phase 1 trial of combined chemotherapy and reirradiation for recurrent unresectable head and neck...

PHASE 1 TRIAL OF COMBINED CHEMOTHERAPY ANDREIRRADIATION FOR RECURRENT UNRESECTABLEHEAD AND NECK CANCER

Sharon Spencer, MD,1 Richard Wheeler, MD,2 Glenn Peters, MD,1 Ruby Meredith, MD,1

Sam Beenken, MD,1 Lisle Nabel, MD,1 Ann Wooten, RN,1 Seng-jaw Soong, PhD,1

Merle Salter, MD1

1 University of Alabama at Birmingham, Department of Radiation Oncology, 619 South 19th Street, WTI #119,Birmingham, Alabama 35233. E-mail: [email protected] University of Utah, Oncology Division, Salt Lake City, Utah

Accepted 28 May 2002Published online 13 November 2002 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.10178

Abstract: Background. The management of recurrent unre-sectable head and neck cancer remains a challenging problem.Based on the circadian rhythm concept, we sought to determinethe maximum tolerated dose (MTD) of infusional 5-flourouracil(5-FU), hydroxyurea (HU), and reirradiation (RT).

Method. Bolus 5-FU was escalated from 300mg/m2/d to a10-hour infusion beginning at midnight, increased at 150 mg/m2/dincrements. HU, 1.5 g, remained constant. Chemotherapy wasgiven on weeks 1 and 4. RT was given daily, 2.0 Gy per fractionon weeks 1 and 2 followed by a 1-week break, then hyperfrac-tionated weeks 4 and 5, total dose 50 Gy. The goal was to delivera continuous course of RT to 60 Gy after the MTD was deter-mined with an additional week of chemotherapy.

Results. Six cohorts were treated to establish the 5-FU MTDof 900 mg/m2/d. The seventh cohort received continuous RT and5-FU, 750 mg/m2/d, one dose level below the MTD. Two hema-tologic, three skin, and six mucosal � grade 3 toxicities werenoted in 7 of 16 patients. The median survival was 10.2 months

and the 1-year survival was 41%. The median survival for theentire group was 9.4 months, with a 1- and 2-year survival of 39%and 15%, respectively.

Conclusion. RT can be given in a continuous fashion withconcurrent 5-FU and HU. Because radiation sensitization shouldbe achievable at nontoxic doses of 5-FU, we recommend 600mg/m2/d in phase a II setting. © 2003 Wiley Periodicals, Inc.Head Neck 25: 118–122, 2003

Keywords: reirradiation; recurrent head and neck; chemo-therapy

Studies published by ourselves and others havedemonstrated that reirradiation with concurrentchemotherapy in patients with recurrent, previ-ously irradiated head and neck cancer is feasible,tolerable, may achieve an improved median sur-vival compared with chemotherapy alone, andcan produce a prolonged duration of disease con-trol for a minority of patients.1–5 However, mostpatients treated with reirradiation and chemo-therapy fail within the treatment field. Clearly,

Correspondence to: S. Spencer

© 2003 Wiley Periodicals, Inc.

118 Phase I Trial of CT and RT for Recurrent Unresectable H & N Cancer HEAD & NECK February 2003

approaches that could increase local control needto be evaluated.

Although most early studies using irradiationalone used standard fractionation therapy,6–8 vir-tually all recent studies using chemoradiationhave used split-course irradiation. Historicalevaluations, as well as recent randomized stud-ies, have indicated that treatment breaks reducethe efficacy of irradiation as a single modality.9,10

This suggests that reducing the number of treat-ment breaks could improve local control with re-irradiation.

One of the goals of the study reported here wasto determine whether the alternate-week treat-ment plan used previously could be modified toremove treatment breaks. A treatment programpatterned after the “late concomitant boost” con-cept described by Ang and Peters was selected.11

The initial patients were treated with a planned1-week break between the first 2 weeks of single-daily fraction therapy and the final 2 weeks oftwice-daily therapy. A final group of patients wastreated without this planned break.

