The authors present a critical appraisal of the biological bases of altered fractionation and a brief overview of published randomized trials with conventional fractionation as the control arm, reviews and meta-analysis on altered fractionation radiotherapy in head and neck cancer. The major controversial issues emerging from these studies are reviewed and the limiting factors which so far have prevented the widespread use of altered fractionation regimens in current clinical practice are analyzed. Future perspectives regarding predictive biological assays for patient selection and the integration of altered fractionation regimens with radiochemotherapy protocols, biomodulators and novel radiotherapy techniques are also reviewed and summarized.
FuK.K., PajakT.F., TrottiA., JonesC.U., SpencerS.A., PhillipsT.L., GardenA.S., RidgeJ.A., CooperJ.S., AngK.K.: A Radiation Therapy Oncology Group (RTOG) Phase III randomized study to compare HF and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003.Int J Radiat Oncol Biol Phys,48: 7–16, 2000.
2.
BourhisJ., SyzN., OvergaardJ., AngK.K., DischeS., HoriotJ., HilniakA., PoulsenM., O'SullivanB., DobrowskiW., FallaiC., PintoL., SkladowskiK., HayJ.H., FuK.K., SylvesterR., PignonJ.: Conventional vs modified fractionated radiotherapy in head & neck squamous cell carcinoma: a meta-analysis based on individual patient data (abst).Int J Radiat Oncol Biol Phys,54(Suppl): 71–72, 2002.
3.
AngK.K.: Altered fractionation trials in head and neck cancer.Sem Radiat Oncol,8: 230–236, 1998.
4.
BernierJ., BentzenS.M.: Altered fractionation and combined radio-chemotherapy approaches: pioneering new opportunities in head and neck cancer oncology.Eur J Cancer,39: 560–571, 2003.
ThamesH.D., PetersL.J., WithersH.R., FletcherG.: Accelerated fractionation vs. hyperfractionation: rationales for several treatments per day.Int J Radiat Oncol Biol Phys,9: 127–138, 1983.
7.
ThamesH.D., BentzenS.M., TuressonI., OvergaardM., Van den BogaertW.: Time-dose factors in radiotherapy: a review of the human data.Radiother Oncol,19: 219–235, 1990.
HoriotJ.C., Le FurR., N'GuyenT.: Hyperfractionated versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy.Radiother Oncol,25: 231–241, 1992.
10.
SkladowskiK., MaciejewskiA.W., GolenM., PileckiA.W., PrzeorekA.W., TarnawskiR.: Randomized clinical trial on 7-day continuous accelerated irradiation (CAIR) of head and neck cancer - report on 3-year tumour control and normal tissue toxicity.Radiother Oncol,55: 101–110, 2000.
11.
OvergaardJ., HansenH.S., SpechtL., OvergaardM., GraiC., AndersenE., BentzenJ., BastholtL., HansenO., JohansenJ., AndersenL., FevensenJ.: Five compared with six fractions per week of conventional radiotherapy of squamous cell carcinoma of the head and neck: DAHANCA 6 & 7 randomised controlled trial.Lancet,362: 933–940, 2003.
12.
MarciaiV., PajakT., ChangC., TupchongL., StetzJ.: Hyperfractionated photon radiation therapy in the treatment of advanced squamous cell carcinoma of the oral cavity, pharynx, larynx and sinuses, using radiation therapy as the only planned modality: (preliminary report) by the Radiation Therapy Oncology Group (RTOG).Int J Radiat Oncol Biol Phys,13: 41–47, 1987.
13.
DattaN.R., ChoudryA.D., GuptaS., BoseA.K.: Twice a day versus once a day radiation therapy in head and neck cancer (abstr).Int J Radiat Oncol Biol Phys,17(suppl. 1): 132, 1989.
14.
SanchizF., MillàA., TornerJ., BonetF., ArtolaN., CarrenoL., MoyaL., RieraD., RipolS., CireraL.: Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer.Int J Radiat Oncol Biol Phys,19: 1347–1350, 1990.
15.
PintoL., CanaryP., ArayoC., BacelarS., SouhamiL.: Prospective randomized trial comparing hyperfractionated versus conventional radiotherapy in stages III and IV oropharyngeal carcinoma.Int J Radiat Oncol Biol Phys,21: 557–562, 1991.
16.
StuschkeM., ThamesH.D.: Hyperfractionated radiotherapy of human tumors: overview of the randomized clinical trials.Int J Radiat Oncol Biol Phys,37: 259–267, 1997
17.
Beck-BornholdtH.P., DubbenH.H., Liertz-PetersenC., WillersH.: Hyperfractionation: where do we stand?Radiother Oncol,43: 1–21, 1997.
18.
JacksonS.M., WeirL.M., HayJ.H., TsangV.H.Y., DurhamJ.S.: A randomised trial of accelerated versus conventional radiotherapy in head and neck cancer.Radiother Oncol,43: 39–46, 1997.
