8.4 Radiation Therapy-Related Toxicity: Esophagus
Maria Werner-Wasik
M. Werner-Wasik, MD
Associate Professor, Department of Radiation Oncology, Kimmel Cancer Center of Jefferson Medical College; Thomas Jefferson University Hospital; Department of Radiation Oncology; 111 South 11th Street; Philadelphia, PA 19107, USA
Acknowledgement: Part of this work will be pub- lished in the Hematology and Oncology Clinics of North America, 2004.
8.4.1
Pathophysiology and Clinical Picture of Esophagitis
The esophagus is lined with a convoluted squamous epithelium, a basal cell layer, submucosa and a layer of striated muscle fi bers underneath, without sur- rounding serosa. In mice irradiated with a single ra- diation therapy (RT) fraction to the thorax (Phillips and Ross 1974), evidence of damage to the esophagus was observed at 20.0 Gy, three days after RT. This in- cluded vacuolization of the basal cell layer, absence of mitosis and submucosal edema. Some regeneration was evident by 1–2 weeks after RT, including prolif- erating basal cells, regenerating epithelium and scat- tered areas of complete esophageal denudation. At three weeks, the regeneration of the esophageal lining was complete, and after 4 weeks the appearance of the
irradiated esophagus was normal. For fractionated RT doses, the LD
50/28(or RT dose causing death in 50% of the animals over 28 days) was estimated as 57.45 Gy (in 10 fractions).
Radiologic fi ndings of esophageal injury were described in 30 symptomatic patients who received thoracic RT to 45–60 Gy (Goldstein et al. 1975).
The most common fi ndings consisted of esophageal dysmotility, such as failure to complete primary peri- staltic waves, nonperistaltic or tertiary contractions and failure of distal esophageal sphincter relaxation.
Smooth esophageal strictures were demonstrated in some patients, and one frank ulceration of the irradi- ated site was observed.
Abnormal esophageal motility was noted to occur within 4–12 weeks from RT alone and as early as one week from concurrent chemotherapy and RT (Lepke and Libshitz 1983). Strictures generally developed at 6–8 months but were seen as early as 4 months.
The fi rst symptoms of acute esophagitis start usu- ally in the second or third week of thoracic radiation therapy, commonly at the dose of 18.0–21.0 Gy of standard fractionated RT, and include a sensation of diffi cult swallowing (dysphagia). This may progress to painful swallowing of food and saliva (odynopha- gia) and later to constant pain not necessarily related to swallowing. In severe cases, patients may not be able to swallow at all and may require intravenous hydration, feeding through the gastric tube and, in extremely rare cases, parenteral nutrition. In patients receiving concurrent chemotherapy and thoracic RT, acute esophagitis symptoms peak within 30 days from start of RT in 23% of patients and within 60 days in 36% (Werner-Wasik et al. 2002). Symptoms of acute esophagitis commonly persist for 1–3 weeks after completion of RT. Esophageal damage may develop at 3–8 months from completion of RT and manifests most often as dysphagia to solids, caused by a per- manent narrowing of the esophagus (stricture). The presence of stricture requires periodic surgical dila- tion of the esophagus, usually with excellent results.
Acute esophagitis may be very severe and disabling, resulting in hospitalization, placement of a feeding
CONTENTS
8.4.1 Pathophysiology and Clinical Picture of Esophagitis 373
8.4.2 Evaluation of Esophagitis 374 8.4.3 Incidence of Esophagitis and Predisposing Factors 376 8.4.4 Dosimetric Factors Associated with Esophagitis 377
8.4.5 Intensity-Modulated Radiation Therapy as a Tool of Lowering RT Dose to Esophagus 378 8.4.6 Strategies Used to Prevent or Treat Esophagitis 379 References 380
tube in the stomach or intravenous feedings for a pe- riod of time. Additionally, the course of RT may need to be halted temporarily in order to allow for healing of the esophageal lining. Treatment breaks in turn have been unequivocally demonstrated to decrease survival of patients with unresectable lung cancer (Cox et al. 1993). Therefore, a proper diagnosis, treat- ment and prevention of esophagitis as a dose-limit- ing toxicity of chemoradiotherapy may have a direct impact on tumor control and the patient’s chance of survival.
