CARCINOMA OF THE ESOPHAGUS

Radiation therapy of carcinotna of the esophagus

Tl IOMAS J K EANE, MB, MR CPI, FRCPC

ABSTRACT: Radical radiation therapy with curative intent for esophageal squamous carcinoma is used both as a single modality and combined with chemotherapy. Failure to eradicate disease at the primary tumour site represents the greatest cause of failure of curative radiotherapy. The aim of curative radiotherapy is to deliver the highest dose of radiation aL the tumour site while minimizing radiation delivered to the surrounding tissues. The best survival results are obtained in patients with tumours less than 5 cm in length, confined to the upper one-third of the esophagus. Regular endoscopic examinations two to three times per year in the first Lwo years post treatment should rule out the vast majori ry of treaLment failures. Can J Gastroenterol 1990;4(9) :608-611

Key Words: Carcinoma of the esophagus, Radiation therapy

Radiotherapie du cancer de l' oesophage

RESUME: La radiotherapie radicale a visee curative est utilisee seule ou associee a la chimiotherapie dans le carcinome epidermo'ide de l'oesophage. La non­eradication de la maladie au site de la wmeur primaire constitue la cause majeure d'echec therapeutique. L'object if de la ra<liotherapie curative est de delivrer la dose de radiation maximum au niveau de la localisation prima1re sans leser les tissus environnants. Les meilleurs resultats de survie sent obrenus chez !es patients dom les turneurs som d'un diarnetre infcrieur a 5 cm et limitees au premier tiers supcrieur <le l'oesophage. Des examens endoscopiques reguliers effectues deux ou trois fois par an dans !es deux premieres annees qui suivent le traitement permettent de deceler la grande majorite des echecs therapeutiques.

The Princess Margaret Hospital, Toronto, Onrario Correspondence and reprmts: Dr TJ Keane. The Princess Margaret Hospiral, 500

Sherboume Street , T oronw, Ont.arm M4X I K9

IT JS NOW ALMOST 80 YEARS S1Nl1 G ubez ( l) reported on the use of

radiat ion therapy in the management of carcinoma of the esophagus. This paper reviews the role of radical radia­tion therapy with curative intent both as a single modali ty and combined with chemotherapy. Unless indicated other, wise, o nly treatment of squamous car, cinoma is discussed.

TREATMENT WITH CURATIVE INTENT

Rad iation therapy shares with surgery a major limitat ion as a curative modality by vmue of being a nonsys, temic therapy. It can, at best, only trulr cure patients whose disease is localiied within a volume amenable to a radical dose of radiatio n prior to the develop, ment of occult distant metastases. In prac tice, therefore, cure will only be possible in patien ts whose disease is lo­cal ized to the primary tumour me, and perhaps in a subset of patients with metastases limi ted to lymph nodes in adjacent tissues. T he potential for cure

608 CAN J GASTROENTEROL VOL 4 No 9 DECEMBER 1990

Radiation therapy of carcinoma of the esophagus

TABLE 1 Sites of recurrence of squamous carcinoma of the esophagus

Number Radiotherapy Recurrence (% ) Distant Reference of patients dose (rods) Local Margin Neck metastases

Robertson et al (17) Eiken et al (18)

39 30

3000-7800 6525

56 36 25· 25 10 25 64t 27 43 66

Pierquin et a l ( 19) 115 4500-8000 82 37 Pearson (3)' 157 5000 61 23 Beatty et al (20) 176§ 4000-6000 84 47 Margin of treatment. ·Stage I d isease; 1 Stage II and Ill disease; t Site causing dea th only;§ Includes 30 paffents who hod surgery and radiotherapy. (Reprinted from Cancer Treat Symp 1983:2:87)

TABLE 2 Radiation tolerance dose and c linical sequelae for normal tissues

Cllnlcolly normal tissue Clinical manifestation

Spinal cord Transverse myelitis. TD 5/5" 45Gy

Usual time of onset

6-36 months Brown-Sequard syndrome

Heart Pericardia ! effusion. 45Gy 12-60 months (tfflo volume) constrictive pericorditis

Lung (single) Acute pneumonitis stomach Ulceration. fibrosis.

