External beam radiotherapy in the management of ovarian carcinoma

External beam radiotherapy in the management of ovarian carcinoma

26 Radiotherapy and Oncology, 26 (1993) 26-32 © 1993 Elsevier Scientific Pubfishers Ireland Ltd. All fights reserved. 0167-8140/93/$06.00 RADION0105...

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Radiotherapy and Oncology, 26 (1993) 26-32 © 1993 Elsevier Scientific Pubfishers Ireland Ltd. All fights reserved. 0167-8140/93/$06.00

RADION01059

External beam radiotherapy in the management of ovarian carcinoma M a r i a n Reinfuss, Z b i g n i e w K o j s a n d J a n S k o I y s z e w s k i Center of Oncology, Maria Sktodowska-Curie Memorial Institute, Cracow, Poland (Received 12 February 1991, revision received 16 June 1992, accepted 3 July 1992)

Key words: Ovarian carcinoma; External beam radiotherapy

Summary Between 1970 and 1983, 345 patients with ovarian cancer clinical stage I, II, and III were irradiated postoperatively. Five-year NED survival was achieved in 41.7% of patients. The most important prognostic factors were histological grade and clinical stage of cancer. Postoperative external beam radiotherapy appeared to be highly efficient for the patients with microscopic residual disease, giving 70 ~o 5-year survival, and moderately efficient for patients with small, i.e. ~<3 cm in diameter residual disease, giving 40~o 5-year survival. The optimal technique of irradiation appeared to be the irradiation given to the entire abdominal cavity with additional irradiation coned down to the pelvis. External beam radiotherapy was ineffective in patients with gross residual disease, i.e. > 3 cm in diameter, and useless as palliative treatment given to patients with inoperable cancer of the ovary.

Introduction

External beam radiotherapy in ovarian cancer is mostly limited to postoperative treatment, delivered after incomplete surgery. External beam radiotherapy for these patients is only one of the therapeutic options. The others are: systemic chemotherapy, intraperitoneal administration ofcytostatic drugs or radioisotopes in less advanced cases [ 16-18,26,35,37,41 ]. There were also attempts to apply external beam radiotherapy for palliative and pre-operative (induction) treatment in patients with advanced ovarian cancer. [2,34]. The aim of this study is to present our experience with primary postoperative, and also palliative, radiotherapy in ovarian cancer.

Material and methods

Between 1970 and 1983 at the Department of Radiation Therapy of the Center of Oncology in Cracow, 345 women with histologically confirmed ovarian carcinoma received abdominopelvic radiotherapy. All these women were referred to our Department after previous

surgery, which was performed in 90 ~o of cases in other hospitals. Two-hundred and forty-five patients, that is 71.0~o, were referred to our Center after routine procedures applied in such cases, comprising: bilateral salpingo-oophorectomy, total hysterectomy, subcolic omentectomy, inspection and palpation of abdominal organs and diaphragm, peritoneal washing for cytology and biopsies of suspected areas. In 12 patients surgical procedure also included selective paraaortic and pelvic lymphadeneetomy. Debulking surgery only was done in 43 cases, that is in 12.5~o o f o u r patients. In 52 women (15.1 ~o) with advanced cancer, even debulking surgery was not possible, and only exploratory laparotomy and biopsy were done. Five patients were referred to our Department after unilateral oophorectomy only. They were all young women, under 35 years of age, with stage I cancer, who wished to preserve fertility.

Staging work-up and evaluation Clinical investigations before surgery included a careful history and complete physical examination, routine biochemical analysis (renal and liver function tests), complete blood count and chest radiography. In most

Address for correspondence: M. Reinfuss, Center of Oncology, Maria Sldodowska-Curie Memorial Institute, Garncarska Street 11, Cracow, Poland.

