# Radiation Oncology/Head & Neck/Nasopharynx/Advanced Stage

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Nasopharyngeal Cancer - Advanced Stage

## Chemotherapy with radiation

* Because Stage III-IV NPC has a fairly poor prognosis with RT alone, multiple efforts were made to add chemotherapy to the regimen
* Induction chemotherapy was evaluated in 5 randomized trials; two showed small benefit for disease-free survival, but none showed an overall survival benefit. As a result, induction chemotherapy is currently not indicated
* Adjuvant chemotherapy was evaluated in 3 randomized trials; there was no benefit
* Phase II RTOG 81-17 demonstrated the feasibility of concurrent cisplatin with RT in advanced H&N cancers; it included 22% NPC. Subsequent Intergroup trial 0099 showed a survival benefit for concurrent cisplatin with RT, followed by adjuvant chemotherapy. This was the first trial to do so; however, the RT only arm had an unexpectedly low survival, compared with results from RT alone in Asian (endemic) studies
* Concurrent chemo-RT benefits were confirmed by a randomized trial from Taiwan in an endemic population, which used concurrent cisplatin + 5-FU. However, a re-analysis of the data suggests that concurrent chemo-RT is only beneficial for "low-risk" advanced stage patients. "High-risk" advanced stage patients did not gain any benefit from that chemo regimen, and may require more intense, neoadjuvant, or further adjuvant chemotherapy
* A Singaporean trial used the INT 0099 regimen, and again demonstrated a survival benefit
* Concurrent chemo-RT is now considered a standard of care in Stage III-IV NPC; given previously different staging, some IIB patients were included in the trials and may benefit from concurrent chemotherapy as well. The INT 0099 regimen is the best characterized; unfortunately, compliance with the regimen is only 60-70%
* Because concurrent chemo-RT results in reasonable local control, but adjuvant chemo has not resulted in good systemic control, efforts are underway to try induction -> concurrent chemo-RT. Several Phase II trials have reported encouraging results in patients with significant N disease
* Meta-analysis; 2006 PMID 16377415 -- "Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients." (Baujat B, Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):47-56.)
** 8 trials, 1753 patients (concurrent: INT 0099, PWH-QEH Hong Kong, QMH Hong Kong, induction: PWH Hong Kong, AOCOA, VUMCA, Hokkaido, adjuvant: Taiwan). Individual updated patient data. Median F/U 6 years
** Outcome: Addition of chemo absolute survival benefit of 6% at 5 years (56% to 62%), absolute EFS benefit of 10% (42% to 52%)
** Significant interaction between timing of chemo and OS; highest benefit from concurrent chemo
** Conclusion: Chemotherapy has small but significant benefit for OS and EFS, seen when administered concomitantly
* Meta-analysis; 2002 - PMID 12040275 — "Combined chemoradiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: results of a meta-analysis of 1,528 patients from six randomized trials." (Huncharek M et al. Am J Clin Oncol. 2002 Jun;25(3):219-23.)
** 6 trials, 1528 patients (concurrent: INT 0099; induction: Hong Kong, Guangzhou, AOCOA, VUMCA; adjuvant: Italian). Chemoradiation vs radiation alone in locally advanced patients, either adjuvantly, neoadjuvantly, or concurrently.
** Outcome: DFS/PFS improved 2 years 37%, 3 years 40%, 4 years 34%. OS improved 2 years 20% (NS), 3 years 19% (NS), 4 years 21% (SS)
** Conclusion: Addition of chemotherapy improves DFS/PFS and OS

