Chemotherapy For Advanced Nasopharyngeal Carcinoma Research Articles

A Rulefit-based prognostic analysis using structured MRI report to select potential beneficiaries from induction chemotherapy in advanced nasopharyngeal carcinoma: A dual-centre study

Background and purposeStructured MRI report facilitate prognostic prediction for nasopharyngeal carcinoma (NPC). However, the intrinsic association among structured variables is not fully utilised. This study aimed to investigate the performance of a Rulefit-based model in feature integration behind structured MRI report and prognostic prediction in advanced NPC. Materials and methodsWe retrospectively enrolled 1207 patients diagnosed with non-metastatic advanced NPC from two centres, and divided into training (N = 544), internal testing (N = 367), and external testing (N = 296) cohorts. Machine learning algorithms including multivariate analysis, deep learning, Lasso, and Rulefit were used to establish corresponding prognostic models. The concordance indices (C- indices) of three clinical and six combined models with different algorithms for overall survival (OS) prediction were compared. Survival benefits of induction chemotherapy (IC) were calculated among risk groups stratified by different models. A website was established for individualised survival visualisation. ResultsIncorporating structured variables into Stage model significantly improved the prognostic prediction performance. Six prognostic rules with structured variables were identified by Rulefit. OS prediction of Rules model was comparable to Lasso model in internal testing cohort (C-index: 0.720 vs. 0.713, P = 0.100) and achieved the highest C-index of 0.711 in external testing cohort, indicating better generalisability. The Rules model stratified patients into risk groups with significant 5-year OS differences in each cohort, and revealed significant survival benefits from additional IC in high-risk group. ConclusionThe Rulefit-based Rules model, with the revelation of intrinsic associations behind structured variables, is promising in risk stratification and guiding individualised IC treatment for advanced NPC.

Induction Chemotherapy for Advanced Nasopharyngeal Carcinoma—Is This the New Standard of Care?

Induction Chemotherapy for Advanced Nasopharyngeal Carcinoma—Is This the New Standard of Care?

Evolutionary role of chemotherapy in advanced nasopharyngeal carcinoma: a literature-based network meta-analysis.

PurposeThe role of chemotherapy has evolved greatly in advanced nasopharyngeal carcinoma (NPC). We undertook this network meta-analysis to establish the optimal chemotherapy strategy in advanced NPC.Materials and methodsThis network meta-analysis recruited randomized clinical trials involving patients with advanced NPC randomly allocated to induction chemotherapy plus concurrent chemoradiotherapy (CRT; induction + CRT), CRT plus adjuvant chemotherapy (CRT + adjuvant), CRT or radiotherapy (RT) alone. Pairwise meta-analysis was first conducted, then network meta-analysis was performed using the frequentist approach. Effect size was expressed as HR and 95% CI.ResultsIn total, we analyzed 15 studies involving 4,067 patients with 880 (21.6%) patients receiving induction + CRT, 897 (22.1%) receiving CRT + adjuvant, 1,421 (34.9%) receiving CRT, and 869 (21.4%) receiving RT alone. Induction + CRT achieved significantly better distant failure-free survival (HR, 0.67; 95% CI, 0.53–0.86) and locoregional failure-free survival (HR, 0.69; 95% CI, 0.54–0.89) than CRT, and CRT + adjuvant achieved better overall survival than CRT (HR, 0.82; 95% CI, 0.67–1.00). However, no significant survival difference was found between the induction + CRT and CRT + adjuvant groups. Additionally, RT alone is always worse than the other three treatments. In terms of P-score, induction + CRT ranked best for distant and locoregional failure-free survival, while CRT + adjuvant ranked best for overall survival.ConclusionBoth induction + CRT and CRT + adjuvant were equally effective and feasible choices for patients with advanced NPC.

