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.

Combined stereotactic body radiotherapy and trans-arterial chemoembolization as initial treatment in BCLC stage B-C hepatocellular carcinoma.

PURPOSE: We retrospectively evaluated the efficacy and safety of stereotactic body radiotherapy (SBRT) combined with trans-arterial chemoembolization (TACE) as initial therapy in Barcelona Clinic Liver Cancer (BCLC) system stage B-C hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Seventy-two patients received a single dose of TACE followed by SBRT 4 weeks later. All patients had tumor sizes ≥5 cm, at least 700 ml of disease-free liver, Child-Pugh (CP) score ≤ B7 and tumor nodules ≤5. SBRT dose, ranging from 6â€¯× 5-8 Gy or 5-10â€¯× 4 Gy, was individualized according to normal tissue constraints. No subsequent scheduled treatment was delivered unless disease progression was observed. Local control (LC), overall survival (OS), progression-free survival (PFS), response rate (RR), and toxicity were evaluated. RESULTS: The patients' characteristics were: median age 60 years (range 28-87 years); CP score A/B (n = 68/4); BCLC stage B/C (n = 51/21); solitary/multifocal (n = 37/35); portal vein invasion (n = 18). The median tumor size and GTV were 11.2 cm (range 5.0-23.6 cm) and 751 cm3 (range 41-4009 cm3), respectively. The median equivalent dose in 2 Gy per fraction (EQD2, α/ß = 10) was 37.3 Gy2 (range, 28-72 Gy2). The median follow-up time was 16.8 months (range, 3-96 months). The objective RR was 68% and the 1­year LC rate was 93.6% (95% CI, 87.6-100%). The median OS was 19.8 months (95% CI, 11.6-30.6 months). SBRT-related grade 3 or higher adverse gastrointestinal events and treatment-related death occurred in three (2.8%) and one patient (1.4%) respectively. No patient developed classical radiation-induced liver injury. CONCLUSION: Our experience suggests that combined TACE and SBRT can be a safe and effective initial therapy for BCLC stage B-C HCC with appropriate patient selection. Further prospective trials are warranted.

Lipiodol versus diaphragm in 4D-CBCT-guided stereotactic radiotherapy of hepatocellular carcinomas.

PURPOSE: The purpose of this work was to investigate the potential of lipiodol as a direct tumor surrogate alternative to the diaphragm surrogate on four-dimensional cone-beam computed tomography (4D-CBCT) image guidance for stereotactic radiotherapy of hepatocellular carcinomas. METHODS: A total of 29 hepatocellular carcinomas (HCC) patients treated by stereotactic radiotherapy following transarterial chemoembolization (TACE) with homogeneous or partial defective lipiodol retention were included. In all, 4-7 pretreatment 4D-CBCT scans were selected for each patient. For each scan, either lipiodol or the diaphragm was used for 4D registration. Resulting lipiodol/diaphragm motion ranges and position errors relative to the reconstructed midventilation images were analyzed to obtain the motion variations, and group mean (ΔM), systematic (Σ), and random (σ) errors of the treatment setup. RESULTS: Of the lipiodolized tumors, 55 % qualified for direct localization on the 4D-CBCT. Significant correlations of lipiodol and diaphragm positions were found in the left-right (LR), craniocaudal (CC), and anteroposterior (AP) directions. ΔM and σ obtained with lipiodol and diaphragm were similar, agreed to within 0.5 mm in the LR and AP, and 0.3 mm in the CC directions, and Σ differed by 1.4 (LR), 1.1 (CC), and 0.6 (AP) mm. Variations of diaphragm motion range > 5 mm were not observed with lipiodol and in one patient with diaphragm. The margin required for the tumor prediction error using the diaphragm surrogate was 6.7 (LR), 11.7 (CC), and 4.1 (AP) mm. CONCLUSION: Image-guidance combining lipiodol with 4D-CBCT enabled accurate localization of HCC and thus margin reduction. A major limitation was the degraded lipiodol contrast on 4D-CBCT.

Comparison of platelet-albumin-bilirubin (PALBI), albumin-bilirubin (ALBI), and child-pugh (CP) score for predicting of survival in advanced hcc patients receiving radiotherapy (RT).