### Concurrent chemo-RT vs RT alone

* Hong Kong NPC-9902 (T-disease) (1999-2004)
** Randomized, 2x2 design. Closed early due to slow accrual. 189 patients, WHO grade II-III, Stage T3-4N0-1 (AJCC-5)(key problem locoregional failure; see companion trial NPC-9901). Arm 1) conventional RT alone vs. Arm 2) accelerated RT vs. Arm 3) conventional RT + concurrent chemo vs. Arm 4) accelerated RT + concurrent chemo. Conventional RT >=66 in 2 Gy/fx, 5 days/week. Accelerated same regimen but 6 days/week. Technique 2D or 3D-CRT or IMRT boost. Concurrent chemo cisplatin 100 mg/m2 q3 weeks, adjuvant chemo cisplatin 80 mg/m2 + 5-FU 1000 mg/m2
** 3-years; 2006 PMID 16904519 -- "Preliminary results of a randomized study (NPC-9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma." (Lee AW, Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):142-51.). Median F/U 2.9 years
*** Outcome: 3-year FFS RT 70%, AFRT 63%, chemo-RT 74%, chemo-AFRT 94% (SS). On multivariate analysis, concurrent chemo significant, accelerated RT not significant. OS 83%, 73%, 87%, 88% (NS)
*** Toxicity Grade 3-5: Acute: RT 55%, AFRT 70%, chemo-RT 83%, chemo-AFRT 86% (concurrent chemo SS worse). Late: 17%, 21%, 27%, 32% (chemo-AFRT borderline p=0.05 worse). Most late toxicity otologic.
*** Conclusion: Preliminary, concurrent chemo with accelerated fractionation could significantly improve local tumor control
* Hong Kong NPC-9901 (N-disease) (1999-2004)
** Randomized. 348 patients, WHO grade II-III, T1-4N2-N3 (AJCC-5)(key problem distant failure; see companion trial NPC-9902). Arm 1) RT alone vs. Arm 2) RT + concurrent cisplatin 100 mg/m2 q3 weeks. RT >= 66 Gy (2D, 3D-CRT or IMRT)
** 3-years; 2005 PMID 16192584 -- "Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group." (Lee AW, J Clin Oncol. 2005 Oct 1;23(28):6966-75.) Median F/U 2.3 years
*** Outcome: DFS chemo-RT 72% vs. RT alone 62% (SS), LRC 92% vs. 82% (SS), DM 76% vs. 73% (NS), OS 78% vs. 78% (NS)
*** Toxicity: acute chemo-RT 84% vs. RT alone 53% (SS); late 28% vs. 13% (SS), most late toxicity otologic
*** Conclusion: Preliminary, significant benefit for tumor control at the cost of higher toxicity. No early OS benefit
* Singapore SQNP01 (1997-2003)
** Randomized. 221 patients, WHO II-III, T3-4 or N2-3 (AJCC-5). Arm 1) RT alone vs. Arm 2) RT + concurrent cisplatin 100 mg/m2 q3 weeks + adjuvant cisplatin 80 mg/m2 + 5-FU 1000 mg/m2 x3 cycles. RT technique 70 Gy primary, 60 Gy neck + 10 Gy electron boost to lymph nodes. 71% patients received all 3 cycles of concurrent chemo
** 3-years; 2005 PMID 16170180 -- "Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety." (Wee J, J Clin Oncol. 2005 Sep 20;23(27):6730-8.) Median F/U 3.2 years
*** Outcome: 3-year DFS chemo-RT 72% vs. RT 53% (SS); OS 80% vs. 65% (SS); 2-year DM chemo-RT 13% vs. RT alone 30% (SS)
*** Toxicity: Grade 3-5 in 48%, mucositis chemo-RT 48% vs. RT 32% (SS), anorexia 22% vs. 4% (SS), emesis 5% vs. 0% (SS). Also significant hematologic toxicity
*** Conclusion: Confirmation of INT 0099 results; also applicable in endemic NPC
* Queen Mary Hospital, Hong Kong (1995-2001)
