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Clinical Cancer Research Vol. 6, 847-854, March 2000
© 2000 American Association for Cancer Research

Clinical Trials

Phase I Trial of All-Trans Retinoic Acid in Patients with Treated Head and Neck Squamous Carcinoma1

So Hyang Park, William C. Gray, Iris Hernandez, Maria Jacobs, Robert A. Ord, Mohan Sutharalingam, Ruth G. Smith, David A. Van Echo, Suhlan Wu and Barbara A. Conley2

Division of Hematology-Oncology, Department of Medicine [S. H. P., R. G. S., D. A. V. E., B. A. C.], and Department of Radiation Oncology [M. J., M. S.], University of Maryland School of Medicine and Program of Oncology; Division of Developmental Therapeutics, Program of Oncology [S. H. P., S. W., B. A. C.]; and Department of Oral and Maxillofacial Surgery, University of Maryland School of Dentistry and Program of Oncology [R. A. O.], Greenebaum Cancer Center at the University of Maryland, Baltimore, Maryland 21201; Division of Otolaryngology-Head/Neck Surgery, Department of Surgery, University of Maryland School of Medicine [W. C. G.], Baltimore, Maryland 21201; and Division of Hematology-Oncology, Department of Medicine, Baltimore Veterans Administration Medical Center, Baltimore, Maryland 21201 [I. H.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although retinoids show promise for prevention of second primary upper aerodigestive tract tumors, the optimum retinoid, dose, and schedule are unknown. All-trans retinoic acid (ATRA) has greater affinity for retinoic acid receptors and may be more active than other retinoids but has a shorter plasma half life and may up-regulate its own metabolism. We defined the maximum long-term tolerable dose, dosing frequency, pharmacokinetics, and toxicity of ATRA in patients with treated squamous cell carcinoma of the head and neck (SCCHN). Twenty-one patients were randomized to 45, 90, or 150 mg/m2 ATRA either once daily, or as divided doses every 8 h, for 1 year. Pharmacokinetics were assessed periodically. Fourteen men and seven women with previous SCCHN of initial stage I–IV were treated. Grade >=3 toxicities (reversible) included headache and hypertri-glyceridemia in 5 and 6 patients each, mucositis in 2 patients, and hyperbilirubinemia, elevated alkaline phosphatase, colitis, lipasemia, xerostomia, eczema, and arthritis in 1 patient each. The 150-mg/m2 dose was not tolerable. Doses were reduced for grade >=3 toxicity in seven of eight patients at 90 mg/m2 daily. Three of nine patients at 45 mg/m2/day required dose reduction, two at the once-daily dose. Day 1 ATRA area under the plasma concentration versus time curve (AUC) increased with dose, and after 1–2 months of continued dosing, the AUC declined in 7 of 13 patients (54%) studied. ATRA AUC did not correlate with toxicity severity or frequency. Fifteen mg/m2/day every 8 h is a tolerable dose for 1 year in patients with treated SCCHN. ATRA pharmacokinetics did not correlate with toxicity.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
SCCHN3 is one of the most common malignancies worldwide and represents 4–5% of cancers diagnosed in the United States yearly (1) . Despite improvements in surgical and radiation techniques, which have resulted in fewer local recurrences (2) , second primary tumors in the upper aerodigestive tract remain a significant cause of morbidity and mortality (3) . It is estimated that these second primary tumors develop at the rate of 4–7% per year (4) . This rate of development puts even those patients with early-stage disease, who have an excellent probability of cure of the original primary tumor, at significant risk of death from cancer. During the last several decades, epidemiological studies have suggested that retinoids may protect against the development of SCCHN. Case-control studies have found lower plasma retinoid