Intraperitoneal chemotherapy in ovarian cancer: who and when?

PURPOSE OF REVIEW: Intraperitoneal chemotherapy in ovarian cancer has been studied for several years and developed in many countries. However, despite positive results from well-conducted clinical trials, its clinical application is still controversial. A review of recent advances is presented. RECENT FINDINGS: Intraperitoneal chemotherapy has been studied in two situations: in the first line, combined with intravenous chemotherapy, or as a consolidation treatment, after surgery and systemic chemotherapy. In the first line, two randomized studies showed an increased survival in patients with intraperitoneal chemotherapy. In patients with pathological complete remission, the theoretical principle remains valid, treating minimal disease, but definitive results from randomized studies are lacking. SUMMARY: Intraperitoneal chemotherapy is a regional treatment for ovarian cancer. Its development is limited by the reluctance of the medical oncologist community to include this technique in the whole strategy of treatment, despite positive results. However, intraperitoneal chemotherapy should be considered in patients optimally debulked and with minimal residual disease.     

Patient preferences regarding side effects of chemotherapy for ovarian cancer: do they change over time?

OBJECTIVE: The goals of this study were to: (1) systematically evaluate patient preferences regarding side effects of high-dose chemotherapy with stem cell support for treatment of advanced ovarian cancer; and (2) assess whether patients' preferences changed over time. METHODS: Forty patients with stage III or IV disease were enrolled in this study. Patients' preferences regarding 12 health states (side effects) were assessed using visual analogue scale (VAS) and time trade-off (TTO) methods during mobilization chemotherapy (T(1)) and 6-7 weeks later after high-dose chemotherapy and stem cell transplant (T(2)). Each assessment involved a 45-min interview conducted at the patient's bedside. RESULTS: The three most preferred health states were no evidence of disease (NED), a chemotherapy with few or no side effects, and alopecia, while the least preferred health states were chemotherapy with multiple severe side effects, hepatotoxicity, and nausea and vomiting. These results were observed at both T(1) and T(2) using both preference assessment methods. Pancytopenia scores significantly increased from T(1) to T(2) using the VAS method (P < 0.05), but decreased using the TTO method. CONCLUSIONS: Chemotherapy-experienced women with ovarian cancer have consistent preferences for the best and worst health states associated with the side effects of chemotherapy. Patients are more averse to nausea and vomiting than many other symptoms. Women's perceptions of pancytopenia may be dependent upon the number of prior cycles of chemotherapy and site of care for anemia, thrombocytopenia, and febrile neutropenia.     

How many ovarian cancer patients are eligible for fertility-sparing surgery?

Objective

To assess how many epithelial ovarian cancer (EOC) patients are eligible for fertility-sparing surgery (FSS) in a population-based study.

Study design

Using data from the Geneva Cancer Registry, we conducted a retrospective review of all women diagnosed with epithelial ovarian cancer (EOC) between January 1979 and December 2008. Patients were classified into two age groups (“young group” ≤ 45 years and “old group” > 45 years) and as “eligible for FSS” (FIGO IA, G1-G2 or unilateral ICG1) and “non-eligible for FSS” (FIGO IA, G3; IC G2-G3; IB or II–IV). Patients and tumor characteristics were tested with the chi-square test. Estimates of survival were calculated using the Kaplan-Meyer method and differences between groups were analyzed by the log-rank test.

Results

A total of 888 EOC patients were analyzed. The young group included 87 patients (9.8%): eleven (1.2%) were identified as eligible for FSS and 6 (0.6%) were nulliparous. The annual incidence of EOC women eligible for FSS in Geneva was 0.48/100,000 (0.5 women/year) and the expected annual incidence rate for Switzerland (8 million inhabitants) is 6.5 women/year.

Conclusion

Only a very small proportion of EOC patients are eligible for FSS. These results highlight the need to centralize FSS data in dedicated European units, in order to maintain expertise and quality of care for these patients.     