** Randomized, 2x2 design (concurrent chemo vs. none, adjuvant chemo vs. none). Ho's Stage T3 or N2-3 or LN >=4 cm (AJCC 6th II-IV). Arm 1) RT alone vs. Arm 2) concurrent chemo-RT vs. Arm 3) RT + adjuvant chemo vs. Arm 4) concurrent chemo-RT + adjuvant RT. Concurrent chemo was FU prodrug uracil/tegafur, adjuvant chemo was cisplatin/5-FU and vincristine/bleomycin/MTX x3+3 cycles. RT 1995-1997 62.5/25 split course with 1 week break; 1997-2001 68/34 primary and 66/33 neck. If parapharyngeal extension or residual disease, 10 Gy boost
** 3-years; 2004 PMID 15226332 -- "Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study." (Kwong DL, J Clin Oncol. 2004 Jul 1;22(13):2643-53.)
*** Outcome: 3-year concurrent CRT vs. RT alone FFS 69% vs. 58% (NS), OS 86% vs. 77% (p=0.06), LRC 80% vs. 72% (NS), DM 15% vs. 29% (SS). 3-year adjuvant chemo vs. none FFS 62% vs. 65% (NS), OS 80% vs. 83% (NS), no difference on LRC or DM.
*** Conclusion: Trend to improvement with concurrent chemo-RT over RT alone (p=0.06), no benefit to adjuvant chemo
* Prince of Wales Hospital / Queen Elizabeth Hospital, Hong Kong (1994-1999)
** Randomized. 350 patients, Ho's Stage N2-3 or N1 with LN >=4 cm (AJCC-6 Stage II-IVB). Arm 1) RT with concurrent cisplatin 40 mg/m2 q week vs. Arm 2) RT alone. RT 66 Gy, parapharyngeal boost 10-20 Gy allowed. Primary end point PFS
** 2-years; 2002 PMID 11956263 -- "Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial." (Chan AT, J Clin Oncol. 2002 Apr 15;20(8):2038-44.) Median F/U 2.7 years
*** Outcome: 2-year PFS chemo-RT 76% vs. RT alone 69% (NS). Subgroup analysis benefit for Ho's T3
*** Conclusion: Concurrent chemo-RT well tolerated, but no benefit
** 5-years; 2005 PMID 15812080 -- "Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma." (Chan AT, J Natl Cancer Inst. 2005 Apr 6;97(7):536-9.) Median F/U 5.5 years
*** Outcome: 5-year OS chemo-RT 70% vs. RT 59% (p=0.07). Subgroup analysis no benefit for T1-2, but benefit for T3-4 (HR 0.51)
*** Conclusion: Trend for survival benefit; promising treatment strategy
* Taiwan (1993-1999)
** Randomized. 284 patients, NPC Stage III-IV M0, histology WHO I (3%), WHO II (73%), WHO III (24%). Arm 1) RT 70-74 Gy alone vs. Arm 2) concurrent cisplatin 20 mg/m2 + 5-FU 400 mg/m2 during week 1 and 5. RT: CTV = GTV+2cm, included entire base of skull, sphenoid sinus, 2cm beyond mastoid process, posterior half of maxillary sinus/nasal cavity. Dose 70-74 Gy primary tumor and LN+, 50-60 Gy N0 neck. Chemo completed by 94% patients
** 5-years; 2003 PMID 12586799 -- "Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival." (Lin JC, J Clin Oncol. 2003 Feb 15;21(4):631-7.). Median F/U 5.4 years
*** 5-year outcome: PFS RT alone 53% vs. chemo-RT 72% (SS); OS 54% vs. 72% (SS)
*** Toxicity Grade 3-4: mucositis 35% vs. 45%, skin 26% vs. 35%
*** Conclusion: Concurrent chemo-RT superior to RT alone for advanced NPC
** Re-analysis; 2004 PMID 15337551 -- "Another way to estimate outcome of advanced nasopharyngeal carcinoma--is concurrent chemoradiotherapy adequate?" (Lin JC, Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):156-64.)
*** Original (AJCC 1992) stage: Stage III 20%, Stage IV 80%. Restaged (AJCC 1997): Stage II/III 71%, Stage IV 29%. New risk definition: high-risk (LN >6cm or SCV LN or AJCC 1992 T4N2 or multiple LN mets with 1 LN >4cm) 42% vs. low-risk 58%
*** Low-risk group (chemo-RT vs. RT): LC 95% vs. 77% (SS), neck control 100% vs. 96% (NS), DM 90% vs. 78% (SS), PFS 87% vs. 61% (SS), OS 83% vs. 60% (SS). Chemo-RT significantly better
*** High-risk group (chemo-RT vs. RT): LC 75% vs. 68% (NS), neck control 92% vs. 87% (NS), DM 60% vs. 60% (NS), PFS 44% vs. 43% (NS), OS 56% vs. 46% (NS). No difference with concurrent chemo
*** Conclusion: Concurrent chemo-RT superior for low-risk patients, but inadequate for high-risk patients
* NYU; 2000 (1995-1997) - PMID 10863053 — "Improved outcome secondary to concurrent chemoradiotherapy for advanced carcinoma of the nasopharynx: preliminary corroboration of the intergroup experience." (Cooper JS et al. Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):861-6.)