concentrations in patients who developed SCCHN than in patients who did not (4) . Initial trials of carotenoids, the retinoid 13-cRA, fenretinide, as well as vitamin A, have suggested that retinoids can cause reversible disappearance of premalignant changes, such as leukoplakia, or may reduce the frequency of second primary cancers (4, 5, 6, 7) . The possible mechanisms of action (or resistance to) retinoids have not yet been elucidated but are thought to be mediated through retinoid binding to specific nuclear retinoid receptors, with modulation of gene expression. ATRA is a naturally occurring compound that shows more avid binding to retinoic acid receptors than does 13-cRA (8 , 9) . However, initial clinical trials of ATRA demonstrated its short plasma half life compared with 13-cRA (0.7 versus 18 h), and that its metabolism is apparently up-regulated with continued dosing, resulting in decreasing plasma concentrations of drug (10 , 11) . This decreased concentration has not been correlated with toxicity or response to date. However, if plasma ATRA concentrations are a surrogate for tissue ATRA concentrations and because ATRA half life is short, then it is likely that multiple daily dosing will be required for drug effect. We therefore initiated a randomized trial of three doses and two schedules of ATRA in patients with treated SCCHN. The objectives of the study were: (a) to establish the optimal tolerable dose and schedule of ATRA given p.o. to this patient population for 1 year; (b) to evaluate the toxicities of ATRA, at the doses and schedules studied, in this population; (c) to search for differences in plasma pharmacokinetic parameters in patients treated with different schedules and doses of ATRA, as well as changes in an individual’s pharmacokinetic parameters with time on drug; and (d) to correlate plasma pharmacokinetics and pharmacodynamics at the different doses and schedules of ATRA.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
Patients who had a histologically proven SCCHN and had received definitive treatment (stages I–IV, or second primary SCCHN), had recovered from all toxicities of previous treatment, and were clinically free of disease at study entry were eligible. Patients with locally advanced disease were initially allowed into the study if they had completed adjuvant chemotherapy and/or radiation at least 4 weeks prior to study entry. However, because of the high risk for early recurrence, the protocol was amended so that such patients were only eligible if they had remained disease-free for 6 months after completing initial treatment. Because the study was designed to define the tolerable long-term dosing schedule for ATRA and not as a chemoprevention trial, it was deemed appropriate to enter patients with advanced disease who were likely to survive at least 1 year. Patients were required to be >=18 years of age, of performance status Eastern Cooperative Oncology Groups 0–2, have a life expectancy of >=2 years, and able to comply with the treatment regimen. In addition, adequate hematopoietic (WBC >=3500 cells/mm3), renal (serum creatinine <2 mg/dl), and hepatic (bilirubin <1.6 mg/dl) function was required. Patients who did not meet the above criteria or had any uncontrolled medical illness or any history of major psychiatric disorder, seizure, or brain tumor, or had hypertriglyceridemia or hypercholesterolemia of >300 mg/dl (cholesterol-lowering drugs were allowed), or were pregnant or nursing were not eligible. All sexually active, fertile patients agreed to use effective birth control measures. All female patients capable of becoming pregnant had a negative serum pregnancy test prior to treatment. All patients gave written informed consent, which had been approved by the Institutional Review Board at the University of Maryland at Baltimore and NCI.