27 cases intravenous pyelography and barium contrast studies of the colon were also performed. The disease extent after laparotomy was defined according to the following criteria: nontesidual disease (absence of macroscopic and microscopic evidence of tumor with negative peritoneal cytology and negative random biopsies); minimal residual disease (positive cytology and/or random biopsies); small residual disease (the presence of isolated peritoneal metastases equal to or less than 3 cm in diameter); gross residual disease (the presence of peritoneal metastases more than 3 cm in diameter). Clinical staging and pathological grading were based on UICC 1987 classification [38]. The patients were qualified retrospectively to the clinical stages and histological grades according to this classification. Treatment

All our patients received postoperative primary external beam radiotherapy with a 6°Co machine, using 80 cm SSD. Irradiation was started 3-7 weeks after surgery. Over the years 1970-1975 two irradiation techniques were applied:

(1) Whole abdominal cavity irradiation. The irradiated volume comprised the whole abdominal cavity from the diaphragm down to the bottom of the true pelvis. Two opposed fields, anterior and posterior, were used. The tumor dose, calculated at the mid-distance between the fields, was 3500-3900 cGy given in 28-30 fractions over 6-7 weeks. After 1875-2000cGy, posterior shielding of kidneys and anterior shielding of the liver were used. (2) Pelvic irradiation. The irradiated volume comprised the whole pelvis. Two opposed fields, anterior and posterior, were used. The tumor dose calculated at middistance between the fields was 3600-4500 cGy delivered in 24-30 fractions over 5-6 weeks. The selection of patients to one of the two above described techniques was a physician's choice, depending on the preferences of the treating team. The third technique, i.e. entire abdominal irradiation with pelvic "boost" was introduced in 1976. At the first phase of treatment the whole abdominal cavity was irradiated. Two opposed, anterior and posterior, fields were used. The upper borders of the fields reached

TABLE I Clinical ~ a t u r e s i n t h r ~ ~oups ~ p ~ t s ~ e a t e d Clinical features

~

~ e d i f f e r ~ t ~a~afionteclmiques.

Technique I: whole abdominal cavity No.

Technique II: pelvic only

%

No.

Technique III: whole abdominal with pelvic "boost" %

No.

%

Age: ~<50 > 50

39 43

47.6 52.4

38 42

47.5 52.5

88 95

48.1 51.9

Histology: Serous carcinoma Mutinous carcinoma Undifferentiated carcinoma Endometroid carcinoma Clear-cell carcinoma

38 19 II I1 3

46.3 23.2 13.4 13.4 3.7

38 18 I1 I0 3

47.5 22.5 13.7 12.5 3.8

86 42 26 22 7

47.0 23.0 14.2 12.0 3.8

30 52

36.6 63.4

29 51

36.3 63.7

66 117

36.1 63.9

Clinical stage (UICC 1987) I + II III

48 34

58.5 41.5

46 34

57.5 42.5

105 78

57.4 42.6

Extent of cancer after surgery: Nonresidual Minimal residual Small residual Gross residual

