The Royal Marsden Study reviewed 194 patients with stage I epithelial ovarian cancer who had received no adjuvant treatment but were under regular follow-up with physical examination, CA 125, and CT scan. At a median follow-up of 54 months, 5-year disease-free survival of patients with stage IA disease was 87%; stage IB, 65%; and stage IC disease, 62%. Five-year overall survival for stage IA patients was 93.7%; stage IB, 92%; and stage IC, 84%. It was observed that factors associated with an increased risk of relapse in multivariate analyses included extraovarian spread, grade 3 histology/ poorly differentiated, rupture of capsule, dense adhesions, clear cell histology, extracystic tumor, and positive peritoneal washing (130).
The first trial in the United States was in patients with good prognosis and early stage 1A or 1B. A total of 92 patients were randomized to either melphalan or no treatment. Their 5-year disease-free survival was 91 versus 98%, respectively, while 5-year overall survival was 94 versus 98%. The authors concluded that patients with early good prognoses do not require adjuvant treatment (77). The second trial involved 141 patients with stages I and II disease and poorly differentiated histology. They were given melphalan versus intraperitoneal chronic phosphate (P-32). The 5-year disease-free survival was 80% for both arms (77). The 5-year overall survival at 81% (melphalan arm) versus 78% (P-32) was not statistically significant. It was concluded, after multivariate analysis showed clear cell tumor and histologic grading to be related to outcome, that the preferred adjuvant treatment was P-32 for high-risk patients.
The Gruppo Interregionale Collaborativo in Ginecologia Oncologica (GICOG) then had two randomized trials comparing adjuvant cisplatin (CDDP) versus no treatment and CDDP versus P-32. In total, there were 271 patients with stage I ovarian cancer after radical surgery. In the first trial, patients were randomized to receiving CDDP versus no adjuvant treatment. The 5-year disease-free survival was 65% in the control arm and 83% in the CDDP arm; the 5-year overall survival was 82% in the control arm and 88% in the CDDP arm. The second trial randomized 161 patients to CDDP versus P-32. The 5-year disease-free survival was 65% in the P-32 arm and 85% in the CDDP arm (p = .008); the 5-year overall survival was 79% in the P-32 arm and 81% in the CDDP arm (p = .354). Both trials were criticized as containing too few patients, thus resulting in low statistical power, and the dose of CDDP was considered to be suboptimal (131).
At the same time, a Norwegian trial randomized patients to CDDP versus P-32 or whole abdominal radiotherapy (WAR) as adjuvant treatment (N = 347). Patients with early epithelial ovarian cancer (EOC) were accrued (a few FIGO stage III patients were included) from 1982 to 1988. CDDP was given at 50 mg/m2 every 3 weeks for six cycles (N = 169), P-32 or WAR (N = 171, WAR, N = 28), or WAR and abdominal pelvic radiotherapy (RT). Anteroposterior (AP) fields received 2200 cGy in 20 patients and 11 patients were given 2200 cGy to the pelvis. The 5-year disease-free survival for patients who received P-32 was 81%, while it was 75% for those who received CDDP (p = .57 NS). The 5-year overall survival (OS) for P-32 was 83%; and for CDDP, it was 81% (p = .6 NS). It was concluded that CDDP should be standard of treatment in view of its lower toxicity compared to P-32 (132).
The GOG 95 trial studied stages IC and II and poorly differentiated stages IA and IB. The 205 evaluable patients were randomized to intraperitoneal P-32 (N = 98) versus cyclophosphamide (1000 mg/m2 every 21 days for three cycles) and cisplatin 100 mg/m2 (CP) every 21 days for three cycles) (N = 107). The 5-year disease-free survival for P-32 was 66%, while it was 77% (p = .08) for CP, with a 31% reduction in time to progression. The 5-year overall survival for P-32 was 76%; for CP, it was 84% (not significant). It was concluded that although there were no statistical differences between two groups, CP was preferred standard treatment because of a better progression-free interval (133). The largest international randomized trials, the ACTION and ICON trials, in early ovarian cancer were reported in 2003 (134). Between November 1990 and January 2000, a total of 925 patients who had had surgery for early-stage ovarian cancer were randomly assigned to receive platinum-based adjuvant chemotherapy (N = 465) or observation (N = 460) until chemotherapy was indicated. When the ACTION (Adjuvant Chemotherapy in Ovarian Neoplasms) trial was analyzed alone, the overall survival was not significant and the recurrence-free survival advantage was limited to suboptimally debulked patients (135). However, when all the patients in the ICON (International Collaborative Ovarian Neoplasm) trial and ACTION trials were combined, the overall survival at 5 years was 82% in the chemotherapy arm and 74% in the observation arm. Recurrence-free survival at 5 years was also better in the adjuvant chemotherapy arm than it was in the observation arm. Both of these results were significant. In conclusion, it is the consensus that patients with early-stage ovarian cancer can also benefit from adjuvant chemotherapy.