Patients with esophagitis symptoms require steady supportive care, starting with a low-acid and bland diet when the fi rst sensation of a diffi culty in swallowing is reported (grade 1). Patients should be instructed to avoid coffee, hot beverages, spicy foods, citrus fruit and juices, tomato products, alcohol and tobacco. In addition, a mixture of a local anesthetic (2% viscous lidocaine), coating substance (Benadryl elixir) and saline/baking soda (“Magic Mouthwash”) is frequently prescribed and should be taken liberally before meals to facilitate swallowing. Once symptoms progress with more severe pain and only a soft diet is feasible (grade 2), stronger oral analgesic agents should be prescribed (hydrocodone with acetamin- ophen; liquid morphine; prolonged action opiate preparations etc.) to control pain and allow good nu- trition. High-calorie liquid oral nutritional supple- ments are very helpful in maintaining a satisfactory caloric intake and minimizing weight loss and ane- mia. If an adequate oral intake of fl uids is impaired (as determined by the dietary interview, positional changes in blood pressure and low urinary output), intravenous fl uids should be promptly initiated in order to break the vicious cycle of dehydration–poor oral intake–further dehydration. A simple initial step is to give fl uids intravenously on an outpatient basis for a day or two, while continuing thoracic RT (grade 2 in the new version 3 CTC scale; grade 3 in the older scales). When the patient is unable to swallow despite optimal oral analgesics, hospitalization is indicated for intravenous hydration and intravenous pain con- trol (grade 3). In extreme cases, placement of a gas- tric tube or parenteral nutrition may be necessary (grade 4).
The speed of recovery from acute esophagitis seems related to the recovery from neutropenia in- duced by concurrent delivery of chemotherapy.
Prolonged neutropenia does not allow suffi cient healing of the esophageal mucosa. This situation is a classic indication for a temporary suspension of RT, which allows the administration of granulocyte-stim- ulating factor preparation to shorten the neutropenic
period. Otherwise, thoracic RT should be continued as dictated by clinical judgment, since RT breaks are strongly associated with decreased chances of tumor control.
8.4.2
Evaluation of Esophagitis
Historically, various criteria have been used to grade acute esophagitis (Tables 8.4.1, 8.4.2). Radiation Therapy Oncology Group (RTOG) criteria and ver- sion 2.0 of National Cancer Institute’s (NCI) Common Toxicity Criteria (CTC) were based on the clinical as- sessment of patient symptoms, need to change diet, analgesic requirements, weight loss and need for in- tervention (such as intravenous fl uids and/or feeding tube or parenteral nutrition). However, in order to diagnose grade 4 esophagitis, endoscopic or radio- graphic tests may be necessary (see Table 8.4.1a).
The next version of CTC – on the NCI’s Common Terminology Criteria for Adverse Events, v3.0, CTCAE scale, introduced in October 2003 (http://ctep.info.
nih.gov/reporting/ctc.html) – removed the need for analgesics and weight loss as evaluation criteria, for both “Dysphagia” and “Esophagitis,” and is based nearly entirely on symptoms, altered diet and the need for intervention. An exception exists in the case of the asymptomatic patient who is found to have en- doscopic or radiographic fi ndings and, consequently, assigned a grade 1 esophagitis (Table 8.4.1b).
Hirota et al. (Hirota et al. 2001) were successful in their attempt to correlate acute esophagitis, assessed with endoscopy, with the RTOG grade in patients treated with RT +/– chemotherapy. With a Spearman coeffi cient 0.428 (p<0.0001), the result of their work gives validity to the currently used clinical grading of esophagitis.
