Download Cytoreductive Surgery in Ovarian Cancer

Pierre Auguste Renoir (French, 1841-1919), Moulin Galette, 1876.
Cytoreductive Surgery in Ovarian Cancer: Why, When, and How?
William S. Roberts, MD
Retrospective evidence supports the value of optimal cytoreductive surgery in the initial therapy of patients with advanced ovarian cancer. Specialized
procedures, including radical pelvic surgery, bowel resection, and diaphragm resections, are frequently necessary to accomplish optimal cytoreduction.
Cytoreduction and total gross tumor removal are possible more frequently with new surgical instruments such as the Cavitron ultrasonic surgical aspirator
and argon beam laser. Pelvic and periaortic lymph node resection is an important aspect of cytoreductive surgery, and systematic removal of grossly
uninvolved lymph nodes may improve survival. Secondary cytoreductive surgery appears to benefit a select group of patients.
Introduction
Ovarian cancer is an insidious disease and the fourth leading cause of cancer deaths in women in the United States. The majority of women who contract this disease
will die as a result, mostly due to uncontrolled, large-volume disease within the peritoneal cavity. More than 70% of women are initially diagnosed with disseminated
intraperitoneal disease. Generally, ovarian cancer is surgically diagnosed. In addition to diagnosis, two other classic aims of ovarian cancer surgery are the appropriate
determination of extent of disease (staging) and the removal of as much tumor as is feasible (debulking or cytoreduction) to maximize postoperative therapy. This
discussion focuses on issues regarding debulking surgery in both primary and subsequent therapy.
Ovarian cancer metastasizes by breaking through the ovarian capsule and spreading noncontiguously along parietal and visceral peritoneal surfaces. It tends not to
invade deeply or into hollow organs, and in most patients the disease remains confined to the peritoneal cavity until death. The disease may become focally confluent
and can form large-volume masses anywhere in the peritoneal cavity. Typical locations include the omentum, sigmoid colon serosa, and pericolonic gutters. Patients
become symptomatic usually as a result of intraperitoneal pressure increases due to solid masses or fluid. Some patients are asymptomatic in spite of surprisingly large
volumes of intraperitoneal disease. The regional lymph nodes, namely pelvic and periaortic lymph nodes, are frequently involved. This is particularly true in stage III and
IV disease in which Burghardt et al[1] reported involvement in 74% of patients.
Because ovarian cancer metastases usually are relatively superficial, the disease lends itself technically to cytoreductive surgery often without major organ resection. The
question arises as to the benefit of this surgery to the patient. In theory, benefits could include symptomatic relief, prolongation of survival even without further therapy,
and enhancement of postoperative therapy in terms of both survival duration and chance for cure. All of these apply to ovarian cancer debulking surgery.
Primary Cytoreductive Surgery
The initial study suggesting that cytoreductive surgery is of value in the primary therapy of ovarian cancer was published in 1975.[2] In this study, patients who were
cytoreduced to a maximum residual diameter of 1.5 cm or less survived as well as patients with residual disease of 1.5 cm or less without cytoreduction. Survival of
these two groups was markedly superior to patients with maximum residual disease greater than 1.5 cm in diameter. Since this initial study, multiple retrospective
studies have demonstrated superior survival in patients whose residual disease was 1 to 3 cm in maximum diameter compared with patients with larger residual masses.
[3-10] In summarizing these studies, Hoskins[11] noted a median survival of 36.7 months in 388 patients who were optimally cytoreduced vs 16.6 months in 537
patients with suboptimal residual disease.
These studies demonstrate that the size of residual disease has a profound impact on survival. However, they do not prove unequivocally that cytoreductive surgery
resulting in small residual disease is responsible for the improved survival in these patients. A large randomized, prospective study would be necessary to demonstrate
this, and to date this has not been done. Because of the large volume of retrospective evidence suggesting that cytoreductive surgery is beneficial in the primary therapy
of ovarian cancer, most physicians treating these patients believe in its value. As a result, it is very likely that a prospective, randomized study will never be done, even
in a cooperative group setting. Given these circumstances, cytoreductive surgery is firmly entrenched in the initial management of ovarian cancer patients.
