Carcinoma of the uterine cervix treated with external irradiation alone

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0 Original Contribution CARCINOMA OF THE UTERINE CERVIX TREATED WITH EXTERNAL IRRADIATION ALONE Y. AKINE, :M.D.,* I. HASHIDA, M.D.,* Y. KAJIURA, M.D.,* K. WATAI, M.D.,* I. TSUIUYAMA, M.D .,* S. EGAWA, M.D.,* T. YAMADA, M.D.,? K. TANEMURA, M.D.,? R. TSUNEMATSIJ,M.D.,? K. OHMI, M.D.,t Y. MATSUMOTO, M.D.,? T. SONODA, M.D.t AND T. KASAMAT~U, M.D.? The National Cancer Center Hospital, Tokyo One hundred and four out of 2701 patients with carcinoma of the uterine cervix were treated with a curative intent

by external irradiation alone at the National Cancer Center Hospital from1962to1979.All patients were judged for the combined treatment of intracavitary and external irradiation, which was the treatment of inappropriate choice for patients with advanced carcinoma of the uterine cervix in the hospital. The S-year survival rate was 17% overall and 36, 17., and 5% for patients with Stage II, III, and IV disease, respectively. The local control rate was 20%, at 2 years, for all patients. Major complications were observed in five patients. There were no major complications in patients given a total dose of less than 115 in the Time Dose Fractionation factor (TDF). External irradiation combined with interstitial irradiation and/or hyperthermia is being considered to improve the results. Carcinoma of the uterine cervix, External irradiation alone, Results of treatment. INTRODUCI’ION

radiotherapy. Out of the 1320 patients we identified 190 patients who were treated with external irradiation alone. We excluded 27 patients who were given a total dose of less than 50 Gy, 2 patients who had another primary cancer, 55 patients who were found to have distant metastasis at the time of the first course of treatment, and 2 patients who had carcinoma of the cervical stump. The present

A combination of external and intracavitary irradiation is the treatment of choice: for patients with advanced carcinoma of the uterine cervix in the National Cancer Center Hospital. When a patient is judged inappropriate for intracavitary irradiation, she is treated with external irradiation alone. In this retrospective study, we present the

retrospective study is based on clinical maining 104 patients.

results of patients treated :for cure with external irradiation alone. METHODS

.4ND MATERIALS

records of the re-

Radiotherapy Twenty-two of the 104 patients were treated by a ‘j°Co teletherapy unit with a source axis distance of 80 cm. The remaining 82 patients were treated by a linear accelerator

Eligibility Two thousand seven hundred and one previously un-

treated patients with carc:inoma of the uterine cervix were registered at the Department of Gynecology and the Department of Radiation Therapy, at the National Cancer Center Hospital in Tokyo from 1962, when the hospital was opened, to 1979. Approximately 1320 of these patients were initially treated by radiotherapy alone, and the remaining patients were treated by surgery with or without

of 6 MeV X rays with a source axis distance of 100 cm. Three of the 104 patients were treated with the rotation field during their entire treatment course. The size of the treatment field was 10 cm X 10 cm for two patients and 10 cm X 12 cm for one patient. The total doses were 60.8 Gy in 6 weeks, 72.3 Gy in 7.5 weeks, and 80.5 Gy in 8

Presented at the 44th Annual Meeting of the Japanese Radiological Society, Kagoshima, April 3-5, 1985. * Department of Radiation Therapy. t Department of Gynecology. Reprint requests to: Y. Akine, M.D., Dept. of Radiation Therapy, National Cancer Center Hospital, Tsukiji 5-chome, Chuo-ku, Tokyo, Japan. Acknowledgements-Patients in the present series were treated by a number of physicians who have worked for the National

Cancer Center Hospital. We express our special gratitude to Drs. Y. Umegaki and T. Kitagawa who were Directors of the Department of Radiation Therapy. We also thank Dr. K. Kishi who reviewed pathological specimens and Mrs. H. Arimoto who computerized the patients’ data for the present study. Accepted for publication 24 March 1986.

161I

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Fig. 1. The typical irradiation field currently used. weeks. One hundred and one of the 104 patients were initially treated with the anterior-posterior parallel opposing fields that included the pelvis. The size of the irradiation field varied considerably, ranging from 15 cm X 11 cm to 16 cm X 23 cm. It has gradually evolved to become the present irradiation field in the department. Its upper margin is between the fourth and the fifth lumbar vertebrae and the lower margin is at the center of the obturator foramen. The lateral margins are placed to include the points at which the pulsation of the femoral

