COPENHAGEN, DenmarkRadiation in 6 fractions per
week is significantly better than the same dose given on a more leisurely
5-fractions-per-week schedule for treating squamous-cell head and neck cancer,
according to investigators from the Danish Head and Neck Cancer Study Group (DAHANCA).
Jens Overgaard, MD, of Aarhus University Hospital, Aarhus,
Denmark, Hanne Sand Hansen, MD, of Rigshospitalet, Finsen Centre, Copenhagen,
and their colleagues reported data from a large randomized controlled trial
comparing the two schedules in the September 20 issue of The Lancet
(362:933-940, 2003). They also reported the results at the ECCO 12 meeting in
"Six fractions per week is significantly more effective
than 5 fractions per week with regard to 5-year locoregional control, primary
tumor control, voice preservation in laryngeal cancer, and disease-specific
survival," Dr. Hansen told ONI. The 6-fractions-per-week schedule
is now standard treatment for head and neck cancer in Denmark.
The 6/wk schedule did not improve outcomes for patients with
N2 or N3 tumors, and Dr. Hansen said that the research group is now planning a
combined approach with radiation and surgery for such patients.
The trial randomized 1,476 patients with invasive squamous-cell
carcinomas of the head and neck to 5 (n = 726) or 6 (n = 750) fractions per
week of radiotherapy. Radiotherapy was given with 4 to 6 MV photons to standard
fields including the primary tumor and involved lymph nodes. The minimum tumor
dose was 62 to 68 Gy, with larger tumors receiving larger doses.
The idea behind the accelerated 6-fractions-per-week
schedule is that it might improve tumor control by reducing the development of
resistant clones, which are thought to arise through radiation-induced
accelerated proliferation of clonogenic tumor cells.
The trial included two subprotocols: DAHANCA 6, including
all glottic carcinomas, and DAHANCA 7, including tumors of the supraglottic
larynx, pharynx, and oral cavity. Patients with distant metastases were
All patients except those with glottic cancer also received
nimorazole as a radiosensitizer given at 1,200 mg/m2 orally with the first 30
radiation treatments, to a total dose of about 36 g/m2. Nimorazole was given 90
minutes before radiation.
The investigators noted that in other countries many of
these patients might be treated initially by surgery, but the Danish standard
is primary radiotherapy because it is more organ conserving and leaves more
patients with voice intact.
The primary study endpoint was locoregional control, defined
as "complete and persistent disappearance of disease in the primary tumor
and regional lymph nodes after radiotherapy." The study was powered to
detect an improvement in locoregional control from 55% to 65%.
The accelerated schedule produced better locoregional
control than a conventional schedule with identical dose and fractionation
(odds ratio 0.66) (see Table). The accelerated schedule also significantly
improved disease-specific survival (odds radio 0.71) but did not improve
Analysis of tumor-site (T site) and nodal-site (N site)
failures showed that the entire benefit was due to improved disease control at
the primary tumor site. This was also demonstrated by significantly higher
preservation of the larynx and voice in patients with laryngeal cancer (80% vs
68%, P = .007).
There was a significant increase in acute confluent
mucositis with the 6- vs 5-fractions-per-week schedule (53% vs 33%, P
< .0001), and the mucositis persisted longer in the 6/wk patients. "The
mucositis subsides spontaneously. We treat it with local analgesics and with
antibiotics and antiviral medication if necessary," Dr. Hansen said. All
mucositis resolved within 3 months of the start of treatment.
"The window of opportunity for the benefit of
acceleration is narrow, and with the applied radiation technique, a 1-week
reduction seems to be the optimum balance between improved tumor control and
avoidance of excess late morbidity," the investigators said in The
Patients with large nodal burden (N2-N3) did not benefit
from the accelerated schedule, regardless of the tumor site. Those with no or
small nodal involvement had substantially better locoregional control with the
6/wk schedule. The reduction in treatment time was also more beneficial to
patients with moderately to well-differentiated tumors than to those with
poorly differentiated tumors.
The researchers suggest that the mechanism of repopulation in squamous-cell
head and neck carcinomas might resemble the repair mechanisms of normal mucosa:
The primary tumor might respond to the trauma of irradiation with a typical
epithelial attempt at quick recovery. "Furthermore, the reaction might be
controlled by signaling from the surrounding normal mucosa, and the response
is, therefore, seen only in the T site and not in the nodal metastases,"