While Griffiths' initial study[2] suggested that patients with large volume metastatic disease who were cytoreduced to small volume residual disease did as well as
patients with small volume metastatic disease, this result is not supported in subsequent studies. The initial size of metastatic deposits did impact on survival in patients
who were optimally cytoreduced in a study by Hacker et al[3] in 1983. The survival curves in this study are shown in Fig 1. Optimally cytoreduced patients with initial
metastatic disease between 1.5 and 10 cm did better than optimally cytoreduced patients with initial metastatic disease greater than 10 cm, but they did worse than
patients with initial metastatic disease less than 1.5 cm. In a more recent Gynecologic Oncology Group study[12] involving a much larger number of patients, a similar
result was reported. Patients with microscopic upper abdominal metastatic disease survived significantly longer than patients with grossly evident disease less than 1 cm.
In turn, the latter group survived significantly longer than patients with upper abdominal metastatic disease greater than 1 cm in diameter who were cytoreduced to less
than 1 cm. Tumor biology cannot be completely negated with aggressive cytoreductive surgery. Given equal size of residual disease, patients with larger volume initial
metastatic disease will survive less well.
Along similar lines, the number of metastatic lesions affects survival despite optimal cytoreductive surgery. Farias-Eisner et al[13] reported on 78 patients who were
cytoreduced to 5 mm or less as the maximum tumor diameter. Patients with scattered residual nodules survived significantly better than patients with extensive
carcinomatoses. More specifically, Hoskins and colleagues[12] noted that 20 or more residual lesions resulted in a significantly poorer survival in patients optimally
cytoreduced to 1 cm or less.
Optimal Residual Disease
The term optimal cytoreductive surgery refers to the maximum diameter of residual disease. The size in various papers has arbitrarily been set anywhere from 5 mm
to 3 cm. Optimal cytoreduction may represent a threshold below which survival no longer improves or above which survival no longer improves. The Gynecologic
Oncology Group has demonstrated that survival for patients with advanced ovarian cancer progressively decreases as the maximum residual disease increases from
microscopic to 2 cm (Fig 2),[14] which demonstrates that optimal survival occurs when there is no gross residual disease. In the same paper, the upper threshold after
which survival no longer improves was demonstrated to be 2 cm (Fig 3). Patients with 3-cm residual disease do not survive longer than patients with 10-cm residual
disease.
This is particularly useful information for the surgeon who operates on ovarian cancer patients. Every reasonable effort should be made to remove all gross tumor. If
that cannot be accomplished, then 1 cm is better than 2 cm of residual disease. If a maximum residual disease of 2 cm or less is not possible, then aggressive surgery
such as bowel resection is not appropriate, since survival is not improved.
The percentage of patients with advanced ovarian cancer who are optimally cytoreduced depends on the aggressiveness, patience, and training of the initial surgeon.
Taken as a whole, only 42% of the 925 patients in the nine retrospective studies summarized by Hoskins et al[11] were optimally cytoreduced. However, in the most
contemporary of the above series reported in 1988,[10] 87% of patients were cytoreduced to less than 2 cm of residual disease. In a retrospective study[15]
comparing gynecologic oncologists with nongynecologic oncologists as the initial surgeon, 82% of stage IIIC or IV ovarian cancer patients were optimally cytoreduced
by gynecologic oncologists compared with 29% for nongynecologic oncologists. Most importantly, survival was significantly better in patients cytoreduced by
gynecologic oncologists. The surgery done by the gynecologic oncologists was more aggressive since it was associated with a significantly higher operative time,
estimated blood loss, hospital stay, need for transfusion, incidence of intestinal resection, and incidence of adynamic ileus. Operative mortality, however, was actually
significantly less for the gynecologic oncologists.
Specialized Procedures
Many patients with advanced ovarian cancer can be optimally cytoreduced with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy.