Treatment Plan.
Patients were assigned randomly to receive ATRA at a dose of 45, 90, or 150 mg/m2/day, either as a single daily dose (qd) taken in the morning or as one-third of the daily dose taken every 8 h with the fat equivalent of 8 ounces of whole milk. These doses were chosen because they spanned the range of doses either in use [i.e., 45 mg/m2/day for acute promyelocytic leukemia (12) ] or were found to be tolerable in previous Phase I trials (13 , 14) . Dosing on a q8h schedule was chosen as the alternative to single daily dosing because this schedule is feasible for long-term compliance. All doses were rounded to the nearest 10 mg below the calculated dose.

The formulation consisted of oval, soft-gelatin capsules, supplied by NCI, which was responsible for its stability and purity. Each capsule contained 10 mg of ATRA as well as butylated hydroxyanisole, disodium EDTA, refined soy bean oil, and a wax mixture consisting of purified beeswax, hydrogenated soy bean oil flakes, and hydrogenated vegetable oil. The capsules were stored at room temperature and protected from light.

Dosing continued daily for 1 year unless unacceptable toxicity (temporarily discontinued) or cancer developed, or the patient refused to continue. An evaluable course was defined as 28 days of treatment. Doses were not escalated in the same patient, but dose reductions were allowed as follows: (a) severe or intolerable toxicity (grade >=3) encountered after the initial 28-day evaluation period prompted discontinuation of drug, with dose reduction by 25% after resolution of the toxicity; (b) severe toxicity during the initial 28-day evaluation period prompted discontinuation of drug with 50% dose reduction after the resolution of the toxicity; and (c) moderate toxicity (grade 2), which did not improve with symptomatic treatment, prompted a 25% dose reduction without discontinuation of drug. All patients were treated with topical skin moisturizing formulations and lip balm prophylactically to ameliorate mucocutaneous dryness.

Toxicities were graded with the NCI Common Toxicity Criteria, version 1.0. In addition, skin toxicity was graded as follows: grade 1, dryness, asteatosis, pruritis, xerosis; grade 2, erythema with mild eczematous changes; grades 3, severe eczematous changes; and grade 4, desquamation with erythema. Elevation of cholesterol and triglycerides were graded as follows: grade 1, 201–300 mg/dl; grade 2, 301–400 mg/dl; grade 3, 401–500 mg/dl; and grade 4, >=501 mg/dl.

The optimal dose and schedule was defined as that dose at which fewer than two of up to six patients had grade >2 toxicity for periods of 1 year.

Follow-Up.
A history and physical examination, weight, performance status, toxicity evaluation, complete blood count, differential count, platelet count, urinalysis, blood urea nitrogen, creatinine, liver function studies (alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase), albumin, chemistry studies (serum electrolytes, uric acid, calcium, phosphorus, and total protein), and fasting cholesterol/triglycerides were obtained prior to treatment, weekly for the initial month in the study, every other week for the following 2 months of treatment, then monthly to the end of the study. A chest radiograph and electrocardiogram were performed prior to study entry and afterward according to standard practice guidelines. Patients were followed monthly for an additional year after drug treatment had stopped, with monthly history, physical examination, and laboratory studies as described above.

Pharmacokinetics.
ATRA pharmacokinetics were assessed at days 1, 15, 60, and 1 year. Blood was collected in heparinized tubes prior to and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 7–8 h after the dose of ATRA. Plasma was immediately prepared from whole blood by centrifugation at 1000 x g for 10 min at 4°C. Collection tubes were foil wrapped to protect the sample from light, and samples were stored at -70°C until analysis. ATRA and 4-oxo-trans retinoic acid were measured with a modification of the assay of Bugge et al. (15) . The performance and validation of this assay in our laboratory have been reported (13) . Internal standard, Ro 11-5036, was kindly provided by Hoffman-LaRoche, Inc. (Nutley, NJ). Pharmacokinetic data were modeled as a one-compartment, open, linear model, assuming first-order absorption and elimination, with a lag time. Modeling was accomplished with PC NONLIN (Statistical Consultants, Inc., Lexington, KY) or ADAPT II (Biomedical Simulation Resource, University of Southern California, Los Angeles, CA) software.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics.
Twenty-one patients were treated. Patient characteristics are shown in Table 1Citation . Fifteen patients have completed 1 year of treatment. Three patients were withdrawn from the study because of recurrence of the primary tumor (at day 24, day 43, and 7 months). One patient was withdrawn from the study after 2 months of treatment because of significant toxicity. Another patient refused to continue the drug after 8 months of treatment because of skin dryness (grade 2). One other patient withdrew prior to 28 days, without significant toxicity.