The grade of esophagitis describes toxicity at one point in time, but it does not provide information about the length of time during which the patient ex- periences the symptoms of esophagitis
The Esophagitis Index (Fig. 8.4.1) (Werner-Wasik
et al. 2001, 2002) is a novel measure of toxicity and
may be applied to any irradiated organ. The Index is
obtained by plotting the esophagitis grade over time
measured in weeks, and it is presented as a single nu-
merical value, based on calculation of the area under
the curve (AUC) (Rowland and Tozer 1995). It may
be a more comprehensive measure of normal tissue
toxicity than maximum grade alone. Its calculation
requires the accumulation of prospective data points
Table 8.4.1b. NCI CTCAE v3.0 Scale: Acute esophagitis (dysphagia-esophageal, related to radiation) Grade
1 2 3 4 5
Dysphagia Symptomatic, able to eat regular diet
Symptomatic and altered eating/swallowing (e.g.altered dietary habits, oral supplements);
iv fl uids, indicated <24 hrs
Symptomatic and severely altered eating/swallowing (e.g. inadequate oral caloric or fl uid intake);
iv fl uids, tube feedings .or TPN indicated >24 hrs
Life-threatening consequences (e.g. obstruction, perforation)
Death
Remark: Dysphagia requiring dilation is graded as stricture/stenosis Esophagitis Asymptomatic
Pathologic, radiographic or endoscopic Findings only
symptomatic; altered eating/swallowing (e.g. altered dietary habits, oral supplements);
iv fl uids indicated <24 hrs
Same as above Same as above Death
Table 8.4.1a. NCI CTC v2.0 Scale
0 1 2 3 4
None Mild dysphagia, but caneat regular diet
Dysphagia,
requiring predominantly pureed,
soft or liquid diet
Dysphagia,
requiring feeding tube, IV hydration or hyperalimentation
Complete obstruction (cannot swallow saliva);
ulceration with bleeding, not induced by minor trauma
Table 8.4.2. RTOG/EORTC Late Esophagitis Criteria
Grade
0 1 2 3 4
ESOPHAGUS No symptoms Mild fi brosis;
slight diffi culty in swallowing solids;
no pain on swallowing
Unable to take solid food normally;
swallowing semi- solid food;
dilatation may be indicated
Severe fi brosis;
able to swallow only liquids;
may have pain on swallowing;
dilatation required
Necrosis/Perforation Fistula
Fig. 8.4.1. Calculation of Esophagitis Index.
e m i T . s V e d a r G s i t i g a h p o s E e t u c A f o t o l P a f o e l p m a x E n A
x e d n I s i t i g a h p o s E f o n o i t a l u c l a C g n i w o l l A
c i c a r o h t f o d n E
* y p a r e h t o i d a r
2 2 2 2
2 3+0 x4=14.5
3 + + + 2 2 + + 1 4 1 x + + 1 1 +
= 0 ) I E ( x e d n I s i t i g a h p o s E
0 1 2 3 4
7 1 6 1 5 1 4 1 3 1 2 1 1 1 0 1 9 8
* 7 6 5 4 3 2 1
s k e e W
AcuteEEsophagitisGrade (RTOG) *End of thoracic
radiotherapy
Acute Esophagitis Grade (RTOG)
1 2 3 4 5 6 7* 8 9 10 11 12 13 14 15 16 17 4
3 2 1 0
Esophagitis Index (EI) = 0+12 1+1
2
1+2 2
2+3 2
3+0
+ × 4+ + + 2 × 4 = 14.5
An Example of a Plot of Acute Esophagitis Grade Vs.
Time Allowing Calculation of Esophagitis Index
Weeks
of toxicity over time and, therefore, its applicability may be limited to investigational pursuits. However, a broader application of the Esophagitis Index may allow a more precise defi nition of normal tissue tox- icity, facilitate toxicity comparisons between various treatment regimens and be a useful tool in investiga- tions of the quality of life.
In a recently completed study performed by the Radiation Therapy Oncology Group (RTOG) 98–01 (Movsas et al. 2003), other measures of esophagitis were implemented, based on physician assessment (weekly Physician Dysphagia Log), as well as on daily patient assessments of diffi culty swallowing (Patient Swallowing Diary). These measures allowed a direct comparison of healthcare worker-based vs. patient- based esophagitis endpoints.
