| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2006. Published by Oxford University Press.
ARTICLE |
Randomized Phase III Trial of Low-dose Isotretinoin for Prevention of Second Primary Tumors in Stage I and II Head and Neck Cancer Patients
Affiliations of authors: Winship Cancer Institute/Emory University, Atlanta, GA (FRK, DMS); University of Texas M. D. Anderson Cancer Center, Houston, TX (JJL, SML, ESK, BW, LF, HG, WKH); Maimonides Medical Center, New York, NY (JSC); University of California, San Francisco, CA (KF); Hamilton Regional Cancer Center, Hamilton, Ontario, Canada (IH); Southwest Oncology Group, San Antonio, TX (SML); Radiation Therapy Oncology Group, Philadelphia, PA (FRK, JSC, RW, TFP, GS, IH, KF, DMS); Protein Design Labs, Freemont, CA (SEB); University of Chicago, Chicago, IL (EEV); National Quality Forum, Washington, DC (RW); McGill Unversity, Montreal, Quebec, Canada (GS); Cancer and Leukemia Group B, Chicago, IL (EEV); Community Clinical Oncology Programs, Washington, DC (RW, SEB); Texas Community Oncology Network, Houston, TX (RW)
Correspondence to: Fadlo R. Khuri, MD, Winship Cancer Institute/Emory University School of Medicine, 1365 Clifton Rd., NE, Bldg. C-3094, Atlanta, GA 30322 (e-mail: fkhuri{at}emory.edu).
 |
ABSTRACT |
|---|
 TopNotes Abstract IntroductionPatients and methodsResultsDiscussionReferences |
|---|
Background: Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical and clinical studies of high-dose isotretinoin in patients with head and neck squamous cell cancer (HNSCC) have produced encouraging results. We conducted a phase III randomized trial of low-dose isotretinoin versus placebo in early-stage HNSCC patients to assess its effect on second primary tumor incidence and survival. Methods: We randomly assigned 1190 patients who had been treated for stage I or II HNSCC to receive either low-dose isotretinoin (30 mg/day) or placebo for 3 years. The patients were monitored for up to 4 more years. Survival was analyzed by the Kaplan–Meier method, and Cox proportional hazards models were used for multivariable survival analysis. All statistical tests were two-sided. Results: Isotretinoin did not statistically significantly reduce the rate of second primary tumors (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.83 to 1.35) or increase survival (HR = 1.03, 95% CI = 0.81 to 1.32) compared with placebo in patients with early-stage HNSCC. Current smokers had a higher rate of second primary tumors than that of never (HR = 1.64, 95% CI = 1.08 to 2.50) or former (HR = 1.32, 95% CI = 1.01 to 1.71) smokers. The hazard ratio of death from any cause for current smokers versus never smokers was 2.51 (95% CI = 1.54 to 4.10) and for current smokers versus former smokers was 1.60 (95% CI = 1.23 to 2.07). Major sites of second primary tumors (n = 261) included lung (31%), oral cavity (17%), larynx (8%), and pharynx (5%). Conclusions: Low-dose isotretinoin was not effective in reducing the rate of second primary tumors or death or smoking-related disease. Smoking statistically significantly increased the rate of second primary tumors and death. Ongoing trials are testing higher doses of isotretinoin as part of combination bioadjuvant therapeutic methods for patients with locally advanced HNSCC.
|
INTRODUCTION |
|---|
|
TopNotesAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
More than 600 000 new cases of head and neck cancer were diagnosed worldwide in 2002 (1,2). Head and neck squamous cell cancers (HNSCCs) are frequently tobacco- and alcohol related and were the fifth most common, and the sixth leading, cause of cancer-related death in the United States in 2005 (1). Although substantial advances in treatment, especially for early-stage (stage I or II) disease, have been made over the last two decades, local disease control (e.g., minimizing metastasis and managing recurrence) (3,4) and the development of second primary tumors (5–7) remain challenging problems. In fact, second primary tumors are a major cause of morbidity and mortality among patients who have been effectively treated for early-stage HNSCC (5–7).
Retinoids, both synthetic and natural vitamin A derivatives, induce differentiation, modulate growth, and induce apoptosis in head and neck cancer models, including cell lines and mice (8). Sporn et al. (8) demonstrated that retinoids are effective in reversing premalignant lesions in mouse models of oral carcinogenesis.
On the basis of these promising results, a randomized clinical trial was conducted that demonstrated that isotretinoin reverses oral premalignancy (9). In a subsequent trial, Hong et al. tested adjuvant high-dose (i.e., 50–100 mg per m2 of body surface area per day) isotretinoin (13-cis-retinoic acid) versus placebo for 1 year in 103 patients with stages I–IV HNSCC (10). After a median follow-up of 32 months, statistically significantly fewer patients in the treatment group than the placebo group developed second primary tumors (4% versus 24%; P = .005), and treatment benefit was greatest for smoking-related second primary tumors, including cancers of the head and neck, lung, esophagus, and bladder. Patients treated with isotretinoin continued to have statistically significantly fewer second primary tumors than patients treated with placebo for up to 3 years after completion of treatment, but the difference between the groups disappeared with longer follow up (54.5 months). Moreover, the toxic effects from isotretinoin were substantial, with 70% of patients requiring a dose reduction and 25% discontinuing therapy altogether. Also, isotretinoin did not improve overall survival in this small-scale, short-term trial (10,11). Two subsequent larger trials of retinoids and second primary tumors gave mixed results (12,13).