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  		Table 1 Patient characteristics

 
Toxicity.
Nineteen patients are evaluable for toxicity. All toxic effects were reversible. Table 2Citation presents toxicity by schedule and toxicity grade. Two patients, who initially had stages III and IV SCCHN, respectively, were treated with 150 mg/m2/day in divided doses q8h but had recurrence of the primary tumor shortly after initiation of ATRA treatment (days 24 and 43) and were removed from the study. Both patients had severe mucocutaneous toxicities. Both patients had initial treatment with radical surgery and adjuvant radiation therapy. All four patients treated with ATRA at a dose of 90 mg/m2 on the q8h schedule (30 mg/m2 q8h) developed grade 3 or 4 toxicities. One patient developed grade 3 headache on day 2. ATRA was discontinued and restarted at a 50% reduced dose 2 weeks after resolution of the headache without further dose-limiting toxicity. A second patient developed grade 4 hypertriglyceridemia 1 week after treatment initiation. The drug was discontinued and restarted at a 50% dose reduction 6 weeks later. Triglycerides returned to normal shortly after drug discontinuation. However, after retreatment at the lower dose, the patient developed colitis and lipasemia within 2 weeks. Endoscopy documented inflammatory bowel disease, and steroid treatment was initiated. ATRA was discontinued permanently. Two other patients required stopping ATRA and 50% dose reduction because of severe xerostomia or hypertriglyceridemia within the first 2 months of treatment. Three of four patients treated with ATRA, at 90 mg/m2 as a single daily dose, required stopping ATRA and dose reduction because of grade 3 headache developing within the first week of treatment. The remaining patient required a 25% dose reduction at 8 months because of skin toxicity. In all, seven of eight patients treated with ATRA at a dose of 90 mg/m2/day required temporary discontinuation of the drug in the initial month of treatment because of severe toxicities, and all eight patients required dose reduction within the 1-year treatment period. However, after dose reduction to a dose of 45 mg/m2/day, three of four patients on the single daily dose schedule and three of four patients on the divided dose schedule were able to complete the year of treatment without further dose reduction.


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  		Table 2 Toxcities associated with ATRA administration, by dose and schedule

The number in parentheses refers to the number of patients who experienced the particular toxicity.

 
All five patients treated with ATRA at the initial dose of 45 mg/m2/day in divided doses (15 mg/m2 q8h) tolerated the drug without complaints of severe toxicity. One patient had dose reduction for hypertriglyceridemia. At the single daily dose of 45 mg/m2/day, two of four patients had dose reduction for toxicity. One patient, with a history of arthritis, developed severe pain and swelling of multiple joints after 4 months of ATRA treatment at a dose of 45 mg/m2 qd as a single dose. Despite a 50% dose reduction, the symptoms did not improve. ATRA was discontinued, and the patient was treated with piroxicam with symptom improvement. ATRA was reinitiated 3 weeks later at the 50% reduced dose. The patient was able to tolerate the reduced dose for the remainder of the year of treatment, without recurrence of severe arthritis, although he required continued piroxicam treatment. A second patient required dose reduction for grade 3 hypertriglyceridemia and grade 2 headache within the first 6 weeks.

Pharmacokinetics.
Pharmacokinetic parameters are detailed in Table 3Citation . Pharmacokinetics were obtained on day 1 for 15 patients and were repeated at least once at the scheduled times for the initial dose in 10 patients. Nine patients had dose reductions. Pharmacokinetics at initiation of a lower dose, after at least a 1-week period off treatment, are available for four patients (patients 4, 5, 7, and 9 in Table 3Citation ). Pharmacokinetics continued to be assessed at the scheduled times (see "Patients and Methods") for four additional patients who had dose reduction but without a pharmacokinetic assessment on day 1 of the reduced dose of ATRA (patients 3, 6, 8, and 10 in Table 3Citation ).