Pharmacokinetics of intraperitoneal chemotherapy with continuous washing methods for patients with ovarian cancer

<正> Objective: To compare the pharmacokinetics of the routine intraperitoneal chemotherapy (RIP) and continuous washing intraperitoneal chemotherapy (CWIP) of cisplatin (CDDP) in 38 patients with ovarian cancer.Methods:The patients had a performance status of II -IV on the FIGO scale.38 patients were randomized into CWIP group (16 patients) and RIP group (22 patients). CDDP was used as intraperitoneal chemotherapy (IP) with 70mg/m2. In 72h, the samples from serum, ascites and urine were collected respectively and their platinum density were determined with electrochemistry polarographic analysis. On the third day and one month after IP, liver and kidney function and blood routine were examined. Results: The maximum concentration (Omax) of plasma in CWIP and RIP groups were 3.84μg/ml and 1.27μg/ml respectively; the Cmax of ascites were 7.04μg/ml and 4.43μg/ml respectively in the two groups.The area under the plasma concentration-time curve(AUC) in CWIP and RIP groups were 1067.77μg/ml and 191. 72μg.h/m     

Routine pelvic examination during front-line chemotherapy for ovarian cancer: should it play a role?

OBJECTIVE: To determine if pelvic examination affected management in patients undergoing first-line chemotherapy for ovarian cancer and to determine a threshold of change in tumor size reliably detectable by pelvic examination. STUDY DESIGN: We reviewed 501 encounters among 47 women with ovarian cancer to see if pelvic examination prompted a management change. Clinicians then evaluated synthetic model "tumors" and were retested at intervals of 3-48 hours to determine change needed for reliable detection. RESULTS: The median number of examinations was 3 during 8 cycles of chemotherapy. Fifteen examinations (10.5%) revealed palpable anomalies, attributable to known tumor in 10 instances. The most common events preceding management change were elevation in serum CA-125 (57%) or chemotherapy toxicity (20%). No changes were made based on pelvic examination alone. When assessing "tumor" volume in a model, estimates ranged from 33-309% of actual volume. Determination of volume change following a delay was poor. No reliable threshold of detection of volume change was established. CONCLUSION: Pelvic examination findings rarely dictated management changes in this study. Further, our results call into question the potential of routine pelvic examination to add significantly to clinical management during initial treatment given the wide range of error in "tumor" size estimates.     

Is time to chemotherapy a determinant of prognosis in advanced-stage ovarian cancer?

OBJECTIVES: Clinicians often question when to start chemotherapy after patients undergo surgery for ovarian cancer. A major unproven concern is whether a long postoperative delay reduces the benefits of an extensive procedure and leads to disease progression. Our objectives were to evaluate the correlation between clinical and pathologic variables and to evaluate the effect of the "time to chemotherapy" (TTC) interval on survival. METHODS: We retrospectively studied data from 218 patients with International Federation of Gynecology and Obstetrics stage IIIC or IV ovarian cancer (TNM stage T3c or T4) who were consecutively treated between January 1, 1994, and December 31, 1998. RESULTS: Mean age at diagnosis was 64 years (range, 24-87 years; median, 65 years), and 206 patients received postoperative platinum-based chemotherapy. Mean TTC interval was 26 days (range, 7-79 days; median, 25 days). No correlation was found between operative time and TTC interval length (P=0.99). Age and performance of rectosigmoidectomy were correlated with longer TTC interval (P=0.009 and P=0.005, respectively), but TTC was not a predictor of overall survival (odds ratio, 1.00; 95% confidence interval, 0.98-1.01; P=0.85). Differences in TTC interval length (< or =17 days, 18-26 days, 27-33 days, or > or =34 days) did not affect survival (P=0.93). Even after categorizing patients by residual disease (<1 cm or > or =1 cm), no statistically significant effect of TTC on prognosis was identified. CONCLUSIONS: Concerns about the TTC interval should not be used to justify spending less time in the operative arena or using a more conservative approach for patients with advanced ovarian cancer.     

Is it possible to define an optimal time for chemotherapy after surgery for ovarian cancer?

Objective

The aims of this study are to investigate the actual time from primary surgery for epithelial ovarian cancer (OC) to initiation of chemotherapy (TI) amongst Danish women in 2005–2006, and to compare the survival for groups with early initiation (≤ median TI) and late initiation of adjuvant chemotherapy (> median TI).