(entire organ) bleeding

15Gyf 45Gy

2-6 months 6-l2 months

Dose estimates ore approximate for fractions of 2 Gy/doy. five days per week. ·s% risk within five years; 1 Uncoffected for he terogeneity

among this la tter group is not available in the radiation therapy literature, as stagir ,g is clinical and the status of mediastinal nodes has not usually been stated. However, if infonnation in the surgical literature is a va lid comparison, then the work of Skinner and his col­leagues (2) is not encouraging. For all carcinomas in their series, only two of 17 patients survived, even when lymph node metastases were confined to one or two nodes. The proportion of pa­tients in radiotherapy series who are Judged suitable for potentially curative treatmen t based on clinical staging varies from a high of 63% when radio­therapy was virtua lly the on ly approach to radical treatment ( 3 ) to a much low­er proportion of 19% for cura tive radio­therapy alone ( 4). The degree of selec­tion and the criteria used for such treatment decision making must be known before an y judgement can be made as to the va lue of any rad icc1 I treatmen t approach . It is probably fa ir to say that many cla ims for improved treatment represen t triumphs of selec­tion rather than triumphs of treatmen t per se.

It can be seen from Table 1 tha t

fa ilure to eradicate disease at the pri­mc1ry t umour site represents the great­est cause of fa ilure of therapy, and any improvement in cure rates must sta rt wich improvements in control of the primary tumour. It should be remem­bered chat not all patients whose pri­mary tumo urs are controlled will survive, as many will succumh to dis­tant metastases by virtue of living long enough for such me tastases to become apparent.

RADIATION TREATMENT PLANNING

The a im of curative radiotherapy for carcinoma of the esophagus is to de liver the h ighest dose of radiation to the site of the tumour while minimizing radia­tion de livered to the surround ing nor­mal t issues. T he obvious expectation is co maximize local tumour control while minimizing complications to normal tissues. The c ritical tissues are the esophagus itself, the lung, the heart, and perhaps of most concern, the spinal cord . The radiation tole rance of these organs varies considerably, as does the functional tole rance of the organs themselves. The latter concept

CAN J GASTROENTEROL VOL 4 No 9 DECEMBER 1990

depends on the volume of the organ which must be radiated at a given J o~e to produce a clinical complication. For example, t he radiation to lerance of a small volume of lung can be exceeded without cl inical consequence, whereas exceeding the radiation to lerance of any length of the spinal cord will a lways result in serious neurological sequelae. T able 2 outlines the tolerance dose and clinical seque lae for some relevant nor­mal tissues. External beam therapy: Figure 1 shows a typica l computed tomography-as­sisted treatment plan . By a rranging a combination of anterior posterior fields fo llowed by o ne ante ri or and two posterio r obi ique fie lds, the distribution of radiation dose is kept wi rhin the tolerance of crit ical structures. A beam energy of 8 to IO Me V is used m this example. At ene rgies of 8 to 10 MeY or greater, dose distributio ns similar to

those shown in Figure I can usua lly he obtained irrespect ive of the anatomical size of the pat ient . lntraluminal therapy: Rece n t improvements in J ose de livery systems for intraluminal therapy have rev ived interest in th is form of treatmen t. Be, cause of rhe physics of dose gradients from line sources, thb form of trea tmt:n t can only be used alone as curative treat ­ment for very superficia l lesions which are ra rely e n co unte red in No rth American patienr populat ions. When combined with externa l beam therapy to deliver a curative dose to the primary tumour, it offers the best hope of im­proving the therapeutic ra tio for radia­tion t rea tment. T he la rgest serie5 employ ing this techniq ue as a boost combined with external heam therapy by Flores et a l ( 5) reports a 26% survival at two years for a se ries of 171 pat ients, of whom 145 received no treatment other than radiation .