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  		Table 3 Pharmacokinetics of ATRA in patients with previous SCCHN

 
The ATRA AUC generally increased with increasing dose, with moderate interpatient variability (Table 3Citation and Fig. 1Citation ). Of note, the AUC decreased in 7 of 13 assessable patients (54%) continuing to receive the same dose of ATRA (patients 1, 3, 8, 9, 10, 12, and 13 in Table 3Citation ). Interestingly, some patients’ AUCs fluctuated, rather than remained low.



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  		Fig. 1. Dose (mg/m2/dose) versus ATRA AUC (µg/ml x h), day 1.

 
Four patients had an increase in the AUC after dose reduction. Patient 3 (Table 3)Citation had a 25% dose reduction, without a hiatus of ATRA treatment, at about 8 months but had ATRA AUC of 1.34 µg/ml x h at 1 year, compared with an AUC of 0.9 µg/ml x h on day 1 of the initial, higher dose. Patient 6 had a 50% reduction of dose after 2 months, without a treatment hiatus, but had an AUC of 1.04 µg/ml x h at 1 year, compared with an AUC of 0.92 µg/ml x h at day 1 of the initial dose. Patient 7 had a 50% dose reduction after a treatment hiatus. This patient’s ATRA AUC on day 1 of the reduced dose was 0.61 µg/ml x h, compared with an AUC of 0.38 µg/ml x h on day 1 of the initial dose. This patient experienced severe (grade 4 colitis) on the lower dose of ATRA. Patient 8 had a dose reduction of 25% at about 8 months without a treatment hiatus. The ATRA AUC at 1 year was 0.15 µg/ml x h, compared with a day 1 AUC on the initial dose of 0.34 µg/ml x h on day 1 and an AUC of 0.05 µg/ml x h on day 60 of the initial dose. Patient 9 had a dose reduction of 50% for severe headache. After a treatment hiatus, during which the headache resolved, the AUC on day 1 of the reduced dose was 0.36 µg/ml x h, compared with a day 1 AUC on the initial dose of 0.37 µg/ml x h. Interestingly, this patient did not experience severe headache on the reduced dose of ATRA. The ATRA AUC decreased with dose reduction on day 1 of the reduced dose, compared with day 1 of the initial dose, in two patients (patients 4 and 5).

Pharmacokinetic-Pharmacodynamic Relationships.
In patients who had dose reduction (nine patients) or refused to continue in the study (one patient) because of grade 2 (but intolerable) skin dryness or who were removed from the study because of progression of the tumor but had grade 3 toxicity (2 patients), peak plasma ATRA concentration at the time point prior to the toxic event ranged from 0.004 to 0.49 µg/ml, with a median value of 0.15 µg/ml. Fig. 2Citation shows the relationship between the highest toxicity grade experienced by each patient and ATRA AUC at the time point closest to the onset of the toxicity and suggests no correlation between ATRA AUC and toxicity grade.