8.4.3
Incidence of Esophagitis and Predisposing Factors
The evolution of therapeutic approaches for lung cancer illustrates the trend for treatment intensifi - cation, with hopes that dose-intense chemotherapy regimens and/or higher RT doses, or novel fraction- ation schemes, will result in the prolongation of sur- vival. To date, the best cooperative group results of intense chemoradiotherapy for LA–NSCLC report median survival times (MST) as high as 26.0 months (Gandara et al. 2003).
In the RTOG trial (94–10)(Curran et al. 2000), 610 patients were randomized to receive induction chemotherapy (vinblastine and cisplatin), followed in sequence by standard thoracic radiotherapy, or the same chemotherapy delivered concurrently with standard RT or the same chemotherapy given con- currently with hyperfractionated RT. The results sup- port the superiority of the concurrent approach over the sequential approach, with best median survival time of 17.1 months (standard RT) and 15.6 months (hyperfractionated RT) observed in both concur- rent arms of the trial, vs. 14.6 months in the sequen- tial arm (p=0.038). Based on these data and another phase III randomized trial from Japan (Furuse et al.
1999), the paradigm for the nonoperative treatment of lung cancer is clearly no longer the previously-ac- cepted standard of sequential treatment but, instead, the use of concurrent regimens.
The incidence of severe, acute esophagitis (grade 3 or higher) in patients treated for lung cancer with standard (once daily) radiation therapy alone is 1.3%.
Induction chemotherapy increases the risk of severe acute esophagitis slightly, compared with standard radiotherapy alone (Werner-Wasik et al. 2000;
Byhardt et al. 1998). In contrast, the strong radio- sensitizing effect of chemotherapy given concur- rently with standard thoracic RT is evident from the incidence of severe esophagitis of 6–14% (Byhardt et al. 1998), as well as from values on the Esophagitis Index that are more than twice as high for the con- current chemotherapy/standard RT group as for the RT-alone group (Werner-Wasik et al. 1999, 2000). It had been reported in the literature that agents such as Adriamycin (Boal et al. 1979; Umsawasdi et al. 1985) cause severe primary or recall esophagitis at RT doses as low as 20.0 Gy. Vokes et al. (Vokes et al. 2002) de- scribed an incidence of 49% of acute grade 3 or higher esophagitis with concurrent gemcitabine and thoracic RT. Whether the degree of esophagitis is related to the type or scheduling of chemotherapy used (daily vs.
weekly, or every three weeks) is uncertain.
Aggressive types of RT fractionation have also been reported to be associated with a worsening of the esophagitis grade and the duration of the condition. This is evident in the report of 100 pa- tients treated in Australia (Ball et al. 1995) in a four-arm, randomized study, as well as in our analy- sis (Werner-Wassik et al. 2000). The duration of symptomatic esophagitis was 1.4 months (mo) in the conventional RT arm, 1.6 mo in the conventional RT arm with concurrent carboplatin, 3.2 mo in the accelerated arm and 2.4 mo in the accelerated RT plus carboplatin arm (Ball et al. 1995). In fact, in the Ball et al. multivariate analysis (Ball et al. 1995), accelerated radiotherapy (defi ned as fractions of 2.0 Gy delivered twice daily) was the only signifi - cant factor infl uencing the duration of esophagitis.
In our study (Werner-Wasik et al. 2002), a simi- lar pattern was observed, with hyperfractionated radiotherapy predicting very strongly for both the Esophagitis Index and the worst esophagitis grade, as well as longest time of suffering from esophagi- tis. Hyperfractionated RT to a total dose of 69.6 Gy was associated with a 24–34% incidence of severe esophagitis (Byhardt et al. 1998). During the most intense thoracic RT ever reported (used without CT for locally advanced non-small cell lung cancer), CHART regimen (Continuous Hyperfractionated Accelerated Radiation Therapy) resulted in 19% of patients having severe esophagitis (Saunders et al.
1996). In addition to the studies cited above, con-
comitant boost technique with concurrent chemo-
therapy (Dubrai et al. 1995) resulted in a dose-lim-
iting incidence of esophagitis of 33%.
