Second-look laparotomy for stage III epithelial ovarian cancer: rationale and current issues

Cancer Treatment Reviews (1995)

21,499-511

Second-ldok laparotomy ovarian cancer: rationale Laila Muderspach,

for stage Ill epithelial and current issues

Franc0 M. Muggia

and Peter S. Conti

Departments of Gynecology & Obstetrics, Medicine Radiology, University of Southern California-Norris Los Angeles, CA 90033, U.S.A.

and Diagnostic Cancer Center,

Abstract During the past two decades, the initial treatment of an advanced ovarian malignancy has been generally uniform: it begins with an exploratory Iaparotomy surgically to remove as much tumor as possible (I) and to stage the cancer (2). For the 70% of patients classified as stages III and IV, surgery is then followed by combination chemotherapy. Although opinions differ as to the optimal regimen, the standard involves a platinum-based program (31, recently also including paclitaxel (4). A second-look Iaparotomy is often performed in all patients who achieve a clinical complete remission, that is the inability to detect disease by physical examination and non-invasive laboratory tests. This surgical procedure is able to detect clinical disease not apparent on computerized axial tomography (CT scan), ultrasound, magnetic resonance imaging (MRI), serum CA-125 levels or physical examination (5-7). Major questions, however, have arisen around the need for such a procedure, and whether one can justify it in terms of an improved outcome or merely as an assessment of prognosis (8-14). We shall review: (i) the technique; (ii) the rationale; (iii) the results that have been reported from its routine application; and (iv) controversial issues, particularly as they relate to the evolution of therapeutic strategies.

Technique The second-look surgery involves, first and foremost, a careful and methodical exploration of the abdomen and pelvis. In the absence of any obvious tumor, the procedure entails obtaining cytologic washings and multiple biopsies in an attempt to detect any residual microscopic disease. Previously known involved areas and bowel adhesions should be biopsied. If there is residual omentum, this should be removed. Resection of the ovarian pedicles with overlying 0305-7372/95/060499

0 1995 W. B. Saunders

+ 13 $12.00/O 499

Company

Ltd

500

Figure

7. Focus of pleomorphic resected at second-look

L. MUDERSPACH

ETAL.

ovarian adenocarcinoma laparotomy ( x 200).

No

cells in a section of an ovarian recurrence in 16 + months.

pedicle

peritoneum is recommended (Figure 1). Peritoneal biopsies from the cul-de-sac, paracolic gutters, diaphragm and pelvis are routinely performed. In addition, selective sampling of aortic and pelvic lymph nodes is included in this procedure. An appendectomy as well as removal of previously unresected residual uterus, tubes, and ovaries may be accomplished at this time (15). If residual tumor is identified, complete resection of this disease is attempted. Tumor debulking and hemostasis is facilitated by the use of techniques such as ultrasonographic cautery (CUSA). Some physicians have performed assays of in vitro chemotherapy sensitivity on resected tumor with the objective of guiding subsequent therapy. lntraperitoneal (IP) catheters have often been placed when conditions appeared favorable for subsequent intracavitary therapies. No data are available that such maneuvers result in superior outcome, but the relevant trials have not been done. Laparoscopy has been recommended (and also condemned) as a replacement for second-look surgery. With current technology, laparoscopy provides an opportunity to look at most of the peritoneal surfaces, particularly the diaphragms. It is also possible to perform retroperitoneal sampling of lymph nodes and occasionally resection of other areas of disease using the laparoscope. In fact, the use of laparoscopy may prove advantageous over other second-look operations in women who have suspected unresectable disease, because it has the potential to spare the morbidity of a more extensive procedure. There are also some patients who will agree to a laparoscopic procedure but who will decline the larger skin incision required for an exploratory laparotomy. Additionally, some will consent to procedures

SECOND-LOOK

LAPAROTOMY

FOR STAGE

associated with presumed intermediate Since no data exist on the systematic principally cover formal Iaparotomies.