SURVIVAL FOLLOWING RADICAL RADIOTHERAPY

ALONE The results of treatment are heavily

dependent on the degree of selection for any particular therapy. Parucular at­ten tion should be paid t o the total number of patien ts receiv ing rad ical treatment as a proport ion of all patients

609

KEANE

Figure l) Typical com/>ucecl tomography isodose distrihwion at the central axis for a comhmed five field technique using 18 McV photons iuith dose currection for lunR heterogeneity

TABLE 3 Squamous cell carcinoma of the esophagus radiotherapy-chemotherapy studies

Study / reference

Radlother,opy + bleomycin versus radiotherapy (randomized) Earle et al 1980 (9)

Radiotherapy + methotrexate versus radiotherapy Roussel et al 1988 (15)

Radiotherapy + DDP + 5FU + mitomycln C +bleomycin Leichman et a l 1985 (13)

Radiotherapy + mitomycin C + 5FU Keane et al 1985 (11)

Radiotherapy + mltomycln C + 5FU Chan et al 1989 (12)

Radiotherapy + 5FU Byfield e1 al 1979 (16)

DDP Cls-plofinum: FU Fluorourocil

m any series, and the extent to which surgery and radiation therapy are ap­plied as curative treatment within any centre. T he best results show a 17% five year survival ra te for a subset of 248 patients representing 40% of all cases treated with curative intent over an 18 year period in Edinburgh, Scotland (6). The degree to which this series repre­sents selection can be inferred by the fact that the overall five year survival for all patients was between 7 and 9% for the entire period. A further analysis

No. of Median Radiotherapy patients survival dose

40 6.4weeks 50-60 Gy1n 37 6.2 months 5to6weeks

72 9 months 56.25Gy in 70 8months 5weeks

20 22months 50Gy in lSweeks

35 12months 45-SOGy in 4 to8weeks

21 13months 45-SOGy in 8weeks

6 22 months 60Gyln 12weeks

of data from Edinburgh for an overlap­ping time penoJ was carried out by Newaishcy anJ colleagues (7). When the definition of curative intent was inferred only by the prescription of radical Jose, the five year survival rare among 444 of 848 patients so defined was 9%. This figure is within one stan­dard deviation of the mean 6% five year surviva l rate derived by Earlam and Cunha-Melo (8) from 49 papers and a total of 8489 patients following esophageal cancer rad iut herapy.

PROGNOSTIC FACTORS There are a number of prognostic fac­

tors which appear to be advantageolb in rem1S of survival fo llowing ra<lical raJja. t ion therapy. Improved survival ftJ female patients has been reported in several series. Newaishey and associates (7) reported a 5.67°A, five year cnide sur­vival for males compared to 11.6% fir females. A comparison of survival rat· terns suggested that this difference only reached statistical s1g111ficance after five years of follow-up. ThL, ~urvival dd­ference was only demonstrated f~ tumours greater than 5 cm in length.

Tumour location has been con­sidered important m several series wah a general trend towards improved sur­vival for lesions in the c.ervical and up­per one-th ird of the esophagus. Other prognostic foe tors arc di~putcd and may reflect d1fficulttcs wirh univariate analysis and small numbers of pauents. Based cm the available evidence 1t wou lJ appear reasonable to suggest that the best survival resul ts with rad1c~ radi<1tion therapy arc obtained m patients wtth tumours less th.an 5 cm m length, confined to the upper one-third of the esophagu~.

