Evaluation of whole abdominal irradiation in ovarian carcinoma with a four orthogonal fields technique

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0 Clinical Original Contribution

Int. J. Radiation Oncology Biol. Phys., Vol. 30, No. 5, pp. 1083-1090, 1994 Copyright 0 1994 Ekvier Science Ltd Printed in the USA. All rights reserved

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EVALUATION OF WHOLE ABDOMINAL IRRADIATION IN OVARIAN CARCINOMA WITH A FOUR ORTHOGONAL FIELDS TECHNIQUE

LAURENCE THOMAS,* JACQUES PIGNEUX,* JACQUES CHAUVERGNE,~ EBERHARD STUCIUE,~ EMMANUEL BUSSI&RES,~ ANTONY CHEMIN* AND CLAUDE TOULOUSE§

*Department of Radiation Oncology, +Department of Medical Oncology, *Department of Surgery, “Department of Biostatistics, Fondation Bergon%, Comprehensive Cancer Center, 180, rue de Saint-Gengs, 33076 Bordeaux Cedex, France

Purpose: The purpose of this study is to evaluate the toxicity and the results of ahdominopelvic irradiation with a four orthogonal field’s technique in patients with ovarian carcinoma. Methods and Materials: Between May 1981 and December 1990, 167 patients with ovarian carcinoma have been treated with whole abdominal irradiation: 62 patients with no or minimal residual disease < 2 cm after initial surgery (group 1) and 105 patients with no residual disease or macroscopic residual disease < 2 cm assessed by second-look surgery after incomplete debulking surgery and cisplatin-based polychemotherapy (group 2). Irradiation was performed by a four orthogonal field’s technique. Thirty grays were given with a 25 MV photon beam (1.5 Gy/fraction/day, 20 fractions over 30 days). Boosts were performed in 50 cases (median dose of 15 Gy). Results: With a median follow-up of 68 months, the 5-year actuarial survival rate was 50% in the entire group, -group 1,40% in group 2, and 84% in Tl, 61.5% in T2,38% in T3. Five-year actuarial survival was analyzed according to the residuum: (a) after initial surgery (no residual disease: 70%, residual disease: 36.5%), (b) after second-look surgery: 76% in patients with a negative second look, 66% in patients with microscopic residual disease, 22% in patients with macroscopic residual disease and secondary surgical reduction, and 10% in patients with small unresectable nodules. Nine percent of the patients failed to complete irradiation acute side effects related. Five percent required surgery for bowel obstruction. Conclusion: The abdominopelvic irradiation with this four orthogonal field’s technique was associated with tolerable acute toxicity and a low risk of serious late complications. Similar late results to have been reported whole abdominal irradiation with chemotherapy in patients with negative or microscopic residual disease after surgery. Randomized trials comparing these two adjuvant treatments are warranted.

Ovarian carcinoma, Four orthogonal fields technique, Whole abdominal irradiation.

INTRODUCI’ION

The nature of further treatment following surgery in the management of ovarian carcinoma is still controversial.

In 1980, Dembo and Delclos have published the results of a randomized study comparing pelvic radiation therapy alone or with chlorambucil and abdominopelvic radiotherapy in patients who had minimal residual disease after primary surgery. They concluded that whole abdominal irradiation was curative for patients Stage Ib, II, III with small residuum ( 12- 14).

At the same time, the use of cisplatin containing chemotherapy extended because of excellent response rates in advanced ovarian disease (7, 10,37). It raised the ques- tion of the real benefit of whole abdominal irradiation in the treatment of ovarian carcinoma. To answer this ques- tion, in 1982 a multicenter trial in French Centers was initiated. In this trial, the patients with no residual disease or minimal residual disease < 2 cm after initial surgery,

were randomized to receive abdominopelvic irradiation or adjuvant cisplatin based chemotherapy. The patients with residual disease after initial surgery received cisplatin based chemotherapy (two regimens were randomized). Then, they underwent second-look laparotomy and the patients with no residual disease or disease x 2 cm were randomized to receive abdominopelvic irradiation or chemotherapy. We used in this trial an original open field technique with four orthogonal fields. From these data, all our patients are treated according to this technique.