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  		Fig. 2. Correlation of highest toxicity grade and ATRA AUC at time point closest to onset of the toxicity in each patient.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The maximum tolerable dose of ATRA for patients with treated SCCHN is 45 mg/m2/day, given once daily, and the recommended dose for long-term trials is 45 mg/m2/day, in divided doses q8h, when given for 1 year. When patients who were able to tolerate 1 year of treatment at 45 mg/m2/day after dose reduction from 90 mg/m2/day are included, then six of nine patients at the single daily ATRA dose of 45 mg/m2/day and seven of eight patients at the ATRA dose of 15 mg/m2 tid tolerated up to 1 year of treatment at these doses. At higher doses, regardless of schedule (daily versus divided doses given tid), ATRA was not tolerable in the majority of patients. These results contrast with previous Phase I trials of ATRA in patients in advanced solid tumors, where the maximum tolerable dose was determined to be 150–215 mg/m2/day (13 , 14) . All eight patients treated with ATRA at 90 mg/m2/day in the present trial had to have dose reduction for intolerable toxicity (100%). In contrast, 12 patients with various carcinomas who were treated with ATRA at a dose of 88 or 110 mg/m2/day as a single daily dose, in a previous Phase I trial (13) , developed seven grade 3 toxicities and no grade 4 toxicity (58%). Notably, in both Phase I trials, most of the severe toxicities developed within the first month after the initiation of ATRA treatment. Most severe headaches occurred within a week of starting ATRA. The population of patients in a typical Phase I trial generally includes a significant proportion of patients whose disease will progress within 2 months and, therefore, would not be expected to remain on the Phase I treatment for long periods of time. However, because most of the toxicities of ATRA occurred within the first month of treatment, this difference in the populations does not account for the difference in toxicity rate and the lower recommended Phase II dose in treated head/neck cancer patients. Plasma ATRA AUC in this trial for patients receiving 90 mg/m2/day ranged from 0.2 to 1.04 µg/ml x h for the single daily dose and 0.34 to 0.38 µg/ml x h in those receiving 30 mg/m2 tid. In our previous Phase I trial (13) , patients treated with ATRA at a dose of 88 mg/m2/day had plasma ATRA AUCs ranging from 0.9 to 3 µg/ml x h (mean, 0.8 µg/ml x h), whereas those treated with ATRA at a dose of 110 mg/m2/day had plasma AUCs ranging from 0.3 to 4.1 µg/ml x h (mean, 2.4 µg/ml x h). Thus, the possible increase in toxicity in patients with SCCHN treated with ATRA, compared with patients in the previous Phase I trial, cannot be attributed to greater ATRA AUCs in the SCCHN patients. Likewise, comparison of mean peak plasma ATRA concentrations indicates that the SCCHN patients had lower mean plasma ATRA concentrations than patients treated in the previous Phase I trial. The mean peak ATRA concentration for SCCHN patients treated with 90 mg/m2 ATRA qd was 0.34 µg/ml, and the mean peak ATRA concentrations for patients treated in the previous Phase I trial with 88 or 110 mg/m2/day ATRA were 0.7 and 0.93 µg/ml, respectively. Meng-er et al. (16) reported that of 24 patients with acute promyelocytic leukemia treated with ATRA at doses of 45–100 mg/m2/day, 100% experienced mucocutaneous dryness, 25% experienced headache, 20.8% had nausea and vomiting, and 12.5% had moderate bone/joint pain. Toxicity was not reported by grade in this report. The reason for the possible lower tolerance of the SCCHN patient population, compared with other patients with solid tumors, is not obvious. All of the SCCHN patients had surgical resection. Nine patients were also treated with adjuvant radiation. However, severe toxicity was not restricted to those with prior adjuvant radiation therapy.

The nature of the toxicities observed in this study are consistent with those reported previously for ATRA: headache, mucocutaneous dryness, and hypertriglyceridemia. The only acute toxicity in our study was headache, which was similar to that reported for acute vitamin A intoxication (17) . The occurrence of inflammatory bowel disease, observed in one patient in this trial, has not been associated previously with ATRA treatment. The hypertriglyceridemia of grade >=3 in our study (>400 mg/dl) did not cause symptoms. However, this level of hypertriglyceridemia was not considered to be desirable for periods of 1 year or longer. All severe toxicities were reversible and ameliorated by reduced dosing.

ATRA plasma pharmacokinetics were not correlated with toxicity. Toxicity grade did not correlate with peak plasma ATRA concentration or AUC. However, in individual patients, toxicity decreased with decreased dose. This observation may imply an individualized sensitivity to plasma ATRA AUC or to peak plasma ATRA concentration. That is, although toxicity frequency or severity may not be related to plasma concentration in a larger population, plasma concentration may well relate to severity of toxicity for an individual patient. Alternatively, this observation could imply that plasma ATRA concentration is not a good surrogate for ATRA activity at the tissue target. There was no noticeable decrease in severity of grade <=2 toxicity with continued time of treatment at the same dose, even in those patients who had decreased plasma ATRA concentrations, and one patient (no. 9) did not have decreased plasma ATRA AUC, even with dose reduction, but did not have recurrence of the toxicity that caused the dose reduction.