To provide a definitive answer to the question of whether low-dose isotretinoin is effective as a chemopreventive agent in patients with early-stage HNSCC, we began a large phase III intervention trial (14). We designed a 3-year intervention trial to test a dose of isotretinoin that was chosen on the basis of the toxic effects seen in the smaller phase III trial of high-dose isotretinoin by Hong et al. (10,11). In contrast to the earlier trials, this trial 1) used a lower dose of isotretinoin; 2) used a longer treatment period (3 years); and 3) included only patients who had been diagnosed with early-stage (stage I or II) HNSCC (14). We also evaluated associations between smoking history and second primary tumor development and survival.
|
PATIENTS AND METHODS |
|---|
|
TopNotesAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
This randomized, placebo-controlled, double-blind phase III trial of low-dose isotretinoin was a multicenter National Cancer Institute Intergroup trial that was led by the University of Texas M. D. Anderson Cancer Center, the Community Clinical Oncology Program Research Base, and the Radiation Therapy Oncology Group. Affiliated institutions of the Southwest Oncology Group, Cancer and Leukemia Group B, and the University of Texas M. D. Anderson Cancer Center also recruited patients to this trial. This trial was approved by the institutional review boards of all participating institutions and cooperative groups. This trial is registered with the National Cancer Institute as trial number C91-0002.
Patient Eligibility
Eligibility criteria included the following: diagnosis with stage I or II HNSCC that had been treated with surgery and/or radiation therapy; free of disease for at least 16 weeks after the end of treatment by physical examination and/or radiographic imaging (computed tomographic and/or magnetic resonance scans); study enrollment within 36 months from the end of treatment; Karnofsky performance status of at least 80%; acceptable hematologic and biochemical parameters (hemoglobin 
10 g/dL, white blood count > 3000/mm3, platelet count > 100 000/mm3; transaminases 
1.5 times the upper limit of normal [ULN] value; serum creatinine 1.5 times the ULN; electrolytes within normal limits; baseline serum cholesterol and, serum triglycerides 2 times the ULN); and no evidence of thoracic malignancy by chest X-ray. To be eligible, patients also had to have no ongoing acute medical illnesses such as uncontrolled coronary artery disease, emphysema, or diabetes mellitus, and they had to sign an informed, study-specific consent form.
Exclusion criteria included prior chemotherapy or immunotherapy, evidence of synchronous or metachronous disease, or additional concurrent malignancies, except for localized non-melanoma skin cancer. Female patients of child-bearing age were required to comply with mandatory contraception and had to have had a negative pregnancy test within 2 weeks before enrollment.
Compliance was tested over an 8–12-week run-in period, during which time patients were asked to take three capsules of placebo per day. Patients were then randomly assigned to one of the two study arms. To be randomly assigned, the patients had to have taken at least 75% of their placebo pills during the run-in period; demonstrated no disease recurrence or no new second primary tumors during the run-in period; not withdrawn their study consent; and not experienced grade III or IV toxicity from the placebo.
Study Design and Treatment Plan
The trial was designed to detect a 50% reduction in the risk of developing a second primary tumor other than basal cell or squamous cell carcinomas of the skin. The baseline annual second primary tumor rate for all sites was assumed to be 3%–7% (5–7). To detect a 50% reduction in rate of second primary tumors, we estimated that 1120 patients with stage I or II HNSCC would have to be randomly assigned to achieve 85% statistical power with a two-sided test of statistical significance set at the 5% level (14). We therefore recruited 1384 patients with stage I or II HNSCC.
The primary endpoint was the rate of second primary tumors, excluding basal and squamous cell skin carcinomas. Secondary endpoints were the rates of smoking-associated cancers, which were defined as upper aerodigestive tract recurrences plus smoking-associated second primary tumors (i.e., lung, HNSCC, esophagus, and bladder); primary tumor recurrence; smoking-associated disease–free survival (defined as time to smoking-associated second primary tumor or recurrence); and overall survival.
Patients received 3 years of low-dose (30 mg/day) isotretinoin or placebo and were monitored through quarterly physician visits during the first year. Patients underwent annual chest X-rays; serial evaluations of lipid levels, complete blood counts, electrolytes, and liver function tests at baseline and at 6–12 months after randomization. Serum cotinine levels, bleomycin fragility test results, and isotretinoin levels were determined at study enrollment or at random assignment and again at 6 and 12 months after the start of treatment on the randomized phase of the trial. During years 2 and 3, patients were evaluated by study physicians at 4-month intervals for disease recurrence, second primary tumor development, and toxicity by use of complete blood counts, white blood cell differentials, electrolyte levels, liver function tests, fasting cholesterol and triglyceride levels, and an annual chest X-ray (14). Treatment was suspended when patients developed grade II toxic effects (15) and resumed after resolution of toxic effects to grade I or less. If grade II toxicity returned, then, upon resumption of treatment, patients were given two pills per day of either 10 mg isotretinoin or placebo. The dose was further reduced to one pill daily in patients with persistent grade II or higher toxicity. Individuals with grade III toxic effects had their doses withheld until resolution of grade III or higher toxicity to grade 1 or lower toxicity and ultimately reduced to one pill daily, until all toxic effects returned to grade I levels or resolved.
Patients were then monitored for up to 4 additional years after completion of study drug for second primary tumor development, primary tumor recurrence, survival, and toxicity. At all visits, patients underwent a physical examination and their disease status, both recurrence and development of a second primary tumor, as well as any toxicity to treatment was evaluated. Patients who had a recurrence while still on the 3 years of study drugs that was treatable by surgery or radiotherapy had their dosing schedule interrupted until their treatments were completed; on completion, they resumed receiving the drugs at previous levels. Patients who developed a second primary tumor or those requiring chemotherapy as part of their treatment were taken off the study.