More recently, one clinical trial involving patients with limited disease was completed. The goal was to determine whether six cycles of carboplatin and paclitaxel would significantly lower the rate of cancer recurrence, compared to three cycles of the same agents following surgical staging operations on patients with stage IA grade 3, stage IB grade 3, stage IC, and completely resected stage II ovarian epithelial cancer. A secondary objective was to compare the toxicities of the two treatments. Following surgical staging laparotomy, TAH (Total Abdominal Hysterectomy), and BSO (Bilateral Salpingo-Oophorectomy), 321 patients were randomized to either three or six cycles of paclitaxel 175 mg/m2 infused over 3 h followed by carboplatin 7.5 AUC (area under the curve) infused over 30 min. Cycles were repeated every 21 days. A total of 70% of these patients had stage I disease. In the standard three-cycle arm, the estimated probability of cancer recurring within 5 years was 27%, compared to 19% in the six-cycle arm. The risk of recurrence was 33% lower for patients treated with six cycles of chemotherapy, with a relative hazard of 0.672. If the treatment comparison includes the patients considered ineligible due to incomplete surgical staging, then the recurrence rate was 24% less on the six-cycle regimen, with a relative hazard of 0.762. It was concluded that the addition of three cycles of carboplatin and paclitaxel over the standard three cycles did not significantly alter the rate of cancer recurrence in patients with early-stage ovarian epithelial carcinoma. In addition, six cycles caused significantly more toxicity than three cycles (136).
Before the 1990s, patients with advanced ovarian cancer had little to look forward to after cytoreductive surgery. There were few studies to suggest that—apart from whole-abdominal radiotherapy—adjuvant therapy made any difference in disease-free and overall survival. Until the 1990s, chemotherapy had been largely based on alkylating agents such as melphalan and cyclophosphamide. Adjuvant chemotherapy with such agents was less than satisfactory. With the development of cisplatin came the first hopes that adjuvant chemotherapy could make a difference in patients' prognosis. Then carboplatin was developed and found to be better tolerated. Soon, it became clear that platinum-containing chemotherapies were superior to nonplatinum-containing regimens.
In 1991, the Advanced Ovarian Cancer Trialist Group (AOCTG) published a meta-analysis considering the role of platinum and the relative merits of single-agent and combination chemotherapy in the treatment of advanced ovarian cancer. This represented a quantitative overview of updated individual patient data from 8139 patients in 45 available randomized trials (137). There were three conclusions. First, the results suggested that, in terms of survival, immediate platinum-based treatment was better than any nonplatinum regimen, with the overall relative risk at 0.93. Second, platinum in combination was better than single-agent platinum when used at the same dose, with an overall relative risk of 0.85. Finally, cisplatin and carboplatin were equally effective, with an overall relative risk of 1.05. A similar conclusion came from two large North American trials: a trial by the Southwest Oncology Group (342 patients with stage III or IV disease randomized to receive cisplatin and cyclophosphamide versus carboplatin plus cyclophosphamide ) and a trial by the National Cancer Institute of Canada (139). None of these failed trials demonstrated a significant difference in overall survival, though the carboplatin regimen was found to have a better therapeutic index and to produce a better quality of life.
In contrast, a French trial involving 144 patients with stage III or IV disease who received either cisplatin or carboplatin had very different results (140). The pathologic complete remission and overall response rates were significantly higher in the cisplatin arm than in the carboplatin arm (33 versus 15% and 73 versus 47%, respectively). The median survival time was 27.9 months for the cisplatin arm and 20.6 months for the carboplatin arm. The actual delivered dose intensity of the drugs in the two arms was not reported.
