Complications after Radiation Therapy for Cervical Carcinoma

FROM THE DEPARTMENT OF RADIATION THERAPY, UNIVERSITY OF PUERTO RICO SCHOOL

OF MEDICINE, SAN JUAN, PUERTO RICO.

COMPLICATIONS AFTER RADIATION THERAPY FOR CERVICAL CARCINOMA

ANTONIO BOSCH and ZENAIDA FRIAS

It has long been an accepted policy to employ radiation therapy as initial treatment of choice for invasive carcinoma of the cervix uteri in all stages of the disease.

The treatment techniques are usually modifications of the Paris or Stockholm methods, using intracavitary application of radioactive sources or a combination of external and intracavitary irradiation. A gradual change in the techniques of treatment in order to improve end results continually occurs, based on clinical experience; but these changes in treatment techniques should be modified to the point where the radiation is distributed more precisely to the target volume, the tumor and its sur- roundings, trying to improve the results, while maintaining a low rate of complications.

The aim of the present report is to present the types and rate of complications encountered with the radiation techniques used at this hospital.

Material. A total of 1 394 cases of invasive carcinoma of the cervix uteri in an intact uterus were seen from January 1956 to December 1965. Seventy-one cases (5%) were not treated, either because their stage of the disease was too advanced, the general condition of the patient too poor to justify treatment, or because the patient refused treatment or left for treatment elsewhere. Incomplete treatment was

Supported in part by N.C.I. Wisconsin Clinical Cancer Center Grant No. CA14520. (The authors are now at Division of Radiation Oncology, University of Wisconsin Hospitals, Madison, Wisconsin 53706, USA.) Submitted for publication 13 September 1976. Acia Radiologica Therapy Physics Biology I6 (1977) F a x . 1 February 53

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54 ANTONIO BOSCH AND ZENAIDA FRIAS

Table 1 Type and frequency of radiation complications

No. of Distribution Frequency cases (per cent) in 1139 cases

(per cent)

Rectosigmoidal 104 72 9.1 Grade I 39

I1 47 111 9 IV 9

Grade I 13 11 1 1 111 1 IV 3

Bladder 28 19 2.5

Fracture of the femur 7 5 0.6 Intestinal obstruction 5 3 0.4 Ureteral obstruction 1 1 0.1

Total 145 100 12.7

given to 184 patients (14%). The material is analysed with special regard to radiation complications occurring in 145 of the 1 139 patients who completed a full course of irradiation according to the standard techniques.

Treatment techniques and dosage considerations

External irradiation followed by intracavitary application of radioactive sources has been the standard policy of treatment employed since 1956 for invasive carcinoma of the cervix uteri in all stages of the disease.

External irradiation. An exposure of 38 Gy (4 000 R, 3 800 rad) calculated at the midplane of the pelvis was administered over a period of eight weeks by means of parallel 18 cm x 12 cm antero-posterior opposing portals, plus 8 cm x 10 cm sciatic fields, with 250 kV, 2.5 mm Cu HVL, and 50 cm FSD. Since late 1958, most of the cases were treated with a CO-60 Eldorado unit, 100 cm SSD, using parallel anterior and posterior opposing portals, and an exposure of 43 Gy (4 500 R, 4 300 rad) was delivered over a period of six weeks calculated at the midplane of the pelvis.

Zntracavitary application. The intracavitary application of radioactive sources al- ways followed the external irradiation of the whole pelvis, and consisted of a single application, delivering in the majority of the patients exposures of approximately 4 000 gamma roentgens (38 Gy) to point A. Exposures ranging from 28.5 to 47.5 Gy were delivered to a limited group of patients.

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COMPLICATIONS AFTER RADIATION THERAPY FOR CERVICAL CARCINOMA 55

Table 2 Frequency of radiation complications by

age group

Age No. of cases Per cent

20-29 30-39 w 9 50-59 60-69 7&79 80 >

Total

3/20 181172 341304 35/281 35/239 17/93 3/30

14511 139

15 10 11 12 15 18 10

13

The standard intracavitary applicator of radioactive sources consisted of an intra- uterine tandem arrangement with three sources containing 10 mg of radium each (or equivalent 6oCo) and a vaginal colpostat with two sources of 10 mg each. The applicators most frequently used were the Fordyce, the Silverstone, and the Ter- Pogossian types. If the vagina is narrow or if residual disease involves the mid or lower portion of it, a long tandem with four or five sources of 10 mg each is inserted in the uterine cavity with one or two of the sources protruding into the vaginal canal.

