The Rationale

for Curative

Radiotherapy

for Ovarian

21

Carcinoma

The Rationale for Curative Radiotherapy for Ovarian Carcinoma Z. FUKS, MD and MALCOLLIA. BAGSHAW, MD Paul A. Bissinger Me?77orial Ce~ztcl- for Rtrdintior7 Tllerap? Departr77ent of Radiology Starzfoud University

School

of Mrriicir7e

Statzforcl, CaliforF7i0

An analysis of treatment results in 174 patients with surface epithelial tumors of the ovary treated with resection and postoperative radiotherapy is presented The actuarial survival at five years was 81°‘o for Stage I patients, 559/o for Stage II, and 8.6O/ofor patients with Stage III disease. Radiation therapy was curative for many patients with postoperative tumor residual in the pelvis, and for patients with lymphographic or surgical evidence of metastases in retroperitoneal lymph nodes. The possible reasons for the failure to cure some patients is discussed. Also proposed is a rationale for elective irradiation of sites of presumptive metastatic dissemination which have generally escaped the attention of clinicians in the past.

INTRODUCTION HE ROLE of definitive postoperative radiation therapy has been the subject of considerable controversy in the literature on ovarian carcinoma, with a wide divergence of opinion as to its value. During the era of orthovoltage radiotherapy, its curative potential for most patients \\.as considered dubious.‘-: Although mcgav,oltage radiotherapy has significantly improved the prognosis of patients with ovarian carcinoma,xm’!’ many patients with apparently curable disease who have been treated with aggressive postoperative radiotherapy still succumb to their malignancy. In this account of the Stanford experience, we review treatment results of postoperative radiotherapy in patients with Stages I-III surface epithelial tumors of the ovary, discuss possible reasons for failure to cure some patients, and propose a rationale for the elective irradiation of sites of presumptive metastatic dissemination which have generally escaped the attention of clinicians in the past.

T

METHODS

AND MATERIALS

The updated rcaults following resection and postoperative radiation therapy in 174 patients with Stages I, II, and III surface epithelial tumors of the ovary are presented. The patients were treated at the Stanford University Medical Center from 1957 to June 1973. Detailed analysis of part of the present group of patients has been previously presented.* I(’ All patients were staged either initially or retrospectively according to the International Federation of Gynecologists and Obstetricians (F.I.G.O.) staging classification”” (Table 1). The initial biopsy specimens were classified by Dr. Richard L. Kempson, Department of Pathology, according to the WHO histopathologic classification proposed by Scullyzl (Table 2 ). The histological sections of 19 patients could not be located; however, the original pathology reports had placed them in the malignant surface epithelial group. It should be noted that only 10 of the 173 patients had xerous tumors of intermcdi-

22

The Rationale

TABLE 1.

for Curative

Distribution of 174 patients with sur face epithelial tumors of the oval-) by stage (FIGO).zO

Radiotherapy

per

week.

viously

Treatment

been

presents

Substage

Stage

radiation

20 II Stage II 75/174 (43”(l) Stage ITI 67,‘174 (38”o)

IIA IIB III-OM,l III-PER’, II I-H
(66 palicnts initially) and their actu:tt ial \LII‘~ i\ al \vas .530,1 at 5 yca1.s (26

1000

23

Carcinoma

patients

at risk)

and 4S”/o at 10 years

(11

patients at risk) (Fig. 1). Patients with Stage III disease shared the worst prognosis of all patients in this series (Figs. 2,3). Most of the patients died with active disease within the first 2 years following diagnosis. Only 6 of 67 patients survived for 4 years or more and the actuarial survival at 5 vears was 8.6O/;1 (Fig. 2). The prognosis of’ Stage III patients in this series \vas poor irrespective of whether they had hepatic involvemcnt, widespread peritoneal involvement or minimal involvement of the omentum only (Fig. 2). When relapse became evident most of the patients xvere treated \vith single agent chemotherapy, but none survived for more than an additional 2 years.