In 1992, another systematic overview of 54 randomized clinical trials testing a variety of chemotherapeutic approaches in advanced ovarian carcinoma was reported. Prolonged follow-up data are available for most patients, and individual patient data were made available for all patients; analysis was made on the basis of "intention to treat." This report concentrated on two comparisons: (1) platinum alone versus platinum in combination, apparently showing a long-term survival advantage for the combination; and (2) carboplatin versus cisplatin, showing no obvious survival differences. It was striking that no single study to date has been large enough to detect the modest survival differences expected from current therapy (141).
As a result of these studies, the ICON group in Europe decided to look at single-agent carboplatin, the least toxic of all chemotherapies, compared to the combination containing carboplatin. ICON II compared the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) with single-agent carboplatin in women with ovarian cancer requiring chemotherapy. A total of 1526 patients were entered from 132 centers in nine European countries. The overall survival curves showed no evidence of a difference between CAP and carboplatin, with a hazard ratio of 1.00. The results indicate a median survival of 33 months and a 2-year survival of 60% for both groups. It was concluded that in view of the greater toxicities of CAP compared to carboplatin, single-agent carboplatin was the appropriate standard of treatment for women with advanced ovarian cancer (142). Meanwhile, in the United States, paclitaxel, extracted from the Pacific yew tree, was discovered by the drug screen of the National Cancer Institute (NCI) in the forests of South America. The success of paclitaxel in recurrent ovarian cancer prompted efforts to look into paclitaxel as a component of frontline therapy. Two large phase III trials were published; these formed the basis for our current standard of care. The first of these was GOG protocol 111, which randomized patients with large-volume advanced disease to cyclophosphamide plus cisplatin or paclitaxel plus cisplatin. This study showed superiority for the paclitaxel-and-cisplatin regimen compared with cyclophosphamide and cisplatin in regard to five parameters: (1) response rate, (2) clinical CR rate, (3) percentage of patients grossly disease-free at second-look laparotomy, (4) progression-free survival (PFS), and (5) overall survival (143). Approximately 11/2 years after the publication of this trial, a confirmatory study from a European-Canadian consortium called OV-10 was presented (144). This study also randomized patients to either cyclophosphamide and cisplatin or paclitaxel and cisplatin. The population here comprised women with stage IIB through IV disease and included both small- and large-volume patients. The combination of paclitaxel and platinum proved to be superior to the cyclophosphamide and platinum combination with regard to response rate, clinical CR rate, PFS (progression-free survival), and overall survival. The numbers also closely reproduced the numbers seen with GOG protocol 111.
That led to the conclusion, in the middle to latter 1990s, that the standard of care in ovarian carcinoma was paclitaxel plus a platinum compound, although the preferred dosing schedule of each agent was not totally clear at that time.
Now that a possibly superior regimen had been found, the question of carboplatin versus cisplatin arose: whether carboplatin could be substituted for cisplatin in order to improve the regimen from the standpoint of both toxicity and ease of administration. Two large trials were done, a German trial and a GOG trial in the United States. The German trial, presented in 1998, randomized 798 patients with advanced ovarian cancer to either paclitaxel and cisplatin or paclitaxel and carboplatin (145). The results showed equivalence between the two regimens with regard to response rate, clinical CR rate, PFS (progression-free survival), and overall survival. The large number of patients in this study, 798, made it possible to conclude that the regimens were equivalent.
Confirmation came from GOG protocol 158, a study that focused on patients with stage III optimal or minimal residual disease. Patients were again randomized to either paclitaxel and cisplatin or paclitaxel and carboplatin. The results showed equivalence between the two regimens with regard to pathologic CR rate and PFS. The study continues to be followed for purposes of survival analysis when enough events have occurred (146). As a result of these two large trials, it was concluded that cisplatin and carboplatin were equivalent in combination with paclitaxel and that it would be not only feasible but also easier to treat these patients with paclitaxel plus carboplatin as opposed to other regimens.