Concurrent chemotherapy has been used withreirradiation primarily as a radiation sensitizer.The most frequent agent used has been 5-fluoro-uracil (5-FU), often used as a continuous infusionprimarily based on the preclinical studies by By-field.12 Cisplatinum or hydroxyurea (HU) are themost common drugs used in combination with5-FU.1–5 We elected in the past to use 5-FU bybolus injection both for ease of administrationand to reduce mucosal toxicity in this fragile pa-tient population. However, the low rate of localcontrol can be viewed as a failure of the chemo-therapy sensitization, as well as resulting fromtreatment breaks in the radiation therapy.Lawrence et al13 have published preclinical stud-ies indicating that optimum radiosensitization isobtained by pretreatment with a low dose of afluoropyrimidine delivered before the dose of ir-radiation. A second objective of this study was toclinically explore this approach by use of a timedinfusion of 5-FU administered before the daily ra-diation fraction (first fraction, during twice-dailytherapy).

The blood level of 5-FU achieved after intra-venous administration depends on the time of daythe dose is administered. This variation in bloodlevel follows a circadian pattern, resulting fromchanges in the level of the enzyme dihydropyrimi-dine dehydrogenase (DPD).14 All 5-FU infusionswere begun at midnight before irradiation andcontinued for 10 hours. The radiation fraction

was administered 8 hours after starting the infu-sion. The dose-rate of 5-FU was escalated in se-quential groups of patients to establish the MTDof the agent given in this fashion with concurrentirradiation. HU was given 2 hours before irradia-tion as we have done previously. The MTD of5-FU was first determined with the single treat-ment break in the radiation treatment plan thenreassessed after the break was removed.

MATERIALS AND METHODS

On the basis of our prior experience, the first doselevel consisted of bolus 5-FU, 300mg/m2, withHU, 1.5gm.1,2 The radiation scheme consisted ofonce-daily RT at 2.0 Gy per fraction for 2 weeksfollowed by a 1-week break, followed by twice-daily RT, 1.5 Gy bid, to a total dose of 50 Gy.Fractions were separated by 6 hours during thehyperfractionated phase. The chemotherapy wasgiven on weeks 1 and 4. For level 2 and thereafter,the 5-FU was given using a timed infusion of5-FU over 10 hours beginning at 12 midnight andcontinuing until 10 AM the following day. The ir-radiation was given at 8 AM each day. The HU wasgiven 2 hours before each AM RT dose. The 5-FUdose was increased at 150 mg/m2 increments. TheHU dose remained stable. For level 7, the treat-ment break was removed; a third week of single-daily fraction RT and a third week of chemo-therapy were added. The treatment scheme canbe seen in Table 1.

The irradiation portals were designed to in-clude all gross disease with a 2.0-cm minimummargin. Parallel opposed lateral, opposed oblique,and single mixed photon electron fields wereused. The spinal cord was excluded from the pri-mary beams to limit the cumulative dose to 50 Gy.CT or MRI was used in the treatment plans of allpatients.

Patients were considered eligible for the pro-tocol if they met the following criteria: recurrentdisease from a primary cancer arising in the up-per aerodigestive tract, salivary gland, skin, or asecond primary cancer arising within a previouslyirradiated volume. Patients with recurrent dis-ease in the nasopharynx were excluded. The re-currence must have bidimensional measurementsby clinical examination or CT scan. All patientswere deemed surgically unresectable. Most(�75%) of the recurrence had to be within a vol-ume that previously received �4 5Gy, and theentire recurrence volume had to be included in atreatment field that limits the spinal cord dose to50 Gy (prior RT and anticipated RT). At least 6

Phase I Trial of CT and RT for Recurrent Unresectable H & N Cancer HEAD & NECK February 2003 119

months between prior RT and study entry wasrequired, and one prior course of chemotherapyfor recurrence was allowed. Patients were re-quired to be �18 years with a Karnofsky statusof �60%. Hematologic and organ function cri-teria were a WBC �4000/mm3, platelet count�100,000/mm3, bilirubin �1.5 mg/dL, and creat-inine �1.5 mg/dL. All participants signed in-formed consent, and this protocol was reviewedand approved by the Institutional Review Boardat the University of Alabama at Birmingham. Pa-tients with asymptomatic distant metastaseswere considered eligible.