However, many patients require specialized procedures to achieve this goal. Radical pelvic surgery often is required in patients with large confluent pelvic disease. This
radical pelvic surgery frequently requires resection of the pelvic peritoneum, cardinal ligaments, uterosacral ligaments, portions of the sigmoid colon and rectum, and
portions of the lower urinary tract. This type of surgery is variously known as radical oophorectomy, modified posterior exenteration, and reverse
hysterocolposigmoidectomy.[16-18] The common element is retroperitoneal mobilization of the pelvic disease with en bloc resection.
Resection of a portion of the lower urinary tract is the rarest component of this radical pelvic surgery, and total resection of the bladder with urinary diversion is rarely
necessary or justified. However, partial resection of the bladder or ureter to achieve optimal cytoreduction is appropriate. In a series by Berek and colleages[19] of 24
patients treated in this manner over a 19-year period at University of California at Los Angeles Medical Center, eight patients had partial cystectomies, and 16 had
partial ureteral resection. Morbidity was acceptable, and survival was significantly longer for those patients who were successfully optimally cytoreduced compared
with those who were not.
Resection of a portion of the sigmoid colon and/or rectum is a frequent component of radical pelvic surgery in advanced ovarian cancer. As a result of modern stapling
devices, most of these patients do not require colostomies. In a series by Soper et al[20] of 40 patients, only 12 required colostomy. Serous morbidity and mortality
are acceptable with these procedures but are not trivial. Postoperative mortality occurred in two of 117 patients in three combined recent series.[17,18,20] Serous
postoperative morbidity ranged from 20% to 39% including wound infection, pulmonary embolus, pelvic abscess, prolonged ileus, and postoperative hemorrhage.
Specialized procedures for optimal ovarian cancer cytoreduction also are frequently necessary in the upper abdomen. This most often involves small bowel resection or
resection of colon proximal to the sigmoid colon. Other procedures include splenectomy, resection of diaphragmatic peritoneum, nephrectomy, cholecystectomy, and
partial resection of organs such as the liver, pancreas, and stomach. Little is published regarding these specialized procedures. Sonnendecker et al[21] reported six
patients out of a total of 79 (7%) with advanced ovarian cancer who underwent splenectomy as part of their primary cytoreductive surgery. Four of these patients had
significant late thromboembolic complications with one death. Three of these patients are alive without evidence of disease with a maximum follow-up of 32 months. In
another report[22] of 14 patients who underwent diaphragmatic resections, optimal cytoreduction was achieved in 13 patients, and in one patient the procedure was
abandoned due to laceration of the liver capsule. Other than the liver capsule injury, there was no other serious morbidity.
Retroperitoneal Cytoreduction
As previously mentioned, pelvic and periaortic lymph nodes are frequently involved in patients with advanced ovarian cancer. The retroperitoneal space as well as the
intraperitoneal space, therefore, must be considered in any cytoreductive strategy, and grossly involved lymph nodes should be removed if feasible to achieve optimal
cytoreduction. A study[23] published in 1986 addressed the question of the role of the lymph node resection if they are not grossly involved. Seventy patients with
stage III ovarian cancer underwent standard intraperitoneal cytoreduction and systematic pelvic and periaortic lymphadenectomy starting at the level of the renal
vessels. These patients were compared to 40 similar patients who underwent only intraperitoneal cytoreduction without lymphadenectomy. The actuarial five-year
survival was 53% in the lymphadenectomy group and 13% in the nonlymphadenectomy group. In the lymphadenectomy group, those with negative lymph nodes had a
survival rate of 74.7%, and those patients with positive lymph nodes had a survival rate of 45.9%. A Japanese study[24] published in 1993 showed similar results in 25
patients with stage III ovarian cancer. A statistically significant survival advantage was shown for 15 patients who underwent lymphadenectomy compared with 10
patients who did not. These studies suggest that systematic pelvic and periaortic lymphadenectomy improves survival in patients with advanced ovarian cancer when
combined with optimal intraperitoneal cytoreduction. A prospective, randomized study is needed to determine if this outcome is a true effect or the result of selection
bias.
