# Radiation Oncology/Head & Neck/Second Primary

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Second Primary Tumors in Head & Neck

## Overview

* Second primary tumors are a major source of morbidity and mortality, particularly for patients who have been effectively treated for early stage HNSCC
* The risk of developing a second primary is ~5%/year. Majority occur in H&N, esophagus, or lung; lung is the most common site (31%), followed by oral cavity (17%)
* Continued smoking increases both risk of second primary tumor (HR 1.6) and death (HR 2.5) over that of former smokers (HR 1.3 and 1.6) compared with non-smokers. This is a rationale to promote smoking cessation
* Concurrent treatment with chemotherapy doesn't appear to change risk of second cancers
* A high-dose isotretinoin given for 1 year decreased the risk of second primary in Stage I-IV patients in a randomized trial; however, tolerance was poor with 70% patients requiring dose reduction
* A French trial, using a second generation retinoic acid etretinate did not show any benefit. An Italian and Australian trial using isotretinoin also did not show any benefit
* Finally, a tolerable low-dose isotretinoin given for 3 years to early stage patients in a large Intergroup trial did not decrease risk of second primary tumors or death
* Colorado-SEER; 2008 PMID 18078720 -- "Use of external beam radiotherapy is associated with reduced incidence of second primary head and neck cancer: a SEER database analysis." (Rusthoven KE, Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):192-8.)
** Analysis of 27,985 patients with early stage HNCA entered into SEER database between 1973 and 1997
** Patients treated with RT had significantly reduced incidence of second HNCa (15yr incidence 7.7% vs 10.5%)
** On multivariate analysis, pts with primary tumors of the pharynx (p<0.001) and larynx (p=0.04) had significant reduction in second primary HNCA with RT
* Memorial Sloan Kettering; 2005 (1986–1995) PMID 16265657, 2005 (1984–98) — "Second primary malignancy of the aerodigestive tract in patients treated for cancer of the oral cavity and larynx." (Lin K et al. Head Neck. 2005 Dec;27(12):1042-8. )
** Retospective. 1257 patients with oral cavity (n=595) and larynx (n=662). Endpoint development of second primary (H&N, esophagus, or lung)
** Outcome: 5-year rate larynx 8%, oral cavity 10%. Larynx most common 2nd primary was lung, oral cavity was another H&N.
** Predictors: Smokers 5x increased risk, EtOH 2x increased risk
** Conclusion: Rates comparable, patterns different. Smoking and EtOH independent risk factors
* SAKK 10/94; 2005 PMID 15936546 -- "Risk factors for developing a second upper aerodigestive cancer after radiotherapy with or without chemotherapy in patients with head-and-neck cancers: An exploratory outcomes analysis." (Taussky D, Int J Radiat Oncol Biol Phys. 2005)
** Analysis of Swiss SAKK 10/94 trial (RT +/- cisplatin). 521 patients. Median F/U 4.7 years
** Second primary tumors: No difference as a function of getting chemotherapy, age, PS, gender, T-stage, or N-stage. Concomitant boost fewer SPTs
** Conclusion: Addition of chemotherapy doesn't influence incidence of second cancers
* MDACC; 1989 PMID 2674075 -- "Multiple primary cancer in patients with cancer of the head and neck: second cancer of the head and neck, esophagus, and lung." (Licciardello JT, Int J Radiat Oncol Biol Phys. 1989 Sep;17(3):467-76.)
* RTOG Registry (76-19) (1977–1980)
** 1989 PMID 2674073 -- "Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on the RTOG experience." (Cooper JS, Int J Radiat Oncol Biol Phys. 1989 Sep;17(3):449-56.)
*** Prospective registry of H&N patients seen by RTOG. 928 HNSCC treated with RT only
*** Second tumor risk: 3-years 10%, 5-years 15%, 8-years 23%; most occurred in patients with small primaries due to their longer survival
* MD Anderson; 1989 PMID 2674081 -- "Second malignant tumors in head and neck squamous cell carcinoma: the overshadowing threat for patients with early-stage disease." (Lippman SM, Int J Radiat Oncol Biol Phys. 1989 Sep;17(3):691-4.)

