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The impact of subspecialty training on the management of advanced ovarian cancer
GYNECOLOGIC
ONCOLOGY
47, 203-209 (1992)
The Impact of Subspecialty Training on the Management of Advanced Ovarian Cancer SCOTT M. EISENKOP,
M.D. ,l NICK M. SPIRTOS, M.D.,
THOMAS W. MONTAG,
AND HE-JING WANG, The Center
for Gynecologic Oncology, Encino, Gynecologic Oncology, Los Angeles,
California; California;
M.D.,
RICHARD H. NALICK,
M.D.,
M.P.H.
the Women’s Cancer Center, and UCLA School of Public Los Angeles, California
Palo Alto, California; Health, Department
The Los Angeles of Biomathematics,
Center for
Received April 2, 1992
A retrospectivestudy wasconductedto determinethe influence of subspecialtytraining in gynecologiconcologyaswell as several other covariateson the feasibility, operative mortality, and survival benefitsof cytoreductive surgeryfor 263patientswith stages IIIC and NA epithelial ovarian cancer. Covariatesmost predictive of an optimal (s 1 cm) cytoreductive outcome were the diameterof the largestmetastases beforecytoreduction (G 10 cm vs > 10cm, P < 0.001)and the specialtytraining of the physicians presentat surgery (gynecologiconcologistsvs other, P < 0.001). Age infhrenced operative mortality most (< 60 vs 2 60, P < 0.001). Covariatesfound to most significantly influencesurvival time include the specialty training of the physicianspresent at surgery (gynecologiconcologistsvs other, P < O.OOOl),cytoreductive outcome (complete vs optimal, P = 0.001, optimal vs suboptimal,P < O.OOOl),grade of tumor (grade 1 vs grades2 and 3, P = O.Ol), and pelvic diseasestatus (frozen pelvis vs mobile primary tumor, P = 0.03). We conclude that patients with advancedepithelial ovarian cancer should undergoaggressive cytoreductive surgery by gynecologiconcologists,with the objectiveto removeall macroscopicdisease.Subsequenttreatment with platinum-basedchemotherapy offers the best chance for long-term survival or cure. 0 1992 Academic PWS, Inc. INTRODUCTION
Primary cytoreductive surgery, followed by platinumbased multiagent chemotherapy, improves both prognosis and quality of life for patients with advanced epithelial ovarian cancer [l-6]. Most cytoreductive surgical data is retrospective, includes limited numbers of patients with various stages of disease, and describes individual or departmental experiences of gynecologic oncologists. I To whom reprint requests should be addressed at The Center for Gynecologic Oncology, 16542 Ventura Boulevard, Suite 510, Encino, CA 91436.
Hence, while the therapeutic value of attaining a diseasefree or minimal residual tumor burden status is uniformly reported, controversy remains over the influences of other specific issues on the feasibility of cytoreduction, operative mortality, and prognosis. The contribution or necessity of subspecialty training in gynecologic oncology, in particular, has not been specificly addressed. We therefore have reviewed the results of primary cytoreductive operations for previously untreated patients with stages IIIC and IVA epithelial ovarian cancer from several hospitals. The purpose of this study is to determine the importance of subspecialty training in gynecologic oncology along with other previously uninvestigated determinants of resectability, operative mortality, and long-term survival and to confirm the previously suggested significance of others. METHODS AND MATERIALS
From January 1985 to December 1988, the charts of all patients with a diagnosis of epithelial ovarian cancer listed in the tumor registries of 14 hospitals serviced by the authors in the greater Los Angeles, Denver, and San Francisco Bay areas were reviewed. When necessary, approval was obtained from institutional review boards. All patients with tumors of low malignant potential (borderline histology), primary operations performed at other hospitals, stages of disease other than IIIC and IVA, and those pretreated with chemotherapy were excluded. Hence, 263 patients were accrued. Information obtained by chart review included age, duration of symptoms, tumor grade, histology, size and location of metastatic disease, extent of pelvic tumor, operative time, blood loss, hospital stay, transfusion status,
203 All
0090-8258/92 $4.00 Copyright 0 1992 by Academic Press, Inc. rights of reproduction in any form reserved.
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ascitic volume, procedures attempted and completed, cytoreductive outcome, and the specialty training of the physicians performing the operative procedures. The influence of these covariates on the probability of attaining an optimal cytoreductive result and on postoperative mortality was evaluated. “Optimal cytoreductive surgery” was defined as the outcome of no residual solitary lesion(s) larger than 1 cm in diameter. “Complete cytoreductive surgery” is defined as the removal of all macroscopic disease. Frozen pelvis refers to the confluent involvement of reproductive organs, sigmoid colon, and pelvic peritoneum by tumor. Operative mortality and morbidity are defined as death and any untoward result occurring within 28 days of surgery. In addition to the previous covariates, the influence of cytoreductive outcome, location of largest residual disease, and time delay prior to initiation of chemotherapy were analyzed to determine their influences on survival. Follow-up information was obtained by review of tumor registry information and direct contact with the patient, her family, or her physician. Variables were analyzed with respect to their influence on tumor resectability (to an optimal state) and mortality by the x2 test and then further evaluated by stepwise logistic regression. Comparisons between groups of patients were accomplished by the corrected x2 or Fisher’s exact test (for categorical data), and two-tailed, t test (for continuous numerical data). The Cox proportional hazards regression model was used to quantify the relationship between survival and some covariates. The KaplanMeier method was used to estimate the survival distribution for subgroups of patients. Log rank statistics were employed for testing the equality of survival curves. P values greater than 0.05 were reported as not significant (NS). Survival time was calculated from the day of primary cytoreductive surgery to the date of last contact or death.
RESULTS The mean age was 60.9 years (range, 22 to 92). Two hundred thirty-seven patients were stage IIIC and 26 were stage IVA (1989 FIGO). There were 16 grade 1 lesions, 62 grade 2, 181 grade 3; the grade was not obtainable for 4 patients. There were 205 serous and unspecified adenocarcinomas, 19 mutinous, 21 endometroid, 4 clear cell, 6 anaplastic, and 8 mixed histologies. The largest metastatic lesion was described qualitatively as “massive” or at least 10 cm in largest dimension in 144 (54.8%) patients. The omentum was the most common site of largest metastatic disease for 155 (58.9%). Fifty-four (20.5%) had p e 1vie involvement consistent with the description of a “frozen pelvis.” Of 186 patients with re-
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corded volumes of ascites, 114 (61.3%) had in excess of 1 liter. The mean operative time was 2.6 hr, the mean estimated blood loss was 795 ml, and the median postoperative stay was 9.5 days. Two-hundred sixteen (82.1%) patients had varying degrees of cytoreduction accomplished, and 47 (17.9%) underwent laparotomy with omental or adnexal biopsy only. Two-hundred fourteen (81.4%) had removal of the upper reproductive organs present, and 75 (28.5%) had a large or small bowel resection (excluding palliative colostomy). Additionally, 191 (72.6%) underwent omentectomy, 135 (51.3%) had peritoneal implant excision or ablation, 20 (7.6%) had a diaphragm stripping procedure, 77 (29.3%) underwent various forms of retroperitoneal lymph node dissection, 3 (1.1%) had a splenectomy, and 4 (1.5%) required a urologic procedure. Eleven gynecologic oncologists functioned as primary surgeons. Additionally, 120 obstetrician gynecologists, 85 general or oncologic surgeons, and 40 physicians with miscellaneous specialties served as primary surgeons and assistants (or cosurgeons). Optimal cytoreduction was documented for 143 of 263 patients (54.4%), and complete cytoreduction was accomplished for 32 (12.2%). The type of incision, diameter of largest metastases, specialty training of the surgeons, age, and extent of pelvic tumor influenced tumor resectability (x’) (Table 1). Stepwise logistic regression revealed the intraoperative presence of a gynecologic oncologist and the diameter of the largest metastases to be the covariates most influencing the attainment of optimal (e 1 cm) cytoreduction (Table 1). No significant differences in severity of disease, adjunctive treatment strategy, or adequacy of follow-up could be detected among the specialties of physicians (Table 2). However, the operative approaches differed, as exemplified by choices of incision, the decision not to attempt cytoreduction, and the completion of pelvic tumor excision for those with a frozen pelvis (Table 2). Age inhibited physicians without subspecialty training in gynecologic oncology from attaining optimal cytoreduction. Thirty-four of 43 (79.1%) patients over 65 years old operated on by gynecologic oncologists underwent optimal cytoreduction, compared to 9 of 60 (15.0%) operated on by other physicians (P = 0.0001). Finally, gynecologic oncologists more frequently performed procedures (other than TAH/BSO and omentectomy) that were required to attain optimal cytoreduction for patients with a frozen pelvis, intestinal metastases, extensive retroperitoneal disease, diaphragmatic metastases, and peritoneal or serosal implants (Table 2). Ninety (34.2%) patients experienced operative morbidity. Complications reported included adynamic ileus in 44 (16.7%) bacterial pneumonia in 14 (5.3%), bacter-
SUBSPECIALTY
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TABLE 1 Variables Determining Respectability
TABLE 2 DiseaseCharacteristicsand Treatment by Specialty
Optimal Total No.