Current chemotherapy – and the RT-intense regimens – should not be intensifi ed further with- out addressing the dose-limiting toxicities, such as esophagitis. It is important to understand factors pre- disposing patients to esophagitis, so that strategies to minimize its severity can be implemented.
8.4.4
Dosimetric Factors Associated with Esophagitis
It is commonly assumed in radiation oncology clinics that the longer the length of the esophagus segment included in the radiotherapy fi eld, the higher the probability of esophageal toxicity, despite that fact that, in the literature, different opinions have been expressed on this topic (Werner-Wasik et al. 2000;
Ball et al. 1995; Choy et al. 1999; Langer 1999).
This assumption is based on murine observations that doubling the length of the irradiated portion of the esophagus leads to a decrease in the LD
50dose, i.e. in the dose causing death in 50% of irradiated animals (Michalowski and Hornsey 1986). The classic fi elds recommended for use in radiotherapy of lung cancer include the primary lesion, ipsilateral hilum, bilateral mediastinum and, often, the ipsi- lateral supraclavicular region, establishing elective nodal irradiation as a standard approach. The cur- rent trend is for smaller, tighter fi elds, frequently encompassing only the grossly visible tumor with a margin (such an approach is used in the RTOG phase II studies of RT dose escalation for non-small cell lung cancer). The benefi ts include less irradi- ated lung volume and a shorter length of irradiated esophagus. However, the evidence that esophageal toxicity is minimized with shorter esophageal length irradiated is inconsistent.
In two studies providing a multivariate analysis of various treatment-related factors, the length of the esophagus was not related to either the severity or the duration of esophagitis. In Ball et al.’s analy- sis (Ball et al. 1995), 100 patients were divided into three groups based on the length of the treatment fi eld (<14.0cm, 14.0–15.9cm and >16.0cm), which presumably correlates with the length of the esopha- gus. No relationship was observed between esopha- geal length and the severity of esophagitis. In Choy’s analysis of 120 patients (Choy et al. 1999), there was no correlation between the esophagitis grade and the length of esophagus in either the primary (p = 0.4) or boost (p = 0.1) radiation fi elds. In contrast, after ana-
lyzing 15 patients treated with chemoradiotherapy, Langer (Langer 1999) observed that grade 1 esopha- gitis occurred in fi ve of six patients with esophageal exposure less than 16cm, and that grade 2 or greater esophagitis occurred in eight of nine patients in whom esophageal exposure exceeded 16cm.
We studied 105 patients with lung cancer receiving concurrent chemo-radiotherapy or RT alone. These patients had precise data on esophageal length as it relates to the fi elds used for irradiation. In a multi- variate analysis of acute esophagitis scored prospec- tively in a uniform fashion, we found two factors to be signifi cantly associated with an increasing maxi- mum esophagitis grade: concurrent chemotherapy with once daily RT and concurrent chemotherapy with twice daily RT (p <0.001, considered jointly) (Werner-Wasik et al. 2002). The duration of acute esophagitis was longest in the concurrent chemo- therapy/twice daily radiotherapy group. An increased length of esophagus in the radiation fi eld did not pre- dict for the severity of acute esophagitis.
Recent advances in three-dimensional conformal radiation therapy provide a unique opportunity for gathering direct volumetric data pertaining to organ damage. These data are far more meaningful than the data from previous studies, obtained through es- timates based on organ length (e.g. of the esophagus) or organ portion (e.g. of the lung or spinal cord).
The tolerance of the normal esophagus to RT has been studied in both animals and humans. The tol- erance doses (TD) for esophageal clinical stricture or perforation in 5% of irradiated patients at 5 years (TD
5/5) are 60 Gy for the entire esophagus, 58 Gy for two thirds of the organ and 55 Gy for one third of the esophagus (Emami 1991).