19.
Van den BogaertW., Van der SchuerenE., HoriotJ.C., De VilhenaM., SchraubS., SvobodaV., ArcangeliG., De PauwM., Van GlabbekeM.: The EORTC randomized trial on three fractions per day and misonidazole in advanced head and neck cancer: prognostic factors.Radiother Oncol,35: 91–99, 1995.
20.
HoriotJ.C., BontempsP., van den BogaertW., Le FurR., van den WeijngaertD., BollaM., BernierJ., LusinchiA., StuschkeM., Lopez-TorrecillaJ., BeggA.C., PierartM., ColletteL.: Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial.Radiother Oncol,44: 111–121, 1997.
21.
JohnsonC.R., Schmidt-UllrichR.K., ArthurD.W., HuangD.T., DuffyE.W.: Standard once-daily versus thrice-daily concomitant boost accelerated superfractionated irradiation for advanced squamous cell carcinoma of the head and neck: preliminary results of a prospective randomized trial (abstr).Int J Radiat Oncol Biol Phys,32(suppl. 1): 162, 1995.
22.
DischeS., SaundersM., BarrettA., HarveyA., GibsonD., ParmarM.: A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer.Radiother Oncol,44: 123–136, 1997.
23.
PoulsenM.G., DenhamJ W., PetersL.J., LambD.S., SpryN.A., HindleyA., KrawitzH., HamiltonC., KellerJ., TripconyL., WalkerQ.: A randomised trial of accelerated and conventional radiotherapy for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group Study.Radiother Oncol,60: 113–122, 2001.
24.
OlmiP., CrispinoS., FallaiC., TorriV., RossiF., BolnerA., AmichettiM., SignorM., TainoR., SquadrelliM., ColomboA., ArdizzoiaA., PonticelliP., FranchinG., MinatelE., GobittiC., AtzeniG., GavaA., FlannM., MarsoniS.: Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy: a multicenter randomized trial.Int J Radiat Oncol Biol Phys,55: 78–92, 2003.
25.
AwwadH.K., KhafaagyY., BarsoumM.: Accelerated versus conventional fractionation in the postoperative irradiation of locally advanced head and neck cancer: influence of tumour proliferation.Radiother Oncol,25: 261–266, 1992.
26.
AngK.K., TrottyA., BrownB., GardenA.S., FooteR., MorrisonW.H., GearaF.B., KlotchD., GoepfertH., PetersL.J.: Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head and neck cancer.Int J Radiat Oncol Biol Phys,51: 571–578, 2001.
27.
SanguinetiG., RichettiA., BignardiM., CorvòR., GabrieleP., SormaniM.P., AntognoniP.: Accelerated versus conventional fractionated postoperative radiotherapy for advanced head and neck cancer: results of a multicenter phase III study.Int J Radiat Oncol Biol Phys, 00: 000–000, 2005 (in press).
28.
KaandersJHAM, van der KogelA., AngK.K.: Altered fractionation: limited by mucosal reactions?Radiother Oncol,50: 247–260, 1998.
29.
TrottiA., BellmL.A., EpsteinJ.B., FrameD., FuchsH.J., GwedeC.K., KomaroffE., NalysnykL., ZilberbergM.D.: Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review.Radiother Oncol,66: 253–262, 2003.
30.
DenhamJ.W., PetersL.J., JohansenJ., PoulsenM., LambD.S., HindleyA., O'BrienP.C., SpryN.A., PennimentM., KrawitzH., WilliamsonS., BearJ., TripconyL.: Do acute mucosal reactions lead to consequential late reactions in patients with head and neck cancer?Radiother Oncol,52: 157–164, 1999.
31.
BrizelD.M., WassermanT.H., HenkeM., StrnadV., MonnierA., EschwegeF., ZhangJ., RussellL., OsterW., SauerR.: Phase III randomized trial of amifostine as a radioprotector in head and neck cancer.J Clin Oncol,18: 3339–3345, 2000.
32.
BourhisJ., De CrevoisierR., AbdulkarimB., DeutschE., LusinchiA., LuboinskiB., WibaultP., EschwegeF.: A randomized study of very accelerated radiotherapy with and without amifostine in head and neck squamous cell carcinoma.Int J Radiat Oncol Biol Phys,46: 1105–1108, 2000.
33.
PetersL.J., AngK.K., ThamesH.D.: Accelerated fractionation in the radiation treatment of head and neck cancer.Acta Oncol,27: 185–194, 1988.
34.
TrottiA.: Toxicity in head and neck cancer: a review of trends and issues.Int J Radiat Oncol Biol Phys,47: 1–12, 2000.
35.
KhalilA.A., BentzenS.M., BernierJ., SaundersM., HoriotJ.C., van den BogaertW., CummingsB., DischeS.: Compliance to the prescribed dose and overall treatment time in five randomized clinical trials of altered fractionation in radiotherapy for head-and-neck carcinomas.Int J Radiat Oncol Biol Phys,55: 568–575, 2003.