Patients completed questionnaires annually on smoking status, including the number of pack-years of cigarettes smoked; nutritional intake; and their use of alcohol and tobacco, both inhaled and smokeless. The number of pack-years was defined as the average number of packs of cigarettes smoked per day times the number of years the individual smoked. A formal smoking cessation program was not included as part of this study.
Endpoint Review
Disease recurrences and second primary tumors were determined by a multidisciplinary endpoint review committee that consisted of a senior head and neck surgeon (H. Goepfert), at least one head and neck medical oncologist (F. R. Khuri, E. S. Kim, and/or S. E. Benner.), and a research nurse (B. Williams). Tumors were defined as second primary cancers if they originated at least 3 cm away from the primary site and occurred at least 3 years after the last known recurrence (16). All endpoint reviewers were blinded to treatment arm.
Statistical Analysis
The chi-square test was used to evaluate associations between categorical variables. Kaplan–Meier estimates were calculated to plot event-free curves for each outcome. The log-rank test was used to compare survival between treatment groups. Multivariable Cox proportional hazards regression was used to model time-to-event endpoints by study stratification variables and treatment. The proportional hazards assumption was evaluated both graphically and analytically [e.g., by examining Martingale and Shoenfeld residuals as described in Grambsch et al. (17)] to ensure the validity of the models. Patients were stratified by disease stage (I versus II), site of primary tumor (oral cavity, oral pharynx, or larynx), and smoking status (current [active or quit smoking within the past 1 year], former [quit smoking 1 or more years ago], or never). We calculated the estimated hazard ratio as a function of time to second primary tumor-free survival, recurrence-free survival, smoking-associated disease–free survival, and overall survival in the isotretinoin group and the placebo group using the S-Plus package (version 6.2; Insightful Corp., Seattle, WA). The log hazard ratio estimation and the bootstrap confidence interval through resampling were given to examine the time-dependent treatment effect (18). Intent-to-treat analysis was applied, and all statistical tests were two-sided. All analyses were also stratified by sex, stage, smoking status, and primary tumor site.
|
RESULTS |
|---|
|
TopNotesAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
We enrolled 1384 patients with stage I or II HNSCC between November 1, 1991 and June 30, 1999, and all data collected through December 15, 2003 were analyzed (Fig. 1). Of 1384 patients enrolled, 1218 completed run-in and were randomly assigned to one of the two treatment arms. The reasons for not randomly assigning enrolled patients (n =166) included the following: ineligible after enrollment (n = 17); patient withdrew consent (n = 62); patient developed progressive disease (n = 27); noncompliance with the treatment plan (n = 25); diagnosis of another primary tumor during the run-in period (n = 12); delay in randomization (n = 10); and other reasons (n = 13). The eligibility of 28 randomly assigned patients could not be verified with supporting documents, and these patients were also excluded from the analysis. Thus, 1190 patients were randomly assigned to isotretinoin (n = 590) or to placebo (n = 600). A total of 478 patients on isotretinoin and 494 patients on placebo were alive 3 years after random assignment. After 3 years of treatment and an additional 4 years of follow-up, 93 patients on isotretinoin and 115 patients on placebo were alive and being monitored.
|
Table 1 shows patient demographics for the 1190 randomly assigned patients. Of these, 160 (13.5%) patients had never smoked, 574 (48.2%) patients were former smokers, and 456 (38.3%) patients were current smokers; median number of pack-years among all current and former smokers was 37 (range, 1–72). Most patients reported having consumed alcohol previously (N = 400, 33.6%) or currently (N = 545, 45.8%). Most patients (75.5%) received radiation therapy as part of their treatment for HNSCC, with 735 (61.8%) receiving radiation therapy alone. Prior treatment with radiation and/or surgery was statistically significantly associated with the site of primary disease (P<.001); most larynx cancer patients received only radiation (84.7%), most oral cancer patients received only surgery (66.9%), and oropharynx cancer patients received radiation (64.4%) or radiation plus surgery (25.0%). The frequency distributions of the three stratification variables—stage of disease, disease site, and smoking history—were well balanced across the treatment arms (Table 1).
|
Adherence
Percentages of patients with at least 85% adherence (i.e., the actual number of pills taken divided by the number of pills the subject was given) in years 1, 2, and 3 were 86.3%, 88.6%, and 86.9%, respectively, in the isotretinoin arm and 90.3%, 91.0%, and 90.3%, respectively, in the placebo arm. Overall, 484 (85.1%) of the patients in the isotretinoin arm and 534 (90.8%) of those in the placebo arm maintained a level of adherence of at least 85%, with 6.5% of patients on isotretinoin and 3.2% of those on placebo having less than 75% adherence.
Toxicity
Toxic effects were generally of grades I and II, with grade I toxic effects reported in 49.7% of patients in both arms. Grade II, III, and IV toxicities were experienced by 28.0%, 6.4%, and 0.3% of patients in the isotretinoin arm and by 7.5%, 2.2%, and 0.8% of those in the placebo arm, respectively (P<.001). Eighteen patients in the placebo arm experienced grade III or IV toxic effects, including 10 patients with grade III or IV pruritis; one patient each with grade III conjunctivitis, headache, cheilitis, sensory deficits, or hypertriglyceridemia; and one patient each with grade IV cardiac ischemia, thrombocytopenia, or pain. The percentages of patients who required a dose reduction or drug discontinuation were 29.5% in the isotretinoin (n = 174) arm and 9.2% (n = 55) in the placebo arm (odds ratio [OR] = 4.15, 95% CI = 2.98 to 5.76). Most toxic effects in both arms were skin toxic effects, cheilitis, or conjunctivitis, and these were the major reasons for dose reduction or drug discontinuation on the study. All toxic effects resolved upon withholding or discontinuing treatment.