Many primary lung tumors or involved mediasti- nal lymph nodes are centrally located and lie in close proximity to the esophagus. Therefore, exclusion of the entire esophageal length/volume from the high dose radiation region is extremely diffi cult. However, partial exclusion and lowering the radiation dose de- livered to the entire circumference of the esophagus may be feasible. A dosimetric study by MaGuire et al. (Maguire et al. 1999) established a relationship between irradiation of the entire circumference us- ing high doses to the risk of esophagitis. In a detailed multivariate analysis of 91 patients treated using a median corrected dose of 78.8 Gy, MaGuire et al.
found that the percent of esophageal volume treated
by >50.0 Gy and the maximum percent of esophageal
circumference treated by >80.0 Gy were signifi cant
predictors of late (but, interestingly, not of acute)
esophagitis. Overall, a total of 12/91 (18%) patients
developed late esophageal toxicity in their patient population. A novel concept emerging from the data described above is the importance of sparing a por- tion of the esophageal circumference to prevent or decrease the incidence of late damage to the esopha- gus. A potential explanation for the benefi t of such sparing may be that epithelial healing in the portion of the esophageal circumference receiving a subcriti- cal RT dose will be suffi cient to maintain organ func- tion even though the remainder of the wall circum- ference is irradiated using doses causing irreversible late damage.
Another analysis of the three-dimensional RT dose distributions of 26 patients with lung cancer who re- ceived 50–60 Gy of thoracic RT concurrently with carboplatin/paclitaxel chemotherapy (Hirota et al.
2001) concluded that the length of the esophagus (to- tal circumference) treated using >45 Gy (>9.5 cm), as well as the percentage of esophageal volume receiv- ing >45 Gy (>40%), were predictive of severe radia- tion esophagitis.
Predictors of radiation-induced esophageal tox- icity in 207 patients with non-small cell lung cancer treated with three-dimensional conformal radio- therapy (26% with concurrent chemotherapy) were studied by Singh et al (Singh et al. 2003). Concurrent chemotherapy and a maximal esophageal point dose
>58.0 Gy were associated in the multivariate analysis with a high risk of grade>3 esophagitis. In addition, all assessable patients who developed grade 3–5 esopha- geal toxicity had a mean dose to the entire esophagus
>34.0 Gy, but this dose was not predictive on multi- variate analysis.
Because RT doses of 90.0–100.0 Gy are commonly believed necessary to achieve a local control of lung tumors measuring >3cm (Fletcher 1973), several dose escalation trials were initiated both in the US and in Europe. The maximum RT dose levels in these trials were 102.9 Gy (Hayman et al. 2001) or 90.3 Gy (Bradley et al.). The RTOG study evaluated the feasi- bility of dose escalation for patients with LA–NSCLC treated with three-dimensional (3D) conformal RT to the gross tumor only, without elective nodal ir- radiation. Maximum doses of 77.4 –90.3 Gy were prescribed, depending on the percentage of the total lung receiving more than 20.0 Gy.
Given that such doses differ signifi cantly from those used in current clinical practice (60.0–
64.0 Gy), restraints had to be placed on the doses to be delivered to the dose-limiting normal organs in the chest, such as lung, esophagus and spinal cord.
With non-coplanar beams and 3D planning, allow- ing improvement of the target volume defi nition,
doses to critical structures can often be reduced and esophageal toxicity less pronounced, compared with standard RT.
The RTOG 93–11 trial of thoracic RT-alone esca- lated the dose to the tumor for group 1 to 90.3 Gy (<25% of both lungs receiving >20 Gy), for group 2 to 83.8 Gy (25–37% of lungs receiving >20 Gy) and for group 3 to 77.4 Gy (>37% of lung receiving >20 Gy).
The maximum dose allowed to 1/3 of esophageal volume was 65 Gy; to 2/3 of the volume, 58 Gy; and to the whole esophagus, 55 Gy. The clinical endpoint for this TD
5/5is a stricture or perforation. No severe acute esophagitis was observed even with the highest RT dose. However, late esophageal toxicity was mani- fested in 8%, 0%, 4% and 11% of group 1 and in 0%
and 10% of group 2 (Bradley et al. 2003), suggesting a dose–response relationship.