** Retrospective single institution. Repeated regimen of Intergroup 0099. Stage III-IV.
** Outcome: 3-year OS was 93% and DFS was 65%; both substantially better than historical controls
** Conclusion: INT 0099 regimen should be standard of care
* Intergroup 0099 / RTOG 88-17 (1989-1995)
** Randomized. Trial stopped early due to significant survival benefit. 147 patients. NPC Stage III-IV (Stage IV 91%; but also included few N1 patients, which are IIB today), histology WHO I (25%), WHO II (35%), WHO III (41%). Arm 1) RT 70 Gy alone vs RT 70 Gy with concurrent cisplatin 100 mg/m2 q3 weeks and adjuvant cisplatin + 5-Fu . CT-based treatment planning. Fields: included 2 cm margin on gross disease and included entire base of skull and sphenoid sinus, 2 cm posterior to mastoid process; anteriorly included posterior 1/3 of maxillary sinus and nasal cavity. Dose: 70 Gy to primary. For neck to clavicle, 50 Gy for N0 disease, 66 Gy for nodes <= 2 cm, and 70 Gy for nodes > 2 cm. Cisplatin given every 3 weeks at 100 mg/m2 x 3 cycles. Then adjuvant chemo began 4 weeks after finishing RT: cisplatin 80 mg/m2 and 5-FU 1000 mg/m2/d by 96-hr infusion q4w x 3 cycles. Partial or radical neck dissections for persistent neck disease. Chemo completed by 55%
** 1998 PMID 9552031 - "Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099." Al-Sarraf et al. J Clin Oncol. 1998 Apr;16(4):1310-7. Median F/U 2.7 years
*** 3-year outcome: PFS chemo-RT 69% vs. RT alone 24% (SS); OS 78% vs 47% (SS). Median OS not reached for chemo-RT vs. 2.5 years for RT alone.
*** Toxicity Grade 3-4: stomatitis 29% vs. 19%, nausea 14% vs. 5%, leukopenia 23% vs. 1%
*** Conclusion: Concurrent chemo-RT superior to RT alone for advanced NPC
** Comment: First randomized trial to show a survival benefit for the use of concurrent chemo, unexpectedly low RT alone outcome (several retrospective series showed >70% OS with RT alone in endemic patients), RT technique considered less aggressive than that practiced in Asia (particularly lack of parapharyngeal and intracavitary boost), not applicable to non-US patients
* RTOG 81-17 (1981-1984)
** Phase II. 124 patients, locally advanced inoperable H&N cancer (oropharynx 39%, nasopharynx 22%, oral cavity 18%, hypopharynx 7%, larynx 7%, sinuses 7%). Stage III 18%, Stage IV 82%. Concurrent RT 66-73.8 Gy with cisplatin 100 mg/m2 q3 weeks. 60% completed planned treatment
** Overall; 1987 PMID 3802013 -- "Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study." (Al-Sarraf M, Cancer. 1987 Jan 15;59(2):259-65.)
*** Severe toxicity: stomatitis 31%, leukopenia 11%, anemia 8%, N/V 6%
*** Outcome: 1-year DFS 51%, OS 66%. Nasopharynx CR 82%
*** Conclusion: Concurrent cisplatin effective and safe in advanced H&N
** NPC Subset; 1990 PMID 2199621 -- "Chemo-radiotherapy in patients with locally advanced nasopharyngeal carcinoma: a radiation therapy oncology group study." (Al-Sarraf M, J Clin Oncol. 1990 Aug;8(8):1342-51.)
*** Subset analysis, 27 NPC patients, 96% Stage IV, 67% poorly differentiated. All patients received >64.5 Gy. Median F/U 1.5 years
*** Severe toxicity: stomatitis 41%, xerostomia 15%
*** Outcome: 4-year DFS 45%, OS 55%
*** Conclusion: Chemo-RT in NPC effective, should be evaluated in phase III