September 1986, Volume 12, Number 9

artery is felt. The bilateral upper portions of the irradiation fields are shielded (Fig. 1). For 56 of the 101 patients, the irradiation fields were reduced after about 50 Gy were given. One of these patients received an additional 40 Gy in 4 weeks with the rotation field of 10 cm X 15 cm after she was given 40 Gy in 4 weeks to the pelvis. The four-field box technique was used for one patient to give a booster dose of 22.6 Gy in 2.5 weeks after 51.3 Gy in 5.5 weeks was given to the pelvis. Seven patients were treated with the lateral parallel opposing fields to give a booster dose to the primary site. The size of the lateral irradiation fields ranged from12cmX18cmto10cmX11cm.Thetotaldose ranged from 69.5 Gy in 7 weeks to 8 1.4 Gy in 8 weeks with an average of 74 Gy. For 24 patients, the anteriorposterior parallel opposing fields with the reduced size were used to boost the dose at the primary site. On laparotomy 2 of the 24 patients were found to have metastatic tumors in the para-aortic nodes; the nodes as well as the pelvis were irradiated. The size of the reduced field for the primary site ranged from 20 cm X 13 cm to 6 cm X 7 cm. The total dose ranged from 60 Gy in 6 weeks to 81.6 Gy in 8 weeks with an average of 65.8 Gy. The remaining 23 patients were irradiated to boost the primary site by the method of conformation radiotherapy,6 which is essentially rotation therapy with the changing fields using a cam attached to the multileaf collimator. Typical treatment fields taken with the linear accelerator laterally and antero-posteriorly are shown in Figure 2 and Figure 3, respectively. The total dose ranged from 59.4 Gy in 6 weeks to 70 Gy in 7 weeks with an average of 65.6 Gy. Forty-five of the 10 1 patients who started their irradiation with the anterior-posterior parallel opposing fields were treated with the initial irradiation field during their entire

Fig. 2. and 3. Typical treatment field in conformation radiotherapy taken with the linear accelerator laterally and antero-posteriorly, respectively. A rod was inserted in the cervical canal and a ring was placed at the cervix.

Cervix carcinoma treated with external irradiation 0 Y.

treatment course. The size of the irradiation field ranged from15cmX11cmto15cmX21cm.Thetotaldose ranged from 50 Gy in 5 weeks to 8 1.6 Gy in 8.5 weeks, with an average of 65 Gy. Fifty-one patients who were treated before 197 1 were irradiated through either the anterior or the posterior port on alternate treatment days. Fifty-three patients who were treated after 197 1 were irradiated through both the anterior and the posterior ports every treatment day. Three patients were irradiated with 3 Gy a day, 3 days a week. The remaining 101 patients were irradiated 5 days a week with the daily dose ranging from 1.5 Gy to 2.5 Gy with an average of 2 Gy. The total dose for all 104 patients ranged from 50 Gy to 8 1.6 Gy with an average of 65.7 Gy. Because patients were treated with different fractionations, we converted the total dose to Time Dose Fractiona.tion factors (TDF), using Or-ton and Ellis’ tables.5 The distribution of the TDF given is shown in Figure 4. Follow-up We have obtained complete data on the vital status of all patients for 5 years from the first treatment or until death. The vital status of patients who stopped visiting the clinic was obtained from the family registration in their hometown. Survival rates were calculated by the Kaplan-Meier’s methods3 If a patient was followed for 2 years or more, without any evidence of local relapse, she was considered to have the disease locally controlled. The number of patients with the disease locally controlled was divided by the total number of patients at risk to obtain the rate of local control. The local relapse rate was calculated by dividing the number of patients in whom local recurrence was observed by the total number of patients at risk.

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AKINE et al.

Table 1. Distribution Stage

of stages No. of patients

IA IIA IIB IIIA IIIB IVA

1 0 11 1 71 20

Total

104

squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma for 10 1, 1, and 2 patients, respectively. The distribution of the clinical stages given at the initial examination, according to the FIG0 classification,’ is shown in Table 1. External irradiation alone The distribution of the reasons for treating patients with external irradiation alone is shown in Table 2. Survival rate The survival rates by Stage are shown in Figure 5. Fiveyear survival rates were 17, 36, 17, and 5% for all patients in the present series and Stage II, Stage III, and Stage IV patients, respectively. There was only one patient with Stage I disease in the present series and she survived for more than 14 years.

RESULTS

Local control rate Local recurrence was found in 5 1 patients with the local relapse rate being 49% for all patients. In all 5 1 patients, local recurrence was within 2 years from the initial treatment. Twenty-one of the 28 patients who continued to visit the clinic for 2 years had no local recurrence. Local recurrence was observed in 6 and was suspected but not

Patient characteristics The ages of the patients ranged from 37 to 81 years with an average of 60 ye.ars. Pathological diagnoses were:

Table 2. Reasons for treatment with external irradiation alone Anatomy in pelvis

1

F

Fig. 4. Distribution

of TDF.