36.
GearaF.B., PetersL.J., AngK.K., WikeJ.L., BrockW.A.: Prospective comparison of in vivo normal cell radiosensitivity and normal tissue reactions in radiotherapy patients.Int J Radiat Oncol Biol Phys,27: 1173–1179, 1993.
37.
TerryN.H.A., PetersL.J.: Predictive value of tumor cell kinetics parameters in radiotherapy: considerations regarding data production and analysis.J Clin Oncol,13: 1833–1836, 1995.
38.
Corvo’R., GiarettiW., SanguinetiG., GeidoE., OrecchiaR., BarraS., MargarinoG., BacigalupoA., VitaleV.: Potential doubling time in head and neck tumors treated by primary radiotherapy: preliminary evidence for a prognostic significance in local control.Int J Radiat Oncol Biol Phys,27: 1165–1172, 1993.
39.
AntognoniP., BignardiM., CazzanigaL.F., PoliM., RichettiA., BossiA., RampelloG., BarberaF., SoattiC., BardelliD., GiordanoM., DanovaM.: Accelerated radiation therapy for locally advanced squamous cell carcinomas of the oral cavity and oropharynx selected according to tumor cell kinetics. A phase II multicenter study.Int J Radiat Oncol Biol Phys,36: 1137–1145, 1996.
40.
WilsonG.D.: Tpot and head and neck cancer: where are we now?Anticancer Res,18: 4081–4086, 1998.
41.
BeggA.C., HaustermansK., HartA.M., DischeS., SaundersM., ZackrissonB., GustaffsonH., CouckeP., PaschoudN., HoyerM., OvergaardJ., AntognoniP., RichettiA., BourhisJ., BartelinkH., HoriotJ.C., CorvòR., GiarettiW., AwwadH., ShoumanT., JouffroyT., MaciorowskiZ., DobrowskyW., StruikmansH., RugersD., WilsonG.D.: The value of cell kinetics parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.Radiother Oncol,50: 13–23, 1999.
42.
HaustermansK., FowlerJ.F.: Is there a future for cell kinetics measurements using IdUrd or BdUrd?Int J Radiat Oncol Biol Phys,49: 505–511, 2001.
43.
SlevinN.J., WestC.M.L., WilsonG.D., HendryJ.: The potential benefit from individualised radiotherapy scheduling for head and neck tumours on the basis of both histological grade and kinetics.Radiother Oncol,51: 109–111, 1999.
44.
CorvòR., AntognoniP., SanguinetiG.: Biological predictors of response to radiotherapy in head and neck cancer: recent advances and emerging perspectives.Tumori,87: 355–363, 2001.
45.
WithersH.R.: What Tpot is not.Int J Radiat Oncol Biol Phys,35: 633–634, 1996.
46.
AntognoniP., TerryN.H.A., RichettiA., LuraghiR., TordiglioneM., DanovaM.: The predictive role of flow cytometry-derived tumor potential doubling time (Tpot) in radiotherapy: open questions and future perspectives (Review).Int J Oncol,12: 245–256, 1998.
47.
BorgmannK., RoperB., El-AwadyR.A., BrackrockS., BigalkeM., DorkT., AlbertiW., DikomeyE., Dahm-DaphiJ.: Indicators of late normal tissue response after radiotherapy for head and neck cancer: fibroblasts, lymphocytes, genetics, DNA repair, and chromosome aberrations.Radiother Oncol,64: 141–152, 2002.
48.
AndreassenC.N., AlsnerJ., OvergaardJ.: Does variability in normal tissue reactions after radiotherapy have a genetic basis: where to look for it?Radiother Oncol,64: 131–140, 2002.
49.
DobrowskyW., DobrowskyE., WilsonG.D.: In vivo cell kinetic measurements in a randomized trial of continuous hyperfractionated accelerated radiotherapy with or without mitomycin C in head-and-neck cancer.Int J Radiat Oncol Biol Phys,55: 576–582, 2003.
50.
FowlerJ.F., HarariP.M., LeborgneF., LeborgneJ.H.: Acute radiation reactions in oral and pharyngeal mucosa. Tolerable levels in altered fractionation schedules.Radiother Oncol,69: 161–168, 2003.
51.
BaumannM., HolscherT., BeggA.C.: Towards genetic prediction of radiation responses: ESTRO's GENEPI project.Radiother Oncol,69: 121–125, 2003.
52.
AndreassenC.N., AlsnerJ., OvergaardM., OvergaardJ.: Prediction of normal tissue radiosensitivity from polymorphisms in candidate genes.Radiother Oncol,69: 127–135, 2003.
53.
BrizelD.M.: Radiotherapy and concurrent chemotherapy for the treatment of locally advanced head and neck squamous cell carcinoma.Sem Radiat Oncol,8: 237–246, 1999.