No.
Grade of tumor 1 2 3
16 62 181
12 35 94
75.0% 56.5% 51.4%
NS
Incision Vertical Transverse
245 18
139 4
56.7% 22.2%
o.ocl5
Diameter of largest metastases c 10cm > 10cm
119 144
81 62
68.1% 43.1%
Specialty training Gynecologic oncologist Other General surgeon present General surgeon absent
126 137 98 39
103 40 28 12
81.7% 29.2% 28.6% 30.8%
Age 2 60 <60
149 114
70 73
46.9% 63.1%
0.001
Volume of ascites ~1OOOml < 1000 ml
114 72
64 45
56.1% 62.5%
NS
Site of largest metastases Omentum Other
155 108
89 54
57.4% 50.0%
NS
Histology Serous or unspecified Other
205 58
109 34
53.2% 58.6%
NS
Frozen pelvis Yes No
54 209
22 121
40.7% 57.9%
0.02
Duration of symptoms > 8 weeks s 8 weeks
100 148
53 81
53.0% 54.7%
NS
Covariate variable
(%I
P
value”
NS
a x2 test. ’ Covariates selected by stepwise regression analysis.
emia in 12 (4.6%), small bowel obstruction, transient renal failure, deep vein thrombophlebitis, and disseminated intravascular coagulation, each in 5 (1.9%), and postoperative hemorrhage requiring reoperation in 3 (1.1%) patients. Additionally, myocardial infarction, stroke, enterocutaneous fistula, pulmonary embolus, and aspiration pneumonia were each reported for 2 (.76%) patients. Non-life-threatening morbidity, operative time, blood loss, and hospital stay were increased among patients operated on by gynecologic oncologists (Table 3). Sixteen (6.1%) patients died postoperatively. Age, cytoreductive outcome, and subspecialty training significantly influenced the mortality rate (x2). Stepwise logistic
Gynecologic oncology N = 126
Characteristic Grade 3 lesions Serous histology Stage IVA Largest metastases >lO cm Omentum site of largest metastases Frozen pelvis Vertical incision Omental or adnexal biopsy only Frozen pelvis tumor completely excised Intestinal resection Peritoneal implant excision or ablation Diaphragm striping Adjunctive treatment” Platinum multiagent Other None Mean cycles chemotherapy Mortality Lost to follow-up
Other specialty N = 137
P
value”
(71.4%) (77.4%) (8.8%) (57.7%)
NS NS NS NS
79 (63.2%) 20 (15.9%) 126 (100%)
76 (55.5%) 34 (24.8%) 119 (86.9%)
NS NS
0
47 (34.3%)
20 (100%) 56 (44.4%)
2 (5.9%) 19 (13.9%)
106 (84.1%) 20 (15.9%)
29 (21.1%) 0
114 (92.7%) 2 7 7.1 3 (2.4%) 5 (3.9%)
112 (90.3%) 4 8 7.4 13 (9.5%) 8 (5.8%)
NS
86 99 14 65
(68.3%) (78.6%) (11.1%) (51.6%)
95 106 12 79
NS 0.02 NS
a x2 or t test. ’ Excludes operative mortality (4 pts).
TABLE 3 Operative Morbidity by Specialty
Variable Mean operative time Mean hospital days Mean estimated blood loss Median number of transfu sions (RBC) Adynamic illeus Small bowel obstruction (reoperation required) Pneumonia/ARDS Bacteremia Renal failure Deep vein thrombosis Coagulopathy Hemorrhage (reoperation required) Othe?
Gynecologic oncology N = 126
Other specialty N = 137
P
value”
3.5 hr 13.9 1092 ml
1.9 hr 10.1 483 ml
2.6 units 29 (23%)
1.1 units 15 (10.9%)
3 7 7 2 3 3
(2.4%) (5.5%) (5.6%) (1.2%) (2.4%) (2.4%)
2 (1.2%) 4 (3.2%)
2 9 5 3 2 2
(1.5%) (6.5%) (3.6%) (2.2%) (1.5%) (1.5%)
NS NS NS NS NS NS
1 (.73%) 4 (2.9%)
NS NS
’ x2 or t test. b Gynecologic oncology and other specialties (one each): myocardial infarct, stroke, enterocutaneous fistula, pulmonary embolus.
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EISENKOP
ET AL.
TABLE 4 Variableshlluencing Mortality Covariate variable
Total No.
Mortality No. (%)
99 149
TABLE 5 VariablesDetermining Survival N
Median survival (months)
P value (log rank)
value”
Covariate
6 (4.0%) 10 (6.9%)
NS
Grade of tumor 1 2 3
16 59 172
>43 21 21
150 113
15 (10.0%) 1 (0.9%)
235 15
33 22
NS
Estimated blood loss >lOOOml c 1OOOml
Incision Vertical Transverse
55 201
3 (5.5%) 13 (6.5%)
NS
139 111
19 32
0.004
Operating time > 4 br < 4 hr
Size of largest metastases > 10 cm 6 10 cm
41 222
3 (7.3%) 13 (5.9%)
NS
120 143
11 (9.2%) 5 (3.5%)
0.05
121 129 91 38
35 17 15 21
Cytoreductive outcome Suboptimal Optima1
Specialty training Gynecologic oncologist Other General surgeon present General surgeon absent
Specialty of physicians Gynecologic oncology Other
126 137
3 (2.4%) 13 (9.5%)
0.026
Age 260 <60
142 108
20 32
0.0002
Ascitic volume ~1OOOml
114 72
11 (9.6%) 5 (6.9%)
NS
Volume of ascites 2 1OOOml < 1OOOml
109 68
18 32
0.0008
Size largest metastases > 10 cm 6 10 cm
144 119
11 (7.9%) 5 (4.2%)
NS
Site of largest metastases Omentum Other
149 101
22 27
NS
Chemotherapy before dischg Yes No
55 180
1 (1.9%) 3 (1.7%)
NS
Histology Serous Other
193 57
23 23
NS
Frozen pelvis Yes No
53 197
18 26
0.03
Duration of symptoms > 8 weeks s 8 weeks
93 143
21 25
NS
Cytoreductive outcome NED (complete) 0.1-l cm (optimal) > 1 cm (suboptimal)
28 109 113
41 32 16
Chemotherapy before discharge Yes No
55 180
28 21
NS
Site of largest disease remaining Milliary Specific
129 93
22 19
NS
Duration of symptoms > 8 weeks i 8 weeks 3 60 years < 60 years
Intestinal resection Yes No
75 188
2 (1.7%) 14 (7.4%)
P
NS
’ x2 test. b Covariates selected by stepwise logistic regression.