Long-Term Prognostic Effects of Plasma EBV DNA Load after Induction Chemotherapy in Advanced Nasopharyngeal Carcinoma

Induction chemotherapy (IndCT) has become an option of initial treatment for advanced nasopharyngeal carcinoma (NPC) patients. We hypothesized that plasma EBV DNA (pEBV DNA) status afterIndCT could predict long-term treatment outcome. This retrospective study included 206 previously untreated, pathologically-proven NPC patients with stage II-IVB diseases and available pEBV DNA data after IndCT before radiotherapy (RT). All patients received a uniform protocol of ten weekly IndCT consisting of cisplatin 60 mg/m2 on day 1 and 5- fluorouracil 2500 mg/m2 + leucovorin 250 mg/m2 on day 8, repeated every 2 weeks for 5 cycles, followed by RT 70-74 Gy. After a median follow-up of 90 months, there were 71 recurrences and 85 deaths. Pretreatment pEBV DNA (median, 1550 copies/ml; interquantile range, 375-5688) was detectable in 95.1% (196/206) patients. Only 40.8% (84/206) patients had detectable pEBV DNA (> 0 copy/ml) after IndCT with very lower copy numbers (median, 18 copies/ml; interquantile range, 7-153, for these 84 patients). Patients with a higher N-classification (N3 vs. N0-2, P<0.0001) and overall stage (IV vs. II-III, P=0.0400) had a higher detectable pEBV DNA after IndCT. Forty-twor of 84 (50.0%) patients with detectable pEBV DNA (> 0 copy/ml) developed tumor relapse, whereas 23.8% (29/122) patients with undetectable pEBV DNA (= 0 copy/ml) had tumor relapse (P<0.0001). The patterns of failure revealed that patients with detectable post-IndCT pEBV DNA had more distant (39.3% vs. 17.2%, P=0.0004) and neck (7.1% vs. 1.6%, P=0.0650) failures but not local recurrence (11.9% vs. 9.8%, P=0.6366), compared with those of undetectable EBV DNA.The 5-year overall survival rates were 63.1% and 70.4% for patients with post-IndCT viral load > and = 0 copies/ml (P=0.0010). The corresponding figures of relapse-free survival rates were 54.4% and 78.4% (P<0.0001). Post-IndCT pEBV DNA status can predict long-term outcome for NPC patients. More intensive treatment strategy for these high-risk patients with persistently detectable pEBV DNA after IndCT should be studied further.

336P EBV DNA and neutrophil-lymphocyte ratio as predictive biomarkers for induction chemotherapy in advanced nasopharyngeal carcinoma

336P EBV DNA and neutrophil-lymphocyte ratio as predictive biomarkers for induction chemotherapy in advanced nasopharyngeal carcinoma

Expression of RRM1 and its association with resistancy to gemcitabine-based chemotherapy in advanced nasopharyngeal carcinoma

Gemcitabine has high activity against nasopharyngeal carcinoma (NPC). The level of ribonucleotide reductase subunit M1 (RRM1) expression is closely related to the efficacy of gemcitabine on non-small cell lung cancer and pancreatic cancer. However, the expression of RRM1 and its association with sensitivity to gemcitabine-based chemotherapy in advanced NPC is not known. In this study, we retrospectively collected 48 formalin-fixed, paraffin-embedded NPC tissues to evaluate the expression of RRM1 using immunohistochemistry. All patients were diagnosed and treated with gemcitabine-based chemotherapy at Sun Yat-sen University Cancer Center. RRM1 expression was positive in 17 (35%) patients. RRM1 expression was not associated with sex, age, performance status, WHO histological type, number of distant metastases, previous treatment, or cycles of gemcitabine-based chemotherapy (P > 0.05). The progression-free survival of the RRM1-positive group was shorter than that of the RRM1-negative group (5 months vs. 7 months, P = 0.036), and the response rate of the RRM1-positive group was somewhat lower than that of the RRM1-negative group (51.6% vs. 35.3%, P = 0.278). There was no significant difference in median survival between the RRM1-positive and RRM1-negative groups (22 months vs. 19 months, P = 0.540). Our results show that RRM1-negative expression is related with longer progression-free survival in advanced NPC patients treated with gemcitabine-based regimens.