Systematic pelvic and periaortic lymphadenectomy generally is not part of cytoreductive surgery in the United States. The only report[25] in the American medical
literature described systematic pelvic and periaortic lymphadenectomy in 56 patients with stage III and IV ovarian cancer. In 21 additional patients, either the
procedure was technically not possible or the patient could not be optimally cytoreduced intraperitoneally. Positive lymph nodes were present in 64% of patients, and
within this group, 64% had macroscopically positive nodes and 36% had microscopically positive nodes. Survival was comparable in patients with negative,
microscopically positive, and macroscopically positive lymph nodes (43% to 50%). No major morbidity could be attributed to the lymphadenectomy.
Systematic lymphadenectomy is feasible in most patients with advanced ovarian cancer. Since its employment may have a profound effect on survival, it is worthy of a
prospective, randomized study in a cooperative group setting.
Specialized Instruments
When aggressively pursued, cytoreductive surgery is challenging and often associated with serious morbidity. As a result, there has been interest in the development of
techniques such as the Cavitron ultrasonic surgical aspirator (CUSA) that allow more precise tumor removal that may obviate the need for major organ removal. The
CUSA fractures the tumor with high-intensity sound energy and removes it with suction while sparing vessels and hollow organ walls. It can be used safely in relatively
inaccessible areas. Two initial reports describing its use in ovarian cancer were published in 1988. Adelson et al[26] noted no organ resections in 10 patients with a
mean CUSA operating time of 49 minutes. A similar experience was noted by Deppe et al,[27] although they noted that the value of the CUSA was limited in patients
with relatively fibrotic tumors. In a later report[28] the CUSA was used in 22 of 45 advanced ovarian cancer patients to effect optimal cytoreductive surgery. Sites
where the CUSA was used included colon, diaphragm, gallbladder, spleen, stomach, small bowel, and fixed retroperitoneal lymphadenopathy. The report noted only
one patient with a fibrotic tumor in which the CUSA was not effective.
Several other techniques have been used to compliment standard surgical techniques in ovarian cancer cytoreductive surgery. Brand and Pearlman[29] reported the use
of the argon beam laser in this setting with particular emphasis on diaphragmatic lesions as well as bowel serosa and mesenteric lesions. The advantages of this
instrument include minimal thermal damage beyond what can be seen and clearance of blood and debris away from the operative site. Other modalities used in this
same setting include the carbon dioxide laser and the loop electrosurgical excision procedure.[30,31]
One advantage of the CUSA and argon beam laser is more expeditious removal of widespread, small peritoneal implants. As stated earlier, widespread peritoneal
implants in optimally cytoreduced patients are associated with a survival disadvantage. A strategy to overcome this would be the systematic removal of these implants.
Eisenkop et al[32] reported a case-control study in which 26 patients who underwent peritoneal implant excision (using both the CUSA and argon beam laser) were
compared with seven patients without residual disease and without peritoneal implant excision and 34 patients who were cytoreduced to residual peritoneal implants of
less than 1-cm in diameter. While the operative time in the peritoneal implant excision group was statistically significantly longer, survival was significantly greater
(P=0.003) compared with that in the group with residual implants. No major morbidity was attributable to peritoneal implant excision. This study supports a meticulous
attempt at total peritoneal implant excision in otherwise optimally cytoreduced ovarian cancer patients. A randomized, prospective study is needed to prove this.
In spite of well-trained, aggressive surgeons and modern technology, some patients with advanced ovarian cancer cannot be optimally cytoreduced. Examples of
nonresectability include extensive liver parenchymal disease, involvement of the superior mesenteric vessels, and involvement of the porta hepatitis. Some patients will
have overwhelming disease, and others will be too medically compromised to tolerate extensive surgery. In our experience, only 20% to 25% of patients fit in this
category.
Secondary Cytoreduction
Although the scientific basis is not perfect, aggressive cytoreductive surgery is widely accepted in the initial management of ovarian cancer patients. However, the role
of secondary cytoreductive surgery is not so well defined. The term secondary cytoreductive surgery encompasses a variety of different clinical scenarios (Table 1).