## Prevention Trials

* Quebec (1994–2000) -- alpha tocopherol/beta-carotene vs placebo
** Randomized. 540 patients, Stage I-II HNC, treated with RT. Arm 1) alpha-tocopherol 400 IU/day and beta-carotene 30 mg/day (beta-carotene discontinued after 156 patients due to ethical concerns) x3 years vs Arm 2) placebo.
** 2005 PMID 15812073 -- "A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients." (Bairati I, J Natl Cancer Inst. 2005 Apr 6;97(7):481-8.) Median F/U 4.3 years
*** Outcome: 2nd primary supplement 23% vs. placebo 19%. During supplementation, higher rate of 2nd primary than placebo (HR 2.9, SS), which lowered after supplementation was discontinued
*** Conclusion: Alpha-tocopherol produced unexpected higher occurrence of second primary cancer
** Weight loss; 2010 PMID 20187097 -- "Predictors of weight loss during radiotherapy in patients with stage I or II head and neck cancer." (Nourissat A, Cancer. 2010 Feb 24. [Epub ahead of print])
*** Patients weighed before and after RT. Mean weight loss 2.2 kg (SD 3.4 kg). Baseline characteristics assessed
*** Outcome: Predictors for weight loss: non-glottic site, higher baseline weight, Stage II disease (vs Stage I), baseline dysphagia/odynophagia, lower KPS. No association with diet
*** Conclusion: Predictors for weight loss identified
* Italian Head and Neck Chemoprevention Study Group 2004 (1992–1996) -- low-dose isotretinoin
** Randomized. 267 patients. Radically treated Stage III-IV HNSCC. Arm 1) placebo vs. Arm 2) isotretinoin 0.5 mg/kg vs. Arm 3) isotretinoin + Interferon alpha-2a (only 15 patients assigned due to financial problems) x1 year
** 2004 PMID 15138569 — "13-cis retinoic acid in head and neck cancer chemoprevention: results of a randomized trial from the Italian Head and Neck Chemoprevention Study Group." (Toma S, Oncol Rep. 2004 Jun;11(6):1297-305.) Mean F/U 3.2 years
*** Outcome: 5-year OS isotretinoin 59% vs. placebo 57% (NS); RFS 49% vs. 56% (NS)
*** Toxicity: Grade III-IV in 4%, Grade I-II 69%
*** Conclusion: Low-dose isotretinoin ineffective at chemoprevention
* Retinoid Head and Neck Second Primary Trial (INT/RTOG 91-15) (1991–1999) -- low dose isotretinoin
** Randomized. 1190 patients, treated, with Stage I-II HNSCC (oral cavity, larynx, pharynx), disease-free at least 4 months. Arm 1) low-dose isotretinoin (30 mg/day) vs. Arm 2) placebo x3 years
** Smoking; 2001 PMID 11489748 -- "The impact of smoking status, disease stage, and index tumor site on second primary tumor incidence and tumor recurrence in the head and neck retinoid chemoprevention trial." (Khuri FR, Cancer Epidemiol Biomarkers Prev. 2001 Aug;10(8):823-9.)
*** Outcome: second primary tumor rate 5.1%/year; active smoker 5.7% vs. never smoker 3.5% (p=0.05); Stage I 4.3% vs. Stage II 6.4% (SS)
*** Conclusion: Significantly higher second primary tumor rate in active smokers, intermediate rate for former smokers compared with never smokers
** 6-years; 2006 PMID 16595780 -- "Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients." (Khuri FR, J Natl Cancer Inst. 2006 Apr 5;98(7):441-50.) Median F/U 6 years
*** Outcome: Second primary tumors rate 4.6%/year in both arms (NS); no difference in primary tumor–free survival, RFS, smoking-associated DFS, and OS
*** Predictors: second cancers 261 (22%); current smokers (HR 1.64, SS) more risk than former smokers (HR 1.32, SS) compared with non-smokers. Risk of death current smokers 2.51 vs. former smokers 1.60
*** Sites of 2nd tumors: lung (31%), oral cavity (17%), larynx (8%), pharynx (5%)
*** Conclusion: Low-dose isotretinoin not effective at reducing second primary tumors
* France -- etretinate
** Randomized. 316 patients, SCHNN T1-2N0-1 <=3 cm. Arm 1) etretinate 25 mg/day vs. Arm 2) placebo x2 years
** 5-years; 1994 PMID 7917535 -- "Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study." (Bolla M, Eur J Cancer. 1994;30A(6):767-72.) Median F/U 3.4 years
*** Outcome: second primary tumor 18% (NS). No difference on LR or DM rate. 5-year OS and DFS no difference
*** Toxicity: discontinued in etretinate 33% vs. placebo 23% (SS)
*** Conclusion: Etretinate does not prevent second primary tumors
* Queensland (Australia) -- high-dose or low-dose isotretinoin
** Randomized. Trial stopped early by sponsor after early analysis showed no benefit. 151 patients. T1-4N0-2 HNSCC. Arm 1) high-dose isotretinoin 1 mg/kg x1 year, then low-dose isotretinoin 0.5 mg/kg x2 years vs. Arm 2) low-dose isotretinoin x3 years vs. Arm 3) placebo x3 years. 67% did not complete therapy (~1/3 in high-dose due to side effects)
** 2005 PMID 15781758 -- "Chemoprevention of head and neck cancer with retinoids: a negative result." (Perry CF, Arch Otolaryngol Head Neck Surg. 2005 Mar;131(3):198-203.)
*** Outcome: Second primary cancer high-dose 9% vs. low-dose 17% vs. placebo 14% (NS); no difference in DFS, RFS, or OS
*** Toxicity: No difference between groups
*** Conclusion: Use of isotretinoin not indicated for prophylaxis
* MD Anderson -- high-dose isotretinoin
** Randomized. 103 patients, treated Stage I-IV HNSCC. Arm 1) high dose isotretinoin 50–100 mg/m2 vs Arm 2) placebo x1 year.
** 3-years; 1990 PMID 2202902 — "Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck." (Hong WK, N Engl J Med. 1990 Sep 20;323(12):795-801.) Median F/U 2.7 years
*** Outcome: second primary tumors isotretinoin 4% vs. placebo 24% (SS). 93% tumors in H&N, esophagus, or lung. No difference in local, distant, or regional recurrence of primary tumor.
*** Conclusion: High dose isotretinoin effective in prevention of second primary
** 5-years; 1994 PMID 8271298 -- "Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: long-term follow-up." (Benner SE, J Natl Cancer Inst. 1994 Jan 19;86(2):140-1.) Median F/U 4.5 years
*** Outcome: second primary tumors isotretinoin 14% vs. placebo 31% (SS); but impact diminishes with time. By 8 years, estimated rates of 19% vs. 44%. No patients developed second primary tumor while on drug
*** Toxicity: 70% required dose reduction, 25% stopped
*** No difference in OS. No impact on behavior of primary tumor.