Efficacy
The primary endpoint of the study was time to development of a second primary tumor. After a median of 6 years of follow-up, a total of 261 patients developed a second primary tumor, and approximately 70% of the secondary primary tumors were smoking-associated cancers. Also, 21 patients were diagnosed with a third primary tumor. The most common sites for smoking-associated second primary tumors (Table 2) were lung (30.7%), oral cavity (16.9%), larynx (8.0%), pharynx (5.0%), bladder (4.6%), and esophagus (2.7%). The overall annual second primary tumor rate in both study arms was 4.6% (95% CI = 4.1% to 5.2%). The rates of smoking-associated annual second primary tumors in the isotretinoin and placebo arms were 3.0% (95% CI = 2.4% to 3.7%) and 3.3% (95% CI = 2.7% to 4.1%), respectively. The most common non–smoking-associated second primary tumor in both study arms was prostate cancer, with 13.4% of all second primary tumors occurring in the prostate. Given that this study population was composed predominately of elderly men, this finding is not surprising.
|
Figure 2 shows second primary tumor–free survival, recurrence-free survival, smoking-associated disease–free survival, and overall survival by treatment arm. There was no statistically significant difference in second primary tumor–free survival (P = .63) between the isotretinoin and placebo arms (HR for second primary tumor = 1.06, 95% confidence interval [CI] = 0.83 to 1.35). Although some improvements in recurrence-free survival (HR of death from recurrence = 0.79; 95% CI = 0.55 to 1.14) and smoking-associated disease–free survival (HR of death from smoking-associated disease = 0.84, 95% CI = 0.67 to 1.07) were seen, they were not statistically significant. A transient reduction in primary tumor recurrence was observed in patients treated with isotretinoin compared with patients treated with placebo.
|
Similar and non–statistically significant reductions in smoking-associated cancers were found in nonsmokers (HR = 0.77; 95% CI = 0.37 to 1.60), former smokers (HR = 0.87; 95% CI = 0.61 to 1.23), and current smokers (HR = 0.82; 95% CI = 0.58 to 1.16). In addition, unlike the Intergroup Lung Trial (19), no harmful effects for isotretinoin in current smokers were seen.
To determine whether primary tumor site, stage, or smoking status influenced second primary tumor rate, recurrence-free survival, smoking-associated disease–free survival, and overall survival, we analyzed the associations by stratifying on these three variables. Stage was statistically significantly associated with the occurrence of second primary tumors and the other three outcomes. In particular, compared with stage I HNSCC, stage II disease was associated with a statistically significantly higher rate of second primary tumors (HR = 1.33, 95% CI = 1.04 to 1.71), recurrence–free survival (HR for death from recurrence = 1.64, 95% CI = 1.14 to 2.35), smoking-associated disease–free survival (HR for death from smoking-associated cancers = 1.58, 95% CI = 1.25 to 1.99), and overall survival (HR for death from any cause = 1.51, 95% CI = 1.18 to 1.94). The primary disease site was associated with second primary tumor–free (HR for death from any second primary tumor among patients with cancer of the pharynx compared with those with cancer of the larynx = 1.67, 95% CI = 1.18 to 2.37) and recurrence–free survival (HR for death from any second primary tumor among patients with oral cancer compared with those with cancer of the larynx = 1.78, 95% CI = 1.21 to 2.62). Primary disease site was statistically significantly associated with the development of smoking-related cancers, with the pharyngeal primary site (HR = 1.72, 95% CI = 1.22 to 2.42) having the highest second primary tumor rates followed by oral cavity (HR = 1.48, 95% CI = 1.15 to 1.91) as compared with larynx. By contrast, primary disease site was not associated with overall survival (HR of death = 1.37, 95% CI = 0.94 to 1.98; HR of death for oral versus larynx = 1.12, 95% CI = 0.85 to 1.47). Current smokers had a statistically significantly higher risk of developing other smoking-associated cancers, either recurrence of the original cancer or second primary tumors, than that of former (HR = 1.33, 95% CI = 1.04 to 1.71) or never (HR = 1.68, 95% CI = 1.12 to 2.51; Fig. 3) smokers. Current smokers also had a higher rate of developing second primary tumors than never smokers (HR = 1.64, 95% CI = 1.09 to 2.48) (Fig. 3). Differences in overall survival by smoking status were highly statistically significant (Fig. 3, HR for former versus never smokers = 1.53, 95% CI = 0.94 to 2.49; HR for death from any cause in current versus former smokers = 1.66, 95% CI = 1.28 to 2.15). Smoking status did not affect recurrence of HNSCC across treatment groups (HR for current versus never smokers = 1.22, 95% CI = 0.69 to 2.17; HR for former versus never smokers = 1.00, 95% CI = 0.56 to 1.77) (Fig. 3). Table 3 shows the 5-year event-free rates by treatment group for each of the subgroups defined by the stratification variables for early-stage HNSCC patients. The 5-year overall survival rates in the isotretinoin and placebo groups were comparable and were 0.82 (95% CI = 0.79 to 0.85) and 0.83 (95% CI = 0.80 to 0.87), respectively. Smoking status had a major impact on overall survival, second primary tumor–free survival, and smoking-related second primary tumor–free survival but not recurrence. Both stage and site also played important roles in all endpoints.