We report here the acute and late toxicity of this technique and the results.

METHODS AND MATERIALS

Patients From May 198 1 through December 1990, 167 patients

with ovarian carcinoma have been treated with whole ab-

Reprint requests to: Laurence Thomas, M.D. Accepted for publication 1 July 1994.

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Table 1. Patient Characteristics

Group

(n =’ 62) Group 2

(n = 105)

Stage (TNM) Tl NO MO

:

T2CN0 MO

:

T2CNl MO

:

T3CN0 MO

:

T3CN1 MO

: C

Residual disease after initial surgery

None Microscopic Macroscopic 5 2 cm

Residuum after second look surgery

None Microscopic Micronodules (scarce) Macronodules (multiple) Nodules < 2 cm (scarce)

Grade

iI III nonassessed

Histology Serous Endometrioid Mutinous Clear cell Undifferentiated Carcinoma

23 5 6 0

16 21

5 3

13 2 1 1 0

13 4 6 3 3

0 2

54 10 4 43 4 52

10 35 3 25

13 31 36 14

28 15 I 2 8 2

4 8

4 3

0 0

64 2

26 36 19

1 3

15 1 T2b Nl Ml 4T3Nl Ml

lb 3c

3T3NOMl lb 2c

38 43

7 12 3

76 11 5 2

10

dominal irradiation at the Fondation Bergon& The patients with T 1 a and T 1 b well and moderate differentiated were not included in this study: they were treated only by surgery. Characteristics of these patients are reported in Table 1. The median age was 54 years (range 26-75). All patients underwent initial surgery. For all patients,

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the treatment protocols were chosen according to the amount of residual disease following initial surgery.

In 62 patients, the abdominal irradiation was done im- mediately after initial laparotomy (group 1). In 58 patients, no macroscopic residual disease remained following initial surgery. Four patients with residual disease < 2 cm were considered as having minimal residual disease and were treated as the first ones.

One hundred and five patients with residual disease following initial surgery, were treated with cisplatin-based chemotherapy, second-look surgery before radiotherapy. The abdominal irradiation was done if no residual disease or minimal residual disease 5 2 cm was documented (group 2). From January 1987, whole abdominal irradiation was done only in patients with no residual disease or macroscopic residual disease s 1 mm (n = 80).

Treatment Surgery. Forty-two patients underwent initial surgery

at the Fondation Bergonit. Among 125 patients who have been operated in another hospital, 34 have been reassessed either by a laparoscopy (20 patients) or by a second laparotomy (14 patients) because the staging procedure was not complete. The surgical staging was done according to the TNM classification (39).

Initial surgery was an abdominal hysterectomy and bi- lateral salpingoophorectomy, omentectomy, multiple peritoneal biopsies, and peritoneal cytology. Pelvic and paraaortic dissection was not routinely performed except in 19 cases (limited to retroperitoneal nodes in nine cases).

Second-look procedures were performed to assess the degree of response to chemotherapy (77 laparotomies, 28 laparoscopies). It consisted in resection of macroscopic residual disease, multiple peritoneal biopsies, and peritoneal cytology. The second-look outcome according to stage, grade, and residuum after first surgery is reported in Table 4.

Chemotherapy. Chemotherapy used was cisplatin based chemotherapy with different regimens detailed in Table 2. The median number of cycles was six. Radiotherapy. Whole abdominal irradiation was given with an open field technique initially described by De- louche et al. (11) using four orthogonal 25 MV photons beams. The treatment fields extended from 1 cm above

Table 2. Postsurgical chemotherapy

Administered combinations Number of patients

CHAP 69 AVEC 5 CAF 1 CAP 8 CAP FU 1 CP 16

A: adriamycin; C(E): cyclophosphamide; F(FU): 5-fluoroura- cil; V(VM26): teniposide; P: cisplatin; H: hexamethylmelamine.

Whole abdominal irradiation 0 L. THOMAS et al. 1085

the diaphragms to below the peritoneal reflections. For the anterior and posterior fields, a liver shield was made for the right liver only. Its shape ensured an adequate irradiation of the right hemidiaphragm, the paraaortic area, and the right paracolic gutter. A posterior renal shield was set at the beginning of irradiation.