CHEMOTHERAPYASAN ADJUVANT TO CURATIVE

RADIOTHERAPY Much of the recent interest m

chemothcrapy/radic1therapy combina­tions has centred on concurrent aJmm. 1stration of chemotherapy with radia­tion. ln general the admm1stration d drugs 1s usuall y limiteJ to one or two courses <luring or very close to the tune of rad1othcrnpy. While rhe rationale ij not often stated, the general intent ap­pears to be co improve radiation effect on the pnmary tumour rather than m• fluencing systemic disease. Presently, the scientific basis for any advama· geous drug rad iothcrapy interaction re· mains unclear, hut possibilities range from simple additivity of effect to true :.ensitizat1on. To date only bleomycm (9) and methotrexate ( 10) haveheen studied in a prospective randomized manner and have not shown a henefu There are now several reports of en· couragmg nonrandomizcd stuJic, cf combinations of 5-tluorouracil infusion

610 CAN J UA::,,ROENTERL)L VOL 4 Nt) 9 DE< :EMlllR 1990

Radiation therapy of carc inoma of the esophagus

with either nmomycin C ( 11,12) or c1s­rlatin (13). The results of ranJom izcd studies of these combinations being conducted by the Eastern Conrcrarivc Oncology Group (ECO<.,) and the Radi­ation T herapy O ncology Group (RTOG) arc still awaited. A summary of the bleomycin and methmrexatc ran­domized trials and the rhase 11 studie, of miromycin C/SFU and cbplarin/SFU 1s shown in Tahle 3.

POST RADIOTHERAPY MANAGEMENT

The vast majority of local tr.:-mment failures arpear w1thm the first 18 months after radical dose radiotherap). It is important to J 1stingubh persistent or recurrent tumours from post radio-

REFERENCES I. Guisez J. fasais Jc mtire1m:nc de

quclquc cas d'cprthelroma de l'oesophage par h:s applicat1nm lucale, d1rectcs Jc red1um. Bull Soc Mcd J kip Pans 1909;27:717.

2. Skinner DB, Dowiarshahi Kn. DeMeestcr TR. Pmcnrn1lly rnrnhle cancl.'r of the ocs.iphagw,. Cancer 198'"'50:2571.

3. Pcarwn JG. The value of rndiCllherapy 1n lhe management nf esophageal cancer. Am J Rncntgenol !969;105:500- 13.

4. Barkley I IT, I lu,scy l)l l, Saxton JP, Spans<> WJ. Rad10therapy 111 lhc 1rem­ment of carc111rnna of the oesuphag11,. In: Stroehlein JR, Re,mdahl NM, c,b. GasmHntestmal Cani:cr. New York: Raven Press, l 981 : 1 71.

5. Flores AL), Nclcm, R, hans K, I lay J, Stoller J, Jacblln S. Impact of ncw raJiotherapy nmdal1t 1c, on the surgical management nf cancer of rhc esophagus and card1a Int J Radial Oncol B1ol Phy, 19!{9; 17:917-44.

6. Pearson JG. The prc,cnt status and future potential for radiotherapy 111 lhc managemcnr of esophageal c.inccr. Cancer 1977; W:882.

7. Ncwahhey GA, ReaJ GA. Duncan W. Results of rndrral rnd1mherapy of the squamous caru noma of the esopha1sus. ClinRadrol 1982;33:347.

8. Earlam R. Cunha-Melo JR. E~ophageal squamous ccll c.1rc111011rn 11. A crrtKal

therapy sLrictures. For Lh is reason regu­lar endoscopic examinations twn to three times per year in the first tW\l

years post tre:ument arc required. In addition, dilation of any strictures he­fore they cause serious esophageal ob­sLruction is recommended. Biopsy and/or brushing of strictures should be performed whenever Jouht exists as to the c.u1se of stricture formation. It should nnr he assumed that st ricturt' formation and/or ulceration following raJ,ocherapy is ;:i clue co tumour re­currence, despite the likelihood that this may be the case. Histological pmof uf treatment failure ts essential for decision making regarding the choice of the mnsr aprropnatc subsequent treatment hy whatever modality. le il.

rl'V1cw nf radiotherapy. Rr J Surg ]980;67:457.

9. Earle J, Uelher R, Mllcrtel C. A wn­milled c\·aluam111 of u1mh111<.:d rad1a t 1011 and hleomyun therapy for ,4uam,1us c<.:11 can.:111oma of the esophagus. Int J RaJiat Oncol Bml Phys 1980;6:82 I.