Adjuvant chemotherapy in advanced nasopharyngeal carcinoma based on plasma EBV load

Nasopharyngeal carcinoma (NPC) has been shown to be a radio- and chemosensitive tumor and combined chemoradiotherapy is the standard of care for advanced-stage patients. Different chemotherapy strategies (neoadjuvant, concurrent, adjuvant) are incorporated with radiotherapy to enhance treatment outcome and each mode of combined therapy has advantages and disadvantages. There are many randomized clinical trials investigating the role of adding chemotherapy in NPC management. So far, concurrent and neoadjuvant chemotherapy are more frequently used for locoregionally advanced tumors. However, the current reality is that (1) distant failure is the most frequent site of relapse reported in all studies, (2) patients have already received neoadjuvant and/or concurrent chemotherapy, and (3) only some tumors recur after previous neoadjuvant/concurrent chemotherapy with radiotherapy. So, adjuvant chemotherapy is a reasonable timing to consolidate the treatment outcome for selected patients. Recently, several tumor markers can predict tumors with high probability of recurrence. Among these markers, plasma EBV DNA assay is a simple and reliable one in predicting prognosis. In this mini-review, I will focus on the role of adjuvant chemotherapy based on plasma EBV DNA load.

The Short-term clinical observation of SIB-IMRT in locally advanced nasopharyngeal carcinoma

Objective To evaluate the feasibility , toxicity and clinical efficacy of intensity-modulated radiotherapy using the simultaneous integrated boost (SIB- IMRT) and concurrent chemotherapy for advanced nasopharyngeal carcinoma. Methods Thirty nsopharyngeal carcinoma were treated with full course IMRT including nasopharynx and full neck to supraclavicle. The radiotherapy dosage is 68 Gy to the target. Concurrent chemotherapy was given, and the regimen was DDP 40 mg/m2/weekly.Results The mean dose of covering gross tumor volume(PGTV) (D95) in the nasopharynx was 70.48 Gy, and the mean volume of PGTV1 receiving the 95 % dose(V95) was 98. 46 %. The mean dose of PGTV1, PGTV2, PCTV1 and PCTV2 in the targets were 70.8 Gy, 66.4 Gy, 62.3 Gy and 54.8 Gy. According to the evaluation, the acute skin,mucositis and salivary toxicity with grade Ⅲ in those patients were 3.3 %, 10 %, 6.6 %. The patients developed different blood toxicity, but didn't affect their treatment. The median follow-up time was 6.5 months, and disease free survival rate was 100 %. Conclusion SIB-IMRT yields well dose distribution and acceptable toxicity in advanced stage nasopharyngeal carcinoma. The preliminary clinical result is encouraging. Key words: Nasopharyngeal neoplasms; Radiotherapy; computer--assisted; Drug therapy; Prognosis

Long-term results of concurrent and adjuvant chemotherapy for advanced nasopharyngeal carcinoma

6056 Background: Preliminary results of a factorial trial investigating concurrent chemoradiation (CRT) and adjuvant chemotherapy (AC) for nasopharygngeal carcinoma (NPC) was reported in 2004 (JCO 22 (13): 2643–2653). This is a report on the long-term follow-up results of the study. Methods: Ho's stage T3 or N2 /N3 or > 4cm neck node, M0 disease were eligible. Patients were first randomized to receive CRT or RT alone and then further randomized to receive AC or no AC after completion of CRT/RT. Patients randomized to CRT received UFT (uracil and tegafur in 4:1 molar ratio) 200mg, 3 times a day, during radiotherapy. AC consisted of alternating PF (cisplatin 100mg/m2 D1 and 5FU 1g/m2 D1–3) and VBM (vincristine 2mg, bleomycin 30mg and methotrexate 150mg/m2, all on D1) for 6 cycles. The 4 treatment arms were: A. RT, B. CRT, C. RT + AC, D. CRT + AC. Patients in arms A and C were compared with those in arms B and D (i.e. RT vs. CRT) for efficacy of CRT. Patients in arms A and B were compared with those in arms C and D (i.e. no AC vs. AC) for efficacy of AC. Loco- regional control (LRC), distant metastases free survival (DMFS), failure-free survival (FFS) and disease-specific survival (DSS) were estimated with Kaplan-Meier methods and compared with log-rank test. Results: From May 1995 to October 2001, 222 patients were recruited. 3 patients were excluded from analysis. Median follow up time was 7 years. There were 55, 53, 54, 57 patients in arm A, B, C, D respectively. The 7-year LRC of the 4 arms were 64.2%, 74.8%, 78.7%, 78.8% respectively; DMFS were 71.7%, 85.8%, 65.5%, 80.4%; FFS were 51.7%, 69%, 53.2%, 64.4%; DSS were 71.7%, 75.4%, 66.1%, 81.5%. CRT significantly improved the DMFS and FFS compared with RT (p=0.014 and 0.016 respectively). There was a trend of improvement in DSS with CRT also (p=0.057). The use of AC failed to improve survival. Multivariate analysis showed CRT, T stage and N stage were significant for both FFS and DSS. Conclusions: CRT significantly improved DMFS and FFS in advanced NPC. The benefit of CRT was confirmed on long-term follow-up. No significant financial relationships to disclose.