### Concurrent RT with biologics

* Beijing Hospital, China (2001-2003) -- RT +/- recombinant adenovirus-p53
** Randomized. 82 patients with NPC. Arm 1) RT 70/35 alone vs. Arm 2) RT + recombinant adenovirus-p53 (rAd-p53) injected intratumorally QW x8
** 2008 PMID 19103729 -- "Effect of Recombinant Adenovirus-p53 Combined With Radiotherapy on Long-Term Prognosis of Advanced Nasopharyngeal Carcinoma." (Pan JJ, J Clin Oncol. 2008 Dec 22. [Epub ahead of print]) Median F/U 5.1 years
*** Outcome: p53 mRNA detected in 94% postinjection biopsies, with upregulation of p21 and Bax. 5-year LRF RT 28% vs RT + rAd-p53 3% (SS); 5-year DFS 57% vs. 67% (NS); 5-year OS 59% vs. 67% (NS)
*** Toxicity: Transient fever after rAd-p53 administration
*** Conclusion: rAd-p53 was safe and biologically active, and improves tumor control and survival rate

### Sequential Chemo and RT vs. RT alone

* Pooled long-term AOCOA/Guangzhou data
** Pooled data from 2 similar PIII trials comparing induction chemo->RT vs. RT alone. 784 patients. Induction cisplatin, bleomycin, 5-FU or cisplatin, epirubicin. RT 70 Gy. Median F/U 5.6 years
** 5-years; 2005 PMID 15657403 -- "Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials." (Chua DT, J Clin Oncol. 2005 Feb 20;23(6):1118-24.)
*** Outcome: 5-year DFS induction chemo 63% vs. RT 58% (SS), OS 62% vs. 58% (NS). LRF decreased by 18%, DM decreased by 13%, but no significant difference in failure patterns
*** Conclusion: Induction chemo-RT modest decrease in DFS, but no impact on OS. Concurrent chemo-RT should remain standard of care
** Early Stage NPC; 2006 PMID 16750333 -- "Improvement of survival after addition of induction chemotherapy to radiotherapy in patients with early-stage nasopharyngeal carcinoma: Subgroup analysis of two Phase III trials." (Chua DT, Int J Radiat Oncol Biol Phys. 2006 Aug 1;65(5):1300-6. Epub 2006 Jun 5.)
*** Subset analysis. AJCC 1997 Staging. Group 1 (T1-2N0-1, was entirely IIB) vs. Group 2 (T1-2N2-3) vs. Group 3 (T3-4N0-1) vs. Group 4 (T3-4N2-3).
*** Outcome: no difference in LRC, DM, or OS for Groups 2-4. Group 1 5-year OS induction chemo 79% vs. RT alone 67% (p=0.048), DM 86% vs. 74% (SS)
*** Conclusion: Group 1 (T1-2N0-1; all IIB) relatively poor survival due to mets, improved with induction chemo. No benefit for induction in Groups 2-4
* Guangzhou (1993-1994) - cisplatin, 5-FU, bleomycin
** Randomized. 456 patients. Chinese stage III-IV M0. Arm 1) RT alone vs. Arm 2) Neoadjuvant cisplatin 100 mg/m2, bleomycin 10 mg/m2, and 5-FU 800 mg/m2 x2-3 cycles, followed by RT within 2 weeks. RT 68-72 Gy primary tumor, involved neck 60-62 Gy, uninvolved neck 60 Gy. If residual tumor after RT, could boost 10-14 Gy EBRT or 20-24 Gy HDR in 4-5 fractions
** 5-years; 2001 PMID 11230478 -- "Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma." (Ma J, J Clin Oncol. 2001 Mar 1;19(5):1350-7.)
*** Outcome: 5-year OS induction chemo 63% vs. RT alone 56% (NS); RFS 59% vs. 49% (SS); LRC 82% vs. 74% (p=0.05); no difference on DM
*** Conclusion: No survival benefit for induction chemotherapy
* Hokkaido RTOG (1991-1998) -- cisplatin, 5-FU
** Randomized. 80 patients. Stage I-IV M0. Arm 1) RT alone vs. Arm 2) Neoadjuvant cisplatin 80 mg/m2, 5-FU 800 mg/m2 q3 weeks x2 cycles. RT 66-68 Gy to primary tumor and LN+, 50 Gy to negative LNs
** 5-years; 2002 PMID 12001120 -- "A prospective, randomized trial comparing neoadjuvant chemotherapy with radiotherapy alone in patients with advanced nasopharyngeal carcinoma." (Hareyama M, Cancer. 2002 Apr 15;94(8):2217-23.). Median F/U 4.1 years
*** Outcome: 5-year OS induction chemo 60% vs. RT alone 48% (NS); DFS 55% vs. 43% (NS). No difference in LRC; most patients experienced LR failure before DM failure
*** Conclusion: Neoadjuvant chemo didn't improve DFS or OS
* Asian-Oceanic Clinical Oncology Association (AOCOA) (1989-1993) -- cisplatin, epirubicin
** Randomized. 286 patients. Ho's staging T3 or N2-N3 disease or LN+ >= 3cm. Arm 1) neoadjuvant cisplatin 60 mg/m2 + epirubicin 110 mg/m2 x2-3 cycles followed by RT vs. Arm 2) RT alone. RT dose 66-74 Gy (median 71 Gy) to primary tumor, 60-76 Gy (median 66 Gy) to neck.
** 3-years; 1998 PMID 9840526 -- "Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group." (Chua DT, Cancer. 1998 Dec 1;83(11):2270-83.). Median F/U 2.5 years
*** Outcome: 3-year RFS induction chemo 48% vs. RT 42% (NS); OS 78% vs. 71% (NS)
*** Conclusion: No benefit for induction chemo
* International Nasopharynx Cancer Study Group: VUMCA I (1989-1993) -- cisplatin, epirubicin, bleomycin
** Randomized. 339 patients. Undifferentiated carcinoma (WHO 2 or 3), any T stage, N2-3, M0. Arm 1) RT 70 Gy alone vs. Arm 2) induction BEC (bleomycin, epirubicin, cisplatinum) q3 weeks x 3 cycles followed by RT.
** 1996 PMID 8655368 — "Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival." (No Authors, Int J Radiat Oncol Biol Phys. 1996 Jun 1;35(3):463-9.) Median F/U 4.1 years
*** Toxicity: treatment-related deaths RT alone 1% vs chemo->RT 8%
*** Outcome: 2-year DFS RT alone 40% vs. chemo->RT 60% (per graph), no difference in LRC. No difference in OS.
*** Conclusion: BEC chemotherapy improves DFS, no impact on OS
* Prince of Wales Hospital PWH-88, Hong Kong (1988-1991) -- cisplatin, 5-FU
** Randomized. 82 patients. Ho's classification N3 or LN+ >4 cm. Arm 1) Neoadjuvant cisplatin 100 mg/m2 + 5-FU 1000 mg/m2, 4 weeks later RT 66 Gy with lower neck to 58 Gy, then 4 cycles of adjuvant chemo vs. Arm 2) RT alone. Could boost residual disease after RT to 18-24 Gy in 3 fractions with Ir-192 HDR
** 2-years; 1995 PMID 7558945 — "A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma." (Chan AT, Int J Radiat Oncol Biol Phys. 1995 Oct 15;33(3):569-77.) Median F/U 2.4 years
*** Outcome: 2-year DFS chemo-RT 68% vs. RT alone 72% (NS); OS 80% vs. 80% (NS); no difference in LRC, DM, or time-to-relapse
*** Conclusion: No benefit for sequential chemo-RT