Munnel’l and othcrsl”.zl+Y1: have suggested that a “maximal surgical effort” mav enhance survi\,al in ovarian carcinoma. Although this is desirable, a complctc resection is often impossible, especiallv in Stages IIB and III. Of 66 patients \vith Stage IIB in this series. an apparent complete resection of the tumor \vas accomplished in only 16 patients. The post-

, e-0

90

\

J

STAGE

\

2

80

2 2

70-

IA IN = 201

~-b-*-e-~-*-~-~ “““I

\

&-.-A-.-.-.

STAGE

IB IN = I,,

STAGE

IIA (N = 9)

.*

+

‘*

: P

60-

\

," 50

\

m-m-m-*-

4-a

-

40

\m

0

I

I

I

I

2

4

6

8

TIME

IN

IIE (N = 66)

-

‘*-•

-

0

Frc;r

STAGE

‘*

L-.-. I 10

-, I 12

I 14

16

YEARS

Actuarial analysis of sur~?val in paticnt~ with Stages I and II surface epithelial tumors of the ovary. Numbers in parenRI

I.

[hews indicate iniliallv.

the number- of patients

treated

TIME

IN

YEARS

FIGURE 2. Actuarial analysis of survival in patients with Stage III surface epithelial tumors of the ovarv. OM=omental involvement only. PER=w>despread peritoneal involvement; liver not involved. H= tumor involving hepatic capsule and/or parenchyma.

24

The Rationale

surgical

radiation

employed who

had

and

residual

after

for

the survival Stage

cantly

similar

rates

the

resection

those

surgery.

IIB

and the doses

for

a complete

tumors

of

technique

were

for Curative

with

of

graphic

their tumor

3 shows that

were

not

different.

was studies

always was

tance

the abdomen

radiographically

Nonetheless,

4

Previous

publications

the

feasibility lymph

of

node

detecting

of lymphograms with

and another or stromal incidence

surface

epithelial

9 in patients tumors

4 shows

with

of the ovary.

of positive

the in 74

tumors germ

cell

The total

lymphograms

indi-

II

indicating

tumors

and 5 patients addition,

IIB

was

arial

2

--,

30

-

SURGERY

true

negathe

and

I or

had

Stage

node surface

with Stage II disease).

2 patients

with

in whom

performed,

other-

a lympho-

had

lymph

I In

biopsy

node

involve-

4 shows

the survival

of these

following

irradiation

para-aortic

survival

regions.

at 5 years died,

diagnosis

from

of their

neoplasm

gastric

(N = SO,“A-A

lymph

those

disease,

not

Figure

Stage

lymphograms

(3 patients

para-aortic

the patients

AFTER

of

with

another

wise Stage

pelvis

AESIOUAL

the

patients

patient

with otherwise

Eight

10 patients

GROSS

were

was proved

retroperitoneal

epithelial

ment.

40-

two

interpretation

mctastases.

proven

s

and

11 (21 %I ) had

disease,

gram

:

in three

in the fourth

Of 52 patients

by bipedal

performed

nodes.

to be false positive.

retroperito-

involvement

positive

whereas

reluc-

for biopsy

confirming

diagnosis

lymphographic

have demonstrated

lyn~phography.!l~Y’~“~~~x Table patients

true

tives),

neal

results

(one

Node Imolven~ent

performed great

biopsies

patients,

lymphographic

Lymph

node

in-

lympho-

suspicious

lymph in

node

the

there

obtained

Retvoperitoneul cilzd Survival

Since

were

to explore

Carcinoma

lymph

29%.

postoperatively, of

signifi-

for Ovarian

retroperitoneal

volvement

for these two subgroups

patients

eating

patients

gross

Figure

Radiotherapy

the actu-

was 5390. Five of

4 within

2 years

recurrence and

of The

from

and extension

1 from

a bleeding

ulcer having no evidence

of disease.

