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A Dose Escalation Study With Intensity Modulated Radiation Therapy (IMRT) in Moderately Advanced (T2N0, T2N1, T3N0) Squamous Cell Carcinomas (SCC) of the Oropharynx, Larynx and Hypopharynx Using a Simultaneous Integrated Boost (SIB) Approach.

Phase 2
18 Years
Open (Enrolling)
Carcinoma, Squamous Cell

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Trial Information

A Dose Escalation Study With Intensity Modulated Radiation Therapy (IMRT) in Moderately Advanced (T2N0, T2N1, T3N0) Squamous Cell Carcinomas (SCC) of the Oropharynx, Larynx and Hypopharynx Using a Simultaneous Integrated Boost (SIB) Approach.

Loco-regional failures remain a major concern following irradiation of locally advanced head
and neck cancers. This has led radiation oncologists to investigate novel approaches
offering better therapeutic indexes. Modification of dose fractionation schedules can
improve the therapeutic outcome by using accelerated or hyperfractionated regimes [Ang,
1990; Ang, 1998; Fu, 2000; Gwozdz, 1997]. Intensity Modulated Radiation Therapy (IMRT)
technique allows the planning and irradiation of different targets at different dose levels
in a single treatment session, instead of successive treatment plans. With conventional 2D
radiotherapy, both normal tissues and tumors are irradiated with a similar dose per fraction
of 1.8-2 Gy, whereas with IMRT dose gradients are introduced in such a manner that normal
tissues receive a much lower dose per fraction. Isoeffective relationships based on the
Linear-Quadratic (LQ) model have shown that for a similar total physical (nominal) dose,
lowering the dose per fraction to below 2 Gy will reduce the biological effect, while
increasing the dose per fraction to above 2 Gy will increase that effect [Withers, 1988]. As
the highly conformal dose distribution that is achievable with IMRT makes it possible to
envisage an increase in physical dose while still maintaining the dose to the OAR at a
reasonable level, several options could be considered to attain this objective. In
simultaneous accelerated radiation therapy (SMART) boost technique initially described by
Butler, large fractions of 2.4 Gy were delivered to the primary Planning Target Volume (PTV)
associated with the primary tumor GTV, while conventional fractions of 2 Gy were delivered
to the secondary PTV associated with the regions at risk for microscopic disease up to a
total dose of 60 Gy and 50 Gy, respectively [Butler, 1999]. The treatment was thus completed
in 5 weeks, which corresponded to a moderate shortening of treatment time. The term
"simultaneous integrated boost" (SIB) was introduced later to define such treatment,
delivering different doses per fraction in different target regions [Mohan, 2000]. The
authors proposed either the delivery of the conventional 2 Gy per fraction to the primary
PTV, allowing a significantly lower dose per fraction to the secondary PTV, or the delivery
of 2 Gy per fraction to the lower and intermediate dose volumes, thereby enabling a higher
dose per fraction to be delivered to the primary PTV, with as much as 2.4 Gy for gross
disease. The latter regimen has the advantage of shortening the treatment duration which,
further increases the biological dose. The SIB technique offers the biological advantage of
shortened treatment duration, i.e. 70 Gy over 6 weeks, which has been shown to significantly
increase the loco-regional control compared to the same dose delivered in 7 weeks [Fu,
2000]. With the prescription of a dose per fraction of 2.4 Gy to the primary PTV, the
physical dose is increased to 72 Gy, which corresponds to a biologically equivalent dose of
79.3 Gy (including correction for the overall treatment time [OTT]). Assuming a 37 value of
2, such an increase in the biological dose of 7.5% could be translated into an increase in
loco-regional control in the order of 15% [Bentzen, 2002]. The gain resulting from an
increase in the equivalent dose could be achieved without any further increase in late
normal tissue complications compared to standard treatment (70 Gy in 2 Gy per fraction).
Only the normal tissues embedded in the tumor volume and thus included in the PTV would be
irradiated with a dose per fraction similar to that for the tumor itself. Provided that the
dose per fraction to the OAR was limited to a maximum of 2 Gy per fraction, this increase in
dose intensity would be achievable without undue damage to normal tissue. However, the
concept of increased dose intensity with the SIB technique has to be validated in
well-designed phase I /II and thereafter phase III trials. In line with this, the Radiation
Therapy Oncology Group has initiated an IMRT phase I/II trial (RTOG H-0022) for
oropharyngeal carcinomas. In this protocol, a dose of 66 Gy is prescribed for the primary
tumor PTV and delivered in 30 fractions of 2.2 Gy over 6 weeks; simultaneously, a physical
dose of 54 Gy (30 fractions of 1.8 Gy) is prescribed for the PTV associated with subclinical
disease. The main objectives of this protocol are to assess the adequacy of target coverage
and salivary gland sparing, to determine the rate and pattern of loco-regional recurrence,
and to assess the nature and the prevalence of acute and late normal tissue toxicity and
their relationship to the dose distribution. This feasibility study will be carried out to
assess clinically the SIB approach in moderately advanced carcinomas.

Inclusion Criteria:

- Patients older than 18 years

- Patients with squamous cell carcinoma of the oropharynx, hypopharynx and larynx

- Stage T2-N0-M0, T2-N1-M0 or T3-N0-M0

- World Health Organization (WHO) Performance Status of 0 or 1 or Karnofsky performance
status ≥ 70.

- Provision of written informed consent

Exclusion Criteria:

- Second primary tumor at the time of diagnosis

- Previous history of malignant tumor in the last five years except basal cell
carcinoma and carcinoma in situ of the cervix

- Previous treatment with surgery, radiotherapy or chemotherapy for head and neck

- Any evidence of severe or uncontrolled systemic diseases (e.g., unstable or
uncompensated respiratory, cardiac, hepatic or renal disease), or psychological

- Pregnant or lactating women

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Principal Investigator

Vincent Gregoire, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Cliniques universitaires Saint Luc Brussels Belgium


Belgium: Institutional Review Board

Study ID:




Start Date:

September 2004

Completion Date:

Related Keywords:

  • Carcinoma, Squamous Cell
  • Carcinoma
  • Carcinoma, Squamous Cell