PURPOSE: This work evaluated the prognostic performance of Child-Pugh (CP), albumin-bilirubin (ALBI) and platelet-albumin-bilirubin (PALBI) scores in hepatocellular carcinoma (HCC) patients undergoing radiotherapy (RT). RESULTS: The study included 174 consecutive patients with 63% at CP A5 (n = 110) and 34% at CP A6 (n = 64). The median ALBI score was -2.39 (range: -3.61 to -1.41) with 34.5% at grade A1 (n = 60) and 65.5% at grade A2 (n = 114). The median PALBI score was -2.39 (range -3.39 to -1.24) with 33.3% at grade 1 (n = 58), 41.4% at grade 2 (n = 72) and 25.3% at grade 3 (n = 44). With a median follow-up of 21.7 months, the median OS of the entire cohort was 22.2 months. OS was significantly associated with the PALBI grade (p = 0.002) and for the ALBI grade (p = 0.00495), but not for the CP score (p = 0.46). The PALBI grade has a significantly higher AUC compared than the ALBI grade or CP scores in predicting OS. The PALBI grade was predictive of CP score decline ≥2 (20% grade 3 vs. 5.3% grade 1/2 p = 0.05) but the ALBI and CP scores were not. CONCLUSION: Among CP A HCC patients receiving radiotherapy, the PALBI and ALBI grade maybe a better prognostic tool than the CP score. The role of PALBI in predicting liver toxicity warranted further exploration. METHODS: We retrospectively reviewed HCC patients treated with individualized hypo-fractionated radiotherapy (IHRT) using stereotactic technique from 2006 to 2015. We collected CP, ALBI and PALBI scores prior to treatment and analyzed their correlation with overall survival (OS) and liver toxicity.

Analysis of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Cancer After Chemoradiation to Identify High-Risk Patients for Adjuvant Chemotherapy: A Randomized Controlled Trial.

Purpose The contribution of adjuvant chemotherapy after chemoradiation therapy (CRT) in nasopharyngeal cancer (NPC) remains controversial. Plasma Epstein-Barr virus (EBV) DNA is a potential biomarker of subclinical residual disease in NPC. In this prospective, multicenter, randomized controlled trial, we used plasma EBV DNA to identify patients with NPC at a higher risk of relapse for adjuvant chemotherapy. Patients and Methods Eligible patients with histologically confirmed NPC of Union for International Cancer Control stage IIB to IVB, adequate organ function, and no locoregional disease or distant metastasis were screened by plasma EBV DNA at 6 to 8 weeks after radiotherapy (RT). Patients with undetectable plasma EBV DNA underwent standard surveillance. Patients with detectable plasma EBV DNA were randomly assigned to either adjuvant chemotherapy with cisplatin and gemcitabine for six cycles (arm 1) or observation (arm 2). Patients were stratified for primary treatment (RT v CRT) and stage (II/III v IV). The primary end point was relapse-free survival (RFS). Results Seven hundred eighty-nine patients underwent EBV DNA screening. Plasma EBV DNA was undetectable in 573 (72.6%) and detectable in 216 (27.4%); 104 (13.2%) with detectable EBV DNA were randomly assigned to arms 1 (n = 52) and 2 (n = 52). After a median follow-up of 6.6 years, no significant difference was found in 5-year RFS rate between arms 1 and 2 (49.3% v 54.7%; P = .75; hazard ratio for relapse or death, 1.09; 95% CI, 0.63 to 1.89). The level of post-RT plasma EBV DNA correlated significantly with the hazards of locoregional failure, distant metastasis, and death. Conclusion In patients with NPC with detectable post-RT plasma EBV DNA, adjuvant chemotherapy with cisplatin and gemcitabine did not improve RFS. Post-RT plasma EBV DNA level should be incorporated as the selection factor in future clinical trials of adjuvant therapy in NPC.

Intercostal nerve blockade for cancer pain: effectiveness and selection of patients.

