Epithelial ovarian cancer accounts for 20-25% of genital tract cancers. Approximately 1 in 100 women will develop the disease and two thirds will die from their malignancy. It is a disease of middle and upper socioeconomic classes, more common in highly industrialized countries. Those affected are usually postmenopausal. The average age at diagnosis is 50 years. It is uncommon under the age of 40.
Ovarian cancer is rarely diagnosed in a symptom-free patient. The most common presentation is abdominal swelling (mass + ascites). Abdominal discomfort, gastrointestinal or urinary symptoms, abnormal bleeding and weight loss are frequent symptoms. Rarely does the disease present as a surgical emergency.
Physical signs suggestive of malignant change in an ovarian tumour include bilaterality, fixation in the pelvis, nodularity on the surface or in the Pouch of Douglas, solid or semi-solid consistency and ascites. None of these findings are diagnostic. Ascites and pleural effusion (Meigs Syndrome) can also occur with benign ovarian tumours.
While the majority are sporadic, 5-10% may have an hereditary component. The odds ratio for ovarian cancer in first and second degree relatives of ovarian cancer affecteds is 3.6 and 2.9 respectively.
The most common histological variants include (i) serous (ii) mucinous (iii) endometrioid (iv) clear cell (v) Brenner (vi) mixed and (vii) undifferentiated.
Spread patterns of ovarian cancer include local extension to adjacent pelvic structures along with transperitoneal spread of exfoliated cells. Lymphatic spread is more common than previously thought while haematogenous spread is less common.
Prognostic factors for early stage disease includes (i) grade (ii) dense adherence (iii) ascites while for advanced stage disease prognostic factors include (i) cell type (ii) performance status (iii) age (iv) residual disease (v) ascites and (vi) response to therapy (68, 69).
Preoperative evaluation includes tumour marker assessment, CA125, CEA, CA19.9. Diagnosis is made at laparotomy. The possibility that the disease is metastatic to the ovary must be borne in mind. It is thought that 10-30% of malignant ovarian tumours are metastatic. The most common primary sites are breast, gastrointestinal tract and uterus.
The clinical scenario of apparent advanced ovarian cancer, paradoxically with normal appearing ovaries is designated as extraovarian peritoneal cancer. For all intents and purposes it is staged and treated as for ovarian cancer, as mentioned below.
Stages of ovarian and fallopian tube cancer
The surgical management of patients with ovarian cancer includes performing (i) surgical staging and where indicated (ii) cytoreductive surgery.
Surgical staging accurately determines the extent of disease allowing for tailored postoperative therapy. Based on surgical staging data 20-30% of apparent early staged cancers will be upstaged. Staging has been found to be inadequate when performed by either a general surgeon or general gynaecologist as compared to a trained or certified gynaecologic oncologist. Subspecialists are also more likely to affect optimal cytoreduction and resultant survival advantage (70-75).
Cytoreductive or debulking surgery has been shown to (i) enhance immunologic competence of the patient, (ii) improve tumour perfusion and increased growth fraction, (iii) provide a physiological benefit for the patient by removing a large tumour mass and (iv) increase survival if optimal debulking is performed. There is no prospective data to support the theory that aggressive debulking affects survival. However numerous retrospective studies and a large meta-analysis of 6,885 patients has confirmed a positive correlation between cytoreduction and survival. For each 10% increase in maximal cytoreduction there is an associated increase in median survival of 5.5%(76).
If patients are unable to be optimally debulked for technical reasons, then they may be considered for “interval re-exploration” and “secondary debulking”. The operation is generally performed after 3 cycles of chemotherapy and the disease has been found to be responsive to chemotherapy.
Patients operated upon at other institutions prior to referral will fall into 3 categories (i)
adequate debulking has been performed (ii) debulking has not been performed due to extent of tumour adherence and spread (iii) debulking has not been performed because of inexperience of the surgeon. Management options for patients in categories (i) and (ii) include commencing chemotherapy and possible “interval reexploration” after 3 cycles, while cases in category (iii) may be considered for immediate re-exploration.
It is important that all patients with apparent early stage disease be afforded the opportunity of their care being supervised by a Certified Gynaecological Oncologist (77).
Those patients primarily operated upon by a non CGO or considered sub-optimally staged and who are surgically fit should be re-explored and definitive staging performed. This may be done after 3 cycles of induction chemotherapy. At the initial or re-operation our aim is to perform a THBSO, omentectomy, lymph node assessment plus resection of any other residual disease (70-75).
Low Risk Disease: Stages IA and IB, Grades 1 and 2
Defined after complete surgical staging. These patients have a 95% 5-year survival. The addition of either chemotherapy or radiotherapy does not improve survival. Thus patients with “Low Risk” disease need no further treatment (78, 79).
High Risk Disease: Stage IC and Grade 3(Stage IA and IB)
All other high risk early stage disease patients should be offered 6 cycles of combination platinum/taxane chemotherapy. Patients who are either unfit for surgical staging or it is felt that re-staging is inappropriate should be considered for adjuvant chemotherapy. Patients who are unfit and may not tolerate combination chemotherapy should be considered for single agent carboplatin. There is no evidence that SLL improves outcome after completion of therapy and is not routinely recommended.
We believe that patients with clear cell histology have a significantly high risk of recurrence and should be offered 3-6 cycles of combination platinum/taxane chemotherapy.