regression analysis revealed patient age and subspecialty training to be most significant (Table 4). Postoperatively, 229 (87.1%) patients received platinum-based combination chemotherapy. Seven were given alternative therapy. Of those receiving chemotherapy, 55 (23.3%) were treated prior to discharge from the hospital and 180 (76.3%) after a period of convalescence. One patient was treated with whole abdominal radiation therapy. The mean number of treatment cycles and doses of cisplatin (or carboplatin) used were statistically identical when compared between patients operated on by gynecologic oncologists and other physicians, as well as patients subsequently treated by gynecologic oncologists and medical oncologists (Table 2). Of the 263 patients analyzed with regard to operative outcome. 250 (95.1%) had follow-ub data available for
a Covariates selected by Cox proportional
0.01”
NS
<0.0001”
hazards regression analysis
SUBSPECIALTY
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TRAINING
TABLE 6 The Influence of Surgical Procedureson Survival of Patients UndergoingOptimal Cytoreductive Surgery Surgical procedure
:
Time
(months)
FIG. 1. Cumulative proportion of survival subdivided by cytoreductive outcome. Dashed line, complete cytoreduction. Solid line, optimal cytoreduction. Dotted line, suboptimal cytoreduction. P = 0.001 for complete vs optimal. P < 0.0001 for all optimal vs suboptimal.
survival analysis (minimum 6 months, median 23 months, maximum 76 months). The grade of tumor, diameter of largest metastases, specialty training of the surgeons, age, ascitic volume, extent of pelvic disease, and the cytoreductive outcome influenced survival. Stepwise Cox proportional hazards regression analysis confirmed cytoreductive outcome, specialty training of the surgeons, grade of tumor, and extent of pelvic disease to be the most significant covariates (Table 5, Figs. 1 and 2). Patients with complete cytoreduction had statistically superior survival (Table 5, Fig. 1). Those who had optimal cytoreduction ( G 1 cm) also experienced improved survival compared to patients with suboptimal cytoreduction. Specialization of the physicians present at surgery influ-
20
40
Time
(months)
FIG. 2. Cumulative proportion of survival subdivided by subspecialty training of surgeons present. Solid line, gynecologic oncologist present. Dotted line, gynecologic oncologist absent. P < 0.0001.
All suboptimal cytoreduction All optimal cytoreduction TAH/BSO, omentectomy only All others Intestinal resection performed Not necessary Peritoneal implant ablation or excision performed Not necessary Lymph node dissection performed Not necessary
Patients (N)
Median survival (months)
P value (log rank)
113 137
16 37
24 113
32 38
NS
58 79
36 38
NS
100 37
42 32
NS
34 103
36 37
NS
’ Includes all patients with any extent of retroperitoneal dissection for removal of tumor-involved nodes.
lymph node
enced survival in a dependent manner by virtue of the greater probability of gynecologic oncologists to attain optimal cytoreduction. The survival of patients optimally or completely cytoreduced did not vary when stratified by specialty of the surgeons. Stratification of the patients who underwent optimal cytoreductive surgery by the procedures required to attain optimal cytoreduction did not reveal any significant differences in survival among the subgroups (Table 6). DISCUSSION
This report is the first to evaluate the feasibility of attaining optimal cytoreduction, operative mortality, and survival benefits of cytoreductive surgery among a large (263) population of patients with uniformly advanced disease (stages IIIC and IVA) operated on by physicians with and without subspecialty training in gynecologic oncology. Those with stages IIIA and IIIB were excluded due to comparatively simple requirements to attain optimal cytoreduction and inherently better prognosis [ 11. The decision to accrue data from multiple hospitals was essential to allow establishment of a data base representative of a large enough number of physicians with different training to assure realistic evaluation of the significance of subspecialty training. Additionally, the large number of patients studied permitted analysis of several other issues relating to resectibility, operative mortality, and survival which have previously received minimal or no attention in the literature. Confirmation of the importance of other previously investigated variables per-
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EISENKOP
taining to the accomplishment of optimal cytoreduction and survival confirms the validity of our data collection and analysis. Finally, the equivalence of treatment programs among patients undergoing optimal and suboptimal cytoreduction, as well as between patients operated on by physicians with different specialty training, eliminated variations in adjunctive treatment as explanations for the observations and conclusions of this study (Table 2). Most reports on cytoreductive surgery present operative results and survival data. In distinction, Heintz analyzed 70 patients to determine the feasibility of cytoreduction [7]. The probability of attaining an optimal cytoreductive outcome was influenced by the diameter of the largest metastases before cytoreduction, the volume of ascites, and the experience of the surgeons. Our experience confirms Heintz’s conclusions that the size of the initial metastases influences resectibility. Our failure to demonstrate ascitic volume as having an influence on resectibility may be a consequence of inconsistent reporting of data. The volume of ascites was recorded for only 186 (70.7%) patients. Our experience substantiates that the type of incision, age, extent of pelvic disease, and specialty training of the surgeons influences the probability of attaining optimal cytoreduction (Table 1). Regression analysis revealed the presence or absence of a gynecologic oncologist intraoperatively to be the most significant covariate. Optimal cytoreduction occurred in 81.7% of patients operated on by a gynecologic oncologist, compared to 29.2% in patients operated on by other surgeons, even though the extent and distribution of disease reported by physicians with different specialty training were identical (Table 2). In the absence of a gynecologic oncologist, the frequency of optimal cytoreduction was similar for patients operated on with (28.6%) or without (30.8%) a general surgeon present. Hence, general surgeons did not function as adequate replacements for gynecologic oncologists (Table 1). A similar observation has been reported by Chen, who notes that 46 of 47 patients (97.9%) operated on by gynecologic oncologists attained optimal cytoreduction, compared to 14 of 37 (37.8%) operated by non-gynecologic oncologists [4]. Details about the numbers of physicians involved and their training were not provided. The importance of subspecialty training in facilitating optimal cytoreductive surgery may be explained by several observations. Although choice of incision, age, and the presence of a “frozen pelvis” did influence resectability, stratification of the data according to specialty training revealed these to be significant covariates only in the absence of a gynecologic oncologist: Only gynecologists with and without general surgeons used low transverse incisions, and only 9 of 60 (15%) patients over 65 years old and 2 of 34 (5.9%) described as having a “frozen pelvis” underwent optimal cytoreduction. Hence,
ET AL.
