# Radiation Oncology/Head & Neck/Recurrent

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Recurrent H&N Cancer

## Overview

Results of treatment:
* Chemotherapy alone: MS 7-9 months, 5-10% long-term survival
* RT alone (hyperfractionated): LRC 40%
* RT + 5-FU/hydroxyurea: 5-yr OS 14.6%
* RTOG 96-10: BID RT + 5-FU/hydroxyurea, MS 8 mos, OS 1 yr 41.7%, 2 yr 16.9%
* RTOG 99-11: BID RT + cisplatin/taxol, 2 yr OS 25.2%
    See also: Radiation Oncology/Head & Neck/Nasopharynx/Advanced Stage#Reirradiation for reirradiation of the nasopharnx

## Surgery +/- Reirradiation

Randomized studies:
* GETTEC/GORTEC (1999-2005) -- salvage surgery +/- reirradiation + chemotherapy
** Randomized. 130 patients, H&N cancer, either recurrence or second primary in a previously irradiated area, no major sequelae. Treated with R0-R1 surgery. Arm 1) adjuvant salvage chemotherapy + re-irradiation vs. Arm 2) observation. RT given 60 Gy over 11 weeks with concurrent 5-FU and hydroxyurea
** 2008 PMID 18936479 -- "Randomized Trial of Postoperative Reirradiation Combined With Chemotherapy After Salvage Surgery Compared With Salvage Surgery Alone in Head and Neck Carcinoma." (Janot F, J Clin Oncol. 2008 Oct 20. [Epub ahead of print])
*** Outcome: DFS improved (HR 1.68, SS), OS no difference
*** Late toxicity: 2-years Grade 3-4 RT arm 39% vs. observation arm 10% (p=0.06)
*** Conclusion: Full-dose reirradiation combined with chemo after salvage surgery significantly improved DFS but not OS. Toxicity was higher
Non-randomized:
* U. Penn (1998-2001) -- salvage surgery + reirradiation + chemotherapy
** 16 pts, pilot study. Chemo/RT given with 1.5 Gy BID given for 2 weeks (to 30 Gy), followed by a break of ≥1 week, then additional RT (w/ reduced fields, if feasible) to cumulative dose of 54-66 Gy given in 5-5.5 weeks. (Median 60 Gy; pts with negative margins given 54 Gy.) Cisplatin (25 mg/m2 on days 1-3, total 75 mg/m2) and 5-FU (continuous infusion, 500 mg/m2/d for 4 days) given weeks 1 and 5.
** 2004 PMID 15093901 -- "Pilot study of postoperative reirradiation, chemotherapy, and amifostine after surgical salvage for recurrent head-and-neck cancer." (Machtay M, Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):72-7.)
*** LRC 2-yr 100%, 3-yr 81%. OS 2-yr 81%, 3-yr 63%. EFS 2-yr 81%, 3-yr 50%. FFDM 2-yr 88%, 3-yr 80%
*** Tox: Grade 3 or higher late effects in 38% (3 - grade 4; 1 - death due to bilateral stroke).
*** Conclusion: Feasible, with acceptable acute toxicity, but with significant severe late effects.
* Institut Gustave-Roussy (1991-96) -- salvage surgery + reirradiation + chemotherapy
** 25 pts. Chemo/RT given with 5-7 cycles of 2 Gy/day (days 1-5), hydroxyurea (days 1-5), and 5-FU (days 1-5); 1 week rest between cycles; median was 6 cycles giving 60 Gy.
** 2001 PMID 11391587 Full text -- "Full dose reirradiation combined with chemotherapy after salvage surgery in head and neck carcinoma." (De Crevoisier R, Cancer. 2001 Jun 1;91(11):2071-6.)
*** Median f/u 66 mo. DFS 2-yr 36% and 5-yr 26%. OS 4-yr 43%. Of 9 pts still living, 6 were in CR at a median f/u of 67 mo.
*** Tox: acute gr3-4 mucositis (40% and 12%). Late toxicities -- 16% osteoradionecrosis, 40% gr2-3 cervical fibrosis.
*** Post-operative re-irradiation + chemotherapy was feasible with acceptable toxicity. (Note: led to the GETTC/GORTEC randomized trial.)

