced locoregional nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Eligible patients with stage III-IVB nonkeratinizing NPC were randomly assigned to radiation therapy alone (RT: 218 patients) or chemoradiation therapy (CRT: 223 patients) using 3 cycles of cisplatin (100 mg/m2) concurrent with RT, followed by 3 cycles of cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/day for 4 days). All of the patients were irradiated with conventional fractionation to ≥66 Gy. The median follow-up was 13.9 years. RESULTS: Intention-to-treat analysis confirmed that the CRT group achieved significant improvement in 10-year failure-free rate (FFR: 62% vs 52%, P = .016), progression-free survival rate (PFS: 56% vs 44%, P = .008), and overall survival rate (OS: 60% vs 50%, P = .044). There was no significant increase in overall late toxicity rate (51% vs 48%, P = .34) or noncancer deaths (19% vs 16%, P = .52). Exploratory studies showed no difference in disease control between 2 or 3 cycles of concurrent cisplatin; however, patients given 3 concurrent cycles had a significant increase in hearing impairment (40% vs 24%, P = .017). Only those who continued to receive 2 or more cycles of adjuvant cisplatin-fluorouracil achieved significant improvement in distant control (73% vs 65%, P = .037) and maximal survival gain. CONCLUSION: The addition of concurrent cisplatin plus adjuvant cisplatin-fluorouracil could significantly improve overall survival and disease control without incurring a significant increase in late toxicity or noncancer deaths. Exploratory analyses suggested that both the concurrent and the adjuvant phases contributed to tumor control. Furthermore, the number of concurrent cycles could be reduced from 3 to 2 cycles in order to achieve a similar survival benefit without incurring an excessive increase in hearing impairment. This is a useful hypothesis that warrants further validation.

Reirradiation with intensity-modulated radiotherapy for locally recurrent T3 to T4 nasopharyngeal carcinoma.

BACKGROUND: The purpose of this study was to assess the efficacy and toxicities of reirradiation using intensity-modulated radiotherapy (IMRT) in patients with locally advanced recurrent nasopharyngeal carcinoma (NPC). METHODS: Thirty-eight patients with consecutive rT3 to rT4 NPC treated between 2005 and 2013 were retrospectively analyzed. RESULTS: The 3-year overall survival (OS), progression-free survival (PFS), and local control rate were 47.2%, 17.5%, and 44.3%, respectively. Gross target volume (GTV) D95 , GTV D50 , and age were all important prognostic factors for OS and PFS, but only GTV D95 was an important determinant for local control. A total of 73.7% patients experienced ≥1 grade 3 late toxicities and 3 patients died of massive epistaxis. Temporal lobe necrosis (TLN) developed sooner with a higher total biological equivalent dose. CONCLUSION: Adequate tumor dose coverage was important for treating rT3 to rT4 NPC. Although late complications were common, treatment-related mortality was solely vascular in nature. Dose constraints of neurologic structures for reirradiation should be revised with the latest information on late toxicities. © 2016 Wiley Periodicals, Inc. Head Neck 39: 533-540, 2017.

Global Pattern of Nasopharyngeal Cancer: Correlation of Outcome With Access to Radiation Therapy.

PURPOSE: This study aimed to estimate the treatment outcome of nasopharyngeal cancer (NPC) across the world and its correlation with access to radiation therapy (RT). METHODS AND MATERIALS: The age-standardized mortality (ASM) and age-standardized incidence (ASI) rates of NPC from GLOBOCAN (2012) were summarized, and [1-(ASM/ASI)] was computed to give the proxy relative survival (RS). Data from the International Atomic Energy Agency (IAEA) and the World Bank were used to assess the availability of RT in surrogate terms: the number of RT equipment units and radiation oncologists per million population. RESULTS: A total of 112 countries with complete valid data were analyzed, and the proxy RS varied widely from 0% to 83% (median, 50%). Countries were categorized into Good, Median, and Poor outcome groups on the basis of their proxy RS (<45%, 45%-55%, and >55%). Eighty percent of new cases occurred in the Poor outcome group. Univariable linear regression showed a significant correlation between outcome and the availability of RT: proxy RS increased at 3.4% (P<.001) and 1.5% (P=.001) per unit increase in RT equipment and oncologist per million population, respectively. The median number of RT equipment units per million population increased significantly from 0.5 in the Poor, to 1.5 in the Median, to 4.6 in the Good outcome groups, and the corresponding number of oncologists increased from 1.1 to 3.3 to 7.1 (P<.001). CONCLUSIONS: Nasopharyngeal cancer is a highly treatable disease, but the outcome varies widely across the world. The current study shows a significant correlation between survival and access to RT based on available surrogate indicators. However, the possible reasons for poor outcome are likely to be multifactorial and complex. Concerted international efforts are needed not only to address the fundamental requirement for adequate RT access but also to obtain more comprehensive and accurate data for research to improve cancer outcome.

Treatment outcomes of postradiation second head and neck malignancies managed by a multidisciplinary approach.