OBJECTIVES: To review treatment results of intercostal nerve blockade at our centre and those reported in the literature, and to determine which patients benefit most from this procedure. DESIGN: Retrospective study. SETTING: Regional palliative care centre in a regional hospital in Hong Kong. PATIENTS: Oncology patients who had intercostal nerve blockade at Tuen Mun Hospital from 1995 to 2005 were divided into three groups: (1) those who appeared not to tolerate opioids; (2) those deemed to have inadequate pain control, despite high doses of analgesics; and (3) those referred to avoid early use of high-dose opioids and tolerance. MAIN OUTCOME MEASURES: The effectiveness and complications of intercostal nerve blockade, and the extent of benefit derived from intercostal nerve blockade in different patient groups. RESULTS: This study found that 80% of the 25 patients noted optimal local pain control and 56% experienced reduction in analgesic use after intercostal nerve blockade. About 32% did not notice recurrence of the targeted pain till the end of their lives. None of the patients developed pneumothorax. Most benefit from intercostal nerve blocks were derived by group 2 patients, 90% of whom obtained optimal local pain control (P=0.23) and enjoyed a significant reduction in analgesics use (P=0.019), and in 40% their target pain was controlled till the end of life. Only about one third of group 3 patients had subsequent reduction in use of analgesics, mainly because they had co-existing pain other than at the target selected for treatment. Half (50%) of group 1 patients achieved optimal pain control. CONCLUSION: Our treatment results from intercostal nerve blockade are comparable to those reported in the literature. The procedure is safe if closely monitored. Good selection of cases is important for optimising the therapeutic gain. The largest benefit is obtained in patients who have inadequate pain control after high-dose morphine.

Treatment results of high-dose-rate remote afterloading brachytherapy for cervical cancer and retrospective comparison of two regimens.

PURPOSE: To review the treatment results and complications of high-dose-rate (HDR) intracavitary brachytherapy for patients with carcinoma of the cervix in a single institute and to compare them with those of low-dose-rate (LDR) brachytherapy reported in the literature. METHODS AND MATERIALS: Two hundred twenty patients with carcinoma of the cervix were treated by primary radiotherapy between 1991 and 1998. The median age was 63 (range 24-84). The distribution according to Federation of Gynecology and Obstetrics (FIGO) staging system was as follows: Stage IB, 11.4%; IIA, 9.1%; IIB, 50.9%; IIIA, 3.6%; IIIB, 23.2%; and IVA, 1.8%. They were treated with whole pelvic irradiation giving 40 Gy to the midplane in 20 fractions over 4 weeks. This was followed by parametrial irradiation, giving 16-20 Gy in 8-10 fractions. HDR intracavitary brachytherapy was given weekly, with a dose of 7 Gy to point A for three fractions and, starting from 1996, 6 Gy weekly for four fractions. The median overall treatment time was 50 days (range 42-73 days). The median follow-up time was 4.7 years (range 3 months to 11.1 years). Multivariate analysis was performed using the Cox regression proportional hazards model. RESULTS: The complete remission rate after radiotherapy was 93.4% (211/226). The 5-year actuarial failure-free survival (FFS) and cancer-specific survival (CSS) rates for stage IB, IIA, IIB, IIIA, IIIB, and IVA were 87.7% and 86.6%, 85% and 85%, 67.8% and 74%, 46.9% and 54.7%, 44.8% and 50.4%, 0% and 25%, respectively. On multivariate analysis, young age (< 50) (p = 0.0054), adenocarcinoma (p = 0.0384), and stage (p = 0.0005) were found to be independent poor prognostic factors. The 5-year actuarial major complication rates (Grade 3 or above) were as follows: proctitis, 1.0%; cystitis, 0.5%; enteritis, 1.3%; and overall, 2.8%. On multivariate analysis, history of pelvic surgery was a significant prognosticator. The two HDR fractionation schedules were not a significant prognosticator in predicting disease control and complications. CONCLUSION: Our experience in treating cervical cancer with HDR intracavitary brachytherapy is encouraging. Our treatment results and complication rates were compatible with those of the LDR series. Further studies are eagerly awaited to better define the optimal fractionation schedule for HDR brachytherapy and the schedule on how chemotherapy may be combined with it.

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.

Clinical outcomes of 174 nasopharyngeal carcinoma patients with radiation-induced temporal lobe necrosis.