1

0

I

I

1

I

I

2

4

6

8

10

TIME

IN

The

YEARS

FIGURE 3. Actuarial analysis of survival in patients with Stage IIB disease; effect of the presence of gross residual tumor after initial surgery. Numbers in parentheses indicate the number of patients treated initially. TABLE4. Incidence malignant

of lymphograms indicating tumors of the ovary. Surface epithelial tumors

Stage Stage Stage Stage

I II III IV

DISCUSSION

I 12

3112 5131 lo/25

3j6

rates

present lished

of

series reports

survival

observed

is comparable on the results

tive radiation therapy in ovarian carcinoma.“-‘!‘.21~26 retroperitoneal

Germ cell and stromal tumors

216

l/3 none none

involvement

in

of postoperapatients with Furthermore,

in 83 patients

Total 5/18 6/34 lo/25 316

the

to many pub-

(27%) (18%) (40%) (50%)

with

The Rationale

for Curative

10 -20

\

Radiotherapy

,STAGE

.-rn

for Ovarian

Ill (N = 671

-m-m 00

I

I

I

I

I

2

4

6

8

10

TIME

IN

12

YEARS

FIGURE 4. Actuarial analysis of survival in patients with surface epithelial tumors of the ovary. Survival of Stage II and III patients is compared to the survival of 10 patients and/or histologic eviwith lymphographic dence of retroperitoneal lymph node involvcment (PA+) but with otherwise Stage I or II disease. Numbers in parentheses indicate the number of patients treated initially.

our data provide evidence that radiation may be potentially curative for many patients with ovarian carcinoma. Fifty patients with initial Stage IIB disease in whom a complete surgical removal was not possible, were treated with radiation postoperatively. Of these, nearly 5Ono of the patients at risk between 5 and 10 years survived without clinical evidence of neoplasm. Although some of the patients may still be at risk of a relapse, it seems that high dose radiation therapy aimed at the tumor bearing area has resulted in a permanent eradication of the disease in a substantial fraction of them. However, the most challenging problem is that despite the curative potential of postoperative radiotherapy, nearly 20% of the treated patients with initial Stage I disease, 60O0 of Stage II patients, and 90°; of the pato their ovartients in Stage III succumb ian neoplasm. One of the basic concepts of curative radiotherapy implies the utilization of tumoricidal doses in an attempt to induce a permanent control of treated areas. The assessment of tutnoricidal dose levels requires a knowledge of the time-dose relationship for tumor sterilization and the

Carcinoma

25

acceptable limits of normal tissue tolerance. Since the details of time-dose relationship for ovarian tumors are unknown, the dose levels employed in patients with carcinoma of the ovary have been pox’ erned by the limits of tolerance of the normal tissues encompassed by treattncnt fields, such as the gastrointestinal tract. kidney, liver, bone marrow, and spinal cord. The most common dose employed for pelvic it-radiation in this series was 5500 I-ad delivered at a rate of 800-1000 rad per week. This dose seemed highly effective in eradicating known residual tumor in patients. However, it is clear that many t 11~~ dose was determined by presumption of normal tissue tolerance Icvels rathetthan by any real quantitative knowledge of the radiosensitivity of ol,arian carcinoma. For example, we have previously t-cported a high rate of chronic radiation enteritis (15%) in patients treated to the pelvis with radiation doses in cxcc’xs of 4500 rad.111 It is hoped that the systematic utilization of some of the new and sophisticated techniques of examination, such as repeat lymphangiography, laparoscopy, and second-look operations \vill permit a more accurate assessment of tumoricidal doses for ovarian tumors. MOWO\W-, curative radiotherapy also itnplics the application of radiation fields I\ hich encompass all sites of involvement \\,ith disease. Such fields should be shap~tl to include both sites of gross discasc which arc clinicallv evident and sites of microscopic involvement which mav bc clinically undetectable. The design of such fields should be based on detailed knowledge of the patterns of anatomic distribution and modes of tnetastatic spread of 0\3t-ian carcinoma. It has been estimated that appt-oximately 75O’0 of the patients with ovarian carcinoma will have neoplasm outside the ovar!’ at the time of initial exploration.“: The tnost conltnon sites of metastasis in o\,arian carcinoma are the adjacent pcl\?c organs. These are usually well covered b\ routine pel\.ic radiation fields.

