Choy et al, reported a 46% incidence of
acute Grade 3-4 esophagitis during treatment with 66 Gy of RT (2-Gy daily
fractions) and concurrent weekly paclitaxel and carboplatin
(Choy et al, 1998).
In 1998 Byhardt et al. analyzed the
results of five radiation therapy oncology group (RTOG) trials of sequential
and/or concurrent chemotherapy and radiotherapy for locally advanced
non–small-cell carcinoma of the lung according to response, toxicity, failure
patterns and survival. Totally 461 patients were divided into three groups. In
group I patients were treated with sequential chemotherapy followed by standard
RT (60 Gy in 6 weeks). Group II consisted of patients who received combined
sequential and concurrent chemotherapy and standard RT (60 Gy in 6 weeks). In
group III patients received concurrent chemotherapy and hyperfractionated RT
(69.6 Gy in 6 weeks). Acute toxicity was defined as that occurring within 90
days from the start of RT and late toxicity was defined as that occurring after
90 days from the start of RT. Acute or late toxicity ≥ grade 3 was
defined as severe. Group 3 (concurrent chemotherapy and hyperfractionated RT
arm) had a significantly more severe acute esophagitis rate of 34% compared
with Group 1 (1.3%) and Group 2 (6%) (p< 0.0001). Late esophagitis rate was
also significantly greater in group 3 (8% vs. 2% and 4%; p=0.077). The authors
concluded that concurrent chemotherapy and hyperfractionated RT had a
significantly higher incidence of severe acute esophageal toxicity (Byhardt et
al, 1998).
Singh et al, (2003) evaluated 207
patients with NSCLC who were treated with high-dose, definitive 3D-conformal
radiotherapy and/or sequential or concurrent chemotherapy for investigating the
predictors of radiation esophagitis. The mean dose to the entire esophagus,
maximal point dose to the esophagus, and percentage of volume of esophagus
receiving >55 Gy were analyzed. The median dose was 70 Gy (range 60–74)
delivered in 2-Gy daily fractions/once daily. Of 207 patients, 16 patients (8%)
developed acute Grade 3–5 esophageal toxicity. Late Grade 3–5 esophageal
toxicity was present in 7 patients (3%) and 1 patient died (Grade 5 esophageal
toxicity) of late esophageal perforation. In univariate analysis concurrent
chemotherapy, maximal point dose to the esophagus >58 Gy, and a mean dose to
the entire esophagus >34 Gy were significantly associated with a risk of
Grade 3–5 esophageal toxicity. In multivariate analysis concurrent chemotherapy
and maximal point dose to the esophagus >58 Gy was significant. An important
point was that 14 (88%) of the 16 patients who developed Grade 3–5 esophageal
toxicity had received concurrent chemotherapy (p= 0.0001). Only 2 patients
developed Grade 3–5 esophageal toxicity in the absence of concurrent
chemotherapy that was explained by both’s receiving a maximal esophageal point
dose >69 Gy. In conclusion concurrent chemotherapy and the maximal
esophageal point dose were found as significantly adverse risk factors for
Grade 3–5 esophageal toxicity in patients with NSCLC treated with high-dose
3D-CRT (Singh et al, 2003).
Hirota et al. endoscopically investigated the patients
who received chemoradiotherapy or thoracic radiotherapy alone for esophagitis
and found out that endoscopic grade 3 esophagitis did not occur in any of the
patients who received radiotherapy alone while 27% of patients receiving
chemoradiotherapy had grade 3 esophagitis (Hirota et
al, 2001).
The
results of these trials confirm that concomitant chemoradiotherapy is
associated with the elevated risk of radiation esophagitis and preventive strategies
are necessary to minimize the toxicity.
III. Prevention of radiation esophagitis
In order to reduce the amount of esophagitis several
strategies including the use of 3-D conformal radiotherapy, medical management
and radioprotectors are developed.
The use of conformal radiotherapy is effective in
minimizing the irradiated volume of normal tissues as well as esophagus.
Medical management includes analgesics and nutritional
supplements but most of the patients require further therapies since late reactions
may be severe although they are rare.
In such cases the use of sucralfate may prevent radiation-induced esophagitis as shown in some
trials. Sur et al. analyzed 80 patients with esophageal carcinoma who had acute
radiation esophagitis following external beam and intracavitary radiotherapy.