Description and classification of complications

After a lapse of months or years following a complete course of irradiation, different kinds of injuries may occur, especially in the rectosigmoid and in the bladder, and less frequently in the intestine, ureter and bone. It is important to classify into types and grades the injury that occurs, because minimal injury when it occurs is often taken as a reaction and not as an injury.

Complications were classified into 5 types: rectosigmoidal, bladder, intestinal obstruction, ureteral obstruction, and bone fracture. Based on clinical symptoms, radiography and endoscopy, rectosigmoidal and bladder complications were sub- classified into 4 degrees of severity. Grade I: a single bleeding episode, either rectal bleeding or hematuria, or several episodes of bleeding spaced at long intervals. Grade 11: rectal bleeding, or hematuria, which persists for months, with or without periods of normality. Grade 111: severe rectosigmoidal stenosis, or bleeding that requires colostomy; or severe hematuria that requires surgical intervention. Grade IV: fistulas.

Rectosigmoidal complications. In cases of rectosigmoiditis, grade I, the barium enema is usually negative, and edema of the mucosa is found on the proctosigmoidoscopy. The symptoms and findings eventually subside with conservative treatment.

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Table 3 Frequency of radiation complications by stage

Stage Entire Two-year series survivors*

No. Percent No. Per cent

I 301177 17 281164 17 I1 A 391248 16 391207 19 I1 B 291252 12 251178 14 111 431409 10 351229 15 IV 4/53 8 2/25 8

Total 145/1 139 13 1291803 16

* Excluding 336 cases surviving less than 2 years (29 % of 1 139).

Table 4 Time of onset of symptoms from radiation injury

Time of onset Grade 1-11 Grade 111-IV Other Total

Rectum Bladder Rectum Bladder No. of Cum. cases per cent

Within 6 months 15 1 5 2 1 24 17 6 1 2 months 40 3 7 1 2 53 54 1-14 years 16 3 5 - 4 28 73 14-2 years 5 4 1 1 11 81 2-3 years 8 6 1 - 3 18 93

5 96 3 4 years 2 3 2 6 100 After 4 years - - - 4

Total 86 24 18 4 13 145 100

-

- - -

Rectosigmoiditis, grade 11, may produce anemia and many patients require trans- fusions. The barium enema shows loss of the mucosal folds and areas of narrowing. On proctosigmoidoscopy, ulceration and areas of telangiectasia may be seen. These symptoms and signs also subside with conservative medical measures.

Rectosigmoiditis, grade 111, involves severe rectal bleeding or acute abdominal distress, and grade IV shows rectovaginal fistulas which appear after treatment. Both require colostomy and abdominal surgery.

Bladder compkcations. In cases with vesical complications, grade I, the cystoscopic examination shows small areas of telangiectasia. In grade 11, the findings are those of hemorrhagic cystitis with areas of telangiectasia and ulceration. These symptoms eventually subside under conservative medical treatment.

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z Cumulative distribution of rectosigmoidal (0) and bladder ( 0 ) complications according to time of appearance after irradiation.

20 4 o V

0 1 2 3 4 5 YEARS AFTER TREATMENT

In grade 111, the changes of the bladder mucosa are very severe with pseudotumor formation which in some cases may be confused with tumor involvement, but biopsy of the lesion will confirm the suggested diagnosis of radiation cystitis. Grade IV are vesico-vaginal fistulas for which the patient may require surgical intervention.