28 7 21 26

34.2 8.5 25.6 31.7

27 7 21 25

33.7 8.7 26.3 31.3

60 16 48 59

32.8 8.8 26.2 32.2

Total

82

100.0

80

100.0

183

100.0

Differentiation: G1 G2+ G 3

28

1-2 cm above the diaphragm, at the expiratory phase. The lower borders were set up just below thoe level of obturator foramens, and the side borders 1 cm beyond the peritoneal cavity. The tumor dose calculated at middistance between the fields was 3000 cGy delivered in 24 fractions over 5 weeks. Kidneys were shielded from the back (location was established by intravenous pyelography), and liver was shielded from the front after the dose of 1875-2000 cGy was delivered. At the second phase irradiation was delivered only to the pelvis, using two opposed fields, anterior and posterior. The tumor dose calculated at mid-distance between fields was 2000 cGy given in 10 fractions over 2 weeks. These three groups of patients treated with the different irradiation techniques, were very much alike in respect of their clinical features (see Table I). Patients of the studied group did not receive any complementary chemotherapy. Chemotherapy was administered only in case of inoperable recurrence or distant spread of cancer. In the whole group of 345 patients the complete scheduled treatment with radiotherapy was performed in 91.3 ~ of patients. In 8.4~ of them there was a break of 5-11 days, resulting mostly from leuko- and or thrombocytopenia. In 3.2~ of patients radiotherapy was discontinued due to poor tolerance of treatment: leuko- and or thrombocytopenia (4 patients), nausea and vomiting (3 patients), peritonitis (3 patients) and pulmonary edema (1 patient). One patient died during radiotherapy of acute fight ventricular failure. In 5.2% of our patients further irradiation was discontinued due to tumor progression. Late radiation morbidity grade 3-4, according to the RTOG/EORTC scoring scheme, occurred in 8 women, i.e. in 2.3 ~ of the whole group. Six patients developed bowel obstruction, out of whom 4 required surgery. Two patients developed bowel perforation at 6 and 8 months aRer treatment. Both had surgery and died at the third year after treatment of local recurrence of cancer. In none of our patients has clinical evidence of post-irradiation damage to the kidneys or liver been found, although 4 patients demonstrated biochemical evidence of liver damage with elevation of the alkaline phosphatase level. Statistical methods Every patient in this study was treated at least 5 years prior to the data of analysis. Five-year survival without evidence of disease (NED) is used as the end-point for analysis. The survival time was calculated from the first day of irradiation. The log-rank test was used in order to compare the survival curves, differences being considered statistically sitmificant if p<0.05 [29]. Multi-

variate analysis was conducted by the Cox proportional hazard model [8] to identify the onset of independent prognostic factors for 5-year NED survival. Results

One-hundred and forty-four patients (41.7 %) out of the group of 345 patients treated with postoperative irradiation survived NED for at least 5 years. Table II shows the results according to the clinical features of our patients. In this univariate analysis no statistically si~ificant relation between treatment results and the age of patients and duration of symptoms were found. Of significant influence on the treatment results were the histological type of cancer, the grade of differentiation, and clinical stage assessed according to the UICC 1987 classification. In the Cox multivariate analysis two variables only were independently related to beneficial survival: grade G1, and stage I + II (p<0.001). Figures 1 and 2 present the 5-year NED survival of TABLE II Results of treatment of 345 ovarian cancer patients. Clinical features

No. of patients

5-year NED survival No.

%

Age: ~<50 > 50

165 180

70 74

42.4 41.1

Duration of symptoms" ~<6 months > 6 months

220 125

89 55

40.5 44.0

Histology: Serous carcinoma Mucinous carcinoma Undifferentiated carcinoma Endometroid carcinoma Clear-cell carcinoma

162 79 48 43 13

65 43 9 24 3

40.1" 54.4 18.8 55.8 23.1

Differentiation: Ga G2 G3

125 140 80

85 41 18

68.0* 29.3 22.5

Clinical stage: Ia Ib Ic IIa IIb IIc III

80 25 39 20 28 7 146

68 17 22 11 11 3 12

85.0* 68.0 56.4 55.0 39.3 42.9 8.2

Total

345

144

41.7

* Statistically significant differences (log-rank test).

29

A

-- ~-~,~

NONRESIDUAL - 115PTS MINIMAL RESIDUAL-30 PTS SMALL RESIDUAL - 90 PTS

-x--x-

GROSS RESIDUAL- 110 PTS

100 -

TABLE III Follow-up of 345 patients with ovarian carcinoma. Results

Patients

90. ~ . ~ , 6

No. '~V,

73,0

60.

70,0

70.0

.,0

50'

'-

"

~!3o, ~ - Io

~-.,~,.,~4.s 1

2

3

27

27

4

5

YEARS

Fig. 1. Five-year NED survival according to the extent of after

/

-----

I TECHNIQUE-S2PTS

------ll

100 "

cancer

surgery.

TECHNIQUE- 80 PTS -,..PTS

m 90"

80.