## Induction chemo plus chemo-RT vs primary chemo-RT

* China; 2016 (2011-13) -- "Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial." (Lancet Oncology - Sun)
** Phase 3, multicenter
** Stage III-IVB NPX cancer randomized to CRT with cisplatin +/- induction chemotherapy with TPF
** 3 year FFS (primary endpt) induction 80% vs. none 72% (SS)
** 3 year OS induction 92% vs 86% (SS)
* Prince of Wales, Hong Kong; 2009 (2002-2004) PMID 19064973 -- "Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma." (Hui EP, J Clin Oncol. 2009 Jan 10;27(2):242-9. Epub 2008 Dec 8.)
** Randomized Phase II. 65 patients, Stage III-IVB NPC. Arm 1) Neoadjuvant docetaxel 75 mg/m2 + cisplatin 75 mg/m2 Q3W x2 cycles, followed by concurrent cisplatin 40 mg/m2 with RT vs Arm 2) Chemo-RT alone
** Outcome: 3-year PFS neoadjuvant 88% vs control 59% (HR 0.49, NS), 3-year OS 94% vs 68% (HR 0.24, SS)
** Conclusion: Neoadjuvant chemo followed by chemo-RT well tolerated with positive impact on survival

### Adjuvant chemo after RT

* Queen Mary Hospital (Hong Kong)(1995-2001)
** Randomized, 2x2 design (concurrent chemo vs. none, adjuvant chemo vs. none). Ho's Stage T3 or N2-3 or LN >=4 cm (AJCC 6th II-IV). Arm 1) RT alone vs. Arm 2) concurrent chemo-RT vs. Arm 3) RT + adjuvant chemo vs. Arm 4) concurrent chemo-RT + adjuvant RT. Concurrent chemo was FU prodrug uracil/tegafur, adjuvant chemo was cisplatin/5-FU and vincristine/bleomycin/MTX x3+3 cycles. RT 1995-1997 62.5/25 split course with 1 week break; 1997-2001 68/34 primary and 66/33 neck. If parapharyngeal extension or residual disease, 10 Gy boost
** 3-years; 2004 PMID 15226332 -- "Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study." (Kwong DL, J Clin Oncol. 2004 Jul 1;22(13):2643-53.)
*** Outcome: 3-year concurrent CRT vs. RT alone FFS 69% vs. 58% (NS), OS 86% vs. 77% (p=0.06), LRC 80% vs. 72% (NS), DM 15% vs. 29% (SS). 3-year adjuvant chemo vs. none FFS 62% vs. 65% (NS), OS 80% vs. 83% (NS), no difference on LRC or DM.
*** Conclusion: Trend to improvement with concurrent chemo-RT over RT alone (p=0.06), no benefit to adjuvant chemo
* Taiwan COG (1994-1999) -- observation vs. cisplatin/5-FU/leucovorin
** Randomized. 154 patients. Stage IV M0 (AJCC 1992). Arm 1) RT 70-72 Gy vs. Arm 2) weekly cisplatin 20 mg/m2, 5-FU 2200 mg/m2, leucovorin 120 mg/m2 x9 weeks
** 5-years; 2002 PMID 11955734 -- "A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients." (Chi KH, Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1238-44.) Median F/U 4.1 years
*** Outcome: 5-year OS RT alone 60% vs. adjuvant chemo 50% (NS), RFS 54% vs. 54% (NS)
*** Toxicity: No Grade 3+ mucositis; Grade 3+ leukopenia 2%
*** Conclusion: Adjuvant chemo after RT offers no benefit for OS or RFS
* Italian NRC (1979-83) -- observation vs. vincristine/cyclophosphamide/adriamycin
** Randomized. 229 NPC patients, T1N1-T4N3. Complete remission after RT , then Arm 1) observation vs. Arm 2) VCA (vincristine, cyclophosphamide, adriamycin) x 6 monthly cycles. RT 60-70 Gy to primary tumor, base of skull, and involved nodes, negative LN 50 Gy (frequently split course over 8-10 weeks)
** 4-years; 1988 PMID 3047335 — "Adjuvant chemotherapy with vincristine, cyclophosphamide, and doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: results of a 4-year multicenter randomized study." (Rossi A et al. J Clin Oncol. 1988 Sep;6(9):1401-10.)
*** Outcome: 4-year RFS observation 56% vs. chemo 58% (NS), no difference in OS; Similar pattern of failure with distant mets in about 50% who failed.
*** Toxicity: mild to moderate in most patients
*** Conclusion: No benefit for adjuvant VCA chemo
*** Comment: more patients at low risk for distant failure; less active chemo combination