For lateral fields, we added a shield for the lombar ver- tebrae bone marrow, which allowed the irradiation of the diaphragm reflection and retroperitoneal nodes (Fig. 1). Thirty grays were given to the entire abdomen at half- width in 20 fractions of 1.5 Gy over 30 days. The four fields were treated daily and five fractions of 1.5 Gy were done per week.

The kidney dose was limited to 10 Gy, the right liver dose to 14 Gy at the anterior part and 3 Gy at the posterior part, the bone marrow received 17 Gy, and the middle part of the paracolic gutter 25 Gy. The dose distribution was calculated with computed tomography slices on a do- simetry Target system (GEl).

Boosts were performed for 50 patients: in 17 cases for group 1 and 33 cases for group 2. Boosts were not routinely done, but adapted to surgical findings (difficulties for surgical removal, extension). Before 1987, the median dose given by the boost was 18.3 Gy (4-35) and most time the entire pelvis was irradiated.

From 1987, on the basis of preliminary results con- cerning small bowel obstruction requiring surgery, we have decided to perform boost on reduced volumes at a maximum dose of 15 Gy. From 1987, boosts were given with a median dose of 13 Gy (lo-20 Gy) and only on limited pelvis for half-cases. The frequency of boost was the same during the two periods: 29 out of 87 before 1987 and 21 out of 80 from 1987.

Statistical methods Data for all patients were recorded with a general data-

base management system on PC compatible microcom- puters.

Anterior field Posterior field

Lateral field

Fig. 1. Schedules of irradiation.

03

03

0,7

0,6

0.5

0.4

0,3

0,2

0.1

0 m 6-93

0 12 24 36 48 60 72 months

Fig. 2. Actuarial 5-year survival.

Acute toxicity was analyzed according to the criteria used at the Fondation Bergonit? (5) and late toxicity according to Chassagne glossary (4).

Survival curves were computed according to the Ka- plan-Meier method (21). The origin time was the initial surgery date. Deaths of all causes were considered as events. Date of point was April 1, 1993. Analysis of prognostic factors was performed in two steps. First, univariate analysis using log rank test, then multivariate analysis using a multiple regression model developed by Cox for censored data (8).

RESULTS

Survival The median follow-up was 67 months. The 5-year ac-

tuarial survival for all the patients was 49.7% (Fig. 2) and the disease-free survival 50.7%. The 5-year actuarial and disease-free survival was 67% and 64%, respectively in the first group, 40% and 42.8% in the second group.

The 5-year actuarial survival was analyzed according to stage in the whole series-Tl: 84%, T2: 6 1.5%, T3: 38%, within group I-Tl: 85%, T2: 63%, T3: 50% (Fig. 3), and in group 2-Tl: 80%, T2: 60%, T3: 36% (Fig. 4). Five-year actuarial survival could not be analyzed in each group, according to the subclassification a-b-c, because

I Tl (n=23)

0,7 - t2 (n=24)

0.6 - T3 (n= 15)

0,5 -

0,4 - 0.3 -

0,2 -

0.1 -

0, m 6.93

0 12 24 36 46 60 72 months

Fig. 3. Actuarial survival according to stage in group 1.

1086

1 -

03 - 0.8 -

Or7 -

0.6 -

03 -

0.4 -

03 -

0.2 -

0.1 -

0, m 6-w

0

I. J. Radiation Oncology 0 Biology 0 Physics

Ti (ll=5)

T2 (II = 10)

24 36 46 60 72

months

Fig. 4. Actuarial survival according to stage in group 2.

the subset of patients in each category was too small, except in group 2 for T3b: 4 1% and for T3c: 30%.

The 5-year actuarial survival was analyzed according to histological types in the entire group: serous (43.6%), other types (59.6%).

Five-year survival was analyzed according to grading, but we have to point out that the number of grade 2 was small (grade 1: 62%, grade 2: 24%, grade 3: 38%).