83 of the 97 (85.6%) patients who underwent suboptimal cytoreduction by gynecologists and/or surgeons were elderly (over 65 years old), or had a “frozen pelvis,” and were perceived to have unresectable disease. Additionally 47 of 137 (34.3%) patients operated on by gynecologists and/or surgeons underwent omental or adnexal biopsy only due to perceived unresectability. These observations may represent an excessively conservative attitude toward treatment of the elderly, technical inadequacy, or inexperience when confronted with extensive pelvic and abdominal disease. Ninety (34.2%) patients experienced morbidity and 16 (6.1%) died postoperatively (within 28 days of surgery). These results are within the reported range of zero to 10% [3,4,7-91. Our analysis is the first to suggest the influences of patient age, cytoreductive outcome, and subspecialty training on operative mortality. The increased potential for operative mortality among the elderly emphasizes the need for careful preoperative evaluation and postoperative monitoring. The possible influence of subspecialty training in gynecologic oncology on the reduction of operative mortality is noteworthy, in that this observation occurred despite the more aggressive surgical approach and associated morbidity noted for patients operated on by gynecologic oncologists (Tables 2 and 3). Others have reported the safe use of intestinal anastamosis, urologic procedures, modified exenterative operations, and retroperitoneal lymphadenectomy [ 10-121. Perhaps patients with large tumor burdens remaining are less able to tolerate complications. Hence, anything less than a maximal surgical effort may profoundly diminish long-term prognosis and does not necessarily prevent postoperative mortality. Numerous pathologic and therapeutic covariates have been proved or suggested to independently influence survival for epithelial ovarian cancer [2,3,4,12]. Our data clarifies the importance of patient age, grade of tumor, ascitic volume, size of largest metastases, and cytoreductive outcome. Additionally, our study is the first to establish independent influences of the extent of pelvic disease and subspecialty training in gynecologic oncology on survival. The extent of residual disease remaining after cytoreductive surgery has been widely reported to be the variable which most definitively influences prognosis [2-41. Attempts have been made to define “optimal” cytoreduction as the amount of disease remaining after which further tumor excision or ablation does not alter prognosis. It would appear from our data as well as others that optimal cytoreduction should ideally be defined as the outcome of no visible disease remaining within the abdominal cavity (Table 5, Fig. 1) [13,14]. Unfortunately, a macroscopically disease-free status is uncommonly attained due to the presence of widespread milliary disease
SUBSPECIALTY
after elimination of larger, isolated metastases [3,13-151. Increased utilization of the argon beam coagulator and Cavitron should enable the surgeon to accomplish elimination of these implants with greater frequency [16,17]. Some investigators have emphasized that individual biological behavior of a malignancy and volume of tumor burden present before cytoreduction may independently diminish the potential to alter the natural course of the disease, regardless of treatment [15]. However, our data demonstrated that there was no statistically significant difference in prognosis for patients who attained optimal cytoreduction with upper genital tract excision and omentectomy only, compared to those requiring more radical tumor-reductive surgery (Table 6). Unfortunately, the relative importances of tumor biological aggressiveness, extent of disease, and surgical cytoreductive outcome probably vary with each patient and are not predictable. However, the cytoreductive outcome remains the covariate which most influences survival, as well as the factor which can be most readily controlled by aggressive surgery. The specific impact of subspecialty training on survival has not been previously reported. This is probably due to a tendency of the cytoreductive surgical literature to reflect the isolated experiences of gynecologic oncologists and hence preclude direct comparison of results by physicians with other training. The improved survival of patients operated on by gynecologic oncologists is a result of their tendency to approach cytoreductive surgery more aggressively and consequently realize more optimal outcomes. The large number of gynecologists (120) and general surgeons (85) who functioned as cosurgeons in this study, as well as their infrequency of accomplishing optimal cytoreduction, suggests that it is not realistic for such individuals to maintain an adequate volume of patients with advanced ovarian cancer to acquire or maintain the skills necessary to assure optimal cytoreductive results. In summary, our data strongly suggest that patients with physical and laboratory findings suggestive of ovarian cancer should be operated on exclusively by physicians with training in gynecologic oncology. Unless medically contraindicated, every effort should be made to attain complete cytoreduction. Advanced patient age and massive intraabdominal disease are not contraindications to such an approach. Subsequently, patients should be treated with the most efficacious adjunctive therapy available, or placed on research protocols. Until additional investigation yields treatments which improve the prognosis, this strategy will maximize the possibility of cure or long-term survival.
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REFERENCES 1. DiSaia, P. J., and Creasman, W. T. Clinical gynecologic oncology, The CV Mosby Company, Washington, DC, 3rd ed. (1989). 2. Griffiths, T. C., Parker, L. M., and Fuller, A. F. Role of cytoreductive surgery in the management of advanced ovarian cancer, Cancer Treat. Rep. 63, 235-240 (1979). 3. Hacker, N. F., Berek, J. S., Lagasse, L. D., Nieberg, R. K., and Elashoff, R. M. Primary cytoreductive surgery for ovarian cancer, Obstet. Gynecol. 61, 413-420 (1983). 4. Chen, S. S., and Bochner, R. Assessment of morbidity and mortality in primary cytoreductive surgery for advanced ovarian carcinoma, Gynecol. Oncol. 20, 190-195 (1985). 5. Blythe, J. G., and Wahl, T. P. Debulking surgery: Does it increase the quality of survival?, Gynecol. Oncol. 14, 396-408 (1982). 6. Balvert-Locht, H. R., Coebergh, J. W., and Hop, W. C. J. Improved prognosis of ovarian cancer in The Netherlands during the period 1975-1985: A registry-based study, Gynecol. Oncol. 42, 38 (1991). 7 Heintz, A. P. M., Hacker, N. F., Berek, J. S., Rose, T. P., Munoz, A. K., and Lagasse, L. D. Cytoreductive surgery in ovarian carcinoma: Feasibility and morbidity, Obstet. Gynecol. 67, 783-788 (1986). 8 Hudson, C. N. Surgical treatment of ovarian cancer, Gynecol. Oncol. 1, 370-37s (1973). 9 Papaioannou, A. N., Polycronis, M. D., Avgoustis, A. H., Coca, H. I., and Trichopoulos, D. B. Maximal cytoreduction, chemotherapy and contact nonspecific immunotherapy for stage III carcinoma of the ovary, Surg. Gynecol. Obstet. 149, 837-842 (1979). 10. Eisenkop, S. M., Nalick, R. H., and Teng, N. N. H. Modified posterior exenteration for ovarian cancer, Obstet. Gynecol. 78, 879885 (1992). 11. Berek, J. S., Hacker, N. F., Lagasse, L. D., and Leuchter, R. S. Lower urinary tract resection as part of cytoreductive surgery for ovarian cancer, Gynecol. Oncol. 13, 87-92 (1982). 12. Burghardt, E., Pickel, H., Lahousen, M., and Stettner, H. Pelvic lymphadenectomy in operative treatment of ovarian cancer, Am. J. Obstet. Gynecol. 155, 315-319 (1986). 13. Omura, G. A., Bundy, B. N., Berek, J. S., Curry, S., Delgado, G., and Mortel, R. Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: A Gynecologic Oncology Group study, J. Clin. Oncol. 7,457-465 (1989). 14. Delgado, G., Oram, D. H., and Petrilli, E. S. Stage III epithelial ovarian cancer: The role of maximal surgical reduction, Gynecol. Oncol. 18, 293-298 (1984). 15. Pottier, M. E., Partridge, E. E., Hatch, K. D., Soong, S., Austin, J. M., and Shingelton, H. M. Primary surgical therapy for ovarian cancer: How much and when, Gynecol. Oncol. 40,195-200 (1991). 16. Brand, E., and Pearlman, N. Electrosurgical debulking of ovarian cancer: A new technique using the Argon Beam Coagulator, Gynecol. Oncol. 39, 115-118 (1990). 17. Deppe, G., Malviya, V.K., and Malone, J. M. Debulking surgery for ovarian cancer with the Cavitron Ultrasonic Surgical Aspirator (CUSA)-A preliminary report, Gynecol. Oncol. 31, 223-236 (1988).