Ill EPITHELIAL

OVARIAN

CANCER

501

morbidities, such as mini-laparotomies. use of such approaches, our comments

Rationale The reasons for performing second-look laparotomies have evolved over the past three decades and have adapted to the introduction of various treatment approaches. As the rationale has changed, its use has shifted from ready acceptance as part of a standard treatment to frequent, perhaps uncritical, omission of any consideration of additional reassessment, particularly by medical oncologists following polemics in the literature. Historically, second-look was introduced on a routine basis after chemotherapy principally for stage III epithelial ovarian cancer (16) ‘to assess the status of a patient’s tumor in order to plan future treatment and remove any tumor found if possible’. As used by Smith in sequential studies at MD Anderson, it allowed him and his colleagues to stop therapy and also to compare results following the application of diverse modalities. For example, they made the observation that patients treated with radiation therapy had a poorer survival rate than those who were treated with chemotherapy after positive second-look operations. They also provided some evidence that survival bore a relationship to the extent of disease found at second-look. A disappointing feature of these findings, however, was the poor prognosis of most patients with positive findings and the inevitable relapse in all groups. These concepts, therefore, resulted in the use of second-look as the most sensitive method to detect and classify the extent of post-treatment residual disease, since even CA-125 and computerized tomographic (CT) scans were to prove inadequate in most cases of ‘clinical complete response’ (cCR). Soon, however, critical oncologists raised questions about the futility of such determinations in the absence of adequate salvage regimens. Series appeared showing identical survival of patients subjected to second-look as those that refused (8,17, 18,28,32). This severe criticism has resulted in a drive to provide a more critical appraisal of the possible benefits associated with a secondlook procedure. Its superior ability to detect residual disease is unquestioned. However, in the absence of an established effective salvage treatment, justification remains problematic. Gynecologic oncologists have argued that resection (secondary cytoreduction) may convey benefit to these patients. Some evidence (termed ‘anecdotal’ since it is retrospective) is available that indicates excellent survival (median 5 years) generally accompanies cytoreduction of gross disease to its total absence (19, 20). The proportion of patients in this category is considered to be about 20% of those subjected to second-look by current restaging methods and definitions of cCR. Others (21) have argued that IP therapy may result in long-term survivors and that success-in addition to the drugs to be used-depends on the extent of residuum at second-look, analysis of fluid distribution (22) and lysis of adhesions. All of the experience reported with use of IP therapy at second-look consists of platinum-based treatments. However, the response rates, progression-free survival and median

502

L. MUDERSPACH

ETAL.

survival of patients receiving IP cisplatin or carboplatin has not been convincingly improved over what may be achievable with these drugs given systemically. Comparative trials to resolve this issue have been lacking. These are obviously needed, since reports of long-term survivors include patients who had initially clearly failed systemic therapy (20-23). Other rationales have been advanced to justify second-look operations: accurate determination of prognosis, and adequate evidence to justify cessation of potentially toxic therapy. Finally, second-look may provide useful information as an endpoint for randomized clinical studies. The use of second-look for secondary cytoreduction followed by consolidation treatment of minimal or no residual disease must be viewed against the background of opposing strategies. Current oncologic trialists urge testing consolidation either with high-dose chemotherapy or with other forms of low morbidity therapy. On the other hand, many adopt the philosophy of ‘allowto-relapse’. The first strategy must be tested to seek greater success by consolidation as compared to untreated controls-but such clinical trials are difficult to conduct. On the other hand, if one ‘allows-to-relapse’, any secondary therapy is likely to be less effective. Analysis of IP trial results in relation to volume of disease suggest the adverse consequence of this policy (20). Criticism of second-look must take into account what the alternate strategies offer.

Results The probability of finding residual tumor at the time of second-look surgery is related to the extent and resectability of the disease at the original procedure, histologic grade, response to chemotherapy, number of chemotherapy cycles prior to surgery, and the thoroughness of the surgery (24). Similarly, the rate of relapse after a negative second-look surgery is influenced by these same factors. Survival statistics of the patient population in question (cCR) have been examined in various series, and not found to be encouraging to justify secondlook procedures (Table 1). However, the comparison groups are generally small and do not allow adequate balance for the above prognostic factors. Several authors including Berek (131, Gershenson (18, see Table I), Lund and Williamson (33) and Podratz and colleagues (34) have looked at determinants of outcome of second-look surgery for patients initially presenting at advanced stages. The probability of having a surgically and pathologically negative operation after chemotherapy in patients with stages Ill-IV epithelial ovarian carcinoma without preoperative clinical evidence of disease is approximately 35% (33-35). On the other hand, about 20-50% of patients will still have gross residual disease at time of second-look. For patients initially presenting with stage I disease, the probability of a positive second-look laparotomy was 5% in one series (361, however, grade 3 tumors had a 50% recurrence rate after documentation of negative findings. After a negative second-look procedure, relapse rate is reported to vary widely from 5 to 50%, depending on length of follow-up. On the other hand, long-term survival for women with large unresectable tumors at second-look is rare. Patients with lesser disease would be expected to have an intermediate

SECOND-LOOK Table

1.