Toxicity was scored according to RadiationTherapy Oncology Group criteria. Radiation andchemotherapy were delayed 1 week for mucosaltoxicity grade 3 or more, a WBC <3500/mm3, anda platelet count of <100,000/mm3. A complete re-sponse was defined as clinical disappearance ofall disease. A partial response was defined asmore than 50% reduction in the sum of the prod-ucts of perpendicular diameters compared withbaseline disease for measurable disease, and forevaluable disease, a 50% decrease in tumor bur-den agreed on by two independent observers. Theevaluable disease category was used in caseswhen tumor borders became less distinct on clini-cal examination and by CT scans. Results werefirst assessed 30 days after the last treatment,

and all responses had to persist for at least 1month. Statistical analysis of survival was per-formed using the Kaplan-Meier method. Thestarting point for the analysis was the first day oftreatment. All patients were included in the sur-vival analysis.

RESULTS

Fifty-two patients were entered in the trial from1992–1999. The patient characteristics can befound in Table 2. The median age was 63 years,with a male predominance. Most patients origi-nally had either laryngeal, oral cavity, or oropha-ryngeal primary tumors. Eighty percent of pa-tients had received prior surgery, with only 14%receiving prior chemotherapy. Most patients hadreceived >55 Gy before protocol entry, with mostrecurrences occurring in the original primary or aregional site (Tables 3 and 4).

Patients were escalated safely through six lev-els to a 5-FU dose of 900 mg/m2/d, at which timeone hematologic, two mucosal, and/or, two skintoxicities � grade 3 were encountered in two of sixpatients. One patient had a grade 4 skin reactiondevelop. This level was identified as the MTD forthe 10-hour infusion of 5-FU given for two cyclesduring the 5 weeks of irradiation with 1 weekplanned break (Table 5).

For level 7, the 5-FU dose was reduced to onedose level below the MTD, 750 mg/m2/d. Thetreatment break on week 3 was eliminated. Thetotal dose of RT was increased from 50 Gy to 60Gy by delivering 10 Gy during week 3 using 2-Gyfractions. The chemotherapy was given on weeks1, 3, and 5. Sixteen patients were treated. Threeskin, two hematologic, and/or six mucosal grade 3reactions were noted. There were no grade 4 re-actions noted.

The average overall weight loss during the en-

Table 1. Treatment scheme.

Level

5-FU(mg/m2)

qdx5HU (g)qdx5

Frequency(wk) RT

1 300 bolus 1.5 1, 4 2.0 Gy qd wk 1, 21.5 Gy bid wk 4, 550 Gy total dose

2 300 infusion 1.5 1, 4 2.0 Gy qd wk 1, 21.5 Gy bid wk 4, 550 Gy total dose




6 900 infusion 1.5 1, 4 2.0 Gy qd 1, 21.5 Gy bid wk 4, 550 Gy total dose

7 750 infusion 1.5 1, 3, 5 2.0 Gy qd wk 1, 2, 31.5 Gy bid wk 4, 560 Gy total dose

Table 2. Patient characteristics (n = 52).

Male/female 43/9Age median 63 y (40–80)Original primary site

Oral cavity 13Oropharynx 11Larynx 14Hypopharynx 2Unknown 1° 2Nasopharynx 1*Other (skin, salivary) 9†

*Represents a patient with recurrent unresectable neck disease.†All skin cancers were squamous cell carcinoma.†All salivary tumors were mucoepidermoid.


tire study was 4%. Most patients had feedingtubes placed before study entry. Most patientscompleted planned treatment. Three patients re-fused to complete therapy. One patient died dur-ing the first week of therapy unrelated to treat-ment toxicity. There were no treatment-relateddeaths. One patient died 3 weeks after studycompletion with pneumonia without evidence ofneutropenia. To date, with a median follow-up of60 months for entire group, four late complica-tions have been noted. There were two soft tissueulcers. One patient required hyperbaric oxygen.The second patient required a skin graft. It wasnoted that this patient was receiving methotrex-ate during the course of the protocol therapy forarthritis. A third patient had trismus develop.The fourth patient had a nonhealing clavicularfracture. The late complications occurred in levels2, 5, 6, and 7.

Fifteen patients had unplanned treatment in-terruptions. The average delay was 1 week. Onepatient at the 900 mg/m2 level was delayed 3weeks. In level 7, seven patients had treatmentinterruptions. Two of these interruptions wereunrelated to treatment toxicity. One patient hada wound infection, and another had a central lineinfection without evidence of neutropenia. A thirdpatient received a break, but all of this toxicitywas � grade 2. Only four of the seven patientswere interrupted because of grade 3 treatment-related toxicity (Table 6).