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The Impact of Subspecialty Training on the Management of Advanced Ovarian Cancer SCOTT M. EISENKOP,
M.D. ,l NICK M. SPIRTOS, M.D.,
THOMAS W. MONTAG,
AND HE-JING WANG, The Center
for Gynecologic Oncology, Encino, Gynecologic Oncology, Los Angeles,
California; California;
M.D.,
RICHARD H. NALICK,
M.D.,
M.P.H.
the Women’s Cancer Center, and UCLA School of Public Los Angeles, California
Palo Alto, California; Health, Department
The Los Angeles of Biomathematics,
Center for
Received April 2, 1992
A retrospectivestudy wasconductedto determinethe influence of subspecialtytraining in gynecologiconcologyaswell as several other covariateson the feasibility, operative mortality, and survival benefitsof cytoreductive surgeryfor 263patientswith stages IIIC and NA epithelial ovarian cancer. Covariatesmost predictive of an optimal (s 1 cm) cytoreductive outcome were the diameterof the largestmetastases beforecytoreduction (G 10 cm vs > 10cm, P < 0.001)and the specialtytraining of the physicians presentat surgery (gynecologiconcologistsvs other, P < 0.001). Age infhrenced operative mortality most (< 60 vs 2 60, P < 0.001). Covariatesfound to most significantly influencesurvival time include the specialty training of the physicianspresent at surgery (gynecologiconcologistsvs other, P < O.OOOl),cytoreductive outcome (complete vs optimal, P = 0.001, optimal vs suboptimal,P < O.OOOl),grade of tumor (grade 1 vs grades2 and 3, P = O.Ol), and pelvic diseasestatus (frozen pelvis vs mobile primary tumor, P = 0.03). We conclude that patients with advancedepithelial ovarian cancer should undergoaggressive cytoreductive surgery by gynecologiconcologists,with the objectiveto removeall macroscopicdisease.Subsequenttreatment with platinum-basedchemotherapy offers the best chance for long-term survival or cure. 0 1992 Academic PWS, Inc. INTRODUCTION
Primary cytoreductive surgery, followed by platinumbased multiagent chemotherapy, improves both prognosis and quality of life for patients with advanced epithelial ovarian cancer [l-6]. Most cytoreductive surgical data is retrospective, includes limited numbers of patients with various stages of disease, and describes individual or departmental experiences of gynecologic oncologists. I To whom reprint requests should be addressed at The Center for Gynecologic Oncology, 16542 Ventura Boulevard, Suite 510, Encino, CA 91436.
Hence, while the therapeutic value of attaining a diseasefree or minimal residual tumor burden status is uniformly reported, controversy remains over the influences of other specific issues on the feasibility of cytoreduction, operative mortality, and prognosis. The contribution or necessity of subspecialty training in gynecologic oncology, in particular, has not been specificly addressed. We therefore have reviewed the results of primary cytoreductive operations for previously untreated patients with stages IIIC and IVA epithelial ovarian cancer from several hospitals. The purpose of this study is to determine the importance of subspecialty training in gynecologic oncology along with other previously uninvestigated determinants of resectability, operative mortality, and long-term survival and to confirm the previously suggested significance of others. METHODS AND MATERIALS
From January 1985 to December 1988, the charts of all patients with a diagnosis of epithelial ovarian cancer listed in the tumor registries of 14 hospitals serviced by the authors in the greater Los Angeles, Denver, and San Francisco Bay areas were reviewed. When necessary, approval was obtained from institutional review boards. All patients with tumors of low malignant potential (borderline histology), primary operations performed at other hospitals, stages of disease other than IIIC and IVA, and those pretreated with chemotherapy were excluded. Hence, 263 patients were accrued. Information obtained by chart review included age, duration of symptoms, tumor grade, histology, size and location of metastatic disease, extent of pelvic tumor, operative time, blood loss, hospital stay, transfusion status,
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0090-8258/92 $4.00 Copyright 0 1992 by Academic Press, Inc. rights of reproduction in any form reserved.
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ascitic volume, procedures attempted and completed, cytoreductive outcome, and the specialty training of the physicians performing the operative procedures. The influence of these covariates on the probability of attaining an optimal cytoreductive result and on postoperative mortality was evaluated. “Optimal cytoreductive surgery” was defined as the outcome of no residual solitary lesion(s) larger than 1 cm in diameter. “Complete cytoreductive surgery” is defined as the removal of all macroscopic disease. Frozen pelvis refers to the confluent involvement of reproductive organs, sigmoid colon, and pelvic peritoneum by tumor. Operative mortality and morbidity are defined as death and any untoward result occurring within 28 days of surgery. In addition to the previous covariates, the influence of cytoreductive outcome, location of largest residual disease, and time delay prior to initiation of chemotherapy were analyzed to determine their influences on survival. Follow-up information was obtained by review of tumor registry information and direct contact with the patient, her family, or her physician. Variables were analyzed with respect to their influence on tumor resectability (to an optimal state) and mortality by the x2 test and then further evaluated by stepwise logistic regression. Comparisons between groups of patients were accomplished by the corrected x2 or Fisher’s exact test (for categorical data), and two-tailed, t test (for continuous numerical data). The Cox proportional hazards regression model was used to quantify the relationship between survival and some covariates. The KaplanMeier method was used to estimate the survival distribution for subgroups of patients. Log rank statistics were employed for testing the equality of survival curves. P values greater than 0.05 were reported as not significant (NS). Survival time was calculated from the day of primary cytoreductive surgery to the date of last contact or death.
RESULTS The mean age was 60.9 years (range, 22 to 92). Two hundred thirty-seven patients were stage IIIC and 26 were stage IVA (1989 FIGO). There were 16 grade 1 lesions, 62 grade 2, 181 grade 3; the grade was not obtainable for 4 patients. There were 205 serous and unspecified adenocarcinomas, 19 mutinous, 21 endometroid, 4 clear cell, 6 anaplastic, and 8 mixed histologies. The largest metastatic lesion was described qualitatively as “massive” or at least 10 cm in largest dimension in 144 (54.8%) patients. The omentum was the most common site of largest metastatic disease for 155 (58.9%). Fifty-four (20.5%) had p e 1vie involvement consistent with the description of a “frozen pelvis.” Of 186 patients with re-
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corded volumes of ascites, 114 (61.3%) had in excess of 1 liter. The mean operative time was 2.6 hr, the mean estimated blood loss was 795 ml, and the median postoperative stay was 9.5 days. Two-hundred sixteen (82.1%) patients had varying degrees of cytoreduction accomplished, and 47 (17.9%) underwent laparotomy with omental or adnexal biopsy only. Two-hundred fourteen (81.4%) had removal of the upper reproductive organs present, and 75 (28.5%) had a large or small bowel resection (excluding palliative colostomy). Additionally, 191 (72.6%) underwent omentectomy, 135 (51.3%) had peritoneal implant excision or ablation, 20 (7.6%) had a diaphragm stripping procedure, 77 (29.3%) underwent various forms of retroperitoneal lymph node dissection, 3 (1.1%) had a splenectomy, and 4 (1.5%) required a urologic procedure. Eleven gynecologic oncologists functioned as primary surgeons. Additionally, 120 obstetrician gynecologists, 85 general or oncologic surgeons, and 40 physicians with miscellaneous specialties served as primary surgeons and assistants (or cosurgeons). Optimal cytoreduction was documented for 143 of 263 patients (54.4%), and complete cytoreduction was accomplished for 32 (12.2%). The type of incision, diameter of largest metastases, specialty training of the surgeons, age, and extent of pelvic tumor influenced tumor resectability (x’) (Table 1). Stepwise logistic regression revealed the intraoperative presence of a gynecologic oncologist and the diameter of the largest metastases to be the covariates most influencing the attainment of optimal (e 1 cm) cytoreduction (Table 1). No significant differences in severity of disease, adjunctive treatment strategy, or adequacy of follow-up could be detected among the specialties of physicians (Table 2). However, the operative approaches differed, as exemplified by choices of incision, the decision not to attempt cytoreduction, and the completion of pelvic tumor excision for those with a frozen pelvis (Table 2). Age inhibited physicians without subspecialty training in gynecologic oncology from attaining optimal cytoreduction. Thirty-four of 43 (79.1%) patients over 65 years old operated on by gynecologic oncologists underwent optimal cytoreduction, compared to 9 of 60 (15.0%) operated on by other physicians (P = 0.0001). Finally, gynecologic oncologists more frequently performed procedures (other than TAH/BSO and omentectomy) that were required to attain optimal cytoreduction for patients with a frozen pelvis, intestinal metastases, extensive retroperitoneal disease, diaphragmatic metastases, and peritoneal or serosal implants (Table 2). Ninety (34.2%) patients experienced operative morbidity. Complications reported included adynamic ileus in 44 (16.7%) bacterial pneumonia in 14 (5.3%), bacter-
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TABLE 1 Variables Determining Respectability
TABLE 2 DiseaseCharacteristicsand Treatment by Specialty
Optimal Total No.