JO. Gerard A, G1gnoux M, Rom.sci A, ct al. Prospective anJ controlled snidics on mulridisciplinary treatment nf gm,rr01mesunal cancer. In: Klem 110, ed. Reccnt Results in Cancer Re­search. I lcidelberg: Springer-Verlag, 1981:79.

11. Keane TJ, I larw<x,d AR, Elhak1m T, Cl al. Radical r.1di,1tion therapy with 5-flunni-uracil infu,ion ,ind m11,1myc111 C for t·sopha1s.:al s4uamous cell Lar­Linoma. Rnd1at Oncol 1985;4:205.

12. Chan A, Wnng A, Arthur K. Con­comitant 5-fluorouracil infusion, mitomycin C and radirnl rndrarion therap) 111 esophage,11 s4uamt1us cdl carc111oma. Int J Rad1at Oncol R1ol Phys 1989;16:59-65 .

I 3. Lc1chman I, I lcrskov1c A, Lc1chman CG, ct al. Non-nperativc therapy for squ,1mous cell cancer of the e,nphagus. J Cl111 Oncnl 1987;5:'365.

14. Ais11cr J, Forasticrc A, Ar@c) R. [\a­rcms of recurrence for carc111nma of the lung ,111J oesophagus. Cancer Trear Symp 1983;2:87.

15. R,>ussell A, Jacob 11. I laegcle P, er al. A controlled mal for the treatment nf

CAN J GA',TROENTl·ROI Vrn 4 No 9 l)ff[MB[R 1990

rarely rossihle to offer curnt ive surgical treatment 1,1 p,iriems who fail initial radiation rhcrnpy, even in highly selected cases. The nperat ivt• mnrrnl,ty in such situations may also he unacccp­tahle given the potential benefit.

CONCLUSIONS Primary treatment failure remains

the greatest t.urrent challenge tn the u,e nf radical radiotherapy for esophageal ~quamous carc1ni1ma. Care­ful sclecucm nf cases is necessary to

1demify the approx1marcly IO w I 5% of patients who may be amenahle to

long term cure. Trc,Hment follnwing local radiotherapy failure 1s rarely cura­tive and is prohahly best cnm1dcrcd from a pall iative perspecrive.

patrcm, w1tl1 mnperahle esophageal carcinom,1. A study of the EORTC Ua>tmimcsurn1I T rnct Cancer C,,t1pcr:1t1vt' Grnup. In: Schlag P, I ilichenhergcr P, Metzger U, c,b. Recent Results 111 Cancer Research, Vl,I 110. Hc,dclherg: Sprmger-Vcrlag, 1988.

16. Ryficld J. Banine R, M..:ndelsohn J, ct al. lnfus1onal 5FU and rad1at1011 therapy for nnnrc,cccable csoph,1gcal carcmnma. Cancer I 980;45:703-8.

17. Rnbemon R, Coy P. Mokkhavcsa S. The results of radical ,urgery compared with radica l rnd1mhcrnry 111 the treat­ment of squamous carLinoma of the rhnr.tc1c esophagus. J Thorne Cardi,,va,c Surg 1967;53:430-40.

18. Elknn [), Myu111s Sook L, I lcndnck­son FR. Carcinoma of the c,ophagus: Sires of rcLL1rrt'nce and pall1at1ve benefit, afLcr dcfinnive rad1other.1py. Im J Rad1at Oncol Riol Phys 1978;4:6 15.

19 Picr4u111 B, Wamhcrs,c A, Tub1ana M. Cancer of the thorac 1c esophagw,: Two scnc, ,,fparicnts rrearcd hy 22 MeV hetatron. Rr J Radrnl 1966;39:189-92.

20. &atty JD, De Boer G, Rider WD. Car­cinotmi ,if the csorhagus: Prerrcatmcnt assessment, correlation of radiation lreatmcnt parameters with ,urvival, anJ 1Jcn11ficat1<111 anJ management of rndiatllln treatment f:11lurc. Cancer 1979;4 3:22 54-6 7.

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