Second-look

LAPAROTOMY series:

residuum

FOR and

STAGE relative

Positive we unspecified

III EPITHELIAL

Total no.

Negative no. (%)

Microscopic no. (%)

17

63+

30(48)

ll(17)

18 25 26 27

246 64” 103” 29

85(35) 20(31) 49(48) 12(41)

Comments survival*

22f35)

31 m vs. 25 m for pts not subjected to surgery (not significant) Not given for overall group Not given for stages III/IV Not given for stages III/IV 28.9 m for overall group; 53.1 m for pCR 60 m vs. not reached for 11 refusing surgery 60 m vs. 56 m for 17 pts with no SLL 21 m subset receiving chemo postop vs. 17 m for 57 pts randomized to SLL receiving identical consolidation (not significant) 32 m in 10 with laparoscopy documented CR Not given for overall group, 60 m for micro @ Not given for overall group 33 m vs. same in 47 not subjected to surgery 72% survival at 5y vs. 63% for 48 randomized to no SLL (p= 0.9)

28

39

17(44)

6(15)

16(41)

29

30

38(57)

7(10)

22”(33)

8

109++

17(16)

8(7)

45(47)

30

135

41(30)

13(10)

81(60)

9

88”

38143)

16(18)

34(39)

31 32

89’ 100

41(46) 34(34)

17(19) 17(17)

31f35) 49’(49)

14

54d

35(70)

31(49)

(52)

a Excluding stage l/II. b 6 were cytoreduced to micro. ’ 19 were cytoreduced to micro. d 5 refused second-look. * Estimated from author’s survival + Excludes 10 undetermined stage. + + Includes 7 stage II patients.

(59)

11 (8 refused)

curves

when

503

Gross no. (%I

61(65) 54 17

CANCER

outcome

Ref.

13(20)

OVARIAN

(22)

and

median

not given.

outcome. In fact, Piver reports a series of patients with IP consolidation, all of whom had disease from microscopic to c2cm at second-look. These survival curves as representative of series applying currently available staging and therapeutic modalities are reproduced in Figure 2. Gershenson reported that not only was the amount of residual disease important at second-look, but histologic grade was another important factor. As expected, patients with grade 3 disease relapsed more frequently than grade 1 disease (32% vs. none) in his series (18). Removal of gross tumor at second-look surgery is often feasible but remains somewhat controversial. Carson and Rubin (37) have suggested that benefits exist for secondary cytoreduction at the time of second-look and that it was technically feasible to accomplish with acceptable morbidity. However, Potter disagrees with their assessment since there have been no well-designed prospective randomized trials addressing this issue (38). Nevertheless, there is some concurrence that secondary cytoreduction is most likely to benefit patients

504

L. MUDERSPACH

s 5 mm

ETAL.

(n = 42)

I-I / i-I---

1 s 2 cm\ (n = 15)

I

>2cm(n=6)‘1

0

’ 4.2

I 12.6

I I_----,

1: 21

Months

Figure 2. Roswell look laparotomy.

I 29.4 from

II 37.8

I 46.2

intraperitoneal to last follow-up

1 54.6

I 63

I 71.4

I 79.8

chemotherapy

Park Memorial Institute Series: Survival according to residual disease All patients received intraperitoneal consolidation with cisplatin + (Reprinted with permission from S. M. Piver, M.D.)

at secondcytarabine.

whose residual tumor can be completely resected at the time of second-look surgery (19). Whether surgical removal actually improves patient outcome or if survival related to lesser non-invasiveness of the cancer which allowed for removal is unanswerable. However, failure to relapse on long follow-up suggests debulking has been beneficial. Moreover, the beneficial effect of secondary cytoreductive surgery after three cycles of initial chemotherapy has now been reported in a clinical trial (39). Fiorentino er al. (14) have performed randomized trials addressing the usefulness of second-look laparotomy vs. laparoscopy in detecting disease and in modifying outcome. These studies have suggested that second-look is not helpful in prolonging survival in patients with ovarian cancer. However, the number of patients in their study potentially benefitting from the above considerations and secondary cytoreduction was small. Moreover, the secondline chemotherapy used, systemic cisplatin and 5-fluorouracil, is considered unlikely to have a survival impact (14). On the other hand, to date there is no consensus for what second-line regimen to use.

Issues Purpose

of surgical

reassessment

As noted, the initial proposed determination of the effect

objective of second-look laparotomies was a of therapy. A second major objective was

SECOND-LOOK Table

2.