Analyzed according to the residuum following initial surgery, the 5-year actuarial survival was: with residual disease 36.5%, and with no residual disease 70% (Fig. 5). According to the size of residual disease at second-look laparotomy (Fig. 6), the 5-year actuarial survival in patients with negative second look was: 76%, with microscopic residual disease: 60% (positive cytology or positive random biopsies). In patients with a macroscopic positive second-look laparotomy even after debulking, the 5-year actuarial survival was 22% and 10% with small residual unresectable nodules.

The 5-year recurrence and metastasis rates in patients with negative second-look surgery, were 30% and 15%, respectively. The 5-year recurrence and metastasis rates

006 -

0,5 -

0,4 _

03 -

0,2 -

0,l - b6.93

0,

0 12 24 36 46 60 72

months

Fig. 5. Actuarial survival according to tumor rest at initial surgery.

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o rn6-93

0 12 24 36 46 60 72 monl

Fig. 6. Actuarial survival according to residual disease at second look laparotomy.

in patients with microscopic residual disease at second- look laparotomy were 35% and 14%, respectively, and in patients with macroscopic disease, even after debulking, 80% and 57%, respectively.

We have observed 73 recurrences in the whole series: 21 (group l), 52 (group 2).

Five patients in group 2 have presented progression of

Table 3. Recurrences

Group 1 Group 2 (2 1 out of 62) (52 out of 105)

Stage T Tl 6123

T2 8123 T3 7116

N Nl 1 M Ml 0

Grade 1 2 2 1 3 8 nonassessed 10

Site Regional 14 Metastasis 4 Associated 3

(regional + metastasis)

Residual disease (initial surgery)

None 18 Residual 3

Residuum (second look laparotomy)

None Microscopic Macroscopic

Outcome Dead from cancer 17 Dead (other cause) 1 Alive with cancer 1 Alive 2

115 3110

48190 12 5

13 18 16 5

34 6

12

5 47

12 28 12

46 2 4


the disease during the treatment. The localization of recurrences and the characteristics are reported in Table 3.

The median time between initial surgery and recurrence was 12 months in group 1 and 15 months in group 2. The mean time was 14 months for every group (range 1- 104). In group 2, the majority of relapses have occured within 2 years: 43 out of 52.

Most of relapses were observed in the irradiated area, 14 out of 19 in group 1 and 34 out of 52 in group 2. Forty-six patients (63%) were treated with palliative chemotherapy. The others were treated with surgery, hor- monotherapy, or palliative radiotherapy.

The efficacy of second line treatments was poor: 70% had progression or stabilization of their relapse and only 20% presented a complete response. Their clinical outcome is reported in Table 3. The median time survival after recurrence was 12 months in group 1 and 6 months in group 2.

The results of the univariate analysis of prognostic factors such as age, stage, histologic type, grade, residuum after initial surgery, and after second-look surgery are given in Table 5, in each group of treatment, according to the risk of death and risk of relapse.

In group 1, stage was found to be of prognostic value,

Table 4. Distribution of selected factors by second look outcome (assessed by second look laparotomy)

Factor Negative Microscopic Residual n = 25 n= 17 disease n = 35

Stage Tl NO MO

:

T2CN0 MO

;

T3CN0 MO a b C

T3 NI MO

: C

Grade

0

0 2 1

0 0 1 3 6 6

10 6 17

0 2 3

13 6 5 4 3 12 6 7 11 2 1 7

0 0 0 0 0 0

:, 0 0

0 0

0 0 1 0 1 8

1 T3cNOMl 1 T3bNOMl 1 T3cNl Ml 1 T3cNOMl

1 T3c Nl Ml

Residual disease after first surgery 0 5 1 1 Microscopic 8 8 9 Macroscopic 5 2 12 8 25

cm

in the univariate analysis for the risk of death, and age for the risk of relapse. In the multivariate analysis: age > 55 years; relative risk = 2.4 (0.94-6.14); p = 0.064 and Tl: R = 0.26 (0.07-0.92); p = 0.037, were of prognostic value for the risk of death and only, age > 55 years for the risk of relapse R = 2.8 (1.15-7.09); p = 0.023.