|
|
Although this study was restricted to patients with early-stage disease, it included patients who had been disease free for as little as 16 weeks and as long as 3 years. Inclusion of such patients allowed us to study patients with both dormant primary disease (no recurrence for up to 3 years) and more aggressive HNSCC (recurrence within 1 year). Therefore, we also analyzed whether this broad temporal eligibility influenced the efficacy of therapy. Time from treatment to enrollment was not associated with second primary tumor development (P = .41), and no interaction between the time from treatment to enrollment and treatment was observed (P = .25). Similarly, we observed no association between time from treatment for HNSCC to enrollment (P = .43) and development of smoking-associated second primary tumors, nor did we observe any interaction between the period of time from definitive primary cancer treatment and enrollment on study with treatment with isotretinoin (P = .34). However, as was expected, the time from treatment for HNSCC to enrollment was associated with recurrence (P<.001), such that patients without recurrences who had enrolled up to 3 years after treatment had a lower recurrence rate than those who had enrolled shortly after treatment. There was no interaction between the time from the end of treatment for HNSCC to study enrollment and the effect of treatment with isotretinoin on prevention of recurrence (P = .47).
Multivariable Hazards Models of Disease Outcomes
To delineate patterns of associations between treatment, stage of disease, smoking status, site of the primary tumor, and disease outcome, we performed a multivariable Cox regression analysis. Table 4 shows the results calculated from multivariable hazards models that adjusted for stage, primary cancer site, and smoking status in relation to time-to-event disease outcomes. For second primary tumors, patients whose primary cancer site was the pharynx had a higher hazard rate than those whose primary cancer was in the larynx (HR = 1.54, 95% CI = 1.07 to 2.20). Current smokers had a higher hazard rate of a second primary tumor than former or never smokers (HR =1.32, 95% CI = 1.01 to 1.71; and HR = 1.64, 95% CI = 1.08 to 2.50, respectively). These associations were strengthened when the analyses were restricted to smoking-associated disease–free survival (Table 4). For recurrence-free survival, patients diagnosed with stage II HNSCC had statistically significantly higher hazard of death than those of patients with stage I disease (HR = 1.52, 95% CI = 1.05 to 2.21). In analyses of overall survival, smoking was the factor most strongly associated with the risk of death. Current smokers had 2.51 times the risk of death of never smokers (95% CI = 1.54 to 4.10) and 1.60 times the risk of death of former smokers (95% CI = 1.23 to 2.07). Patients with stage II disease also had a higher risk of death than patients with stage I disease (HR = 1.42, 95% CI = 1.10 to 1.84). No statistically significant two-way or three-way interactions were found. Time from definitive treatment to study enrollment was statistically significantly negatively associated with disease recurrence (P<.001). When the time from definitive treatment to registration variable was included in the multivariable analysis, the conclusions remained unchanged.
|
To assess whether time from definitive treatment of the primary tumor to time to enrollment on study affected the efficacy of the treatment, we examined time-dependent treatment effects. For the recurrence endpoint, the pointwise 95% bootstrap confidence interval of the log hazard ratio (18) excluded 0 during the first 2 years of treatment, suggesting a protective effect of isotretinoin during the early years of treatment (data not shown). A similar transient protective effect was found for smoking-associated disease–free survival. However, no statistically significant time-dependent treatment effect was observed with second primary tumor–free survival or overall survival (data not shown).
|
DISCUSSION |
|---|
|
TopNotesAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
This long-term, large-scale phase III trial of low-dose isotretinoin in patients with early-stage HNSCC did not confirm the promising findings from a previous smaller trial that studied short-term, high-dose isotretinoin in patients with stages I–IV disease (10,11). That is, isotretinoin had no effect on the rates of second primary tumors or smoking-related second primary cancers. However, we observed a substantial impact of smoking on the development of second primary tumors and survival.
The low dose of isotretinoin administered and the exclusion of patients with advanced disease, who have a higher rate of recurrence, may have contributed to the overall negative results of this trial. To see whether isotretinoin produced any benefit in patients with early-stage disease, we tried to disentangle the possible effect of low-dose isotretinoin on locally advanced microscopic disease by varying the time (median time = 0.68 years; range = 0.27 to 3.07 years) from treatment with surgery and/or radiation for HNSCC to the initiation of chemopreventive treatment. Although this approach demonstrated a non–statistically significant reduction in primary tumor recurrence among patients on low-dose isotretinoin, it did not provide convincing evidence to make a compelling case justifying the use of low-dose isotretinoin in this patient population. By contrast, two previous short-term trials showed beneficial effects of high-dose isotretinoin, either as a single agent (10,11) or in combination with interferon 
and vitamin E (20,21) in patients with locally advanced HNSCC (stages III–IV). In this trial, although we observed the provocative association of a reduced recurrence in patients on isotretinoin compared with those on placebo, the overall results did not support those of the short-term trials. This association was seen early and lasted only for the first 2–3 years of follow-up, suggesting that low-dose isotretinoin has activity against microscopic cancer, whether recurrence or synchronous second primary tumors. The results from the previous trials (10,14,20,21), taken together with results from the current trial, raises the possibility that short-term high-dose isotretinoin, alone or in combination with interferon-2 and -tocopherol, is more effective in preventing the transformation of subclinical cancer to overt invasive cancer than in preventing cellular transformation. A phase III trial designed to address whether high-dose isotretinoin in combination with interferon-2 and -tocopherol is an effective adjuvant treatment for locally advanced HNSCC is ongoing (21).