The results of OV 10 and GOG 111 led to another ICON trial. ICON III aimed to compare the safety and efficacy of paclitaxel plus carboplatin with a control of cisplatin, doxorubicin, and cyclophosphamide (CAP) or carboplatin alone. Between 1995 and 1998, a total of 2074 patients from 130 centers in eight European countries were accrued. Women were randomly assigned paclitaxel plus carboplatin or control, the control (CAP or single-agent carboplatin) being chosen by the patient and clinician before randomization. At a median follow-up of 51 months, the survival curves showed no evidence of a difference in overall survival between paclitaxel plus carboplatin and control, the hazard ratio being 0.98. The median overall survival was 36.1 months on paclitaxel plus carboplatin and 35.4 months on control. Median PFS was 17.3 months on paclitaxel plus carboplatin and 16.1 months on control. When this trial was interpreted, it was concluded that single-agent carboplatin and CAP are as effective as paclitaxel plus carboplatin as first-line treatment for women requiring chemotherapy for ovarian cancer. The favorable toxicity profile of single-agent carboplatin suggests that this drug is a reasonable option as first-line chemotherapy for ovarian cancer (147).
Alternative Chemotherapeutic Agents
Docetaxel (Taxotere) is a semisynthetic compound structurally related to paclitaxel. The toxicity of docetaxel is in many ways similar to that of paclitaxel. However, prolonged treatment with docetaxel increases skin toxicity and produces significant edema. A very recent trial by the Europeans concluded that docetaxel could be an alternative to paclitaxel. A total of 1077 patients with FIGO stage IC to IV EOC (epithelial ovarian cancer) were randomized to receive either paclitaxel and carboplatin or docetaxel with carboplatin; the median follow-up in surviving patients was 21 months. Median PFS and overall survival (at 18 months) for patients treated with docetaxel and carboplatin was 15.1 months and 73.5% and for paclitaxel and carboplatin was 15.4 months and 76.6%, respectively. The main on-treatment toxicity differences between the two arms were neurotoxicity (more common with the paclitaxel combination) and myelosuppression (more common with the docetaxel combination). Statistically significantly less neurotoxicity following the docetaxel combination appeared to be still evident at 10 months postrandomization. Global quality-of-life parameters were comparable in both arms. However, there were significantly less arthralgic/myalgic symptoms during treatment with the docetaxel combination at 33.0% compared with paclitaxel combination at 48.0%, as well as less weakness in legs or arms with the docetaxel combination at 33.9%, whereas the combination with paclitaxel had a 47.7% occurrence. The authors concluded that the docetaxel combination appears to be a viable alternative to the paclitaxel combination as first-line chemotherapy in EOC because of an improved therapeutic index while maintaining similar efficacy (148).
Back in North America, the search for better frontline chemotherapy continued. Of interest was the combination of a third agent, creating sequential or combination triplets. In the first trial, GOG 132, patients with large-volume advanced disease were randomized to either single-agent cisplatin; single-agent paclitaxel; or a combination of paclitaxel and cisplatin. In terms of survival, there were no significant differences among these three arms (149). That prompted a further look to determine why the combination did not prove to be superior. What soon became apparent was the fact that in this particular study, if there was any residual disease at the conclusion of frontline therapy, patients immediately received the other agent. Effectively, therefore, instead of studying single-agent therapy versus combination chemotherapy, sequential single-agents versus combination chemotherapy was being tested. This may have affected the results.
Nevertheless, this trial formed the basis for some novel ways of incorporating a third agent into frontline therapy. The agents that GOG focused on were those that had demonstrated the ability to get responses in paclitaxel- and platinum-resistant disease. There are four such drugs, oral etoposide, topotecan, liposomal doxorubicin, and gemcitabine. Oral etoposide, unfortunately, when combined with paclitaxel and carboplatin, induces acute leukemia in a small percentage of patients but one that is high enough to raise concerns. So the focus instead was on topotecan, doxorubicin, and gemcitabine introduced as new agents in frontline therapy.
This has resulted in GOG protocol 182/ICON V. The control arm is paclitaxel plus carboplatin for eight cycles. The experimental arms include two triplet regimens. Regimen II is paclitaxel, carboplatin, and gemcitabine given on each of eight cycles. Regimen V is paclitaxel, carboplatin, and doxorubicin, with the doxorubicin given on cycles 1, 3, 5, and 7. There are also two sequential doublet regimens: (1) regimen III, gemcitabine and carboplatin, followed by paclitaxel and carboplatin, and (2) regimen IV, topotecan and carboplatin, followed by paclitaxel and carboplatin. However, in this now completed phase III trial, investigators have reported no improvement for any arm in comparison with the control arm (150).