## Reirradiation and chemo-reirradiation

With chemotherapy:
* RTOG 99-11 (2000-2003)
** Phase II. 105 patients with recurrent SCCHN or second primary tumor (SPT, 23%) in prior RT field. Oropharynx 40%, oral cavity 27%. Median prior RT dose 65 Gy. RT 1.5 Gy/fx BID x5 days, every 2 weeks, x4. Concurrent cisplatin 15mg/m2 + paclitaxel 20mg/m2. GM-CSF on off weeks. (RT the same as RTOG 96-10).
** 2007 PMID 17947728 -- "Phase II study of low-dose paclitaxel and cisplatin in combination with split-course concomitant twice-daily reirradiation in recurrent squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Protocol 9911." (Langer CJ, J Clin Oncol. 2007 Oct 20;25(30):4800-5.)
*** Outcome: median OS 12 months; 2-year OS 26%
*** Toxicity: Grade 4-5 in 28%, treatment-related death 8% (n=8)
*** Conclusion: Despite high incidence of Grade 5 toxicity, results better than chemo alone
* U. Chicago; 2006 (1986-2001) PMID 16213104 — "Long-term outcome of concurrent chemotherapy and reirradiation for recurrent and second primary head-and-neck squamous cell carcinoma." Salama JK et al. Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):382-91.
** 115 patients. Previously irradiated, recurrent or second primary. Treated on seven consecutive trials of hydroxyurea and 5-FU with an optional 3rd agent (CDDP, Taxol, CPT-11) or 5-FU + Taxol + Gemcitabine. Treated on 14 day cycles with chemo/RT given on days 1-5 followed by a 9 day break. Pts received 4 to 7 cycles. Most were treated at 2 Gy/day or 1.5 Gy BID. At least 70 Gy to gross disease. Included trials are: PMID 2715806 (1989), PMID 1602911 (1992), PMID 7525886 (1994), PMID 9469365 (1998), PMID 10942062 (2000), PMID 15297392 (2004), PMID 15969989 (2005)
* RTOG 96-10 (1996-1999)
** 86 patients. Recurrent squamous cell cancer or a second primary in a previously irradiated field. RT finished > 6 months prior. RT 60 Gy at 1.5 Gy BID, with > 4 hrs between fractions, given on weeks 1, 3, 5, 7. Chemo (5-FU/hydroxyurea) given prior to 2nd daily dose. Dose to spinal cord limited to 50 Gy (prior + current). Fields include tumor with 2 cm margins. Treated with standard fields or 3D-CRT, no IMRT.
** 2001 PMID 11728690 — "RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck." Spencer SA et al. Int J Radiat Oncol Biol Phys. 2001 Dec 1;51(5):1299-304.
** 2008 PMID 17764087 -- "Final report of RTOG 9610, a multi-institutional trial of reirradiation and chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck." (Spencer SA, Head Neck. 2008 Mar;30(3):281-8.)
*** Outcome: 2-year OS 15%, 5-year OS 4%; better survival if >1 year from prior RT. No dose-response
*** Toxicity: Acute Grade 4 in 18%, Grade 5 in 8%. Late (>1-year) Grade 3-4 9%
*** Conclusion: Feasible approach with acceptable acute and late effects
* MSKCC; 2007 PMID 17379449 — "Salvage re-irradiation for recurrent head and neck cancer." (Lee N, Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):731-40.)
** 105 pts w/ recurrent HNSCC. Median time from previous RT 38 mo (all >5 mo). Median previous dose 62 Gy. Only 1 pt w/ new primary, rest recurrent.
** 71% rec'd concurrent chemo; 70% treated w/ IMRT. 25% had gross total resection prior to re-RT.
** Median re-RT dose was 59.4 Gy, mostly delivered in QD fx's (87%). No effort to spare parotids. Cumulative cord dose limited to 50 Gy, brainstem 60 Gy.
** Non-nasopharynx recurrence and non-IMRT pts did worse. Pts w/ LC had better 2-yr survival (56% vs 21%) than those w/ local failure.
** Severe late grade 3-4 complications in 11%, at median time 6 mo.
** Conclusions: achieving local control is crucial in prolonging survival in recurrent HNSCC; IMRT associated w/ better LC
With or without chemotherapy:
* Institut Gustave-Roussy; 1998 (1980-96) PMID 9817275 -- "Full-dose reirradiation for unresectable head and neck carcinoma: experience at the Gustave-Roussy Institute in a series of 169 patients." (De Crevoisier R, J Clin Oncol. 1998 Nov;16(11):3556-62.)
** 169 pts with recurrences or new primary tumors (19%). Treated with either: 1) RT alone 65 Gy over 6.5 weeks at 2 Gy/d (n=27); 2) Chemo/RT with conv. fx RT week-on-week-off, median 60 Gy at 2 Gy/d, with 5-FU + hydroxyurea (n=106); or 3) Chemo/RT with hyperfractionated RT week-on-week-off, 60 Gy at 1.5 Gy BID, with mitomycin + 5-FU + cisplatin (n=36). Median cumulative dose 120 Gy.
** Median f/u 70 months. 37% of pts in complete response at 6 months. 5 died of carotid hemorrhage. OS 21% at 2 yrs, 9% at 5 yrs. MS 10 months. 13 pts were long term survivors (of whom 12 pts were treated with the 2nd regimen: conv. fx. RT wo/wo + chemo).
** Conclusion: full-dose reirradiation was feasible
Attempted studies:
* RTOG 04-21 -- closed due to poor accrual
** Randomized to re-irradiation + concurrent chemotherapy (cisplatin/taxol) vs chemo alone. Chemo is choice of cisplatin/taxol, cisplatin/5-FU, or cisplatin/taxotere
Reviews:
* 2011 PMID 22115554 -- "Practical Considerations in the Re-Irradiation of Recurrent and Second Primary Head-and-Neck Cancer: Who, Why, How, and How Much?" (Chen AM, Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):1211-9.)