Results

The distribution of the complications appears in Table 1 . A total of 145 of the 1 139 patients (12.7%) developed some type of injury. The most frequent complication was rectosigmoiditis, reported in 104 patients, and accounting for 72 per cent of all complications. Thirty-nine cases had rectosigmoiditis grade I, 47 grade 11, and only 18 patients (1.5 %) developed severe rectosigmoiditis grades I11 and IV. Bladder injuries occurred in 28 of the treated patients (2.5%) and only in 4 cases was the hemorrhagic cystitis considered severe. Other types of complications occurred in 13 patients: 7 had a femoral fracture, 5 developed intestinal obstruction, and 1 had ureteral obstruction. Severe complications which include grades I11 and IV rectosigmoiditis or cystitis, intestinal or ureteral obstruction, and bone fracture, were present in only 34 of the cases, which represents 3 per cent of the fully treated cases.

The frequency of complications according to age groups was analysed, and no consistent pattern was observed (Table 2). A slightly higher rate of complications was encountered in women of 50 years of age and over, as compared with those under 50 (14 % vs. 1 1 %), but the difference was not statistically significant.

The frequency of radiation complications with regard to stage of the disease has been evaluated for all cases in general, and for two-year survivors, to correct for deaths occurring within the first 2 years, especially in late stages, thereby allowing for a longer risk period. The percentage of complications was higher in early stages of the disease (Table 3).

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Table 5 Cases with more than one complication

Initial complication Further complications No. of cases

Rectosigmoidal grade I Bladder grade I 7 Bladder grade I1 1 Intestinal obstruction 1

Rectosigmoidal grade I1 Bladder grade I 1 Bladder grade I1 4 Fracture of femur 2

Rectosigmoidal grade 111 Bladder grade I 1 Bladder grade 111 1

Rectosigmoidal grade IV Bladder grade IV 2 Bladder grade I1 Rectosigmoidal grade I 2 Fracture of femur Bladder grade IV 1

Contralateral fracture 1

Total 24

The time of onset of symptoms according to the type of injury appears in Table 4. Rectal injuries occur earlier after irradiation than do bladder injuries and other types of complications. Around 89 per cent of all rectal complications appeared during the first 2 years as compared with 54 per cent of the bladder complications. Severe complications, either rectosigmoidal or bladder, almost invariably appear during the first 13 years after treatment. The cumulative number of rectosigmoidal and bladder complications according to time of appearance after irradiation is given in the figure.

Twenty-four of the 145 patients (16%) developed more than one complication, and the type and grade of the first and second complication appears in Table 5. Usu- ally the grade of the second complication was of the same order as that of the first. Of the 9 patients with rectosigmoiditis, grade I, who developed a second complication, 7 were bladder grade I; and 4 out of 7 patients with rectal injury, grade I1 developed bladder grade 11.

The 5-year survival by type of complication and stage of disease is given in Table 6. Comparison of the 5-year results of patients with complications and those without complications appears in Table 7. Complications have been grouped into minor, and major or severe, the latter including grades I11 and IV rectosigmoidal and bladder complications, obstructions, and fractures. In general, the 5-year survival of cases with complications is similar to the survival of those without complications. Cases with minor complications do consistently better, stage by stage.

Possible cause of the complications. The cases with complications were further evaluated in order to find a plausible explanation for such complications (Table 8). In 51 cases (35%) the standard treatment technique was modified, e.g. more than

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Table 6 Five-year survival by stage and type of complication

Stage Rectal Bladder Intestin. Ureteral Femoral Overall obstruct. obstruct. fracture

1-11 111-IV 1-11 111-IV No. of Per cases cent

I 13/15 516 818 - - - 111 27/30 90 I1 A 21/26 011 718 - 011 - 01 1 28/37 76 I1 B 10115 013 517 - 213 - o/ 1 17/29 59

111 414 23/42 68 - 214 50

Total 59/83 7/18 22/25 113 215 111 517 971142 68

111 14/25 218 212 011 01 1 1v 112 - - - 1 I 2 -

Table 7 Five-year survival by stage (cases lost to follow-up excluded)

Stage With complications Without

Major Minor* complications* *

No. Per cent No. Per cent No. Per cent

I 617 (86) 21/23 91 1211138 88 11 A 013 (0) 28/34 82 1301202 64 I1 B 218 (25) 15/21 71 1171214 55 111 7/15 47 16/27 59 1231362 34 IV 1 I 2 (50) 112 (50) 9/48 19

Total 16/35 51 811107 76 5001964 52

* 3 cases lost to follow-up (3 %). * * 30 cases lost to follow-up (3 %).

one radium application, or the use of anterior and posterior fields only without sciatic fields, when using orthovoltage irradiation. In 46 other cases (32 %) the patient received an overdose with regard to the standard dosage. In 12 cases the cause of the complication was repeat irradiation given for persistence or recurrence of the disease. In 33 cases (23 %) no specific reason was found as a possible explanation for the complication.