Response was determined by use of clinical ex-aminations and serial CT scans. Of the 50 pa-tients evaluable for response, 30% were consid-ered CR, 22% PR, and 30% had stable disease,whereas 18% experienced disease progression.The CR rate in level 7 was 33%, with a 13% PRrate. The median survival for the patients in level7 is 10.2 months, with a 1-year survival of 41%.The median survival for the entire group is 9.4months, with a 1-year survival of 39%. The 2-yearsurvival rate for the entire group is 15%.

The first site of disease progression was pri-marily in the field of reirradiation noted at a rateof 60%. Eighteen percent of patients progressedalong the margins of the irradiation portals. Six-teen percent of patients progressed initially indistant sites. Only 3% of patients had recurrenceout of the irradiation port into a regional area.New primary tumors developed in 3% of patients.

DISCUSSION

The first goal of this study was to determine thefeasibility of removing all planned breaks in theRT treatment plan when given as reirradiation inpatients with recurrent, previously irradiatedhead and neck cancer. The second goal was todetermine the dose of 5-FU that could be given asa daily, 10-hour infusion for 5 consecutive daysevery 2 or 3 weeks during RT. The timing of 5-FU

Table 3. Prior RT doses (n = 52).

No. patients

�55 Gy 555–70 Gy 33>70 Gy 13Unknown 1

Table 4. Sites of recurrence at study entry (n = 52).

No. patients

Primary site 18Regional 20Primary/regional 4New primary 5Regional/distant 1Other 4*

*Dermal metastases.

Table 5. Acute toxicity/grade 3 (n = number of events).

No. patients Hematologic Skin Mucosa

Level1 7 1 0 32 7 0 0 03 5 0 1 14 6 0 0 25* 5 0 0 06† 6 1 2 27 16 2 3 6

*One patient had grade 3 nausea develop.†One patient had grade 4 skin develop.

Table 6. Unplanned treatment interruptions.

Level No. patients No. patients requiring treatment breaks

1 7 32 7 13 5 14 6 15 5 06 6 27 16 7*

*Two patients required a break unrelated to treatment complications: in-dwelling catheter line injection and abdominal wound infection. One pa-tient received a break for grade 2 changes only.

Phase I Trial of CT and RT for Recurrent Unresectable H & N Cancer HEAD & NECK February 2003 121

administration was selected based on the knowncircadian variation in 5-FU blood levels and thepossibility that optimum radiosensitization wouldbe achieved by starting the 5-FU at least 8 hoursbefore the RT dose.13,14 We have established thatthe MTD of the timed 5-FU infusion, given withhydroxyurea, is 900 mg/m2/day for 5 days duringweeks 1 and 4, when 50 Gy of RT is given over 5weeks with a break at week 3. The 5-FU can beadministered at 750 mg/m2 for 5 days given onweeks 1, 3, and 5 when the break is removed andthe RT total dose increased to 60 Gy. On the basisof the acute toxicity, these goals have been accom-plished. Six patients had treatment breaks, butonly four required breaks secondary to treatment-related toxicity. There was only one grade 4 tox-icity noted for the entire group. At 900 mg/m2

of 5-FU, dose level 6, a patient had grade 4skin toxicity that healed uneventfully. The acutemucosal toxicity in dose level 7 was 38%, whichis similar to other aggressive radiation-aloneand combined radiotherapy chemotherapy pro-grams.10,15

Late toxicity was noted in four patients. Twosoft tissue ulcers were noted, with hyperbaric oxy-gen being required in one patient and a skin graftin the other. A third patient had trismus develop.The fourth patient had a nonhealing clavicularfracture that required hyperbaric oxygen therapy.These late effects occurred in levels 2 ,5, 6, and 7.