BACKGROUND: The purpose of this study was to report on the treatment outcomes of patients with postradiation second head and neck malignancies. METHODS: Fifty-seven consecutive patients with postradiation second malignancy were reviewed. Progression-free survival (PFS), overall survival (OS), and prognostic factors were analyzed. RESULTS: Mean time interval between first course of radiation therapy to the development of postradiation second malignancy was 13.2 years. Median PFS and OS for the whole group were 12.0 and 67.0 months, respectively. Postradiation sarcoma conferred a worse PFS (p = .003) and OS (p = .001) as compared to postradiation carcinoma. Multivariate analysis revealed that Eastern Cooperative Oncology Group (ECOG) performance status ≥3 (p = .034), postradiation sarcoma (p = .007), and lack of radical surgery (p = .044) are prognostic of PFS, whereas postradiation sarcoma (p = .002), lack of postprogression surgery (p < .001), and lack of postprogression systemic therapy (p = .011) were prognostic factors of OS. CONCLUSION: Treatment outcomes of postradiation second malignancy seemed promising under a multidisciplinary management.

Current controversies in radiotherapy for nasopharyngeal carcinoma (NPC).

Radiotherapy has a good track record in the treatment of NPC, yet the late toxicity profile and local failure rate for locally advanced disease remain a concern. Modern RT techniques incorporating IMRT and IGRT have widened our potential in treating NPC more effectively, and shall be regarded as the standard of care. Out of the various dose fractionation regimens in IMRT, 70 Gy in 35 fractions or the mini-SIB proves to be safe in combination with chemotherapy, but any further attempt of dose escalation must be tried out with extreme caution to avoid severe toxicities. CT-MRI image fusion improves the accuracy of GTV delineation, whereas the role of PET-CT has yet to be verified. RTOG definition of the CTV provides a reasonable template for the inclusion of sites at risk of microscopic involvement, and fine tuning has to be made in the future based on careful analysis of the pattern of local failure with long term follow-up. Toxicity reduction via radiation volume or dose reduction is tempting, but once again it has to be tested under scrutiny. Retrospective data have emerged that suggest a benefit of using adaptive IMRT replanning in NPC, however the optimal timing or frequency of replanning is still unclear. Future prospective studies are thus required to evaluate the cost-effectiveness of adaptive RT and streamline the workflow logistics before it can be widely accepted in routine practice.

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.

Predictive factors and radiological features of radiation-induced cranial nerve palsy in patients with nasopharyngeal carcinoma following radical radiotherapy.

OBJECTIVES: To identify the key predictive factors of radiation-induced cranial nerve palsy in patients with nasopharyngeal carcinoma (NPC). METHOD AND MATERIALS: From November 1998 to December 2007, all consecutive patients with newly diagnosed NPC who were curatively treated with radiotherapy and subsequently developed radiation-induced cranial nerve palsy (RICNP) were included in our study. Patients with cranial nerve palsy due to disease recurrence were excluded. Their records were retrospectively reviewed. RESULTS: Amongst 965 patients with NPC treated with radical radiotherapy, 41 developed new cranial nerve palsy. After exclusion of 5 patients with cranial nerve palsy due to recurrence, 36 (3.7%) developed RICNP. The median follow-up was 8.9 years (range, 3.2-11.3 years). Ten of the 36 patients had cranial nerve palsy at presentation. Twenty-seven patients had single cranial nerve palsy and 9 patients had multiple cranial nerve palsy. The most commonly involved cranial nerve was cranial nerve XII, with 30 patients having palsy of cranial nerve XII and 6 of them having bilateral cranial nerve XII palsies. Magnetic resonance imaging features of radiation-induced hypoglossal nerve palsy were demonstrated in our study. Multivariate analysis revealed that cranial nerve palsy at presentation was an independent prognostic factor for the development of RICNP. Other factors including T staging, N staging, gender, age, radiotherapy technique and the use of chemotherapy have no significant relationship with the risk of developing RICNP. CONCLUSION: RICNP in patients with NPC is not a rare complication, and cranial nerve palsy at presentation is an important prognostic factor.

RapidArc radiotherapy planning for prostate cancer: single-arc and double-arc techniques vs. intensity-modulated radiotherapy.

RapidArc is a novel technique using arc radiotherapy aiming to achieve intensity-modulated radiotherapy (IMRT)-quality radiotherapy plans with shorter treatment time. This study compared the dosimetric quality and treatment efficiency of single-arc (SA) vs. double-arc (DA) and IMRT in the treatment of prostate cancer. Fourteen patients were included in the analysis. The planning target volume (PTV), which contained the prostate gland and proximal seminal vesicles, received 76 Gy in 38 fractions. Seven-field IMRT, SA, and DA plans were generated for each patient. Dosimetric quality in terms of the minimum PTV dose, PTV hotspot, inhomogeneity, and conformity index; and sparing of rectum, bladder, and femoral heads as measured by V70, V-40, and V20 (% of volume receiving >70 Gy, 40 Gy, and 20 Gy, respectively), treatment efficiency as assessed by monitor units (MU) and treatment time were compared. All plan objectives were met satisfactorily by all techniques. DA achieved the best dosimetric quality with the highest minimum PTV dose, lowest hotspot, and the best homogeneity and conformity. It was also more efficient than IMRT. SA achieved the highest treatment efficiency with the lowest MU and shortest treatment time. The mean treatment time for a 2-Gy fraction was 4.80 min, 2.78 min, and 1.30 min for IMRT, DA, and SA, respectively. However, SA also resulted in the highest rectal dose. DA could improve target volume coverage and reduce treatment time and MU while maintaining equivalent normal tissue sparing when compared with IMRT. SA achieved the greatest treatment efficiency but with the highest rectal dose, which was nonetheless within tolerable limits. For busy units with high patient throughput, SA could be an acceptable option.

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.