70"

~. z

!,o

~ , = , : : : . _ ...~.o

,°I 3O

32.9

32,9

3z.9 32.5

20

i

i

i

I

2

3

i 4 YEARS

I

>

S

Fig. 2. Five-year NED survival according to irradiation technique.

345 patients with ovarian carcinoma treated by postoperative radiotherapy correlated with extent of cancer after surgery and irradiation technique applied. The compared groups of patients treated with the different irradiation techniques were very much alike in respect of prognostic factors (see Table I). Figure 1 presents the effectiveness of postoperative external beam radiotherapy in the treatment of ovarian cancer patients. It proved ineffective in gross residual disease > 3 cm in diameter. Out of 110 patients only three patients, that is 2.7%, survived for 5 years NED. In the group of 90 patients with residual disease ~<3 cm (in 95 % patients located within the pelvis area) external beam radiotherapy gave 40% 5-year survival, and in those with minimal residual disease 70% of the patients survived 5-year NED. Out of 115 patients in whom surgery was complete in both microscopic and macroscopic respects, 31 pa-

5-year NED survival 5-year survival with cancer Died with cancer during the 5-year follow-up period Died during the 5-year follow-up period for reasons not related to cancer

144 2

41.7 0.6

191

55.4

8

2.3

Total

345

100.0

dents (27.0%) failed to survive 5 years, and 28 of them died of ovarian carcinoma. Fifty-two patients had stage IAGI cancer and 50 of them, i.e. 96.1% survived NED for 5 years (two patients died for reasons not related to cancer). In the remaining 63 patients (IAG2 and G3, Ib and Ic) only 34 patients, that is 54%, achieved 5-year NED survival. The technique of irradiation of the entire abdominal cavity plus pelvic "boost", introduced in 1976, has offered a significant statistical improvement in the treatment results (log-rank test, p < 0.025). The relevant survival curves are shown in Fig. 2. In order to assess the effectiveness of external beam radiotherapy as a palliative treatment the results of irradiation of 52 patients with inoperable cancer, who had only laparotomy, were analyzed. According to WHO criteria none of these patients responded. None of the patients survived for more than 2 years after irradiation and 80% of them died within the first year after treatment. The results of the follow-up of our patients are presented in Table III. Five patients died during the 5-year follow-up period of myocardial infarction, two patients died of cerebral hemorrhage, and one died in a car accident. Out of 193 patients with persistent cancer, 186 patients (96.4%) died of cancer within the abdominal cavity, and only seven patients, (3.6%) died of distant metastases to lungs, liver, pleura, bones, skin and brain. Discussion

Out of the whole group of 345 patients with ovarian carcinoma, treated with surgery followed by irradiation, 41.7 % patients survived for 5 years without evidence of disease. Dembo gives 45%, Fuller et al. 41.5%, Goldberg and Peschel 62%, Macbeth et al. 49%. The differences arise mostly from diverse clinical stages in different groups of patients [ 12,20,21,23].