No.
Grade of tumor 1 2 3
16 62 181
12 35 94
75.0% 56.5% 51.4%
NS
Incision Vertical Transverse
245 18
139 4
56.7% 22.2%
o.ocl5
Diameter of largest metastases c 10cm > 10cm
119 144
81 62
68.1% 43.1%
Specialty training Gynecologic oncologist Other General surgeon present General surgeon absent
126 137 98 39
103 40 28 12
81.7% 29.2% 28.6% 30.8%
Age 2 60 <60
149 114
70 73
46.9% 63.1%
0.001
Volume of ascites ~1OOOml < 1000 ml
114 72
64 45
56.1% 62.5%
NS
Site of largest metastases Omentum Other
155 108
89 54
57.4% 50.0%
NS
Histology Serous or unspecified Other
205 58
109 34
53.2% 58.6%
NS
Frozen pelvis Yes No
54 209
22 121
40.7% 57.9%
0.02
Duration of symptoms > 8 weeks s 8 weeks
100 148
53 81
53.0% 54.7%
NS
Covariate variable
(%I
P
value”
NS
a x2 test. ’ Covariates selected by stepwise regression analysis.
emia in 12 (4.6%), small bowel obstruction, transient renal failure, deep vein thrombophlebitis, and disseminated intravascular coagulation, each in 5 (1.9%), and postoperative hemorrhage requiring reoperation in 3 (1.1%) patients. Additionally, myocardial infarction, stroke, enterocutaneous fistula, pulmonary embolus, and aspiration pneumonia were each reported for 2 (.76%) patients. Non-life-threatening morbidity, operative time, blood loss, and hospital stay were increased among patients operated on by gynecologic oncologists (Table 3). Sixteen (6.1%) patients died postoperatively. Age, cytoreductive outcome, and subspecialty training significantly influenced the mortality rate (x2). Stepwise logistic
Gynecologic oncology N = 126
Characteristic Grade 3 lesions Serous histology Stage IVA Largest metastases >lO cm Omentum site of largest metastases Frozen pelvis Vertical incision Omental or adnexal biopsy only Frozen pelvis tumor completely excised Intestinal resection Peritoneal implant excision or ablation Diaphragm striping Adjunctive treatment” Platinum multiagent Other None Mean cycles chemotherapy Mortality Lost to follow-up
Other specialty N = 137
P
value”
(71.4%) (77.4%) (8.8%) (57.7%)
NS NS NS NS
79 (63.2%) 20 (15.9%) 126 (100%)
76 (55.5%) 34 (24.8%) 119 (86.9%)
NS NS
0
47 (34.3%)
20 (100%) 56 (44.4%)
2 (5.9%) 19 (13.9%)
106 (84.1%) 20 (15.9%)
29 (21.1%) 0
114 (92.7%) 2 7 7.1 3 (2.4%) 5 (3.9%)
112 (90.3%) 4 8 7.4 13 (9.5%) 8 (5.8%)
NS
86 99 14 65
(68.3%) (78.6%) (11.1%) (51.6%)
95 106 12 79
NS 0.02 NS
a x2 or t test. ’ Excludes operative mortality (4 pts).
TABLE 3 Operative Morbidity by Specialty
Variable Mean operative time Mean hospital days Mean estimated blood loss Median number of transfu sions (RBC) Adynamic illeus Small bowel obstruction (reoperation required) Pneumonia/ARDS Bacteremia Renal failure Deep vein thrombosis Coagulopathy Hemorrhage (reoperation required) Othe?
Gynecologic oncology N = 126
Other specialty N = 137
P
value”
3.5 hr 13.9 1092 ml
1.9 hr 10.1 483 ml
2.6 units 29 (23%)
1.1 units 15 (10.9%)
3 7 7 2 3 3
(2.4%) (5.5%) (5.6%) (1.2%) (2.4%) (2.4%)
2 (1.2%) 4 (3.2%)
2 9 5 3 2 2
(1.5%) (6.5%) (3.6%) (2.2%) (1.5%) (1.5%)
NS NS NS NS NS NS
1 (.73%) 4 (2.9%)
NS NS
’ x2 or t test. b Gynecologic oncology and other specialties (one each): myocardial infarct, stroke, enterocutaneous fistula, pulmonary embolus.
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ET AL.
TABLE 4 Variableshlluencing Mortality Covariate variable
Total No.
Mortality No. (%)
99 149
TABLE 5 VariablesDetermining Survival N
Median survival (months)
P value (log rank)
value”
Covariate
6 (4.0%) 10 (6.9%)
NS
Grade of tumor 1 2 3
16 59 172
>43 21 21
150 113
15 (10.0%) 1 (0.9%)
235 15
33 22
NS
Estimated blood loss >lOOOml c 1OOOml
Incision Vertical Transverse
55 201
3 (5.5%) 13 (6.5%)
NS
139 111
19 32
0.004
Operating time > 4 br < 4 hr
Size of largest metastases > 10 cm 6 10 cm
41 222
3 (7.3%) 13 (5.9%)
NS
120 143
11 (9.2%) 5 (3.5%)
0.05
121 129 91 38
35 17 15 21
Cytoreductive outcome Suboptimal Optima1
Specialty training Gynecologic oncologist Other General surgeon present General surgeon absent
Specialty of physicians Gynecologic oncology Other
126 137
3 (2.4%) 13 (9.5%)
0.026
Age 260 <60
142 108
20 32
0.0002
Ascitic volume ~1OOOml
114 72
11 (9.6%) 5 (6.9%)
NS
Volume of ascites 2 1OOOml < 1OOOml
109 68
18 32
0.0008
Size largest metastases > 10 cm 6 10 cm
144 119
11 (7.9%) 5 (4.2%)
NS
Site of largest metastases Omentum Other
149 101
22 27
NS
Chemotherapy before dischg Yes No
55 180
1 (1.9%) 3 (1.7%)
NS
Histology Serous Other
193 57
23 23
NS
Frozen pelvis Yes No
53 197
18 26
0.03
Duration of symptoms > 8 weeks s 8 weeks
93 143
21 25
NS
Cytoreductive outcome NED (complete) 0.1-l cm (optimal) > 1 cm (suboptimal)
28 109 113
41 32 16
Chemotherapy before discharge Yes No
55 180
28 21
NS
Site of largest disease remaining Milliary Specific
129 93
22 19
NS
Duration of symptoms > 8 weeks i 8 weeks 3 60 years < 60 years
Intestinal resection Yes No
75 188
2 (1.7%) 14 (7.4%)
P
NS
’ x2 test. b Covariates selected by stepwise logistic regression.