The patients were divided into two different treatment arms. Group 1 (n = 40)
received an antacid containing sodium alginate and Group 2 (n = 40) received a
10% sucralfate suspension during 4 weeks. In sucralfate group, 32 of 40
patients (80%) had a significant relief of symptoms within 7 days of treatment
and it was detected endoscopically that most ulcers had healed by 12 days of
treatment. Patients receiving sodium alginate showed little improvement of
symptoms and had persistent ulcers even after 4 weeks of therapy. The authors
concluded that the use of oral sucralfate was useful in the management of acute
radiation esophagitis (Sur et al, 1994).
There are also trials showing that sucralfate has a
limited effect in the treatment of radiation esophagitis radiation induced
odynophagia. In one of these trials, Taal et al, (1995) administered sucralfate labeled with TC99m to 26 patients
with esophageal carcinoma and endoscopically proven radiation esophagitis. The
degree of coating was evaluated according to persistence of the radionuclide in
the affected esophageal segment. Although scans were positive for radioactivity
in 24 of 26 (92%) patients, only 8 (31%) of these represented selective binding
of sucralfate to tissue. In the other 16 cases, scans were positive for
sucralfate and albumin, indicating nonspecific retention most likely caused by
concomitant esophageal stenosis. Residual radioactivity was observed for 30
minutes or more in 11 (42%) patients, but scans were positive for radioactivity
after 1 to 2 hours in only 4 (15%). These findings suggested that the inability
of sucralfate in alleviating radiation-related odynophagia might be related to
insufficient duration of adherence of sucralfate to the damaged esophageal
mucosa (Taal et al, 1995).
In a different randomized study by McGinnis et al,
(1997) that included 97 patients the preventive effect of sucralfate was
evaluated among patients who received thoracic radiotherapy. The patients
received sucralfate or placebo during radiotherapy. Surprisingly although only 2 placebo patients (4%) stopped their study medication
during the first 2 weeks, in sucralfate group this number reached up to 20
patients (40%) that was thought to be related with the increased incidence of
gastrointestinal toxicity (58% of sucralfate patients vs. 14% of placebo
patients; p < 0.0001). The authors also reported that there was no
substantial benefit of sucralfate in
esophagitis scores and concluded that oral sucralfate solution did not appear
to inhibit radiation-induced esophagitis and was associated with disagreeable
gastrointestinal side effects in this patient population (McGinnis et al,
1997).
As seen, sucralfate at least has a limited
effect on the prevention of radiation esophagitis and the most important point is the continuation
of nutrition by endoscopic dilatation, stent-implantation or endoscopic
percutaneous gastrostomy. There is still no effective prophylactic measure and
local injection of steroids may be used to avoid an early restenosis. Topical
or systemic analgesics can also be useful and calcium antagonists may be used
in cases with esophageal spasm. If the symptoms are complicated with the
presence of gastro-esophageal reflux, proton pump inhibitors shall also be used
(Zimmermann et al, 1998).
IV. The role of amifostine in radiation esophagitis
After the demonstration of the efficacy of
amifostine (WR-2721) as a radioprotector in reducing the severity of acute and
late xerostomia without compromising the efficacy of radiotherapy in patients
with head and neck cancer (Sauer et al, 1999) several randomized trials tested
the role of amifostine in reducing radiation esophagitis and radiation-related
pneumonitis.
Antonadou et al. reported the results of a
phase III randomized trial that tested intravenous amifostine and thoracic
radiotherapy in 146 patients with lung cancer and showed that amifostine
significantly reduced the incidence of esophagitis and pneumonitis (p<
0.001) (Antonadou et al, 2001).
Koukourakis et al. investigated the
efficacy of subcutaneous administration of amifostine in 60 patients with
thoracic malignancies and the results showed that subcutaneous administration
was well tolerated end effectively reduced radiation esophagitis (p<0.04)
(Koukourakis et al, 2000).