Methods

All Danish women who underwent surgery for OC in the period 1 January 2005 to 31 December 2006 and recorded in the Danish Gynaecological Cancer Database (DGCD) were included. The five-year survival was estimated overall and by TI exposure. The Cox proportional hazard regression analysis was used to compute the adjusted hazard ratio (HR).

Results

The median TI was 32 days (25–75% quartile: 24 days; 41 days). The strongest prognostic factors for death were residual tumour and the International Federation of Obstetrics and Gynecology (FIGO) stage.The unadjusted HR for death in patients with TI > 32 days compared with TI ≤ 32 days was 0.85 (95% CI: 0.70; 1.04), p-value 0.12. When adjusted for residual tumour and FIGO-stage the HR was 1.13 (95% CI: 0.92; 1.39), p-value 0.26. The overall five-year survival was 42.8%, (95% CI: 38.9%; 46.5%).

Conclusions

This nationwide population-based cohort study revealed a non-significant increased risk of death for patients with TI > 32 days compared with the reference TI ≤ 32 days. The strongest prognostic factors were residual tumour after surgery and FIGO-stage. The overall five-year survival was 42.8% (95% CI: 38.9%; 46.5%).     

Does intraperitoneal chemotherapy benefit optimally debulked epithelial ovarian cancer patients after neoadjuvant chemotherapy?

Objective

To compare survival of ovarian cancer patients treated with neoadjuvant chemotherapy followed by intraperitoneal (IP) versus intravenous (IV) chemotherapy after optimal interval debulking.

Methods

Optimally debulked patients after neoadjuvant IV platinum paclitaxel based chemotherapy followed by postoperative IP chemotherapy were reviewed. A similar cohort of patients treated postoperatively with IV platinum paclitaxel based chemotherapy was chosen as control. Patient and disease-related demographics were abstracted from electronic hospital medical records. Associations between categorical variables were determined using Chi square test. Cox regression and Kaplan-Meier method estimated progression-free and overall survival.

Results

Fifty-four IV and 17 IP treated patients after interval debulking were studied. The majority of patients had serous histology and grade 3 tumours. There was no significant difference between the two groups with respect to age and proportion of microscopic residual disease. Patients with macroscopic residual disease had a significantly worse prognosis (HR = 2.17, 95% CI = 1.23-3.85, p = 0.008). Clinical complete response after primary treatment was 67% and 88% in the IV and IP group, respectively (p = 0.36). Estimated mean progression-free survival was 18 months in the IV group and 14.1 months in the IP group (p = 0.42). IP chemotherapy was not predictive of progression-free survival in the Cox model adjusted for age and residual disease status (HR = 1.22, 95% CI = 0.62-2.4, p = 0.56). Estimated mean survival was 68.9 months in the IV group and 37.5 months in the IP group (p = 0.85).

Conclusions

Survival benefit associated with IP chemotherapy after optimal upfront surgery may not translate to the neoadjuvant setting.     

Cells of origin of ovarian cancer: ovarian surface epithelium or fallopian tube?

Objective

Ovarian cancer is the fifth most common cancer in women and one of the leading causes of death from gynecological malignancies. Despite of its clinical importance, ovarian tumorigenesis is poorly understood and prognosis remains poor. This is particularly true for the most common type of ovarian cancer, high-grade serous ovarian cancer.

Results

Two models are considered, whether it arises from the ovarian surface epithelium or from the fallopian tube. The first model is based on (1) the pro-inflammatory environment caused by ovulation events, (2) the expression pattern of ovarian inclusion cysts, and (3) biomarkers that are shared by the ovarian surface epithelium and malignant growth. The model suggesting a non-ovarian origin is based on (1) tubal precursor lesions, (2) genetic evidence of BRCA1/2 mutation carriers, and (3) recent animal studies. Neither model has clearly demonstrated superiority over the other. Therefore, one can speculate that high-grade serous ovarian cancer may arise from two different sites that undergo similar changes. Both tissues are derived from the same embryologic origin, which may explain how progenitor cells from different sites can respond similar to stimuli within the ovaries. However, distinct molecular drivers, such as BRCA deficiency, may still preferentially arise from one site of origin as precancerous mutations are frequently seen in the fallopian tube.

Conclusions

Confirming the origin of ovarian cancer has important clinical implications when deciding on cancer risk-reducing prophylactic surgery. It will be important to identify key biomarker to uncover the sequence of ovarian tumorigenesis.