Methods

LAPAROTOMY

of reassessing

FOR

ovarian

STAGE

cancer

other

III EPITHELIAL than

second-look

OVARIAN

CANCER

505

laparotomy

Conventional Physical

examination:

CT scan

(or MRI):

CA-125: Laparoscopy:

Except for vaginal examination, unlikely to show any disease before other methods. Recent study in cCR confirms a 24% false negative rate. However, we would not expect to pick up disease co.5 cm. See Table 3, from Hoskins and Rubin (1991) (40). Recent study indicated it missed disease in 5 of 11 eventually shown to have positive second-look laparotomy. However, does pick up disease obviating laparotomy in about 50%.

Experimental Cytologic

washings:

IP contrast

studies:

PET scanning:

Practical only if IP device is present. Percent of patient where early relapse present not well characterized (see text and refs). Anecdotal evidence so far of positive findings in otherwise negative CT (Figure 3). Under study (see text and refs).

subsequently added, namely secondary cytoreduction. This cytoreduction has been deemed most beneficial when all gross disease can be resected. In fact, repeated cytoreductive surgery has been performed in some patients based on such perception. More recently, a third objective has been added and has become most persuasive: to aid in the selection of secondary treatment. Unfortunately, secondary interventions including IP therapy have been considered to be ineffective in achieving prolonged median survival or resulting in a cohort of long-term survivors. Insertion of an IP device may still be deemed useful, however, for disease-monitoring or may be justified in the context of a clinical trial. Clinical trials of IP consolidation are warranted. Value of cytoreduction The recently published European Organisation for Research and Treatment of Cancer (EORTC) study indicated superior survival in the group undergoing interval cytoreduction following four cycles of cyclophosphamide with cisplatin (39). This result has inspired an ongoing trial by the Gynecologic Oncology Group (GOG 151) having a similar design, but utilizing a combination of cisplatin and paclitaxel. If this study confirms the EORTC findings of interval cytoreduction improving survival, then the argument that second-look laparotomy may benefit those patients capable of having resection of gross disease would be greatly strengthened. Again, one must seek a role of secondary treatment to improve results further. Thus, the evaluation of second-look surgery and salvage therapy are intertwined. Validation through clinical trials constitutes the most reliable method with which to settle these issues. Diagnostic A way out other less this regard refinement series with

non-invasive

alternatives

of the dilemma of second-look laparotomy is to identify disease by invasive or non-invasive means. Some progress has been made in during the past decade with the introduction of the CA-125 and the of radiologic techniques. The accuracy of negative findings including normal CA-125s has been very disappointing (Tables 2 and 3). The

L. MUDERSPACH Table

3.

Ref.

and

CA-125

47 48 49 50 Total

CA-125

(%)

surgical normal

HAL.

findings

(Hoskins CA-125

and

Rubin,

1991)

(40)

elevated

Surgery negative

Surgery positive

Surgery negative

Surgery positive

Total

14 24 18 11

22 18 15 18

1 0 0 0

19 12 16 67

56 55 49 96

67(48)

73(52)

l(1)

114(99)

24% false negativity for CT scan is irrelevant since by definition of technical capabilities lesions c0.5cm would be missed by CT. Several studies have stressed the high negative predictive value of both CT scan and ultrasounds performed prior to second-look laparotomy (40-44). CT may, nevertheless, provide useful information before surgery (45, 46). We have begun to examine positron emission tomography (PET) scans as a possible more sensitive indicator of disease status. Metabolic tumor imaging studies such as PET provide complementary information to the morphological evaluation of human cancers using CT and MRI. Potentially, changes in PET imaging as a result of treatment may take place faster than with techniques relying on morphological changes. PET has been demonstrated to be effective in determining the presence or recurrence of ovarian cancer. In addition, the ability serially to scan patients during treatment with F-18 deoxyglucose (FDG) is a distinct advantage over diagnostic approaches depending on monoclonal antibodies that may elicit human antimurine antibody responses (51). The utility of FDG in detecting the presence of ovarian cancer was first demonstrated by Wahl et al. (52). Imaging at 50-70 min post-injection of FDG yielded a maximal tumor to normal abdomen uptake of the FDG of 32:l. The ability to establish both negative and positive findings were confirmed by Gupta et al. (53). Several studies have subsequently evaluated PET in relation to other diagnostic modalities in ovarian cancer. Hubner et al. (54) compared it with CT in 51 patients. PET had better sensitivity (92.8 vs. 85.7% for CT), specificity (81.8 vs. 54.5%) and accuracy (88 vs. 72%). This study relied both on semiquantitative activity levels along with the uptake curves in distinguishing normal from neoplastic tissue. These same workers extended the study to 203 patients, and continued to demonstrate an excellent negative predictive value (89 vs. 33% for CT). A suggestion was advanced that combined negative CT and PET could obviate second-look Iaparotomy (55). Another study was performed in 13 patients and also evaluated CA-125 and ultrasound. PET had a sensitivity and specificity of 88 and 100% respectively. CT had a sensitivity of 63% and a specificity of 25%. The CA-125 was normal in three of eight patients with documented recurrence; and falsely elevated in one (56). Additional correlations have been reported confirming the accuracy and sensitivity of PET (56-59). However, five of six patients without clinical evidence of disease and negative