The removal of planned treatment breaks inthe RT plan and the use of 5-FU by a timed infu-sion were implemented in an attempt to improvethe local control rate. The treatment program pre-sented also has the advantage of a shorter treat-ment time compared with our prior experience.2 Apotentially negative impact of these changes isthe inability to give chemotherapy with each doseof irradiation. The treatment efficacy, as reflectedby the complete and partial response rate, is simi-lar to the results we have observed previously.1,2

In summary, this study demonstrates that re-irradiation in patients with previously irradiatedhead and neck cancer can be given withoutplanned breaks as 60 Gy over 5 weeks. Chemo-therapy with hydroxyurea orally and 5-FU by in-travenous infusion at a dose rate of 750 mg/m2/dfor 5 days can be given concurrently with the re-irradiation on weeks 1, 3, and 5. For phase IIstudies, a 5-FU dose of 600 mg/m2/d is recom-mended, because a nontoxic dose should have op-

timum radiosensitization effect.13 Randomizedtrials will be required to determine the best reir-radiation program and to determine the overallbenefit of reirradiation compared with chemo-therapy alone.

REFERENCES1. Weppelmann B, Wheeler RH, Peters GE, et al. Treatment

of recurrent head and neck cancer with 5-fluorouracil, hy-droxyurea and reirradiation. Int J Radiat Oncol Biol Phys1992;22:1051–1056.

2. Spencer SA, Wheeler RH, Peters, GE, et al. Concomitantchemotherapy and reirradiation as management for re-current cancer of the head and neck. Am J Clin Oncol1999;22:1–5.

3. Haraf D, Weichselbaum R, Vokes E. Reirradiation withconcomitant chemotherapy of recurrent head and neckcancer: a potentially curable disease. Ann Oncol 1996;7:913–918.

4. Hartsell WF, Thomas CR, Murthy AK, Taylor SG, HaslowRE. Pilot study for the evaluation of simultaneous cisplat-in/5-fluorouracil infusion and limited radiation therapy inregionally recurrent head and neck cancer (EST P-C385).Am J Clin Oncol (CCT) 1994;17:338–343.

5. De Crevoisier R, Bourhis J, Domenge C, et al. Full-dosereirradiation for unresectable head and neck carcinoma:experience at the Gustave-Roussy Institute in a series of169 patients. J Clin Oncol 1998;16:3556–3562.

6. Emami B, Bignardi M, Devineni VR, Spector GJ, Heder-man MA. Reirradiation of recurrent head and neck can-cers. Laryngoscope 1987;97:85–88.

7. Pomp J, Levendag PC, van Putten LJ. Reirradiation ofrecurrent Tumors in the head and neck. Am J Clin Oncol(CCT) 1988;11:543–549.

8. Stevens KR, Britsch A, Moss WT. High-dose reirradiationof head and neck cancer with curative intent. Int J RadiatBiol Phys 1994;29:687–698.

9. Parsons JT, Cassisi NJ, Million RR. Results of twice-a-dayirradiation of squamous cell carcinoma of the head andneck. Int J Radiat Oncol Biol Phys 1984;10:2041–205.

10. Fu K, et al. A Radiation Therapy Oncology Group (RTOG)Phase III RTOG 9003 randomized study to compare hy-perfractionation and two variants of accelerated fraction-ated to standard fractionation radiotherapy for head andneck squamous cell carcinomas: first report of RTOG9003. Int J Radiat Oncol Biol Phys 2000;8:7–16.

11. Ang KK, Peters LJ, Weber RS, et al. Concomitant radio-therapy schedules in the treatment of carcinoma of theoropharynx and nasopharynx. Int J Radiat Oncol BiolPhys 1990;19:1339–1345.

12. Byfield JE. Useful interactions between 5-fluorouraciland radiation in man: 5-fluorouracil as a radiosensitizer.In: Hill BT, Bellamy AS, eds. Anti-tumor drug-radiationinteractions. Boca Raton, FL: CRC Press; 1990. p 87–105.

13. Lawrence TS, Tepper JE, Blackstock AW. Fluoropyrimi-dine-radiation interactions in cells and tumors. Semin Ra-diat Oncol 1998;4:260–266.

14. Heggie GD, et al. Clinical pharmacokinetics of 5-fluoro-uracil and its metabolites in plasma, urine and bile. Can-cer Res 1987;47:2203.

15. Garden AS, et al. Preliminary results of RTOG 9703—Aphase II Randomized Trial of concurrent radiation andchemotherapy for advanced squamous cell carcinomas ofthe head and neck. San Francisco, CA: ASCO; 2001.


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