The results from our trial confirm the long-suspected idea that continuing to smoke is harmful to patients with early-stage HNSCC. Current smoking was statistically significantly associated with the development of second primary tumors and with poorer survival. Although our study did not include a formal smoking cessation program that could definitively show the benefits of smoking cessation, as measured by reduction in primary tumor recurrence and second primary tumor development, our data showed that individuals who continued to smoke had higher rates of tumor recurrence and of second primary tumors than those of people who did not. Therefore, our smoking-associated findings should provide physicians with objective data to help persuade patients to quit smoking.
The substantial impact of smoking on second primary tumors and mortality in this phase III trial resolves the conflicting data in observational HNSCC studies (22–26). Although most of these observational studies found an association between continuation of smoking and second primary tumor development (22–25), this association was somewhat controversial (26) because of the wide 95% confidence intervals and the small sample size (22–26). The association also contrasts with the surprising finding of a previous phase III trial that used the same dose and duration of isotretinoin in early-stage non–small-cell lung cancer patients (19). That trial found that current smoking had no statistically significant impact on lung cancer outcomes in placebo-treated patients. This dichotomy between smoking effects in these two patient populations suggests that molecular targeting of cancer prevention research in HNSCC should strongly factor in patient smoking status (27–29).
This study, which was started in 1991, was unable to address major aspects of the current debate on the clonal origins of head and neck cancers (30,31), because of the scarcity of primary tumors available for molecular analysis. Also, because we used a substantially lower dose of isotretinoin than that used in the previous studies by Hong et al. (9–11), we were unable to definitively confirm or refute the previously demonstrated beneficial effects of this retinoid in a patient population that had more patients with advanced HNSCC (stages I–IV). Absent a preplanned smoking cessation companion study, we were unable to formally quantify the potential effects of smoking cessation on primary tumor recurrence or second primary tumor development.
After two decades of research that has drastically changed the principles and practice of cancer chemoprevention (9–14), the present chapter on translational cancer chemoprevention with retinoid monotherapy in HNSCC closes with this definitive report. A tolerable dose of isotretinoin was ineffective in preventing the development of second primary tumors in this phase III trial, further reinforcing results from two other negative phase III retinoid trials in lung and aerodigestive cancer chemoprevention (19,12,32). However, the book on retinoids in cancer therapy—in the adjuvant setting of locally advanced head and neck cancer, for example—remains open, and new compounds including retinoid-X-receptor agonists (33) and new multitargeted combinations (26,21) may emerge along with other approaches (34–40) for translational cancer prevention in the future.
|
NOTES |
|---|
|
TopNotesAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Supported in part by NCI P01 CA52051 and National Foundation for Cancer Research (WKH) and CA16672, and U01 CA21661-24 (RTOG).
We thank the members of the Data Safety Monitoring Board of the trial (Drs. Steven Piantadosi, Johns Hopkins Kimmel Cancer Center; Gary Goodman,Swedish Medical Center-Tumor Institute; Thomas Carey, University of Michigan;Robert Greenberg, Dartmouth-Hitchcock Medical Center) for their unerring advice and oversight.
Funding to pay the Open Access publication charges for this article was provided by the Blomeyer Chair in Translational Cancer Research. The study sponsor(s) had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.
|
REFERENCES |
|---|
|
TopNotesAbstractIntroductionPatients and methodsResultsDiscussionReferences |
|---|
(1) Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, et al. American Cancer Society. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10–30.
(2) Parkin M, Bray F, Ferlay J, Pisani P. Global Cancer Statistics, 2002. CA Cancer J Clin 2005;55:74–108.
(3) Khuri FR, Kim ES. Primary head and neck cancer. In: Clinical hematology and oncology. Furie B, Cassileth PA, Atkins MB, Mayer RJ (eds). Philadelphia (PA): Elsevier; 2003. p. 999–1011.
(4) Stewart BW, Kleihues P, eds. World cancer report: head and neck cancer. Lyon (France): IARC Press; 2003. p. 232–6.
(5) Vikram B. Changing patterns of failure in advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 1984;110:564–5.
(6) Cooper JS, Pajak TF, Rubin P, Tupchong L, Brady LW, Leibel SA, et al. Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on RTOG experience. Intl J Radiat Oncol Biol Phys 1989;17:449–56.[Web of Science][Medline]
(7) Licciardello JT, Spitz MR, Hong WK. Multiple primary cancers in patients with cancer of the head and neck; second cancer of the head and neck, esophagus and lung. Intl J Radiat Oncol Biol Phys 1989;17:467–76.[Web of Science][Medline]
(8) Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 1976;35:1332–8.[Web of Science][Medline]
(9) Hong WK, Endicott J, Itri LM, Doos W, Batsakis JG, Bell R, et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986;315:1501–5.[Abstract]
(10) Hong WK, Lippman SM, Itri LM, Karp DD, Lee JS, Byers RM, et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990;323:795–801.[Abstract]
(11) Benner SE, Pajak TF, Lippman SM, Earley C, Hong WK. Prevention of second primary tumors with isoretinoin in squamous cell carcinoma of the head and neck: long term follow up. J Natl Cancer Inst 1994;86:140–1.
(12) Bolla M, Lefur R, Ton Van J, Domenge C, Badet JM, Koskas Y, et al. Prevention of second primary tumors with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study. Eur J Cancer 1994;30A:767–72.
(13) Pastorino U, Infante M, Maioli M, Chiesa G, Buyse M, Firket P, et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 1993;11:1216–22.
(14) Khuri FR, Kim ES, Lee JJ, Winn RJ, Benner SE, Lippman SM, et al. 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. Cancer Epidemiol Biomarkers Prev 2001;10:823–9.