regression analysis revealed patient age and subspecialty training to be most significant (Table 4). Postoperatively, 229 (87.1%) patients received platinum-based combination chemotherapy. Seven were given alternative therapy. Of those receiving chemotherapy, 55 (23.3%) were treated prior to discharge from the hospital and 180 (76.3%) after a period of convalescence. One patient was treated with whole abdominal radiation therapy. The mean number of treatment cycles and doses of cisplatin (or carboplatin) used were statistically identical when compared between patients operated on by gynecologic oncologists and other physicians, as well as patients subsequently treated by gynecologic oncologists and medical oncologists (Table 2). Of the 263 patients analyzed with regard to operative outcome. 250 (95.1%) had follow-ub data available for
a Covariates selected by Cox proportional
0.01”
NS
<0.0001”
hazards regression analysis
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TABLE 6 The Influence of Surgical Procedureson Survival of Patients UndergoingOptimal Cytoreductive Surgery Surgical procedure
:
Time
(months)
FIG. 1. Cumulative proportion of survival subdivided by cytoreductive outcome. Dashed line, complete cytoreduction. Solid line, optimal cytoreduction. Dotted line, suboptimal cytoreduction. P = 0.001 for complete vs optimal. P < 0.0001 for all optimal vs suboptimal.
survival analysis (minimum 6 months, median 23 months, maximum 76 months). The grade of tumor, diameter of largest metastases, specialty training of the surgeons, age, ascitic volume, extent of pelvic disease, and the cytoreductive outcome influenced survival. Stepwise Cox proportional hazards regression analysis confirmed cytoreductive outcome, specialty training of the surgeons, grade of tumor, and extent of pelvic disease to be the most significant covariates (Table 5, Figs. 1 and 2). Patients with complete cytoreduction had statistically superior survival (Table 5, Fig. 1). Those who had optimal cytoreduction ( G 1 cm) also experienced improved survival compared to patients with suboptimal cytoreduction. Specialization of the physicians present at surgery influ-
20
40
Time
(months)
FIG. 2. Cumulative proportion of survival subdivided by subspecialty training of surgeons present. Solid line, gynecologic oncologist present. Dotted line, gynecologic oncologist absent. P < 0.0001.
All suboptimal cytoreduction All optimal cytoreduction TAH/BSO, omentectomy only All others Intestinal resection performed Not necessary Peritoneal implant ablation or excision performed Not necessary Lymph node dissection performed Not necessary
Patients (N)
Median survival (months)
P value (log rank)
113 137
16 37
24 113
32 38
NS
58 79
36 38
NS
100 37
42 32
NS
34 103
36 37
NS
’ Includes all patients with any extent of retroperitoneal dissection for removal of tumor-involved nodes.
lymph node
enced survival in a dependent manner by virtue of the greater probability of gynecologic oncologists to attain optimal cytoreduction. The survival of patients optimally or completely cytoreduced did not vary when stratified by specialty of the surgeons. Stratification of the patients who underwent optimal cytoreductive surgery by the procedures required to attain optimal cytoreduction did not reveal any significant differences in survival among the subgroups (Table 6). DISCUSSION
This report is the first to evaluate the feasibility of attaining optimal cytoreduction, operative mortality, and survival benefits of cytoreductive surgery among a large (263) population of patients with uniformly advanced disease (stages IIIC and IVA) operated on by physicians with and without subspecialty training in gynecologic oncology. Those with stages IIIA and IIIB were excluded due to comparatively simple requirements to attain optimal cytoreduction and inherently better prognosis [ 11. The decision to accrue data from multiple hospitals was essential to allow establishment of a data base representative of a large enough number of physicians with different training to assure realistic evaluation of the significance of subspecialty training. Additionally, the large number of patients studied permitted analysis of several other issues relating to resectibility, operative mortality, and survival which have previously received minimal or no attention in the literature. Confirmation of the importance of other previously investigated variables per-
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taining to the accomplishment of optimal cytoreduction and survival confirms the validity of our data collection and analysis. Finally, the equivalence of treatment programs among patients undergoing optimal and suboptimal cytoreduction, as well as between patients operated on by physicians with different specialty training, eliminated variations in adjunctive treatment as explanations for the observations and conclusions of this study (Table 2). Most reports on cytoreductive surgery present operative results and survival data. In distinction, Heintz analyzed 70 patients to determine the feasibility of cytoreduction [7]. The probability of attaining an optimal cytoreductive outcome was influenced by the diameter of the largest metastases before cytoreduction, the volume of ascites, and the experience of the surgeons. Our experience confirms Heintz’s conclusions that the size of the initial metastases influences resectibility. Our failure to demonstrate ascitic volume as having an influence on resectibility may be a consequence of inconsistent reporting of data. The volume of ascites was recorded for only 186 (70.7%) patients. Our experience substantiates that the type of incision, age, extent of pelvic disease, and specialty training of the surgeons influences the probability of attaining optimal cytoreduction (Table 1). Regression analysis revealed the presence or absence of a gynecologic oncologist intraoperatively to be the most significant covariate. Optimal cytoreduction occurred in 81.7% of patients operated on by a gynecologic oncologist, compared to 29.2% in patients operated on by other surgeons, even though the extent and distribution of disease reported by physicians with different specialty training were identical (Table 2). In the absence of a gynecologic oncologist, the frequency of optimal cytoreduction was similar for patients operated on with (28.6%) or without (30.8%) a general surgeon present. Hence, general surgeons did not function as adequate replacements for gynecologic oncologists (Table 1). A similar observation has been reported by Chen, who notes that 46 of 47 patients (97.9%) operated on by gynecologic oncologists attained optimal cytoreduction, compared to 14 of 37 (37.8%) operated by non-gynecologic oncologists [4]. Details about the numbers of physicians involved and their training were not provided. The importance of subspecialty training in facilitating optimal cytoreductive surgery may be explained by several observations. Although choice of incision, age, and the presence of a “frozen pelvis” did influence resectability, stratification of the data according to specialty training revealed these to be significant covariates only in the absence of a gynecologic oncologist: Only gynecologists with and without general surgeons used low transverse incisions, and only 9 of 60 (15%) patients over 65 years old and 2 of 34 (5.9%) described as having a “frozen pelvis” underwent optimal cytoreduction. Hence,