## Dose Escalation

* Queen Mary Hospital; 2006 (Hong Kong)(2000-2004) PMID 16213105 -- "Preliminary results of radiation dose escalation for locally advanced nasopharyngeal carcinoma." (Kwong DL, Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):374-81. Epub 2005 Oct 5.)
** Retrospective. 50 patients, T3-T4 NPC (Stage III 28%, Stage IVA/B 72%). RT dose: GTV 76 Gy (whole NP, tumor extending outside NP, skull-base erosions, intracranial disease), PTV 70 Gy, enlarged LNs 72 Gy, all given in 35 fractions. 34 patients concurrent cisplatin (initial 11 were RT only to establish safety, subsequent patients offered INT 0099 protocol). Median F/U 2.1 years
** Outcome: 2-year LRC 96%, DM-free 94%, DFS 93%, OS 92%. 4 recurrences: 2 LR and 2 DM. All patients with recurrence did not have chemo.
** Toxicity: 1 treatment-related death from adjuvant chemo; 2 late carotid pseudoaneurysms with torrential epistaxis
** Conclusion: Dose-escalation to 76 Gy combined with chemo is feasible in T3-T4 NPC
Brachytherapy boost
* Long Beach Memorial Hospital; 2000 (1978-97) PMID 10889385 -- "Brachytherapy for primary and recurrent nasopharyngeal carcinoma: 20 years' experience at Long Beach Memorial." (Syed AM, Int J Radiat Oncol Biol Phys. 2000 Jul 15;47(5):1311-21.)
** Retrospective. 56 patients (primary n=15, recurrent/persistent n=34, NPC with prior H&N RT n=7). A wide variety of treatments described.
** Conclusion: Interstitial brachytherapy can be effective

## Technique

* RTOG 0225 (2003-2005) Protocol PMID 19564532 -- "Intensity-Modulated Radiation Therapy With or Without Chemotherapy for Nasopharyngeal Carcinoma: Radiation Therapy Oncology Group Phase II Trial 0225." (Lee N, J Clin Oncol. 2009 Jun 29. [Epub ahead of print])
** Phase II. Multi-institutional IMRT use. 68 patients, Stage I-IVb NPC (94% WHO type 2-3). IMRT 70/33; if T2b+ or N+ concurrent cisplatin, adjuvant cisplatin/5-FU.
** Outcome: Prescribed IMRT given to 84%; prescribed chemo 65%. 2-year LC 93%, LRC 89%, DMFR 85%. 2-year PFS 93%, OS 80%
** Toxicity: Acute Grade 4 mucositis 4%; Late Grade 3 dysphagia 5%, xerostomia 3%. Long-term PEG-dependent 4%
** Conclusion: IMRT feasible in multi-institutional setting

## Reirradiation

* Guangzhou; 2007 (China)(1999-2005) PMID 17601682 -- "Outcome of fractionated stereotactic radiotherapy for 90 patients with locally persistent and recurrent nasopharyngeal carcinoma." (Wu SX, Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):761-9.)
** Retrospective. 90 patients with persistent (n=34) or recurrent (n=56) treated with SRT. Median dose 18/3 or 48/6. Median F/U 1.7 years
** Outcome: 3-year PFS 55%, DSS 57%
** Toxicity: late complications 19%, 2 fatal hemorrhage
** Conclusion: SRT effective, lower risk than reported SRS
* Harvard; 1987 PMID 3597157 — "Re-irradiation of recurrent nasopharyngeal carcinoma--treatment techniques and results." Wang CC et al. Int J Radiat Oncol Biol Phys. 1987 Jul;13(7):953-6.