Additional Combination Chemotherapy
Researchers also looked at the addition of anthracycline to make concurrent triplets. It was accepted that either cyclophosphamide (750 mg/m2) plus cisplatin (75 mg/m2) every 3 weeks or cyclophosphamide (500 mg/m2) plus doxorubicin (50 mg/m2) plus cisplatin (50 mg/m2) every 3 weeks (CAP) is acceptable standard therapy. However, four prospective randomized trials comparing cisplatin and cyclophosphamide with the CAP regimen failed to show statistically significant differences in overall survival (151–153). The largest of the above trials was that of the Italian Cooperative Gynecologic Oncology Group (GICOG), which randomized 529 patients to receive CAP, cisplatin/cyclophosphamide, or single-agent cisplatin (151). No statistical difference was seen in overall survival (minimum follow-up 5 years) among the three groups. Meta-analysis of the above four trials (154) revealed a 6-year survival advantage of 7% in patients receiving the doxorubicin-containing regimen, but it remains unclear whether the benefit was a result of doxorubicin or the greater dose intensity reached by adding it. There was also a very large German trial with 1281 patients comparing paclitaxel, epirubicin, and carboplatin with paclitaxel and carboplatin. As presented at the American Society of Clinical Oncology meetings, there were no significant differences in response, PFS, or overall survival even though a meta-analysis 10 years ago suggested that adding an anthracycline might be of benefit. As a result, it does not appear that the addition of either doxorubicin or epirubicin to frontline therapy is beneficial (155).
The preliminary results of a large phase III trial (EORTC55971) showed that neoadjuvant chemotherapy followed by debulking surgery produces similar outcomes to primary debulking followed by chemotherapy in stages IIIC and IV disease (156).
The high risk of recurrent disease after treatment of advanced-stage epithelial ovarian cancer has prompted an intensive search for therapeutic strategies that can be given after standard-of-care therapy to improve patient outcomes. More than 12 phase III trials have been undertaken in this setting, including extension of frontline agents, administration of short duration non-cross resistant chemotherapy, high-dose chemotherapy, whole-abdominal or intraperitoneal radiotherapy, immunotherapy, vaccine therapy, biologic therapy, and single-agent paclitaxel; however, none have shown a survival advantage against various controls (usually no treatment) (51,157). The single-agent paclitaxel strategy has been assessed in two phase III trials giving paclitaxel for 6 or 12 months. Only S9701/GOG178, a phase III trial that administered paclitaxel intravenously for 12 months (versus 3 months) after an initial response to first-line chemotherapy showed improved progression-free survival.
The intraperitoneal administration of cisplatin as primary chemotherapy for debulked epithelial ovarian cancer results in a 20 to 30% improvement in both progressionfree and overall survival times by comparison with intravenous delivery (158–162). However, the randomized trials have been criticized (162) and intraperitoneal chemotherapy has not been universally accepted for at least three reasons: toxic effects, intraperitoneal treatment delivery issues (eg, technical experience with catheter placement and management), and complications (eg, intraperitoneal adhesions, infections) (163). In response to concerns about underuse, a National Cancer Institute clinical announcement made on January 5, 2006, encouraged oncologists to use intraperitoneal cisplatin after optimum cytoreduction in patients with epithelial ovarian cancer. However, for intraperitoneal therapy to become widely accepted, an ambulatory regimen needs to be established with acceptable toxic effects that preserve the survival advantage (164). The Gynecology Oncology Group is also planning a phase III trial that will test whether intraperitoneal chemotherapy is associated with survival benefits by comparison with intravenous chemotherapy when the targeted agent bevacizumab is added to the treatment regimen. Finally, early data suggest that hyperthermic intraperitoneal chemotherapy is promising, but this treatment is still highly investigational (165).
The relationship between the dose of chemotherapy and response and/or survival has been investigated extensively. There have now been seven randomized trials of dose intensity in the treatment of ovarian cancer, and two more with intraperitoneal chemotherapy. Clinically, it is possible for a dose intensity of two- to threefold with cytokine support and five to ten times with stem cell support for cancer treatment.
The landmark meta-analysis was that of a collection of 60 studies where there seemed to be a correlation between the dose intensity of the chemotherapy and response in ovarian cancer. However, the dose intensity studied translated into a difference of 18 mg/m2 compared to 36 mg/m2 (166), a range well below the dose of 50 to 75 mg/m2 that is conventionally used in patients. A similar meta-analysis in 1993 came to the same conclusion for cisplatin up to 75 mg/m2, but again suffered the same handicap of not being able to support dose intensity beyond 75 mg/m2 (167).