26

The Rationale

for Curative

Metastasis by lymphatic channels in ovarian carcinoma is less well appreciated. Figure 5 shows a schematic presentation of the lymphatic drainage of the ovaries. The tunica albuginea of the ovary is probably devoid of IymphaticsZ!’ but the parcnchyma is enriched with a dense lymphatic network X) which converges upon the hilus to form the subovarian Ivmphatic ~ICSLIS.:~ The plesus is continued pcriphcrally by a group of large collecting trunks which ascend bilatcrall\ along the ovarian blood \~csscls and tcrmillatc in the para-aortic group of lymph nodes betlveen the bifrucation of the aorta and the renal pediclcs. “’ i: In less than 50”11 of the women, there is an alternati\,e route of lymphatic drainage, the acccssol-y etferent vessels. :“-::I These lymphatic trunks course within the broad ligament towards the lateral and posterior pelvic wall and terminate in the uppermost external iliac, and less commonly in hypogastric lymph nodes. Still another group

FIGuRI: 5. Schematic presentation ut the efferent routes of lymphatic drainage of the 013ries.

Radiotherapy

for Ovarian

Carcinoma

of cffercnt lymphatic channels, which have been demonstrated expcrimcntally in httmans;:; run along the round ligament and drain into the external iliac and inguinnl group of lvmph nodes. Drainage by this route sc’c’ms to occur infrequently and accounts for the rare but significant incidcncc of metastasis into the inguinal nodes. This anatomic description of the Iymphatics of the ovaries indicates that most of the lymph nodes which drain the ovaries may bc opacificd following lower limb lymphangiography. Our data on Iymphography, indeed, show a high rate of mctastases into the retroperitoneal lymph nodes (Table 4). Unfortunately, our ability to obtain lymphographic-histologic correlation has becn limited. It is therefore inipossible to assess the accuracy of the lymphographic interpretations in our SC*ries. However, when the same rigorous criteria for lymphographic interpretations as used in our series were employed in patients with apparently localized prostatic cancer”‘,.:; and in patients with cancer of the uterine cervix.!’ a high rate of accuracy (89 and Y8%, respectively) was observed when histologic confirmation of Iymphograms suspicious for metastascs was attempted. The rate of false negative interpretation was also relatively high (23 and 22%). It seems reasonable, therefore, tu assume that our finding of 21 %I positive lylnphograms in Stage I and II patients (Table 4) could significantly understate the true rate of rctroperitoneal metastases in such patients. This presumption may provide a partial explanation fol- the failure to cure more patients with Stage I and I1 disease. Only a few of Stage I and II patients in the present study and in other published series received irradiation to the para-aortic region. When attempted in a small group of Stage I and II patients with lymphographic or surgical evidence of metastases, para-aortic irradiation seemed to be of great value in improving the prognosis of some patients (Fig. 4). The true value ot para-aortic irradiation

The Rationale

fol. Curative

Radiotherapy

for Ovarian

in the presence of a negative lymphogram is unknown. The percentage of patients with initial Stage I and II disease who fail because of subsequent retroperitoneal metastascs, has not been established. It may be that prophylactic radiation to the para-aortic lymph nodes may eradicate subclinical microscopic disease and im proire survival of some Stage I and 11 patients. To test this hypothesis, a randomized prospective study of such a therapeutic plan is currently underway. Another major route of metastasis in ovarian carcinoma is through the perito~ neal ca\:ity. Frt~ tumor cells can frequently bc collected from the peritoneal washings even in ca\itI I by peritoneal c*arly clinical stages. Keettcl and Pixley,!’ have shown that primary ovarian tumors lvith intact capsules in patients with Stage I disease, often shed malignant cells into the peritoneal cavity. In the present stud!. 16 of 32 (50%) of the patients lvith Stage I disease and 44 of 75 (58”6) of the Stage II patients had gross and/or microscopic tumor excrescences on the tumor capsule or on the pelvic peritoneum. It is like11 that many of these tumors had been shedding malignant cells directly into the pertoneal cavity prior to initial surgical attempt. It has been shown that the peritoneal fluid, which has a high rate of turnover, is drained through lymphatic channels located in the diaphragms.lO,ll The movemcnt of the peritoneal fluid and free floating cells is determined by changes in intraperitoncal hydrostatic prcssures.“z 14 During quiet respiration the hydrostatic pressure in the subphrenic compartments of the peritoneal cavity falls precipitously with inspiration creating a momentary negative pressure under the diaphragms and rises with cxpiration.lz~‘l Thus, the subdiaphragmatic serve regions as a “pump” which drains the peritoneal fluid from the lower compartments with ever\ inspiration. The fluid and particles or cells having reached the diaphragm are collected into a network of lymphatic capillaries located