Potential improvement of tumor control probability by induction chemotherapy for advanced nasopharyngeal carcinoma

Purpose To assess the reduction of tumor bulk and improvement of tumor control probability (TCP) by using induction chemotherapy for advanced nasopharyngeal carcinoma (NPC). Materials and methods From February to December 2005, 20 patients with Stage III–IVB NPC were treated with induction-concurrent chemotherapy and intensity-modulated radiotherapy with accelerated fractionation. Combination of cisplatin and 5-fluorouracil was used in the induction phase and single agent Cisplatin in the concurrent phase. All patients were irradiated at 2 Gy per fraction, 6 daily fractions per week, to a total dose of 70 Gy. Results Nineteen (95%) patients completed all 3 cycles of induction chemotherapy and 90% had ⩾2 cycles of concurrent chemotherapy. Induction chemotherapy achieved significant down-staging of T-category in 35% of patients ( p = 0.016) and reduction of gross tumor volume (GTV_P) from 55.6 to 22.9 cc (mean 61.4%, p < 0.001). Although the mean radiation dose did not show any substantial change, the volume within GTV_P that failed to reach 70 Gy was reduced from 10.2% to 3.8% ( p = 0.017). The estimated local TCP increased from 0.83 to 0.89 ( p = 0.002). Conclusions Induction chemotherapy using cisplatin–5-fluorouracil could significantly reduce tumor bulk leading to potential improvement in tumor control.

Accelerated fractionated radiation by concomitant boost (AFX-CB) with concurrent cis-platinum (CDDP) for advanced nasopharyngeal carcinoma

5540 Background: Recent data (RTOG 90–03 and RTOG 99–14) strongly suggest that concomitant boost radiation (AFX-CB) and concurrent chemoradiation offer a local control advantage in advanced head and neck cancer patients. Based on our previous experience treating unresectable head and neck cancer, we initiated a phase II trial delivering CDDP concurrent with AFX-CB for advanced nasopharyngeal carcinoma (NPC). Methods: From 2/99–7/05, 44 patients with newly diagnosed stage IIa-IV NPC were treated with AFX-CB to 70Gy/6 weeks (BID RT last 2 weeks with a 3D-conformal plan, 6 hr interfraction interval) with 2–3 cycles of concurrent CDDP (100mg/m2) on day 1, 22, 43 of radiation followed by adjuvant 5-Fluorouracil/CDDP. The median age was 46 (24 to 83) and 20 patients were male. Disease characteristics were as follows: 1997 AJCC stage: II-7; III-14 and IV-23, T3/T4 66%, N2/N3 55%. Results: With a median follow-up of 30 mo. (3–78 mo.), the crude local control rate (LC) was 93%, regional control (RC) was 98%, locoregional control (LRC) 91%, freedom from distant metastasis (FFDM) was 86%, disease-free survival (DFS) was 82%, and overall survival (OS) was 89%. Eighty-six percent of patients were able to receive 2–3 cycles of adjuvant chemotherapy. Four of the 6 distant metastases occurred after 3 years post-treatment. One of the 3 local failures was salvaged with additional chemoradiation and is without evidence of recurrence 23 months later. Thus, the total crude local control is 95%. Among 29 T3/T4 patients, local control was 93%. For all patients, the three year actuarial LC, RC, LRC, FFDM, DFS and OS were 95%, 98%, 93%, 94%, 86% and 87%, respectively. Major grade 3 acute toxicities include mucositis (59%), dysphagia (41%), vomiting (20%) and anemia (4.5%). Average hemoglobin drop was 2.3 gm (17.7%). Ninety percent of patients received erythropoietin support and near 20% required blood transfusion. Late toxicities included grade 3 tinnitus in 1, grade 2 serous otitis in 1, osteoradionecrosis in 1 and brain necrosis in 2. Conclusions: AFX-CB with concurrent and adjuvant chemotherapy for advanced NPC provides excellent locoregional control and acceptable toxicity. Future efforts will focus on decreasing toxicity and increasing systemic control. No significant financial relationships to disclose.