In the current ongoing RTOG trial (L-0117) of tho- racic 3D RT dose escalation with concurrent pacli- taxel and carboplatin chemotherapy, a mean esoph- ageal dose of <32 Gy and esophageal V55 of <28%
is mandated. “V55” is defi ned as the percentage of esophageal volume exceeding 55.0 Gy. If the esopha- geal dose exceeds the constraint of 28%, the patient cannot be treated in this RT dose escalation and che- motherapy trial. The constraint was derived based on data from a study of acute severe esophageal com- plications in patients previously treated with 3D RT at Washington University, MO (graham et al. 1994).
Table 8.4.3 summarizes the data (RTOG, personal communication).
In the University of Michigan trial (Hayman et al. 2001), one-third of the esophagus was allowed to receive 80.0 Gy (Veff, or effective volume of <0.33).
Only one patient (out of 63 evaluable) experienced acute grade 4 esophagitis, having received a prescrip- tion dose of 63.0 Gy, and six patients experienced acute grade 3 esophagitis. The report did not com- ment on any late cases of esophagitis.
Table 8.4.3. Acute Severe Esophageal Complications
Mean Dose (Gy) % Volume >55 Gy (V55)(%)
<14 14-27 28-41 >41
<19 0/12 0/1 --- ---
20-31 2/18 0/2 0/2 ---
32-40.5 4/17 4/7 3/22 ---
>40.5 0/2 0/3 6/11 5/12
8.4.5
Intensity-Modulated Radiation Therapy as a Tool of Lowering RT Dose to Esophagus
Up to now, standard RT techniques, even those utiliz- ing 3D RT, have not been able to lower the maximum RT doses to the esophagus signifi cantly. Intensity- modulated radiation therapy (IMRT) seems well suited for such a purpose, with its ability to deliver concave-shaped RT dose distributions around organs at risk, such as the esophagus.
Work performed in European institutions (DeGersem et al. 2000; Derycke et al. 1998) in- volved a comparison of 3D conventional thoracic ra- diation therapy vs. noncoplanar intensity-modulated beams (BIM) in 10 patients with Stage III non-small cell lung cancer. Within each group, normal vs. opti- mized plans were compared. In optimized BIM plans vs. optimized 3D plans, the volumes of the esophagus that was irradiated at high doses (60, 70 or 80 Gy) were reduced by the optimization (3D: p = 0.01 at 60 Gy;
p = 0.01 at 70 Gy; p = 0.4 at 80 Gy; and BIM: p = 0.14 at 60 Gy; p = 0.2 at 70 Gy, p=0.1 at 80 Gy; where p is the statistical signifi cance index). Therefore, it ap- pears that for doses at least up to 80 Gy, a signifi cant lowering of the dose to the esophagus can be accom- plished with the optimization of the standard 3D plans, and that IMRT plans, in general, are even better than the best optimized 3D plans.
Figure 8.4.2 illustrates the concept of the conformal avoidance of a portion of esophageal circumference with IMRT, while at the same time allowing the deliv- ery of high-dose RT to the neighboring lung tumor (Xiao et al. 2002). “Bending” of high-dose isodose lines with a relative sparing of part of the organ is evident. For now, the use of IMRT for such purposes is experimental and more work is needed before it can be applied widely in the clinic.
8.4.6
Strategies Used to Prevent or Treat Esophagitis
The complete exclusion of the esophagus from the standard RT fi eld designed to treat a locally advanced lung cancer is most often not feasible due to the cen- tral position of the esophagus in the mediastinum (Emami et al. 1996). Therefore, the main strategies in controlling esophagitis evolve around identifying an effective radioprotecting agent. One such agent is amifostine, an organic thiophosphate that is de-
phosphorylated to its active metabolite (WR-1065) by alkaline phosphatase. Once inside the cell, WR- 1065, the free thiol, acts as a potent scavenger of the oxygen free radicals induced by ionizing radiation. It also provides an alternative target to DNA and RNA for the reactive molecules of alkylating or platinum agents. In a phase III randomized trial, amifostine was demonstrated to have a role in xerostomia pre- vention in irradiated patients with head and neck cancer, which served as the basis of the drug’s FDA approval in 1999 as the fi rst ever radioprotector (Brizel et al. 2000).