Discussion

The effectiveness in controlling carcinoma of the cervix uteri with a relatively low morbidity following properly conducted radiation therapy has made this modality the treatment of choice.

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Table 8 Possible explanation of radiation complications

Explanation Rectal Bladder Intestin. Ureteral Femoral Total

1-11 HI-IV 1-11 111-IV No. Per cent

obstruct. obstruct. fracture

Change in technique Overdosage Repeat irradiation Probably carcinoma Abdominal surgery Unknown Total

34 9 5 1 1 1 51 35 1 46 32 30 5 9 1 - -

I 1 2 - - 1 1 12 8 2 1 1 1

15 2 8 - 4 - 4 33 23 86 18 24 4 5 1 7 145 100

-

_ _ - - - - 2 _ _ - - - 1 -

The frequency of complications after irradiation will depend on the techniques used in different institutions. INGELMAN-SUNDBERG (1947) concluded that the main etiologic factor of the complications was too intense irradiation of the rectum by intracavitary sources, but SMITH et coll. (1969) stated that rectal and small bowel complications were caused essentially by the effect of external irradiation. JOELSSON (1 970) after investigating different radiation treatment modalities concluded that several factors may influence the occurrence of complications and considered it an impossible task to find in each individual case an explicit evaluation regarding the causative factor.

The rate of complications varies in the available literature, and will depend on the type of lesions taken into consideration. Most authors only analyse severe complications grade I11 and IVY and do not take minor complications into account.

In the present material, 145 patients (13%) out of 1 139 cases who received a complete course of irradiation developed some type of complication, but severe complications were present in only 34 cases (3%), comparable with the rate of complications reported by most authors (KOTTMEIER 1964, FLETCHER & CHASSACNE 1968, MAIER 1972, ROSWIT et coll. 1972, EINHORN 1975).

Advanced age has been reported as a contributing factor, because of the diminu- tion of the tissue tolerance and deficient vascularization in the older patient, and may well be the reason for the increased risk of complications (FLETCHER & CHASSAGNE). No significant difference between the rate of complications in older patients, as compared with the younger, was found in the present material.

The rate of complications seems to be higher in early stages. It has been suggested that the rapid fall in survival rates in advanced stages of the disease does not allow time for the complications to develop (BERGSJO & EVANS 1965, STROCKBINE et coll. 1970). If patients who died during the first two years after treatment are excluded the incidence of complications still remains higher for early stages.

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The time of onset of the complications in the present series is in agreement with most reports (KOTTMEIER, ROSWIT e t coll., EINHORN). Rectal injuries appear most frequently 6 to 18 months following initiation of treatment, while bladder complications appear later, between the second and third years. Severe complications usually occur during the first two years after treatment.

The survival rate for the patients with post-irradiation complications did not differ significantly from the rate -of patients without complications. Those cases with minor complications in fact seem to d o better.

Classification of complications by type and grade is essential in order to assess the magnitude of the morbidity resulting from the treatment, as well as to enable valid comparisons of complication rates in different series.

S U M M A R Y

A series of 1 139 patients with invasive carcinoma of the cervix uteri who received a complete course of treatment by means of external irradiation followed by intracavitary curietherapy was evaluated in order to assess the results of treatment and, in particular, the radiation complications induced. Complications developed in 145 instances (12.7%). Severe complications occurred in only 3 per cent. Twenty-four cases had more than one complication. Rectosigmoidal injuries accounted for 72 per cent of all complications, and appeared earlier than did bladder complications and within the first two years after treatment. No apparent correlation between age and the occurrence of complications was found. The rate was higher in early stages. The radiation complications did not adversely affect the survival results.