In group 2, residual disease at the second-look laparotomy and grade were of prognostic value in the univariate analysis for the risk of death and relapse.

In the multivariate analysis, residual disease at second- look laparotomy and age > 55 years were the only sig- nificant prognostic factors.

In patients with residual disease at second-look surgery: relative risk of death = 3.6 (1.8-7.30); p = 0.0001 ; relative risk of failure = 4.1 (2.1-8.21); p = 0.00004.

In patients with age > 55 years: relative risk of failure = 1.7 (0.9-3.3); p = 0.080.

Acute toxicity and complications In the entire series, 9 1% have completed irradiation,

9% failed to complete irradiation (one case in group 1, 14 cases in group 2). In 13 patients, it was due to myelosuppression (thrombopenia), asthenia in one patient, gastrointestinal toxicity in one patient. The mean dose de- livered to the peritoneal cavity was 30 Gy in the group 1 and 25 Gy in group 2. Most of patients (113 out of 167) have presented gastrointestinal toxicity (nausea, vomiting, diarrhea); 14 patients have presented asthenia; 13 patients (8%) have required a treatment interruption: 10 cases (group 2), 3 cases (group 1). The mean time of interruption was 10 days (range 5-30). It was related to gastrointestinal toxicity in one case and to myelosuppression in the other cases (mainly thrombocytopenia).

Late gastrointestinal complications are shown in Table 6. They were unrelated to tumor progression. Seven patients have presented minor bowel obstruction called grade 2 (not requiring surgery but hospitalization). Five patients out of seven belonged to group 2.

In nine cases (5%) bowel obstruction has required surgery. Seven patients out of nine belonged to group 2. Bowel obstruction was related to radiation enteritis (five cases) and to loops obstruction (three cases). Six patients out of nine (3.6%) have required intermittent medication for minor gastrointestinal symptoms (diarrhea) after surgery for bowel obstruction. Two belonged to group 1 and four to group 2. The complications occured 4 months after completion of irradiation in group 1 (l-7 months) and 9 months in group 2 (range 4-30).

No patient died of treatment complication and no radiation hepatitis was recorded. The frequency of late bowel morbidity when patients have received a boost was 0 out of 17 in group 1 patients and 7 out of 33 in group 2 patients (minimum two surgeries and chemotherapy). The frequency of severe bowel obstruction according to the year of treatment was 6 out of 87 before 1987, 3 out of 80 after 1987. We have to point out that after 1987, boost

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Table 5. Prognostic factors analysis

Prognostic Factor

Age > 55

Stage Tl vs.T2+T3

Tl +T2vs.T3 Histology

Serous vs. others Grade

Residual disease after initial surgery 0 + micro/macro

Residual disease after second look laparotomy

Group 1 Group 2

Risk of Risk of Risk of Risk of death relapse death relapse

p = 0.0563 p = 0.0189 p = 0.1312 p = 0.0764 S

p = 0.0169 p = 0.23 p = 0.6949 p = 0.66 S

p = 0.0879 p = 0.27 p = 0.1148 p = 0.10

p = 0.2180 p = 0.93 p = 0.3624 p = 0.95 p = 0.40 p = 0.15 p = 0.04 p = 0.037

S S p = 0.06 p = 0.34 p = 0.1159 p = 0.11

- - p = 0.0005 p = 0.0001

SL SL

were performed on reduced volumes at a maximum dose level of 15 Gy.

DISCUSSION

For patients with ovarian carcinoma, surgical treatment is not sufficient in the great majority of cases. The type of further treatment is still controversial. In our study we

Table 6. Gastrointestinal toxicity

Group 1 Group 2

Number of

patients

Subobstruction

Bowel obstruction Grade 2 Grade 3

Gastrointestinal symptoms

Grade 1

Grade 2

Bowel obstruction Grade 2 Grade 3

Subobstruction Grade 2

Gastrointestinal symptoms

Grade I

Grade 2

1 3 4 16

1 2 3 2 7 9

0 1 6

1 4

treated conservatively treated surgically

bowel obstruction incomplete treated conservatively

toxicity treated with medication In group 1, stage and age were prognostic in the uni- during less than one month variate analysis and in the multivariate analysis: risk of

treatment necessary more than one death = 2.4 in patients with age > 55 years and 0.26 in month patients presenting T 1.

have treated 167 patients with abdominopelvic irradiation either after surgery alone (group 1) or after chemotherapy and second-look surgery (group 2). Our results (5-year actuarial survival of 67% in group 1 and 40% in group 2) are similar to those reported by many authors with abdominopelvic irradiation (13, 23, 25, 27, 40).