Carcinoma

27

underneath the mesothelial cell lining of the undersurface of the diaphragm?” Less than 20% of the lymph collected in these capillaries drains into the upper paraaortic nodes, whereas more than 80% is drained by lymph vessels which permeate through the diaphragm to its subpleural surface.‘” Having reached the subpleural lymphatic trunks, the lymph drains into the diaphragmatic lymph nodes which arc located adjacent to the pericardium and the phrenic nerves, mainly on the right and anterior subpleural surfaces of the diaphragm,‘” (Fig. 6). The lymph is then transported through the retrosternal efferent trunks into the internal mammary group of lymph nodes. The diaphragmatic and retrosternal nodes have been clearly demonstrated in normal human subjects by gamma scintigraphy following intra-

FIGURE 6. Schematic presentation of the lymphatic drainage of the diaphragm (modified after Rouviere”2). A posterior view of a transverse section of the chest at the level of the diaphragm, is shown. The subpleural diaphragmatic lymph trunks converge upon the diaphragmatic lymph nodes (juutaphrenic, lateral, and anterior pericardial) located adjacent to the pericardium and phrenic nerves. Retrosternal efferent trunks connect these nodes with the internal mammary lymph nodes.

28

The Rationale

for Curati\re

peritoneal instillation of !‘!““Tc sulfur colloid. iT This description of the lymphatic drainage of the peritoneum indicates that the peritoneal surfaces of the diaphragm and the subpleural diaphragmatic lymph nodes (and in more advanced cases the retrosternal internal mammary lymph nodes) may frequently be sites of metastases from ovarian carcinoma. Indeed, HolmNielsen**,“’ has described 5 autopsies pet-formed in essentially untreated cases of ovarian carcinoma. In all the cases cxanlined he found invol\rement of the righl diaphragm and in 3 of those there was also involvement of the diaphragmatic and internal mammary lymph nodes. Figure 7 shows chest radiographs and tomograms of a 16 year old patient \vho presented with Stage IV dysgerminoma of the ovaries. The radiographs clearly demonstrate enlarged diaphragmatic lymph nodes at the right cardiophrenic angle and enlarged rctrosternal nodes. In addition mot-c laterally located there is a large metastasis in the right diaphragm. In a recent study, Baglcy et al.;” and Rosenhofl et al.,“’ searching for metastases on the inferior surface of the diaphragm have performed peritoneoscopy on a group of patients with ovarian carcinoma 6 weeks following laparotomy. In 4 01 these 7 patients with otherwise Stage I or II disease unexpected metastases were f’ound on the peritoneal surface ol’ the right diaphragnl. Tl~e rate for similar metastases in Stag past,I:.~,’ 1, It is hoped that new conibiixlions I\ ith FrClrkii 8. Simulalor port film demonstrating a proposed treatment field designed for elective irradiation of the para-aurtic lymph nodes, the medial portions of the diaphragm and the subplcural diaphragmatic Ivmph nodes in patients \\zith Stage I and IT cam.cinema of the o\‘ary (we test).

of

chc~llotl~erap!,

radiation

in sonic

pro\‘c

tlic yrini

pro,enosis

Stagw

111 carcinoma

coupled

perhaps

patients,

\vill

of patients

of the

im\vith

wary.

This investigation was supported i11 part I>! the National Cancer Institute and National Institute of Health and Public Ser\-ice Research Grant Nos. CA 05008 and CA 05838.

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in ()\.a~1970.

Eierxtock. 17, 36hd96.

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of

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N. Blank,

on

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32

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