In 2003 Antonadou et al. reported the
results of a different randomized trial that included 73 patients with
previously untreated Stage IIIA and IIIB NSCLC. Group I received radiotherapy
alone while the patients in group II received radiotherapy and 300 mg/m2
intravenous amifostine. The incidence of Grade >= 3 esophagitis was
significantly lower in patients that received amifostine (38.9% vs. 84.4%;
p<0.0001) (Antonadou et al, 2003).
Cisplatin-based chemotherapy regimens are
associated with a lower incidence of esophagitis given concurrently with
radiotherapy, with significant esophagitis occurring in 14-25% of patients (Albain et al, 1995;
Ardizzoni et al, 1999; Lopez-Picazo et al, 1999; Tan et al, 1999;
Uittterhoeve et al, 2000). For chemoradiotherapy
regimens that use paclitaxel, esophagitis rates are higher (37-70%) (Senzer,
2002), (Leong et al, 2003).
Leong et al. tested concurrent weekly
paclitaxel (60 mg/m2) and 64 Gy radiotherapy with or without
amifostine in patients with stage III lung cancer. The incidence of grade 2-3
esophagitis was %43 in patients who received amifostine while patients who did
not receive amifostine had an esophagitis rate of 70% but the difference did
not reach a significance (Leong et al, 2003).
In a different phase III study Senzer et
al. tested the radioprotective efficacy of amifostine among 100 patients with
NSCLC who received concurrent hyperfractionated radiotherapy (64.8 Gy) with
weekly paclitaxel and carboplatin followed by gemcitabine and carboplatin. The
preliminary results demonstrated no cytoprotective benefit of amifostine
(Senzer, 2002).
Following these studies RTOG conducted a
large trial to test the role of amifostine, RTOG 9801 that included 243
patients with stage II or III NSCLC. The importance of this trial was that it
was the only trial that prospectively analyzed quality of life. The patients
received induction chemotherapy consisting of paclitaxel and carboplatin
followed by concurrent weekly paclitaxel and carboplatin and hyperfractionated
RT (69.6 Gy-1.2 Gy/fraction/twice a day).
They were randomized to with or without intravenous 500 mg amifostine
arms at the beginning of the radiotherapy and esophageal toxicities were
analyzed with NCI Common Toxicity Criteria (NCI-CTC) and RTOG/EORTC Late
Esophagitis Morbidity Grading Criteria. Totally 122 of 245 patients (49%)
received amifostine. Grade 3 or greater esophagitis rates were 30% and 34%
respectively showing no significant difference between two arms (p=0.9).
Although overall quality of life was not significantly different between two
arms the only advantage of amifostine was the significant improvement in pain
and less deterioration at 6 weeks of follow-up on the amifostine arm (p=
0.003). Another finding of this trial was that there was a significant increase
in nausea and vomiting, cardiovascular toxicity (transient hypotension in most
of the patients) and febrile neutropenia in amifostine arm. Amifostine also had
no benefit on survival and the median survivals were similar in both groups (15.5
months in amifostine arm and 15.6 months in no amifostine arm) (Movsas et al,
2003).
Although the results of RTOG trial did not
support that amifostine has an effect on reducing esophagitis in patients who
receive concurrent chemoradiotherapy recent trials investigated its possible
advantages with alternative radiation and chemotherapy schedules.
Recently Werner-Wasik et al. conducted a randomized phase II study of amifostine for patients
with inoperable stage II-IIIA/B or stage IV non-small cell lung cancer with
oligometastases receiving concurrent radiochemotherapy with carboplatin and
paclitaxel followed by optional consolidative chemotherapy as a follow-up study
after RTOG 98-01 and the results are awaited (Werner-Wasik et al, 2004).
In a recent review by Gopal, it was reported that
evidences in the literature suggested that the protective effect of amifostine
appeared to be the result of a reduction in the accumulation of macrophages and
a decrease in plasma and tissue transforming growth factor-beta levels in
radiation-related pneumonitis (Gopal, 2004).
V. Conclusion
As seen above a standard treatment in order to reduce
esophageal toxicity during chemoradiotherapy is yet to be identified and much
additional work investigating new biological modifiers as radioprotectors shall
be performed. Although the effect of amifostine in reducing radiation
esophagitis is not clear, with some encouraging results it shall be tested in
new trials combined with intensity modulated radiotherapy (IMRT) and new biologic
modifiers.
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Gorkem Aksu