## Chemo Alone

* EXTREME (2004-2005) -- Chemotherapy (cisplatin or carbo/5-FU) +/- cetuximab
** Randomized. 442 patients with recurrent or metastatic SCC of H&N. Arm 1) chemotherapy (cisplatin 100 mg/m2 or carbo AUC 5 + 5F-FU 1000 mg/m2) x6 cycles vs. Arm 2) same chemotherapy + cetuximab 250 mg/m2 x6 cycles. If stable disease, cetuximab until disease progression or toxicity
** 2008 PMID 18784101 -- "Platinum-based chemotherapy plus cetuximab in head and neck cancer." (Vermorken JB, N Engl J Med. 2008 Sep 11;359(11):1116-27.)
*** Outcome: Median OS chemo 7 months vs. chemo+cetuximab 10 months (SS)
*** Toxicity: Grade 4 comparable except sepsis worse in cetuximab arm
*** Conclusion: Cetuximab + platinum chemotherapy improved overall survival compared with chemotherapy alone

## SBRT

* Catholic University of Korea; 2009 (2004-2006) PMID 19117695 -- "Fractionated stereotactic radiotherapy as reirradiation for locally recurrent head and neck cancer." (Roh KW, Int J Radiat Oncol Biol Phys. 2009 Aug 1;74(5):1348-55. Epub 2008 Dec 29.)
** Retrospective. 36 patients, 44 sites, recurrent HNC. Median dose 30 Gy (18-40) in 3-5 fractions, prescribed to 65-85%. Prior RT median 70.2 Gy. Median GTV 23 cm3. Median F/U 1.5 years
** Outcome: CR 43%, PR 37%, SD 9%, progression 11%.
** Toxicity: Late Grade 3 in 8% (1 bone necrosis, 2 soft tissue necrosis)
** Conclusion: Effective salvage, with good short-term control; more experience needed

## Pattern of Failure

* Michigan; 2009 PMID 19135312 -- "The pattern of failure after reirradiation of recurrent squamous cell head and neck cancer: implications for defining the targets." (Popovtzer A, Int J Radiat Oncol Biol Phys. 2009 Aug 1;74(5):1342-7. Epub 2009 Jan 8.)
** Retrospective. 66 patients, curative-intent re-RT for unresectable recurrence. Target was rGTV + 0.5 cm margin, no prophylactic LN or subclinical disease around rGTV. Median re-RT dose 68 Gy, concomitant chemo 71%, AHFX 47%. Median F/U 3.5 years
** Outcome: 3rd recurrence or persistent disease in 77%. Majority (96%) of failures were within rGTV
** Toxicity: Late Grade 3+ toxicity 29%, mostly dysphagia
** Conclusion: Confine re-RT targets to rGTV to reduce reirradiated normal tissue