Z U S A M M E N F A S S U N G

Eine Serie von 1 139 Patienten mit einem invasiven Karzinom der Cervix uteri, die eine vollstandige Behandlungsfolge von externer Bestrahlung rnit anschliessender intrakavitarer Curietherapie erhalten hatten, wurde untersucht in der Absicht, die Ergebnisse der Behand- lung, besonders die strahlenhervorgerufenen Komplikationen, festzustellen. Komplikationen entwickelten sich 145 ma1 (12,7%). Schwere Komplikationen traten nur in 3% auf. Vierund- zwanzig Falle hatten mehr als eine Komplikation. Rektosigmoidale Schadigungen machten 72 % aller Schadigungen aus; diese traten friiher als Blasenkomplikationen auf und innerhalb der ersten beiden Jahre nach der Behandlung. Es wurde keine offensichtliche Korrelation zwischen dem Alter und dem Auftreten der Komplikationen gefunden. Die Frequenz war bei den friihzeitigen Fallen grosser. Die strahlenbedingten Komplikationen beeinflussten nicht nachteilig die Uberlebensresultate.

R E S U M E

Les auteurs ont 6tudiC une strie de 1 139 malades atteintes de carcinome envahissant du col de I’utkrus qui ont requ une serie compltte de traitement par une irradiation externe suivie de curiethkrapie intracavitaire; cette ktude a ttk faite pour determiner les rksultats du traitement et, en particulier, les complications dues aux radiations. Des complications sont apparues dans 145 cas (12,7%). Des complications skvtres ne se sont produites que dans

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3 % des cas. Vingt quatre cas ont eu plus d’unecomplication. Les lksions recto-sigmoldiennes ont constituk 72% de toutes les complications et sont apparues plus t6t que les complications vksicales et au cours des deux premitres annkes aprts le traitement. Les auteurs n’ont pas trouvb de corrklation apparente entre 1’8ge et I’apparition des complications. Le taux de complication a ktk plus elevk dans les stades precoces. Les complications des radiations n’ont pas influenck dkfavorablement les rksultats de survie.

REFERENCES

BERGSJO P. and EVANS J. C.: Late radiation reactions in cancer of the cervix. Acta obstet. gynec. scand. (1964) Suppl. No. 7.

EINHORN N.: Frequency of severe complications after radiation therapy for cervical carcinoma. Acta radio]. Ther. Phys. Biol. 14 (1975), 42.

FLETCHER G. H. et CHASSAGNE D.: Causes possibles des recto-sigmoidites et des sigmoidites survenant aprts radiothkrapie pour cancer du col. J. Radio]. Electrol. 49 (1968), 639.

INGELMAN-SUNDBERG A.: Rectal injuries following radium treatment of cancer of the cervix uteri. Acta radio]. (1947) Suppl. No. 64.

JOELSSON I.: Radiotherapy of carcinoma of the uterine cervix with special regard to external irradiation. Acta radio]. (1970) Suppl. No. 302.

KOTTMEIER H. D.: Complications following radiation therapy in carcinoma of the cervix and their treatment. Amer. J. Obst. Gynec. 88 (1964), 854.

MAIER J. G.: Effects of radiation on kidneys, bladder and prostate. Front. Radiat. Ther. Oncol. 6 (1972), 196.

ROSWIT B., MALSKY S. J. and REID C. B.: Radiation tolerance of the gastro-intestinal tract. Front. Radiat. Ther. Oncol. 6 (1972), 160.

SMITH J. P., GOLDEN P. E. and RUTLEDGE F.: The surgical management of intestinal injuries following irradiation for carcinoma of the cervix. In: Cancer of the uterus and ovary, p. 241. Year Book Medical Publishers, Chicago 1969.

STROCKBINE M. F., HANCOCK J. E. and FLETCHER G. H.: Complications in 831 patients with squamous cell carcinoma of the intact uterine cervix treated with 3 OOO rads or more whole pelvis irradiation. Amer. J. Roentgenol. 108 (1970), 393.

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Documents

Complications after Radiation Therapy for Cervical Carcinoma