PURPOSE: To retrospectively study the clinical outcomes of nasopharyngeal carcinoma patients with radiation-induced temporal lobe necrosis (TLN) treated with steroids, surgery, or observation only. METHODS AND PATIENTS: We performed a retrospective analysis of 174 consecutive patients diagnosed with TLN between 1990 and 2008. Before 1998, symptomatic patients were treated with oral steroids, while asymptomatic patients were treated conservatively. After 1998, most symptomatic and asymptomatic patients with a large volume of necrosis were treated by intravenously pulsed-steroid therapy with a standardized protocol. We examined factors affecting grade 4 complication-free survival and overall survival. Outcomes of the three treatment groups, those receiving conservative treatment, those receiving oral steroid, and those receiving intravenous pulse steroid, were compared. RESULTS: The mean follow-up time was 115 months. Rates of grade 4 complication-free survival at 2 years and at 5 years after diagnosis of TLN were 72.2% and 54.1%, respectively. The 2-year and 5-year overall survival rates were 57.5% and 35.4%, respectively. Multivariate analysis revealed that being symptomatic at diagnosis (relative risk [RR], 4.5; p = 0.0001), re-irradiation of the nasopharynx (NP) (RR, 1.56; p = 0.008), salvage brachytherapy to the NP (RR, 1.75; p = 0.012), and a short latency period before the diagnosis of TLN (RR, 0.96, p < 0.0001) were independent prognosticators of poor grade 4 complication-free survival. Patients with all four factors had a 100% risk of developing grade 4 complications within 5 years; whereas if no factor was present, the risk was 12.5%. Intravenous pulse steroid therapy was associated with a higher clinical response rate compared with conventional steroid therapy (p < 0.0001); however, it did not affect complication-free survival in multivariate analysis. CONCLUSIONS: TLN patients with good prognosticators could be observed without active treatment. Although treatment with intravenously pulsed steroid was associated with better clinical response than conventional steroid delivery, it did not affect the complication-free survival rate of TLN patients.

Whole-field simultaneous integrated-boost intensity-modulated radiotherapy for patients with nasopharyngeal carcinoma.

PURPOSE: To retrospectively review the outcomes of our patients with newly diagnosed nondisseminated nasopharyngeal carcinoma treated with intensity-modulated radiotherapy using a whole-field simultaneous integrated-boost technique. METHODS AND MATERIALS: A total of 175 patients treated with WF-SIB between mid-2004 and 2005 were eligible for study inclusion. The distribution of disease by stage was Stage IA in 10.9%, Stage IIA in 2.3%, Stage IIB in 21.7%, Stage III in 41.1%, Stage IVA in 14.9%, and Stage IVB in 9.1%. Of the 175 patients, 2 (1.2%), 10 (5.7%), and 163 (93.1%) had World Health Organization type I, II, and III histologic features, respectively. We prescribed 70 Gy, 60 Gy, and 54 Gy delivered in 33 fractions within 6.5 weeks at the periphery of three planning target volumes (PTV; PTV70, PTV60, and PTV54, respectively). Of the 175 patients, 46 with early T-stage disease received a brachytherapy boost, and 127 with advanced local or regional disease received chemotherapy. RESULTS: The median follow-up period was 34 months. The overall 3-year local failure-free survival, regional failure-free survival, distant failure-free survival, and overall survival rate was 93.6%, 93.3%, 86.6%, and 87.2%, respectively. Cox regression analysis showed Stage N2-N3 disease (p = .029) and PTV (p = .024) to be independent factors predicting a greater risk of distant failure and poor overall survival, respectively. Grade 3 acute mucositis/pharyngitis occurred in 23.4% of patients, and Stage T4 disease was the only significant predictor of mucositis/pharyngitis (p = .021). CONCLUSION: Whole-field simultaneous integrated-boost intensity-modulated radiotherapy with a dose >70 Gy achieved excellent locoregional control, without an excess incidence of severe, acute mucositis/pharyngitis, in the present study. Strategies for using such highly conformal treatment for patients with a large tumor and late N-stage disease are potential areas of investigation for future studies.

Nasopharyngeal intracavitary brachytherapy: the controversy of T2b disease.