(15) National Cancer Institute. Common toxicity criteria. 1999. Available at: http://ctep.cancer.gov/forms/ctcv2nom-4-30-99-final3.pdf.
(16) Warren S, Gates O. Multiple primary malignant tumors: a survey of the literature and statistical study. Am J Cancer 1932;16:1358–414.
(17) Grambsch PM, Therneau TM. Proportional hazards test and diagnostics based on weighted residuals. Biometrika 1994;81:515–26.
(18) Hess KR, Serachitopol DM, Brown BW. Hazard function estimators: a simulation study. Stat Med 1999;18:3075–88.[CrossRef][Web of Science][Medline]
(19) Lippman SM, Lee JJ, Karp DD, Vokes EE, Benner SE, Goodman GE, et al. Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small cell lung cancer. J Natl Cancer Inst 2001;93:605–18.
(20) Shin DM, Khuri FR, Murphy B, Garden AS, Clayman G, Francisco M, et al. Combined interferon-alpha, 13-cis-retinoic acid, and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase II trial. J Clin Oncol 2001;19:3010–7.
(21) Seixas-Silva JA, Richards TJ, Khuri FR, Wieand S, Kim ES, Murphy B, et al. Phase II bioadjuvant study of interferon-, 13-cis-retinoic acid, and alpha-tocopherol in locally advanced squamous cell carcinoma of the head and neck: Long-term follow-up. Arch Otolaryngol Head Neck Surg 2005;131:304–7.
(22) Russo A, Crosignani P, Berrino F. Tobacco smoking, alcohol drinking and dietary factors as determinants of new primaries among male laryngeal cancer patients: a case-cohort study. Tumori 1996;82:519–25.[Web of Science][Medline]
(23) Tucker MA, Murray N, Shaw EG, Ettinger DS, Mabry M, Huber MH, et al. Second primary cancers related to smoking and treatment of small-cell lung cancer. Lung Cancer Working Cadre. J Natl Cancer Inst 1997;89:1782–8.
(24) van Leeuwen FE, Klokman WJ, Stovall M, Hagenbeek A, van den Belt-Dusebout AW, Noyon R, et al. Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst 1995;87:1530–7.
(25) Richardson GE, Tucker MA, Venzon DJ, Linnoila RI, Phelps R, Phares JC, et al. Smoking cessation after successful treatment of small-call lung cancer is associated with fewer smoking-related second primary cancers. Ann Intern Med 1993;119:383–90.
(26) Silverman S Jr, Gorsky M, Greenspan D. Tobacco usage in patients with head and neck carcinomas: a follow-up study on habit changes and second primary oral/oropharyngeal cancers. J Am Dent Assoc 1983;106:33–5.[Abstract]
(27) Khuri FR, Lotan R, Kemp BL, Lippman SM, Feng L, Lee JJ, et al. Retinoic acid receptor (RARbeta) as a prognostic indicator in stage I non-small cell lung cancer. J Clin Oncol 2000;18:2798–804.
(28) Kim JS, Lee H, Kim H, Shim YM, Han J, Park J, et al. Promoter methylation of retinoic acid receptor beta 2 and the development of second primary lung cancers in non-small-cell lung cancer. J Clin Oncol 2004;22:3435–7.
(29) Khuri FR, Lotan R. Retinoids in lung cancer: friend, foe, or fellow traveler? J Clin Oncol 2004;22:3435–7.
(30) Califano J, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 1996;56:2488–92.
(31) Califano J, Westra W, Meninger G, Corio R, Koch WM, Sidransky D. Genetic progression and clonal relationship of recurrent premalignant head and neck lesions. Clin Cancer Res 2000;6:347–52.
(32) van Zandwijk N, Dalesio O, Pastorino U, de Vries N, van Tinteren H. EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the European Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 2000;92:977–86.
(33) Khuri FR, Rigas JR, Figlin RA, Gralla RJ, Shin DM, Munden R, et al. Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer. J Clin Oncol 2001;19:2626–37.
(34) Dannenberg AJ, Altorki NK, Boyle JO, Dang C, Howe LR, Weksler BB, et al. Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer. Lancet Oncol 2001;2:544–51.[CrossRef][Web of Science][Medline]
(35) Dannenberg AJ, Altorki NK, Boyle JO, Lin DT, Subbaramaiah K. Inhibition of cyclooxygenase-2: an approach to preventing cancer of the upper aerodigestive tract. Ann N Y Acad Sci 2001;952:109–15.[Web of Science][Medline]
(36) Khuri FR, Nemunaitis J, Ganly I, Arsenau J, Tannock IF, Romel L, et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 2000;6:879–85.[CrossRef][Web of Science][Medline]
(37) Rudin CM, Cohen EE, Papadimitrakopoulou VA, Silverman S Jr, Recant W, El-Naggar AK, et al. An attenuated adenovirus, ONYX-015, as mouthwash therapy for premalignant oral dysplasia. J Clin Oncol 2003;21:4546–52.
(38) Klass C, Shin DM, Khuri FR. New directions in chemoprevention of head and neck cancer. American Society of Clinical Oncology Education Book. Alexandria (VA): ASCO; 2005. p. 454–60.
(39) Chen Z, Zhang X, Li M, Wang Z, Wieand HS, Grandis JR, et al. Simultaneously targeting epidermal growth factor receptor tyrosine kinase and cyclooxygenase-2, an efficient approach to inhibition of squamous cell carcinoma of the head and neck. Clin Cancer Res 2004;10:5930–9.