30 The present study confirms the role of prognostic factors in ovarian carcinoma such as: histological grade and clinical stage of cancer [ 5,9,11,14,15,19,20,24 ], but not patients' age and histological type of cancer. The main objective of our study was to assess the value of radiotherapy in postoperative treatment of patients with cancer of the ovary. It has been shown that the effectiveness of postoperative external beam radiotherapy depends mostly on the size of residual tumor left in the abdominal cavity. There are three situations that can be distinguished here: (1) Patients with no visible residual. External beam radiotherapy proved to be effective in women with only microscopic residual disease present, and 70% o f 5-year NED survival has been achieved in this group. It is more difficult to assess the role of external beam radiotherapy in patients after complete surgery, i.e. with neither macroscopic nor microscopic residuals. Fiftytwo such patients were classified as IAGx, and 50 patients, i.e. 96.2 70, survived 5 years with no evidence of cancer (two died from intercurrent disease without cancer). Has it been the effect of postoperative radiotherapy? Judging from the data published by other authors, patients at this stage do not require any postoperative treatment at all [6,12,15,17,21,31,32,36,39]. Most of the authors report on nearly 10070 of cures after surgery only for patients with early ovarian cancer having complete surgery [7,10,22 ]. Dembo writes that approximately 95 70 of patients in stage I, having well differentiated tumors are cured by surgery alone and do not require postoperative therapy [ 15]. Still, most authors assume that apart from stage IAGx the remaining stage I patients need postoperative treatment, as even in cases classified as stage I there is a number of patients, equaling several percent, with neoplastic ceils present in peritoneal effusion, subclinical metastases to the regional lymph nodes and or at the top of the phrenic dome where the cells deposit in the subphrenic lymphatic plexus [ 17,25,30,40]. This is in keeping with our observations: strikingly poorer treatment results have been obtained in the 63 stage I patients (apart IAGI) with nonresidual disease (5470 5-year survival rate only). Strangely enough this result is lower than that obtained in patients with minimal residual disease. This is probably due to too optimistic intraoperative assessment of the completeness of surgery in our group, and to inadequate staging, particularly in the years 1970-1975. (2) Patients with small residual disease less than or equal to 3 cm in diameter. In these patients postoperative external beam radiotherapy allowed to cure 40 70 of women. Most authors tend to recotmize 2 cm of

tumor diameter as the border value [ 12,14,20,21,24]. In spite of this difference, our results are close to those given by the other authors, as approximately 40-5070 of patients with small residual lesions were cured [9,14,15,21,24]. (3) In our group external beam radiotherapy was totally ineffective in the treatment of patients with gross residual disease. Only 2.770 of patients survived 5 years without cancer. This is confirmed by other authors, who obtained the 5-year survival rates in these patients ranging from 0% to 1570 [10,12,15,19-21,24,28]. External beam radiotherapy has also proved useless as a method of palliative treatment for patients with inoperable ovarian cancer. At present, the treatment of choice in these patients seems to be the combination chemotherapy based on Cisplatin [1,3,4,11, 17,27,30,37]. The basic reason of treatment failure of patients in our group was persistent cancer within the abdominal cavity (96.470 of patients not cured), which is in keephag with the data from the literature [5,13,17]. In our study the irradiation of the entire abdominal cavity with pelvic "boost" (technique III) gave sit,nificantly better survival rates than irradiation of the pelvis alone (technique II) or of the whole abdominal cavity without "boost" to the pelvis (technique I). This is in keeping with the data presented by Dembo et al. [10,12,14,15]. Technique I and II were applied over the years 1970-1975, technique III over 1976-1983. The intraoperative assessment, staging procedures, and selection of the patients to postoperative radiotherapy may have been more or less different in the compared groups. Although these three groups were very much alike in respect of their clinical features, we have to take into account also the possible influence of different periods of treatment delivery on the results of this study. It has been found that the conventionally fractionated dose of 3000 cGy delivered to the entire abdominal cavity, with adequate shielding of the kidneys and liver, and the dose of 5000 cGy given to the true pelvis are well tolerated; only in 3.270 of patients was irradiation discontinued due to poor tolerance. Late radiation side effects concerning rectosigmoid colon and small intestine were seen in only 2.370 of our patients. Surgery for these complications was required in six (1.770) of our patients. In the literature the frequency of surgical intervention and deaths due to bowel complications of abdominopelvic radiotherapy ranges from 1.47o to 14% [14,15,21,28,33]. Subclinical symptoms of liver damage were found in 1.1% of patients. Dembo says that about 5070 of the patients demonstrate biochemical evidence of liver

31

damage, but at the same time he does not propose shielding to the fiver at delivering the 2500-2800 cGy dose in daily fractions of 100-120 cGy [15]. In our group the fiver was shielded after the dose of 1875-

2000 cGy in 15-16 fractions. Some authors point out that such an early shielding of kidneys and fiver can give a risk of underdosage in some critical sites of possible dissemination, for instance the diaphragm [16].

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