In the animal model of thoracic RT, amifostine administered to mice (400mg/kg intraperitoneally 30 minutes before irradiation) has been demonstrated to increase mean lethal doses (LD
50) of RT from ap- proximately 38.0 Gy to 60.0 Gy, achieving an overall protection factor (PF) of 1.5–1.6 for both acute and chronic esophageal damage (Ito et al. 1986).
Encouraging results of improved esophagi- tis with amifostine have been reported in phase II (Werner-Wasik et al. 2001, 2002; Koukourakis et al. 1996; Antonadou et al. 2002) and III random- ized trials performed in Greece (Antonadou et al.
2001; Antonadou et al. 2002) in patients with non- small cell lung cancer receiving thoracic RT, with or without concurrent chemotherapy. In the fi rst trial (Antonadou et al. 2001), 146 patients with lung can-
Fig. 8.4.2 IMRT conformal avoidance of the portion of esopha- geal circumference. Esophagus is outlined with a blue-green line. Purple line, gross tumor volume; yellow line, isodose line
= 60.0 Gy; blue line, isodose line = 45.0 Gy; red line, isodose line = 40.0 Gy
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cer treated with thoracic RT received daily infusion of amifostine (340 mg/m
2) or no amifostine. Grade 2 or higher acute esophagitis occurred in 32/72 RT patients vs. 6/72 in amifostine/RT patients (p<0.001).
Acute pneumonitis was decreased as well (p<0.001).
In a subsequent study of chemoradiotherapy for lung cancer (Antonadou 2002), a similar signifi cant de- crease in esophagitis or pneumonitis was observed (88% vs. 47% and 59% vs. 21%, respectively).
The team from MD Anderson Cancer Center (Komaki et al. 2002) recently reported a signifi - cant attenuation of acute esophagitis (31% vs. 7.4%;
p=0.03) and pneumonitis (23% vs. 3.7%; p=0.03) in 60 patients receiving amifostine vs. no amifostine during a combined modality therapy course for lung cancer.
A large cooperative group phase III randomized study of amifostine for esophagitis prevention has been completed by the RTOG (98-01) (Movsas et al. 2003; Werner-Wasik et al. 2003). A total of 243 patients with locally advanced non-small cell lung cancer received two courses of induction chemo- therapy (carboplatin and paclitaxel), followed by concurrent twice-daily thoracic RT and weekly low- dose carboplatin and paclitaxel. Patients were ran- domized to receive amifostine (500mg iv four times weekly, preceding the afternoon dose of RT) vs. no amifostine. In contrast to other studies, the NCI CTC assessment criteria and weekly physician dysphagia logs showed that amifostine did not reduce severe esophagitis (the rate was 30% with amifostine vs.
34% without). However, based on patient diaries, the swallowing dysfunction measured over time (equiva- lent Esophagitis Index) was signifi cantly lower with amifostine (p=0.03). Given that only 40% of all RT fractions were “protected” by amifostine infusion in the study, and that only 29% of patients received the medication according to the protocol, further inves- tigation of this agent is justifi ed, possibly with subcu- taneous administration to increase compliance and higher dose intensity.
So far, the search for other clinically important esophageal radioprotectants has been unsuccessful.
Oral sucralfate, although applied commonly in the clinic, turned out not to have value in decreasing acute esophagitis in a double-blind phase III ran- domized trial of 97 patients receiving thoracic RT (McGinnis et al. 1997).
An interesting approach using plasmid/liposome de- livery by the human manganese superoxide dismutase transgene has been reported successful in the preven- tion of radiation esophagitis in mice receiving carbopla- tin, paclitaxel and thoracic RT (Stickle et el. 1999).
In summary, although there has been signifi cant progress in understanding the basis for esophageal injury resulting from thoracic radiation therapy, ad- ditional effort is needed to fi nd effective measures for minimizing or eliminating esophagitis.
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