(40) Zhang X, Chen ZG, Choe MS, Lin Y, Sun SY, Wieand H, et al. Tumor growth inhibition by simultaneously blocking epidermal growth factor receptor and cyclooxygenase-2 in a xenograft model. Clin Cancer Res 2005;11:6261–9.
Manuscript received May 11, 2005; revised December 22, 2005; accepted January 24, 2006.
Editorial about this Article
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2006 98: 426-427.
This article has been cited by other articles:
|
|
 |
|
  S. M. Lippman and E. T. Hawk Cancer Prevention: From 1727 to Milestones of the Past 100 Years Cancer Res., July 1, 2009; 69(13): 5269 - 5284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Lippman Cancer Prevention Research: Back to the Future Cancer Prevention Research, June 1, 2009; 2(6): 503 - 513. [Full Text] [PDF]
|
|
|
|
 |
|
 E. R. Gritz and W. Demark-Wahnefried Health Behaviors Influence Cancer Survival J. Clin. Oncol., April 20, 2009; 27(12): 1930 - 1932. [Full Text] [PDF]
|
|
|
|
|
|
V. A. Papadimitrakopoulou, J. J. Lee, W. N. William Jr, J. W. Martin, M. Thomas, E. S. Kim, F. R. Khuri, D. M. Shin, L. Feng, W. K. Hong, et al. Randomized Trial of 13-cis Retinoic Acid Compared With Retinyl Palmitate With or Without Beta-Carotene in Oral Premalignancy J. Clin. Oncol., February 1, 2009; 27(4): 599 - 604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Freemantle, Y. Guo, and E. Dmitrovsky Retinoid Chemoprevention Trials: Cyclin D1 in the Crosshairs Cancer Prevention Research, January 1, 2009; 2(1): 3 - 6. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Ondrey Peroxisome Proliferator-Activated Receptor {gamma} Pathway Targeting in Carcinogenesis: Implications for Chemoprevention Clin. Cancer Res., January 1, 2009; 15(1): 2 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Goodman, D. S. Alberts, and F. L. Meyskens Retinol, Vitamins, and Cancer Prevention: 25 Years of Learning and Relearning J. Clin. Oncol., December 1, 2008; 26(34): 5495 - 5496. [Full Text] [PDF]
|
|
|
|
|
|
D. Hughes, J. B. Guttenplan, C. B. Marcus, K. Subbaramaiah, and A. J. Dannenberg Heat Shock Protein 90 Inhibitors Suppress Aryl Hydrocarbon Receptor-Mediated Activation of CYP1A1 and CYP1B1 Transcription and DNA Adduct Formation Cancer Prevention Research, November 1, 2008; 1(6): 485 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Wirth, J. F. Krane, Y. Li, M. Othus, A. E. Moran, D. M. Dorfman, C. M. Norris Jr, L. Goguen, M. R. Posner, R. I. Haddad, et al. A Pilot Surrogate Endpoint Biomarker Study of Celecoxib in Oral Premalignant Lesions Cancer Prevention Research, October 1, 2008; 1(5): 339 - 348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. H. Gumus, B. Du, A. Kacker, J. O. Boyle, J. M. Bocker, P. Mukherjee, K. Subbaramaiah, A. J. Dannenberg, and H. Weinstein Effects of Tobacco Smoke on Gene Expression and Cellular Pathways in a Cellular Model of Oral Leukoplakia Cancer Prevention Research, July 1, 2008; 1(2): 100 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. R. Khuri and D. M. Shin In Reply J. Clin. Oncol., May 10, 2008; 26(14): 2418 - 2418. [Full Text] [PDF]
|
|
|
|
|
|
V. A. Papadimitrakopoulou, W. N. William Jr., A. J. Dannenberg, S. M. Lippman, J. J. Lee, F. G. Ondrey, D. E. Peterson, L. Feng, A. Atwell, A. K. El-Naggar, et al. Pilot Randomized Phase II Study of Celecoxib in Oral Premalignant Lesions Clin. Cancer Res., April 1, 2008; 14(7): 2095 - 2101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. R. Khuri and D. M. Shin Head and Neck Cancer Chemoprevention Gets a Shot in the Arm J. Clin. Oncol., January 20, 2008; 26(3): 345 - 347. [Full Text] [PDF]
|
|
|
|
|
|
B. Du, H. Leung, K.M. F. Khan, C. G. Miller, K. Subbaramaiah, D. J. Falcone, and A. J. Dannenberg Tobacco Smoke Induces Urokinase-Type Plasminogen Activator and Cell Invasiveness: Evidence for an Epidermal Growth Factor Receptor Dependent Mechanism Cancer Res., September 15, 2007; 67(18): 8966 - 8972. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Lippman and J. V. Heymach The Convergent Development of Molecular-Targeted Drugs for Cancer Treatment and Prevention Clin. Cancer Res., July 15, 2007; 13(14): 4035 - 4041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Kelloff, S. M. Lippman, A. J. Dannenberg, C. C. Sigman, H. L. Pearce, B. J. Reid, E. Szabo, V. C. Jordan, M. R. Spitz, G. B. Mills, et al. Progress in Chemoprevention Drug Development: The Promise of Molecular Biomarkers for Prevention of Intraepithelial Neoplasia and Cancer--A Plan to Move Forward Clin. Cancer Res., June 15, 2006; 12(12): 3661 - 3697. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Freemantle, K. H. Dragnev, and E. Dmitrovsky The retinoic Acid paradox in cancer chemoprevention. J Natl Cancer Inst, April 5, 2006; 98(7): 426 - 427. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||