The majority of patients with ovarian cancer will present with advanced disease (stage III-IV). The prognosis of these patients is unfortunately quite poor with the median survival for stage III patients being 33 months and for stage IV patients is 13 months. The number of patients who are alive at 10 years is less than 10%. The prognostic features in these patients are the age of the patient, performance status, lower stage, smaller residual volume post surgery, serous pathology and the fall of CA125 following chemotherapy. The optimum treatment involves both surgery and chemotherapy (69).
A meta-analysis involving 1400 patients has revealed platinum containing combinations produce higher response rates than non-platinum regimens but do not improve survival. Platinum combinations have a small (15%) survival advantage over single agent platinum out to the eighth year of follow up. The optimum dose of cisplatin is not known but several trials have failed to show an advantage by increasing the cisplatin dose. One trial comparing 100 mg/m2 vs. 50 mg/m2 of cisplatin in conjunction with cyclophosphamide demonstrated an initial survival advantage that was not seen with further follow up. In a trial of carboplatin AUC 6 vs. AUC 12 there was no difference in survival although the delivered dose in the higher dose arm was significantly lower than planned. Trials to determine the ideal number of cycles have shown that 5 or 6 cycles of chemotherapy are equivalent to 10 or 12 cycles(80-83).
Paclitaxel in combination with cisplatin has been shown to be superior to cisplatin and cyclophosphamide (84). In OV 10 a European – Canadian study the dose of paclitaxel was 175mg/m2 given over three hours demonstrated an increase of 4.6 months for median TTP and 10 months for median OS. This was despite the fact that many of the patients in the non-paclitaxel arm were treated at relapse with paclitaxel.
Two other large randomised studies have looked at the role and sequence of paclitaxel in advanced ovarian cancer. GOG 132 compared cisplatin 100mg/m2 vs. paclitaxel 175mg/m2 vs. the combination in advanced ovarian cancer. The outcomes for the combination arm were not different from the single agent cisplatin arm but the single agent paclitaxel was inferior in terms of survival and response rate. Many of the patients in the cisplatin arm subsequently received paclitaxel on biochemical or clinical relapse .
A large study from Europe (ICON 3) has revealed no differences in the response rates and the median survival in patients with optimal or suboptimal ovarian cancer treated with either carboplatin or carboplatin/paclitaxel (85).
Carboplatin can be successfully substituted for cisplatin. There appears to be no apparent difference in response rates or survival. Nausea and neurotoxicity are less common but myelosuppression more common with carboplatinum (86, 87).
Based upon the preceding analysis of the literature our post surgery protocol is to offer all stage II, III and IV patients 6 cycles of combination carboplatin (AUC=6) and paclitaxel (175mg/m2).
An alternate regimen is single agent carboplatin (AUC 5-6) for 6 cycles in patients who are elderly or who are unable to tolerate paclitaxel.
Consolidation therapy has not been shown to improve survival (88). After achieving remission, prolonged maintainence therapy with 12 cycles of paclitaxel has significantly prolonged progression free survival compared to 3 cycles of paclitaxel (89).
The Japanese GOG have shown in a prospective randomized study of dose dense weekly regimen of carboplatin/taxol with the standard 3 weekly schedule showing an improved survival with the dose dense regimen. 631 patients were eligible and included in the intention to treatment (ITT) population with a median PFS of 28 months compared to 17 months in the DD compared to standard treatment (p=0.0015) with higher overall survival at 3 years (72% vs 65%). Withdrawl due to toxicity was higher in the DD arm. A higher proportion (55%) were suboptimally debulked compared to US trials
There is increasing and compelling evidence that intraperitoneal (IP) chemotherapy will result in prolonged survival in a select group of patients. This route of administration is not advised in patients with bulky residual disease or with significant adhesions. Added to the complications of administration this is not recommended unless there is considerable experience in this route of administration within a specialised unit (90, 91).
Two randomized trials have addressed the role of secondary (interval) debulking after chemotherapy for suboptimally debulked ovarian cancer. If initial surgery is performed by a certified gyneacological oncologist, then interval surgery has not been shown beneficial. However if initial suboptimal surgery is performed by a non certified gyneacological oncologist, then survival may be enhanced.(92, 93). The published survival results would suggest an inferior survival of patients receiving neoadjuvant chemotherapy compared to patients primarily optimally debulked. Patient survival compares to patients with suboptimally debulked disease.
Randomised studies have not shown a benefit for second look surgery. However if the surgery is thought to influence further management then this can be considered. Variables associated with a negative SLL are: (i) initial stage (ii) tumor grade (iii) size of residual tumor (iv) the size of the largest metastatic disease (v) the number of lesions present prior to treatment (vi) the type of chemotherapy (vii) and CA-125 regression (94-97).
There is no consensus as to the optimal way of following patients after primary therapy. There are no randomised data on the role of regular CA125 and ultrasound testing but it is likely that in some patients relapses will be detectable earlier and treatment initiated to control or prevent symptoms. A common scenario is to review the patients every three months in the first year of follow up and then 3-6months after that with CA125 levels and pelvic examination being performed at each visit.
Patients who relapse and have responded previously to platinum based treatment may respond again to the same treatment; the likelihood of response is related to the length of time since the prior treatment (98). Other agents that are active in this setting include paclitaxel, oral etoposide, topotecan, tamoxifen and taxotere (99-104).
Secondary cytoreduction has not clearly been shown to improve survival in patients with recurrent disease but in some patients with small volume recurrence and a reasonable disease free interval this may be considered(105, 106).