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83 of the 97 (85.6%) patients who underwent suboptimal cytoreduction by gynecologists and/or surgeons were elderly (over 65 years old), or had a “frozen pelvis,” and were perceived to have unresectable disease. Additionally 47 of 137 (34.3%) patients operated on by gynecologists and/or surgeons underwent omental or adnexal biopsy only due to perceived unresectability. These observations may represent an excessively conservative attitude toward treatment of the elderly, technical inadequacy, or inexperience when confronted with extensive pelvic and abdominal disease. Ninety (34.2%) patients experienced morbidity and 16 (6.1%) died postoperatively (within 28 days of surgery). These results are within the reported range of zero to 10% [3,4,7-91. Our analysis is the first to suggest the influences of patient age, cytoreductive outcome, and subspecialty training on operative mortality. The increased potential for operative mortality among the elderly emphasizes the need for careful preoperative evaluation and postoperative monitoring. The possible influence of subspecialty training in gynecologic oncology on the reduction of operative mortality is noteworthy, in that this observation occurred despite the more aggressive surgical approach and associated morbidity noted for patients operated on by gynecologic oncologists (Tables 2 and 3). Others have reported the safe use of intestinal anastamosis, urologic procedures, modified exenterative operations, and retroperitoneal lymphadenectomy [ 10-121. Perhaps patients with large tumor burdens remaining are less able to tolerate complications. Hence, anything less than a maximal surgical effort may profoundly diminish long-term prognosis and does not necessarily prevent postoperative mortality. Numerous pathologic and therapeutic covariates have been proved or suggested to independently influence survival for epithelial ovarian cancer [2,3,4,12]. Our data clarifies the importance of patient age, grade of tumor, ascitic volume, size of largest metastases, and cytoreductive outcome. Additionally, our study is the first to establish independent influences of the extent of pelvic disease and subspecialty training in gynecologic oncology on survival. The extent of residual disease remaining after cytoreductive surgery has been widely reported to be the variable which most definitively influences prognosis [2-41. Attempts have been made to define “optimal” cytoreduction as the amount of disease remaining after which further tumor excision or ablation does not alter prognosis. It would appear from our data as well as others that optimal cytoreduction should ideally be defined as the outcome of no visible disease remaining within the abdominal cavity (Table 5, Fig. 1) [13,14]. Unfortunately, a macroscopically disease-free status is uncommonly attained due to the presence of widespread milliary disease
SUBSPECIALTY
after elimination of larger, isolated metastases [3,13-151. Increased utilization of the argon beam coagulator and Cavitron should enable the surgeon to accomplish elimination of these implants with greater frequency [16,17]. Some investigators have emphasized that individual biological behavior of a malignancy and volume of tumor burden present before cytoreduction may independently diminish the potential to alter the natural course of the disease, regardless of treatment [15]. However, our data demonstrated that there was no statistically significant difference in prognosis for patients who attained optimal cytoreduction with upper genital tract excision and omentectomy only, compared to those requiring more radical tumor-reductive surgery (Table 6). Unfortunately, the relative importances of tumor biological aggressiveness, extent of disease, and surgical cytoreductive outcome probably vary with each patient and are not predictable. However, the cytoreductive outcome remains the covariate which most influences survival, as well as the factor which can be most readily controlled by aggressive surgery. The specific impact of subspecialty training on survival has not been previously reported. This is probably due to a tendency of the cytoreductive surgical literature to reflect the isolated experiences of gynecologic oncologists and hence preclude direct comparison of results by physicians with other training. The improved survival of patients operated on by gynecologic oncologists is a result of their tendency to approach cytoreductive surgery more aggressively and consequently realize more optimal outcomes. The large number of gynecologists (120) and general surgeons (85) who functioned as cosurgeons in this study, as well as their infrequency of accomplishing optimal cytoreduction, suggests that it is not realistic for such individuals to maintain an adequate volume of patients with advanced ovarian cancer to acquire or maintain the skills necessary to assure optimal cytoreductive results. In summary, our data strongly suggest that patients with physical and laboratory findings suggestive of ovarian cancer should be operated on exclusively by physicians with training in gynecologic oncology. Unless medically contraindicated, every effort should be made to attain complete cytoreduction. Advanced patient age and massive intraabdominal disease are not contraindications to such an approach. Subsequently, patients should be treated with the most efficacious adjunctive therapy available, or placed on research protocols. Until additional investigation yields treatments which improve the prognosis, this strategy will maximize the possibility of cure or long-term survival.
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REFERENCES 1. DiSaia, P. J., and Creasman, W. T. Clinical gynecologic oncology, The CV Mosby Company, Washington, DC, 3rd ed. (1989). 2. Griffiths, T. C., Parker, L. M., and Fuller, A. F. Role of cytoreductive surgery in the management of advanced ovarian cancer, Cancer Treat. Rep. 63, 235-240 (1979). 3. Hacker, N. F., Berek, J. S., Lagasse, L. D., Nieberg, R. K., and Elashoff, R. M. Primary cytoreductive surgery for ovarian cancer, Obstet. Gynecol. 61, 413-420 (1983). 4. Chen, S. S., and Bochner, R. Assessment of morbidity and mortality in primary cytoreductive surgery for advanced ovarian carcinoma, Gynecol. Oncol. 20, 190-195 (1985). 5. Blythe, J. G., and Wahl, T. P. Debulking surgery: Does it increase the quality of survival?, Gynecol. Oncol. 14, 396-408 (1982). 6. Balvert-Locht, H. R., Coebergh, J. W., and Hop, W. C. J. Improved prognosis of ovarian cancer in The Netherlands during the period 1975-1985: A registry-based study, Gynecol. Oncol. 42, 38 (1991). 7 Heintz, A. P. M., Hacker, N. F., Berek, J. S., Rose, T. P., Munoz, A. K., and Lagasse, L. D. Cytoreductive surgery in ovarian carcinoma: Feasibility and morbidity, Obstet. Gynecol. 67, 783-788 (1986). 8 Hudson, C. N. Surgical treatment of ovarian cancer, Gynecol. Oncol. 1, 370-37s (1973). 9 Papaioannou, A. N., Polycronis, M. D., Avgoustis, A. H., Coca, H. I., and Trichopoulos, D. B. Maximal cytoreduction, chemotherapy and contact nonspecific immunotherapy for stage III carcinoma of the ovary, Surg. Gynecol. Obstet. 149, 837-842 (1979). 10. Eisenkop, S. M., Nalick, R. H., and Teng, N. N. H. Modified posterior exenteration for ovarian cancer, Obstet. Gynecol. 78, 879885 (1992). 11. Berek, J. S., Hacker, N. F., Lagasse, L. D., and Leuchter, R. S. Lower urinary tract resection as part of cytoreductive surgery for ovarian cancer, Gynecol. Oncol. 13, 87-92 (1982). 12. Burghardt, E., Pickel, H., Lahousen, M., and Stettner, H. Pelvic lymphadenectomy in operative treatment of ovarian cancer, Am. J. Obstet. Gynecol. 155, 315-319 (1986). 13. Omura, G. A., Bundy, B. N., Berek, J. S., Curry, S., Delgado, G., and Mortel, R. Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: A Gynecologic Oncology Group study, J. Clin. Oncol. 7,457-465 (1989). 14. Delgado, G., Oram, D. H., and Petrilli, E. S. Stage III epithelial ovarian cancer: The role of maximal surgical reduction, Gynecol. Oncol. 18, 293-298 (1984). 15. Pottier, M. E., Partridge, E. E., Hatch, K. D., Soong, S., Austin, J. M., and Shingelton, H. M. Primary surgical therapy for ovarian cancer: How much and when, Gynecol. Oncol. 40,195-200 (1991). 16. Brand, E., and Pearlman, N. Electrosurgical debulking of ovarian cancer: A new technique using the Argon Beam Coagulator, Gynecol. Oncol. 39, 115-118 (1990). 17. Deppe, G., Malviya, V.K., and Malone, J. M. Debulking surgery for ovarian cancer with the Cavitron Ultrasonic Surgical Aspirator (CUSA)-A preliminary report, Gynecol. Oncol. 31, 223-236 (1988).