Pharmacokinetic studies in patients with acute promyelocytic leukemia and solid tumors have shown that the concentration of ATRA in plasma decreases with continued dosing in the majority of patients (10, 11, 12, 13) . In our study, slightly more than half of the patients (7 of 13) who had assessment of serial ATRA pharmacokinetics had decreased plasma ATRA concentrations with continuous dosing. Dose reduction generally resulted in lower toxicity in our patients but not necessarily in lower ATRA AUCs. The hiatus from treatment may have had a role in the elevated or similar plasma ATRA concentration seen after dose reduction in two of our patients, because recovery of catabolic enzymes has been documented for a similar period of time off ATRA (18) . However, some patients seemed to have increased ATRA AUCs, even on continued dosing (patients 3, 6, and 8 in Table 3Citation ).

Three patients had tumor recurrence during study, which was not unexpected given the initial stage of cancer. This trial cannot assess the chemopreventive effect of ATRA in this population but has defined a dose that can be used for long-term chemopreventive studies. Mature data from initial trials of 13-cRA in patients with treated SCCHN demonstrated a lower rate of second primary tumor development in patients who received 13-cRA versus those who received placebo (19) . If the mechanism of the chemopreventive effect is through retinoic acid receptors, ATRA should be at least as effective as 13-cRA in preventing second primary cancers in patients with treated SCCHN, because ATRA has greater binding affinity for retinoic acid receptor than does 13-cRA or fenretinide (8 , 9) . The induction by ATRA of its own metabolism may dampen enthusiasm for use of this compound for chemoprevention. However, the relationship between plasma ATRA concentration and effect has not been defined, and it is possible that plasma ATRA concentrations may not reflect ATRA concentrations at the target. The persistence of grade 2 toxicities, despite lower plasma ATRA concentrations, may support such a view. On the other hand, studies have shown that intermittent ATRA dosing (i.e., 1–2 weeks without treatment) results in ATRA AUC values similar to the initial dose (18) , and such a dosing schedule may also be considered for chemoprevention trials.

In summary, the toxicities of ATRA are quite similar to those reported for 13-cRA, and a dose for prolonged treatment for patients with treated SCCHN has been defined. The occurrence of severe (grade >=3) toxicity does not seem to be related to ATRA plasma peak concentrations or AUC. Individuals may require dose reduction for toxicity between the first day and several months after treatment begins. All toxicities are reversible. In the individual patient, reduction in plasma ATRA concentration by dose reduction resulted in decreased toxicity severity. The question of whether ATRA concentration correlates with therapeutic response awaits the development of predictive clinical markers of chemoprevention effect. Such markers would make possible comparison of various schedules of chemopreventive agents as well as comparisons between promising chemopreventive agents prior to the initiation of long-term, randomized chemoprevention trials.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by Grant U-01-CA-69854 from the NIH, National Cancer Institute, and by Hoffman-LaRoche, Nutley, NJ. Back

2 To whom requests for reprints should be addressed, at Diagnostics Research Branch, Cancer Diagnosis Program, National Cancer Institute, Room 700, Executive Plaza North, 6130 Executive Boulevard, Rockville, MD 20852. Fax: (301) 402-7819; E-mail: conleyb{at}mail.nih.gov Back

3 The abbreviations used are: SCCHN, squamous cell carcinoma of the head and neck; 13-cRA, 13-cis retinoic acid; ATRA, all-trans retinoic acid; AUC, area under the plasma concentration versus time curve; NCI, National Cancer Institute; qd, once daily; q8h, every 8 hs; tid, three times a day. Back

Received 3/25/98; revised 5/ 5/99; accepted 6/ 1/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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