Large tumor volume Narrow vaginal space Tumorous cavity in vagina Perforated uterine cavity Adjacent organs infiltrated Uterine cavity not suited for insertion of the applicator Fistula Pelvic node metastasis Para-aortic node metastasis Apoplexy Schizophrenia Dementia Severe anemia Older age Patient’s choice Undetermined Total

87 44 6 8 1 11 13 3 1 1 4 1 1 2 1 2 5 104

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September 1986, Volume 12, Number 9

SURVIVAL RATE

I

2

4

3

5

YEAR

Fig. 5. Survival rates by stage.

TOTAL

PATIENTS

104

MINIMUM TWO-YEAR FOLLOW UP

23

78

4

i LOCAL

RELAPSE

UNOETEReNO

NOAVES

LOCALLY

LOCAL

RELAPSE

UNKNOWN

LOCAL

RELAPSE

LOCALLY

CONTROLLED

21

51

32

Fig. 6. Local status for all patients.

clinically confirmed in one of the 28 patients. The local control rate was 20% for all patients and 27, 19, and 15% for patients with Stage II, III, and IV disease, respectively. The one patient with Stage I disease had no local recurrence. The clinical courses described above are shown in Figure 6. Relationship between survival and local control Sixty-four of the 104 patients in the present series were dead at 2 years. Twenty-eight of the remaining 40 patients were continuing to visit the clinic at 2 years. Twelve of the 21 patients with locally controlled disease survived for 5 years or more. Causes of death for the remaining 9 patients, who had locally controlled disease and died within 5 years, were: intercurrent disease, distant metastasis, complication, and unknown cause for 3, 2, 1, and 3 patients, respectively. Six of the 18 patients surviving 5 years or more discontinued visiting the clinic within 2 years (Fig. 7).

Complications Four patients had major complications which required surgical treatment. One patient was reported to have died of rectal bleeding. Two of these 5 patients had the initial irradiation fields during the entire treatment course. The total doses and the size of the fields were 72 Gy in 6 weeks and 12 cm X 16 cm for one patient, and 69.4 Gy in 6.5 weeks and 18 cm X 15 cm for the other. Both patients underwent colostomy for rectal bleeding. One of the 5 patients was given 59.8 Gy in 5.2 weeks to the pelvis with the anterior-porterior parallel opposing fields of 17 cm X 16 cm and a booster dose of 22 Gy in 2.2 weeks with the lateral parallel opposing fields of 10 cm X 15 cm. She

LOCAL CONTROL AT TWO YEARS

Dose-response relationship The dose-response relationship with the 5-year survival rates and the local control rates for 92 patients with Stage

III and IV disease are shown in Figure 8 and Figure 9, respectively.

Fig. 7. Relationship between five-year survival and local control.

Cervix carcinoma treated with external irradiation 0 Y. AKINE et al.

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SURVI’ RATI

26 PTS 13 PTS -

15 PTS 19 PTS -

6 PTS

O-

4

60

90

100

110

I 130

120

6 PTS x

??

1 140

150

TDF

Fig. 8. Five-year survival rates for Stage III and IV patients by TDF.

Both the anterior and the posterior fields were irradiated every treatment day. This group is designated as “Conformation therapy” in Table 3. There was another group of 3 patients who were treated with the rotation field during their entire course. Though treatment techniques were so diverse that it is difficult to subdivide the remaining patients, we have arbitrary divided the patients into two groups. One group consists of 45 patients whose irradiation field was not reduced during their entire treatment course (Subgroup “Not coned down”). The other group consists of 33 patients whose irradiation fields were reduced during the treatment course (Subgroup “Coned down”). The number of patients who survived for 5 years or more, who had locally controlled disease, and who had a major complication are listed in Table 3.

later received a resection of the ileum and urinary bladder for hemorrhage from which she died. Another patient was given 69.6 Gy in 6 weeks to the pelvis with the 15 cm X 15 cm anterior-posterior parallel opposing fields and an additional dose of 12 Gy in 1.2 weeks with the 10 cm X 10 cm anterior-posterior parallel opposing fields. She later underwent colostomy for rectal bleeding. The remaining patient was given 36 Gy in 3 weeks to the pelvis with the 15 cm X 15 cm anterior-posterior parallel opposing fields and a booster dose of 38.4 Gy in 3.2 weeks with the 14 cm X 12.5 cm anterior-posterior parallel opposing fields. She reportedly died of rectal bleeding 28 months after the initial treatment. Treatment technique and outcome of the patients The techniques used in the present series were markedly diverse. However, there w;as a group of 23 patient treated, after 197 1, in a relatively uniform fashion. They were treated with the anterior-posterior parallel opposing fields to receive approximately 50 Gy in the pelvis. The technique of conformation therapy wa used to boost the dose at the primary site. The total dos e9I ranged from 59.4 Gy to 70 Gy. The daily dose was either 1.9 Gy or 2.0 Gy.

