Dr. Rich and colleagues present a compelling argument
for the manipulation of temporal and spatial treatment parameters in
chemoradiation programs. In essence, the authors address the shielding of normal
tissues from the effects of cytotoxic agents. With respect to radiotherapy, this
can be achieved via physical shielding by computer-generated dose algorithms
using elaborate new planning technology (eg, intensity-modulated radiation
therapy [IMRT]), chemical shielding with radioprotectants (eg, amifostine [Ethyol]),
or temporal shielding by altered-fractionation schemes that exploit the
differential alpha/beta ratios between tumor and normal tissue (eg,
With regard to chemotherapy, the authors explore the concept of temporally
shielding normal tissue by chronomodulation of administration schedules based on
circadian cell-cycle rhythms. Potential benefits include dose escalation and a
corresponding reduction in acute and late side effects by maximizing the
tolerance of normal tissues to antineoplastic agents. As the authors point out,
chronomodulated intravenous infusion of fluorouracil (5-FU) has been used in the
treatment of various gastrointestinal malignancies for some time.
Further exploitation of this principle to incorporate other cytotoxic agents
and tumor sites carries the potential for significant gain, and continued
investigation is certainly warranted. As Rich et al have noted, the prospect
becomes even more attractive when cost is considered, especially compared with
the exorbitant price tags associated with cutting-edge refinements in diagnostic
and therapeutic radiology.
Hyperfractionated Radiation Schedules
Alterations in temporal dose sequencing have been explored in detail for
radiation therapy fractionation schemes.[1-9] At the University of Florida,
hyperfractionated radiation schedules have been used since 1978 to treat
malignancies of the head and neck and other sites.[10-14] Advances in physical
shielding have moved away from traditional parallel-opposed blocked fields to
noncoplanar stereotactic setups using sophisticated planning software. We have
also gradually shifted to ipsilateral wedge-pair setups for certain lateralized
head and neck malignancies, with a resultant sparing of contralateral salivary
Patient selection for this method continues to evolve, the critical concept
being that normal tissue excluded from the treatment volume is at low risk of
harboring subclinical disease. More recently, IMRT has been used for
selected lesions. Tumor volumes are carefully outlined using three-dimensional
(3D) computed tomography (CT) planning with intravenous contrast. Typically, the
clinical tumor volumes for 50 Gy and 70 Gy are defined with selective sparing of
the spinal cord, salivary glands, and any other critical structures in which a
high radiation dose is undesirable.
1. Horiot JC, Bontemps P, van den Bogaert W, et al: Accelerated fractionation
(AF) compared to conventional fractionation (CF) improves locoregional control
in the radiotherapy of advanced head and neck cancers: Results of the EORTC
22851 randomized trial. Radiother Oncol 44:111-121, 1997.
2. Mehta MP, Tannehill SP, Janjan NA, et al: Phase II trial of
hyperfractionated accelerated radiation therapy for nonresectable non-small-cell
lung cancer: Results of Eastern Cooperative Oncology Group 4593. J Clin Oncol
3. Pisters PW, Abbruzzese JL, Janjan NA, et al: Rapid-fractionation
preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative
radiation therapy for resectable pancreatic adenocarcinoma. J Clin Oncol
4. Butler EB, Teh BS, Grant WH 3rd, et al: SMART (simultaneous modulated
accelerated radiation therapy) boost: A new accelerated fractionation schedule
for the treatment of head and neck cancer with intensity modulated radiotherapy.
Int J Radiat Oncol Biol Phys 45:21-32, 1999.
5. Mendenhall WM, Stringer SP, Amdur RJ, et al: Is radiation therapy a
preferred alternative to surgery for squamous cell carcinoma of the base of
tongue? J Clin Oncol 18:35-42, 2000.
6. Bernier J, Denekamp J, Rojas A, et al: ARCON: Accelerated radiotherapy
with carbogen and nicotinamide in head and neck squamous cell carcinomas. The
experience of the Cooperative Group of Radiotherapy of the European Organization
for Research and Treatment of Cancer (EORTC). Radiother Oncol 55:111-119, 2000.
7. Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG)
phase III randomized study to compare hyperfractionation 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.
8. Herskovic A, Fisher J, Orton B, et al: Accelerated hyperfractionation in
patients with non-small-cell bronchogenic cancers as a cost-effective and
user- and patient-friendly schedule. Cancer Invest 18:537-543, 2000.
9. Herskovic A, Scott C, Demas W, et al: Accelerated hyperfractionation for
bronchogenic cancer: Radiation Therapy Oncology Group 9205. Am J Clin Oncol
10. Mendenhall WM, Amdur RJ, Siemann DW, et al: Altered fractionation in
definitive irradiation of squamous cell carcinoma of the head and neck. Curr
Opin Oncol 12:207-214, 2000.
11. Mendenhall WM, Parsons JT: Altered fractionation in radiation therapy for
squamous-cell carcinoma of the head and neck. Cancer Invest 16:594-603, 1998.
12. Morgan L, Chafe W, Mendenhall W, et al: Hyperfractionation of
whole-abdomen radiation therapy: Salvage treatment of persistent ovarian
carcinoma following chemotherapy. Gynecol Oncol 31:122-136, 1988.
13. Parsons JT, Mendenhall WM, Cassisi NJ, et al: Hyperfractionation for head
and neck cancer. Int J Radiat Oncol Biol Phys 14:649-658, 1988.
14. Parsons JT, Mendenhall WM, Stringer SP, et al: Twice-a-day radiotherapy
for squamous cell carcinoma of the head and neck: The University of Florida
experience. Head Neck 15:87-96, 1993.
15. O’Sullivan B, Warde P, Grice B, et al: The benefits and pitfalls of
ipsilateral radiotherapy in carcinoma of the tonsillar region. Int J Radiat
Oncol Biol Phys 51:332-343, 2001.
16. Eisbruch A, Kim HM, Terrell JE, et al: Xerostomia and its predictors
following parotid-sparing irradiation of head-and-neck cancer. Int J Radiat
Oncol Biol Phys 50:695-704, 2001.
17. Chao KS, Deasy JO, Markman J, et al: A prospective study of salivary
function sparing in patients with head-and-neck cancers receiving
intensity-modulated or three-dimensional radiation therapy: Initial results. Int
J Radiat Oncol Biol Phys 49:907-916, 2001.
18. Gregoire V, Coche E, Cosnard G, et al: Selection and delineation of lymph
node target volumes in head and neck conformal radiotherapy. Proposal for
standardizing terminology and procedure based on the surgical experience.
Radiother Oncol 56:135-150, 2000.
19. Dawson LA, Anzai Y, Marsh L, et al: Patterns of local-regional recurrence
following parotid-sparing conformal and segmental intensity-modulated
radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys
20. Eisbruch A, Marsh LH, Martel MK, et al: Comprehensive irradiation of head
and neck cancer using conformal multisegmental fields: Assessment of target
coverage and noninvolved tissue sparing. Int J Radiat Oncol Biol Phys
21. Nowak PJ, Wijers OB, Lagerwaard FJ, et al: A three-dimensional CT-based
target definition for elective irradiation of the neck. Int J Radiat Oncol Biol
Phys 45:33-39, 1999.
22. van Dieren EB, Nowak PJ, Wijers OB, et al: Beam intensity modulation
using tissue compensators or dynamic multileaf collimation in three-dimensional
conformal radiotherapy of primary cancers of the oropharynx and larynx,
including the elective neck. Int J Radiat Oncol Biol Phys 47:1299-1309, 2000.