BACKGROUND: Locally persistent nasopharyngeal carcinoma (NPC) carries an increased risk of local failure if additional treatment is not given. It has been shown that intracavitary brachytherapy is effective in the treatment of patients with T1 and T2a NPC, although its role in the treatment of T2b disease had remained uncertain. The objectives of the current study were to evaluate the outcomes of patients with T2b, locally persistent NPC who were treated with high-dose-rate (HDR) intracavitary brachytherapy and to explore whether routine brachytherapy boost could improve the local control of patients who had T2b NPC at initial diagnosis. METHODS: Thirty-four patients with locally persistent NPC who were treated during 1992-2000 with HDR intracavitary brachytherapy were analyzed retrospectively. All patients had T2b disease at initial diagnosis. They were treated with HDR intracavitary brachytherapy at doses of 22.5-24.0 grays (Gy) in 3 weekly sessions. To compare the efficacy of brachytherapy, another 403 consecutive patients with nonmetastatic T2b NPC who were treated with curative intent by external radiotherapy (ERT) during the same period were evaluated. RESULTS: An improvement in the 5-year actuarial local failure-free survival rate (brachytherapy group vs. ERT group: 96.9% vs. 81.5%; P = 0.024), the disease-specific survival rate (84.5% vs. 68.1%; P = 0.021), and the overall survival rate (78.3% vs. 63.1%; P = 0.034) was demonstrated in the group that had locally persistent NPC who were salvaged with brachytherapy. In assessing local control, the addition of brachytherapy was just short of statistical significance on multivariate analysis (P = 0.054). The complication rates were comparable between the brachytherapy group and the ERT group. CONCLUSIONS: The results suggested that patients with T2b NPC who have locally persistent disease can be salvaged effectively with brachytherapy. Their local control was even better than that achieved by patients who had clinical remission of local disease at the completion of ERT. Furthermore, it is possible that routine brachytherapy boost, after the completion of ERT, may improve local control in patients who have T2b disease at initial diagnosis. However, its exact benefit can be elucidated only by prospective, randomized studies.

Survival outcome of patients with nasopharyngeal carcinoma with first local failure: a study by the Hong Kong Nasopharyngeal Carcinoma Study Group.

BACKGROUND: The purpose of this article is to report the overall survival (OS) outcome of patients with nasopharyngeal carcinoma (NPC) with local failure who received salvage treatment and to identify prognostic factors for OS. METHODS: Between January 1996 and December 2000, 2915 patients received primary radiotherapy (RT) with or without chemotherapy for nonmetastatic NPC. At a median follow-up of 3.1 years, 319 patients had developed local failure as the first failure, with or without synchronous regional/distant failure. OS was calculated from the start of primary RT. Univariate and multivariate analyses were performed to identify prognostic factors for OS in patients with isolated local failure. RESULTS: The T classification distribution of the local failure (rT classification) was as follows: 68 (21%) rT1 to T2a, 92 (29%) rT2b, 82 (26%) rT3, and 77 (24%) rT4. The rT classification was the same as the initial T classification in 82% of patients. Two hundred seventy-five patients (86%) had isolated local failure, and 232 (84%) of them did not have any distant metastasis or regional failure develop during follow-up. Salvage treatment was given to 200 patients (73%) with isolated local failure. One hundred fifty-nine patients (80%) received reirradiation (108 external beam RT [EBRT], 44 brachytherapy, and seven EBRT plus brachytherapy), 22 patients (11%) underwent nasopharyngectomy with or without postoperative RT, and 19 patients (9%) were treated with chemotherapy alone. Four patients died of RT complications, and one died of chemotherapy toxicity in the absence of active NPC. The 3-year actuarial OS for patients with isolated local failure was 74%. On multivariate analysis, advanced initial T classification (hazard ratio [HR], 1.44; p = .0006) and the use of salvage treatment (HR, 0.54; p = .0038) were independent prognostic factors. For the subgroups of patients who had the same recurrent and initial T classification, salvage treatment was associated with improved OS only in the subgroup with T1 to T2 local failure (n = 127; p = 0.0446), but not in the subgroups with T3 (n = 48) or T4 (n = 54) disease. CONCLUSIONS: Most patients with first local failure have localized disease. Salvage treatment is feasible in most of the patients with clinically isolated local failure. Patients who had early initial T classification have a more favorable prognosis. Subgroup analysis suggests that salvage treatment only prolongs survival in patients with T1 to T2 recurrent disease.