DISCUSSION

Koeck et al4 and Kakehi’ reported that in patients with carcinoma of the uterine cervix, the results of treatment with external irradiation alone were comparable with those of treatment with a combination of intracavitary and external irradiation. Patients in the above series could

LOCAL coRY::L*

’

1 5 PTS

.40 -

??

‘

6 PTS e .30-

19 PTS

.20-

26 PTS -

.lO-

13 PTS

15 PTS 8 PTS

o-

70

60

90

100

110

120

130

140

150

TOF

Fig. 9. Local control rates for Stage III and IV patients by TDF.

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Table 3. Results of treatment bv the techniaue Subgroup

Number of patients

Conformation therapy Not coned down Coned down Rotation therapy

23 45 33 3

8 6 4 0

8 5 8 0

0 2 3 0

104

18

21

5

Total

5-year survival

be treated with intracavitary irradiation. Because patients in the present series could not be treated with intracavitary irradiation for various reasons, it is meaningless to compare the results in the present series with those in the other two series. Ulmer and Frischbier7 recently reported 75, 30.3, and 13%, 5-year survival rates for patients with Stage II, Stage III, and Stage IV carcinoma of the uterine cervix treated with external irradiation alone. They treated 70 of the 150 patients in their series with external irradiation alone because of vaginal wall involvement of the tumor. Because we treated patients with vaginal wall involvement by intracavitary irradiation, the population of patients in the present series is different from that in their series. Forty of the 104 patients in the present series were alive at 2 years. Twelve of the 40 patients discontinued visiting the clinic by 2 years. Although we have obtained complete data on vital status, the follow-up on the local status was incomplete. This made the local control rates in the present series slightly inaccurate. We estimate the true local control rate to be between 20 and 5 1%. Twentyone of the 104 patients had locally controlled disease at 2 years, whereas 5 1 patients were observed to have local recurrence. The remaining 32 patients were either dead with unknown local status or lost to follow-up. If we assume that all 32 patients had locally controlled disease, the local control rate would be 5 1% (53 of 104). On the other hand, if we assume that all 32 patients had local recurrence, the local control rate would be 20% (21 of 104). It would probably be closer to 20% than to 5 1%.

Local control

Major complication

Therefore, local relapse accounted for a major portion of the treatment failures in the present series. There was no improvement in either the survival rate or local control rate in the group of patients who had a total dose of 115 or more in TDF. Patients who were given higher doses had more radio-resistant tumors. Therefore, it is impossible to draw a conclusion that there is no dose-response relationship in the present series. However, it seems unrealistic to expect much improvement in the local control rate by giving a patient higher doses of external irradiation alone. In the subgroup of 23 patients who were treated with the conformation therapy, the 5-year survival rate and the local control rate is higher than in the other subgroups. There were 4 patients with IIB disease, 18 with IIIB, and 1 with IVA in the subgroup, which does not show marked deviation of the stage distribution from the other patients. It is possible to expect an improvement in the results by extensive use of this technique. We are also considering the use of interstitial irradiation with Ir-192 and/or hyperthermia combined with external irradiation for patients with more radio-resistant tumors. Because 64 of the 104 patients had died within 2 years and the methods of treatment used varied considerably, calculating the complication rate in the present series is not worthwhile. However, it is noted that there were no patients with major complications among the patients who were given 115 or less in TDF. We conclude that irradiation with 50 Gy in 5 weeks for the whole pelvis followed by 20 Gy in 2 weeks for the primary site is safe.

REFERENCES Harmer, M.H. (Ed.): TNM Classification of Malignant Tumows, 3rd edition, Geneva, International Union Against Cancer 1978. Kakehi, M.: Radiotherapy of carcinoma of the uterine cervix by the External Irradiation Using Conformation Technique. Jap. J. Med. Radiol. 35: 16-27, 1975 (in Japanese). Kaplan, E.L., Meier, P.: Nonparametric estimation for incomplete observation. J. Am. Stat. Assoc. 53: 457-48 1, 1958. Koeck, G.P., Jacobson, L.E., Hillsinger, W.R.: Results of

cobalt 60 rotation therapy in carcinoma of the cervix. A.J.R. 96: 81-91,

1966.

Orton, C.G., Ellis, F.: A simplification in the use of the NSD concept in practical radiotherapy. Brit. J. Radiol. 46: 529537, 1973.

Takahashi, S.: Conformation radiotherapy. Acta Radiol. (Suppl. 242.): 1965. Ulmer, H.U., Frischbier, H.-J.: Treatment of advanced cancers of the cervix uteri with external irradiation alone. Znt. J. Radiat. Oncol. Biol. Phys. 9: 809-8 12, 1983.