## Local Radiation in the setting of Metastatic Disease

* No randomized data currently available, but paradigms adding local radiation to chemotherapy are included in the NCCN guidelines due to the low rates of complete response with chemotherapy alone (~0-20%), the morbidity and mortality associated with local tumor progression in this region, and series showing long term survival in the setting of M1 NPCa.
* National Cancer Database (NCDB); 2017 (2004-2013) PMID 28433411 -- Rusthoven CG et al, "Metastatic nasopharyngeal carcinoma: Patterns of care and survival for patients receiving chemotherapy with and without local radiotherapy" Radiother Oncol. 2017 Apr 19
** 718 patients with M1 disease at diagnosis, 39% received chemotherapy alone, 61% receiced chemotherapy and radiation to the primary tumor
** OS improved with local radiation: median OS 21.4 vs 15.5 months; 5-year OS 28% vs 10%, p<0.001
** OS benefits remain on multivariate and propensity score-matched analyses, and models accounting for single vs multi-organ metastases and anatomic sites of metastatic involvement
** RT dose was an independent prognostic factor as both a continuous and categorical variable, with OS benefits observed among patients receiving ≥50 Gy
** Long-term survival of >10 years was only observed in the RT cohort
** Conclusion: "This analysis supports strategies incorporating local RT with chemotherapy for mNPC. Prospective trials evaluating RT integration for mNPC are warranted."
* Memorial Sloan Kettering; 2012 (1999-2008) PMID 22488786 -- Setton J et al, "Definitive treatment of metastatic nasopharyngeal carcinoma: Report of 5 cases with review of literature" Head Neck. 2012 May;34(5):753-7
** Case series of 5 patients with metastatic nasopharyngeal carcinoma at diagnosis
** All patients received platinum-based chemotherapy + 70 Gy of radiation
** At last follow up, 2 had no evidence of diease (at 29 and 91 months). The remaining 3 patients had progression of disease within 12 months of treatment.
** Conclusion: "Long-term disease-free survival is possible in a select group of patients with M1 disease at presentation treated with platinum-based chemotherapy and definitive radiotherapy."

## Proton Therapy

* Orsay; 2002 PMID 12504770 -- "[Comparison with dose-volume histograms of two conformal irradiation techniques used for the treatment of T4N0M0 nasopharyngeal cancer, one with association of photons and protons and another with photons alone] - [Article in French]" (Noel G, Cancer Radiother. 2002 Dec;6(6):337-48.)
** Treatment planning. 5 patients with T4N0 NPC, treated with concurrent chemo-RT using combined photon/proton beams. Photons to 44 or 54 Gy using 3D-CRT, proton boost 16 or 26 Gy in 1.8-2.0 Gy/fx
** Outcome: Conformality ratio for photon/proton plan 3.1 vs. photons only 5.7 for CTV1, no difference for CTV2. Normal tissues favored photon/proton plan
** Conclusion: Combined photons/protons improve conformality over photons alone
* Loma Linda; 1999 (1991-1997) PMID 10551231 -- "Nasopharyngeal carcinoma: repeat treatment with conformal proton therapy--dose-volume histogram analysis." (Lin R, Radiology. 1999 Nov;213(2):489-94.)
** Retrospective. 16 patients with NPC. Initial treatment 50-88 Gy (1 postop RT 50 Gy, 16 primary 65-88 Gy). Retreatment mean dose 62.8 Gy (59.4-70.2 GGE). Mean F/U 2 years
** Outcome: 2-year LRFS 50%, OS 50%. By DVH coverage "optimal" 83% vs "suboptimal" 17% (SS)
** Toxicity: No CNS side effects
** Conclusion: Adequate tumor coverage important for LRC and survival
* Lawrence Berkely Laboratory; 1992 PMID 1618678 -- "Recurrent locally advanced nasopharyngeal carcinoma treated with heavy charged particle irradiation." (Feehan PE, Int J Radiat Oncol Biol Phys. 1992;23(4):881-4.)
** Retrospective. 11 patients. Recurrent NPC, with base of skull invasion, CN deficit 64%. Heavy charged particles. Initial treatment median 70.2 Gy (61-81 Gy). Median time to recurrence 1.5 years. Median retreatment dose 50 GyE (32-62)
** Outcome: LC 45%. 5-year OS 31%
** Conclusion: Results appear superior to others using conventional photon therapy
* Harvard; 1989 PMID 2542199 -- "Proton therapy for carcinoma of the nasopharynx: a study in comparative treatment planning." (Brown AP, Int J Radiat Oncol Biol Phys. 1989 Jun;16(6):1607-14.)
** Treatment planning. Proton vs photon comparison
** Outcome: Proton superior dose-distribution, increase 5 Gy in median tumor dose, substantial reduction in normal tissue dose
** Conclusion: Superior dose distribution of protons should translate into improved control and reduced morbidity