The evidence for the value of secondary cytoreductive surgery in each situation is retrospective in nature except in its use as an interval procedure after suboptimal
primary cytoreductive surgery. An initial report[33] in 1983 that suggested some value for secondary cytoreductive surgery in general involved 32 patients, of whom 11
had no clinical evidence of disease and 21 did have clinical evidence of disease. Twelve patients were optimally cytoreduced (largest diameter of residual disease was
less than 1.5 cm) with a median survival of 20 months, and 20 patients could not be optimally cytoreduced with a median survival of five months. This difference in
survival was statistically significant (P<.01). Survival also was statistically superior in patients cytoreduced with no clinical evidence of disease compared with those
cytoreduced with clinical evidence of disease. >
Subsequent reports have been more focused. Several retrospective studies have analyzed patients undergoing second-look laparotomy with no clinical evidence of
disease. Table 2 summarizes these studies with regard to median survival and the maximum size of residual disease.[34-37] In the study by Lippman et al,[34] survival
in the optimally cytoreduced group dramatically improved compared with that in the suboptimally cytoreduced group. The most dramatic survival advantage in studies
by Hoskins and colleagues[36] and by Podratz et al[37] was seen in those patients whose gross residual disease was completely removed. In neither study was the
median survival reached in this group of patients.
Patients with clinical evidence of disease at the completion of primary chemotherapy probably do not benefit significantly from secondary cytoreduction. This is
particularly true for patients who progress during chemotherapy. Evidence to this effect is shown in a report[38] involving patients with clinical evidence of disease prior
to second-look laparotomy. Of 77 patients, 32 were optimally cytoreduced and 45 had suboptimal residual disease. Both groups had a median survival of 12 months.
Secondary cytoreductive surgery may be of benefit in patients with recurrent ovarian cancer after a significant disease-free interval. Janicke et al[39] aggressively
debulked 30 patients in this category and were able to completely remove disease in 14 patients. In 12 patients, gross residual disease was less than 2 cm, and bowel
resection was necessary in 19 patients. Median survival for those with completely resected disease and those with gross residual disease of less than 2 cm was 29
months and nine months, respectively. The most significant factors associated with improved survival in this study included absence of gross residual disease and a
disease-free interval of more than 12 months. Patients with a disease-free interval of six months or less seldom benefit from secondary cytoreductive surgery.
Interval cytoreduction after suboptimal initial surgery in apparent responders to chemotherapy has been examined more critically. Wiltshaw et al[40] demonstrated a
significant survival advantage in partial responders who underwent secondary cytoreduction vs partial responders who did not undergo surgery. In addition, a
prospective, randomized study[41] by the European Organization for Research and Treatment of Cancer (EORTC) demonstrated a statistically significant improvement
in both disease-free and overall survival in the interval surgery group. In this study involving 278 evaluable patients, 140 were assigned to the interval surgery arm.
Residual disease larger than 1 cm was present in 83 patients in this arm, and the disease could be cytoreduced to less than 1 cm in greatest diameter in 37 of these
patients. This surgery was primarily composed of removal of ovaries that remained after initial surgery. There was no operative mortality, and morbidity was minimal.
Of interest, however, is the lack of difference in complete pathologic responders in the two arms. While interval surgery may improve survival, it does not necessarily
lead to an ultimate cure. Nonetheless, the results of the EORTC study are compelling. A similar study is being conducted by the Gynecologic Oncology Group to
confirm these results.
The benefit of secondary cytoreductive surgery in advanced ovarian cancer is dependent on patient selection. Ideal candidates are those with suboptimal initial surgery
and response to chemotherapy, patients without clinical evidence of disease at the time of second-look laparotomy in whom all gross disease can be removed, and
patients with recurrent disease after a prolonged disease-free interval. The aggressiveness with which secondary cytoreduction should be pursued is questionable. A
total abdominal hysterectomy and bilateral salpingo-oophorectomy should be performed if not done initially. Aggressive specialized procedures such as bowel resection
may be of value in this setting, although evidence to that effect is lacking.
Conclusions
Careful staging and optimal cytoreduction is the desirable standard of care for patients with ovarian cancer. Such surgery has been facilitated by newer instrumentation.
There is good evidence that secondary cytoreduction is of benefit in selected patients, but it is unlikely that evidence from prospective randomized trials to document the
value of primary cytoreduction will ever be produced.
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From the Gynecologic Oncology Program at H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fla.