Induction chemotherapy with cisplatin and gemcitabine followed by accelerated radiotherapy and concurrent cisplatin in patients with stage IV(A-B) nasopharyngeal carcinoma

The purpose of this study was to evaluate the efficacy and toxicity of cisplatin plus gemcitabine as induction chemotherapy in advanced nasopharyngeal carcinoma (NPC). Thirty-seven patients with stage IV(A-B) NPC were treated with 3 cycles of cisplatin plus gemcitabine (cisplatin 80 mg/m(2) on day 1; gemcitabine 1250 mg/m(2) on days 1 and 8) 3-weekly as induction chemotherapy, followed by another 3 cycles of concurrent cisplatin (100 mg/m(2) on day 1) 3-weekly with accelerated radiotherapy (RT) at 70 Gy in 2-Gy fractions, 6 daily fractions per week. The overall response rate to induction chemotherapy was > 90%, and side effects other than uncomplicated hematologic toxicities were uncommon. All patients completed RT, with 92% receiving > or = 5 cycles of chemotherapy. At a median follow-up of 2.9 years, the 3-year overall survival (OS) and disease-free survival (DFS) rates were 76% and 63%, respectively. Cisplatin plus gemcitabine is a well-tolerated, effective, and convenient induction chemotherapy regimen and warrants further studies to confirm its benefit in advanced NPC.

Accelerated fractionated radiation by concomitant boost (AFX-CB) with concurrent cisplatin for advanced nasopharyngeal carcinoma

Accelerated fractionated radiation by concomitant boost (AFX-CB) with concurrent cisplatin for advanced nasopharyngeal carcinoma

Chemotherapy for advanced nasopharyngeal carcinoma with methotrexate, vincristine, cisplatin and adriamycin

Objective: To evaluate the efficacy and toxicity of M-VCA (methortrexate 30 mg/m2, vincristine 2 mg, cisplatin 70 mg/m2, adriamycin 30 mg/m2) combination chemotherapy for advanced nasopharyngeal carcinoma. Methods: Thirty-five patients with advanced nasopharyngeal carcinoma, including 11 patients with untreated local advanced nasopharyngeal carcinoma and 24 patients with local-regional recurrent or metastatic nasopharyngeal carcinoma, received the chemotherapy of M-VCA. The cycle was repeated on day 22 for two cycles. All patients completed the chemotherapy courses. Results: The overall response rate was 75%, with untreated local advanced nasopharyngeal carcinomas 11/11(100%), local-regional recurrent nasopharyngeal carcinomas 12/18(67%), lung metastases 8/9(89%), bone metastases 5/9(56%), and liver metastases 1/2(50%). The main side effects included mild to moderate degree alopecia, nausea/vomiting, and neutropenia. Conclusion: M-VCA is well tolerated and has good efficacy for advanced nasopharyngeal carcinoma and is worth investigating further.

Partially hyperfractionated accelerated radiotherapy and concurrent chemotherapy for advanced nasopharyngeal carcinoma

Purpose:A newly designed concomitant chemoradiotherapy was undertaken to assess the feasibility and efficacy for advanced nasopharyngeal carcinoma (NPC).Methods and Materials:Sixty-three patients with biopsy-proven NPC were entered in this Phase II trial from March 1992 to November 1993. Most patients present with Stage IV disease (93.4%) and poorly differentiated epidermoid carcinoma or undifferentiated carcinoma were the major pathologic type. Radiotherapy was delivered using a telecobalt unit and 10 MV x-rays and by altered fractionation (72–74 Gy/45 fractions/6 weeks). Chemotherapy with cisplatin 75 mg/mm2, 2 h infusion at day 1, followed by 5-FU 400 mg/m2/day, continuosly infused for 4 days was given concurrently during the first and fifth weeks of radiotheraphy.Results:The major toxicity was mucositis (61% belong to Grade 3, 31% to Grade 2). Weight loss, leucopenia, and skin reaction were frequently encountered. Three patients withdrew from treatment at 15, 25, and 55.5 Gy, three patients interrupted the radiotherapy for 1–4.5 weeks, and two patients refused the second cycle of concomitant chemotherapy due to toxicities. The initial tumor response showed 100% overall response rate, with 90.5% complete response. After a median follow-up tiem of 38 months, five patients failed at the primary and/or neck (four recurrent and one persistent), and 14 patients developed distant metastases alone. The 3-year primary disease-free, regional disease-free, distant disease-free, and overall survival rates are 89.1, 92.8, 74.3, and 73.6%, respectively. The late complication rate is acceptable so far.Conclusions:Our data indicates that concurrent chemoradiotherapy for advanced NPC is both feasible and effective, with acceptable toxicities. Distant metastases are the major site of treatment failure. Postradition adjuvant chemotherapy to eradicate subclinical distant metastasis should be further studied.