We have to point out that the tolerance of four orthogonal fields technique was good: only 9% of patients have failed to complete irradiation ( 1 case in group 1, 14 cases in group 2) mainly due to myelosuppression (thrombocytopenia). In the majority of reported data, 30% of patients had a definitive irradiation interruption due to a clinical or hematological toxicity ( 1, 16, 19). Severe small bowel obstruction requiring surgery were observed in nine patients (5%). Higher rates of complications have been reported in the literature especially after chemotherapy (3, 17, 19, 36, 41).

The frequency of late bowel morbidity was high (7 out of 33) in group 2 patients (two surgeries + chemotherapy) who have received a boost. This is in agreement with other authors findings (36,40, 41).

Some factors have been found to be prognostic: age, stage, histology, grade, residual disease after initial and second-look surgery (1,6,9, 13, 16,20,24,28, 34,40,42).

In our series, these factors were studied in an univariate and multivariate analysis in each group of patients. Re- sidual disease after initial surgery was not found as prognostic. The fact that this criteria was chosen as the basis of treatment selection could explain why it did not appear when it was analyzed in each group.


In early stages, controversial results about adjuvant treatment after inital surgery have been reported even in randomized trials (12, 22, 35). This could be explained by the fact that the surgical staging procedures could be different or incomplete. We have to point out with Young, Trimbos, and Monga (30, 38, 42) the importance of a comprehensive surgical staging necessary to select appropriate additional therapy if necessary. Its lack has a sig- nificant impact on final stage.

The value of abdominopelvic irradiation is difficult to assess because of controversial results given by randomized trials (12, 22, 35) and excellent results gained in retrospective studies with no adjuvant treatment after surgery alone (5year actuarial survival: 94% for stage Ic (30) or with cisplatin polychemotherapy (5-year actuarial survival: 93.3% for Tl-T2 (15, 31-33).

In advanced ovarian carcinoma, our results seem bene- ficial if whole abdominal irradiation is applied to microscopic or no residual disease at the second-look laparotomy (5-year actuarial survival of 76% with negative second look, 60% with microscopic residual disease. The same findings (5-year actuarial survival between 67% and 50%) have been reported by Franchin, Haie, and others (3, 16, 19, 20).

In these patients, the multivariate analysis shows that the amount of residual disease at the second-look laparotomy is a high predictor of survival. Risk of death: 3.7; risk of relapse: 4.1. In patients with residual disease at

second-look laparotomy, the same findings have been reported by Haie (20) and Lippman (26).

However, the value of abdominopelvic irradiation is difficult to assess: Menczer (28,29) has obtained excellent results with intraperitoneal chemotherapy (5-year actuarial survival 75%) and others in the same conditions have gained 5-year survival between 49% and 83% with no adjuvant treatment after second-look laparotomy (9, 18,34).

Even in randomized trials the results after second look are controversial. Bruzzone has shown the superiority of cisplatin chemotherapy over whole abdominal irradiation (2), and an unpublished data from French Cancer Centers has shown no differences between the two modalities.

CONCLUSION

On the basis of our results, we can conclude that abdominopelvic irradiation using the four orthogonal fields technique is associated with tolerable acute toxicity and a low risk of serious late complications.

Abdominopelvic irradiation seems valuable in the management of ovarian carcinoma when there is no macroscopic residual disease left after initial surgery or at the second-look procedure.

Therefore, randomized trials after appropriate stratifi- cation are warranted to assess the real value of whole abdominal irradiation compared to other adjuvant treatment after initial surgery and second-look procedures.

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Evaluation of whole abdominal irradiation in ovarian carcinoma with a four orthogonal fields technique