SECOND-LOOK

LAPAROTOMY

FOR

STAGE

III EPITHELIAL

OVARIAN

CANCER

Figure 3. CT scan with IP contrast demonstrating residual cancer in Morrison’s pouch, on a prior CT scan in a patient with known positive cytologic washings at second-look

507

not detected laparotomy.

PET scans had surgical confirmation of microscopic disease at second-look laparotomy (46) rendering the suggestion made by Hubner eta/. (55) somewhat premature. Diagnostic

invasive

alternatives

Laparoscopy constitutes the most viable alternative to second-look laparotomy, and one that has gained favor with improvement in technical capabilities. However, resection is more difficult to accomplish, and in the recent study, by Fiorentino et al. (141, disease verified by laparotomy was present in 11 of 46 patients that had been deemed negative by laparoscopy. Cytology obtained by percutaneous paracentesis has been advocated as a method for monitoring recurrence of ovarian cancer (60). We have employed serial monitoring in patients with intraperitoneal access ports, and verified that it may determine early failure to eradicate the disease following IP chemotherapy (20) (Figure 3). Efforts to enhance the sensitivity of cytologic examinations by monoclonal antibody immunostaining, and using polymerase chain reaction to detect mutations associated with ovarian malignancy, offer some promise for detection of persistent disease, but are currently lacking data concerning clinical usefulness. Prognostic

factors

Determination of disease status after initial treatment yields information of prognostic nature. Foremost is the extent of residual disease. Resectability may further improve chances for favorable prognosis. Other prognostic indicators

508

ETAL.

L. MUDERSPACH

Surgery for ovarian cancer Stages II-IV I InduCtion chemotherapy 6 cycles Evidence of A persistent disease

Select secondary cytoreduction

No evidence of disease by exam,, lab, or imaging (clinical complete remission) Second-look

Salvage* chemotherapy Negative

1 Consolidation* chemotherapy

Observation q *Experimental Figure

4. Conceptual

Consolidation* chemotherapy

regimens.

framework

for

Positive

the

role of second-look ovarian cancer.

laparotomy

in the

management

of

at the outset may also be applicable but have been studied less. Such indicators aid in the design and interpretation of clinical trials. Therefore, this information supports use of second-look laparotomy, but only insofar as trials are in place utilizing these findings.

Conclusions Second-look surgery in patients with advanced epithelial ovarian cancer remains controversial and its objectives ill-defined. It is generally agreed that secondlook surgery currently provides the most accurate determination of disease status after first-line chemotherapy. In addition, second-look surgery allows physicians to select patients for experimental salvage regimens. However, at this time, there is no proven survival benefit to second-look surgery and the patients’ characteristics predicting for improved outcome have not been well defined. It is our opinion that second-look surgeries including both laparotomy and laparoscopy are useful in guiding the treatment of patients with advanced epithelial ovarian cancer. This is especially true when experimental protocols are available for the testing of consolidation treatment. A schema utilizing findings at second-look surgery to guide treatment decisions is shown in Figure 4. Patients with negative second-look should be considered for trials testing consolidation therapy of low morbidity. Women with microscopic or small residual disease are candidates for additional treatment with further systemic or intraperitoneal chemotherapy. Finally, those patients with unresectable residual

SECOND-LOOK

LAPAROTOMY

tumor at second-look have experimental approaches.

FOR

STAGE

an extremely

III EPITHELIAL

poor

prognosis

OVARIAN

and

509

CANCER

could

be offered

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SECOND-LOOK 47. 48. 49. 50.

51. 52. 53.

54.

55.

56. 57. 58.

59.

60.

LAPAROTOMY

FOR

STAGE

III EPITHELIAL

OVARIAN

CANCER

511

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