#649 Non-Platinum Based Chemotherapy in Advanced Nasopharyngeal Carcinoma (NPC) in Children. A Long Term Follow-Up in a Single Institution

Ghim, T.; Briones, M.*; Crocker, I.*; Alvarado, C.; Vega, R.; Bell, B. Author Information

Neoadjuvant Chemotherapy for Advanced Nasopharyngeal Carcinoma

Between October 1990 and November 1991, a total of 16 male patients with advanced nasopharyngeal carcinoma were treated by neoadjuvant chemotherapy before conventional radiotherapy. They belonged to the AJCC stage IV with multiple bulky neck nodes metastases. The chemotherapy consisted of bleomycin, epirubicin, and cisplatin. Six patients completed 3 cycles, 9 patients finished 2 cycles, and 1 patient received 1 cycle of chemotherapy. Seven of the 16 patients (44%) were in complete response, and 50% (8/16) achieved partial response. The overall response rate was 94%. The major toxicities consisted of leucopenia (12/37 cycles had grade III-IV), nausea/vomiting, alopecia. Aplastic marrow developed in 1 patient, and one died of bleomycin-induced pneumonitis. Subsequent radiation therapy was well tolerated. After a minimal follow-up time of 24 months, the 2-year actuarial survival rate was 56%. Although we confirmed the impressively high response rate of this regimen, the toxicities were high and most patients failed at distant site(s). The efficacy of neoadjuvant chemotherapy for advanced nasopharyngeal carcinoma is doubtful and should be further studied in prospective randomized trials.

Adjuvant chemotherapy for advanced nasopharyngeal carcinoma in childhood : Kim, T.H., McLaren, J., Alvarado, C.S., Wyly, J.B., Crocker, I., Winn, K., Singhapakdi, S. and Ragab, A., Cancer (1989) 63/10 (1922–1926)

Adjuvant chemotherapy for advanced nasopharyngeal carcinoma in childhood : Kim, T.H., McLaren, J., Alvarado, C.S., Wyly, J.B., Crocker, I., Winn, K., Singhapakdi, S. and Ragab, A., Cancer (1989) 63/10 (1922–1926)

Adjuvant chemotherapy for advanced nasopharyngeal carcinoma in childhood.

Seven children with advanced nasopharyngeal carcinoma younger than 20 years of age diagnosed between 1975 and 1986 (inclusive) were treated with a uniform adjuvant chemotherapy regimen, which consisted of vincristine (1.5 mg/m2; day 1), doxorubicin (45 mg/m2; day 1), 5-fluorouracil (8 mg/kg; days 1 through 5), and cyclophosphamide (7 mg/kg; days 1 through 5). This combination chemotherapy was given for 12 to 24 months after completion of radiation therapy. The radiation doses to the primary sites ranged from 6000 cGy to a maximum of 6800 cGy. The radiation doses for neck prophylaxis ranged from 4500 cGy to a total of 5000 cGy. Involved sites were irradiated to at least an additional boost of 1000 cGy. One patient had an external dose 6000 cGy to the primary site boosted with brachytherapy of 3000 cGy at the surface of an ovoid. After chemotherapy myelosuppression occurred in all patients and was tolerable. All seven patients are surviving, six disease-free, for 22 months to 12 years (median, 4 years). This study suggests that the combination of radiation therapy and chemotherapy as used here has acceptable toxicity and is effective and further suggests that children with nasopharyngeal carcinoma, even in its advanced stage at diagnosis, may be curable.