Evidence from nonrandomized trials initially led to the observation that higher doses or alternative administration of IP cisplatin resulted in responses in patients who were initially resistant to cisplatin (168). However, a closer look revealed that many of those who were deemed to have responded to reinduction cisplatin had actually responded originally to platinum, but they merely had a shorter relapse interval than the conventional 6 months.
Seven randomized trials have been performed (169–175). These are summarized in Table 28-4.
Table 28–4. Dose-Intensity Trials in Ovarian Cancer ||Download (.pdf)
Table 28–4. Dose-Intensity Trials in Ovarian Cancer
|Trials||N||Platinum Dose||Response Rate||Overall Survival|
|GOG (McGuire 1995) (169)||458||CDDP 16.7 mg/m2/week||65||21|
|CDDP 33.3 mg/m2/week||59||24|
|GICOG (Columbo 1993) (170)||306||CDDP 25 mg/m2/week||61||33|
|CDDP 50 mg/m2/week||66||36|
|GONO (Conte 1996) (171)||145||CDDP 12.5 mg/m2/week||61||24|
|CDDP 25 mg/m2/week||58||29|
|London GOG (Ehrlich 1983) (172)||241||CBDA AUC 6 q 28||57||HR: 0.91|
|CBDA AUC 12 q 28||63|
|Austrian trial (Dittrich 1996) (173)||253||CDDP 25 mg/m2/week||42||38|
|CDDP 25 mg/m2/week+||39||42|
|CBDA 75 mg/m2/week|
|Scottish trial (Kaye 1996) (174)||159||CDDP 16.7 mg/m2/week||34||27% at 4 years|
|CDDP 33.3 mg/m2/week||61||32% at 4 years|
|Hong Kong trial (Ngam 1989) (175)||50||CDDP 15-20 mg/m2/week||30||30% at 3 years|
|CDDP 30-40 mg/m2/week||55||60% at 3 years|
Overall, they seem to conclude that by doubling the dose of platinum, it increased toxicity without providing further therapeutic gain. Five of the seven studies showed no difference in response rate or survival. The other randomized trials showed advantages in dose-intensity regimen. The large Scottish trial also showed a difference in survival but included in its population optimally debulked patients with stage IC to IV disease. However, a separate analysis by the Scottish investigators of patients with advanced ovarian cancer still showed a difference favoring the high-dose arm with respect to PFS and overall survival. Patients on the high-dose arm received the same number of treatment cycles as those in the low-dose arm; as a result, the total dose of cisplatin was 67% higher (174). The Hong Kong trial included stage III to IV patients who showed improved survival with high-dose regimens, but the patient population was small and staging criteria were not uniform (175). Further, the multiple chemotherapy-related toxicities in ovarian cancer preclude marked increases in dose intensity for prolonged periods.
Studies in dose intensification with paclitaxel also began with preclinical studies that seem to suggest a dose-response relationship. However, it soon became apparent that the duration of the infusion was more important than the absolute dose of the paclitaxel (176). In vitro studies have demonstrated that prolonged exposure to paclitaxel increased the cytotoxicity in many different tumor lines to a greater extent than that observed by merely increasing the dose. This, in addition to the fact that this drug exhibits nonlinear pharmacokinetics with saturable parameters of distribution and elimination, meant that increasing the dose would not result in a proportional increase in maximum plasma concentration or drug exposure. Nevertheless, dose intensity studies were performed, but only with the coadministration of growth factors (177,178).
A meta-analysis of phase II studies comprising a total of 191 patients showed that for the majority of patients who were considered platinum-resistant, an increased dose of paclitaxel did not correlate with an improved response rate (177). A randomized study of more than 300 patients was positive, in that a higher 250 mg/m2 q21 dose of paclitaxel was associated with a 36% response rate, while a lower dose of 175 mg/m2 q21 led to a lower response rate of 27%. Both regimens administered the chemotherapy over 24 h. There was no overall difference in the PFS or overall survival. However, the higher dose was associated with higher toxicities (178).
Studies indicate that there is no evidence that dose intensity is crucial in the chemotherapeutic responses of ovarian carcinoma. And, in fact, there is no evidence that going above a cisplatin dose of 75 mg/m2, carboplatin AUC 5, or a dose of 350 to 500 mg/m2, or paclitaxel 175 mg/m2 shows any additional advantage.