     

Inhibition of α4β1 integrin increases ovarian cancer response to carboplatin

Objective

The inability to successfully treat women with ovarian cancer is due to the presence of metastatic disease at diagnosis and the development of platinum resistance. Ovarian cancer metastasizes throughout the peritoneal cavity by attaching to and invading through the mesothelium lining the peritoneum using a mechanism that involves α4β1 integrin and its ligand (vascular cell adhesion molecule) VCAM-1. Integrin α4β1 expression on tumor cells is known to confer protection from therapy in other cancers, notably multiple myeloma. We evaluated the role of α4β1 integrin in response to platinum-based therapy in a mouse model of peritoneal ovarian cancer metastasis by treatment with a humanized anti-α4β1 integrin function-blocking antibody.

Methods

Integrin α4β1 expression on primary human ovarian cancer cells, fallopian tube and ovarian surface epithelia and fresh tumor was assessed by flow-cytometry. The therapeutic impact of anti-α4β1 treatment was assessed in murine models of platinum-resistant peritoneal disease and in vitro using the platinum resistant ovarian cancer cell lines.

Results

Treatment of tumor-bearing mice with human-specific α4β1 integrin function-blocking antibodies, anti-VCAM-1 antibody or carboplatin alone had no effect on tumor burden compared to the IgG control group. However, the combined treatment of anti-α4β1 integrin or anti-VCAM-1 with carboplatin significantly reduced tumor burden. In vitro, the combination of carboplatin and anti-α4β1 integrin antibodies resulted in increased cell death and doubling time.

Conclusions

Our findings support a role for α4β1 integrin in regulating treatment response to carboplatin, implicating α4β1 integrin as a potential therapeutic target to influence platinum responsiveness in otherwise resistant disease.     

Does neoadjuvant chemotherapy impair long-term survival for ovarian cancer patients? A nationwide Danish study

Objective

In Denmark, the proportion of women with ovarian cancer treated with neoadjuvant chemotherapy (NACT) has increased, and the use of NACT varies among center hospitals. We aimed to evaluate the impact of first-line treatment on surgical outcome and median overall survival (MOS).

Methods

All patients treated in Danish referral centers with stage IIIC or IV epithelial ovarian cancer from January 2005 to October 2011 were included. Data were obtained from the Danish Gynecological Cancer Database, the Danish National Patient Register and medical records.

Results

Of the 1677 eligible patients, 990 (59%) were treated with primary debulking surgery (PDS), 515 (31%) with NACT, and 172 (10%) received palliative treatment. Of the patients referred to NACT, 335 (65%) received interval debulking surgery (IDS). Patients treated with NACT–IDS had shorter operation times, less blood loss, less extensive surgery, fewer intraoperative complications and a lower frequency of residual tumor (p < 0.05 for all). No difference in MOS was found between patients treated with PDS (31.9 months) and patients treated with NACT–IDS (29.4 months), p = 0.099. Patients without residual tumor after surgery had better MOS when treated with PDS compared with NACT–IDS (55.5 and 36.7 months, respectively, p = 0.002). In a multivariate analysis, NACT–IDS was associated with increased risk of death after two years of follow-up (HR: 1.81; CI: 1.39–2.35).

Conclusions

No difference in MOS was observed between PDS and NACT–IDS. However, patients without residual tumor had superior MOS when treated with PDS, and NACT–IDS could be associated with increased risk of death after two years of follow-up.     

Is age a barrier to the aggressive treatment of ovarian cancer with paclitaxel and carboplatin?

OBJECTIVE: The objective of this study was to determine whether the toxicities associated with chemotherapy are age related in women treated for ovarian cancer. METHODS: Patients with stage II-IV epithelial ovarian cancer underwent cytoreductive surgery. Adjunctive therapy was given to each patient consisting of intravenous (IV) paclitaxel 175 mg/m(2) over 3 h with a subsequent 30-min IV infusion of carboplatin. Carboplatin dose was calculated to achieve a targeted area under the curve (AUC) of 5.0-7.5. Treatment was repeated at 21- to 28-day intervals for six cycles. Toxicities were graded after each dose of chemotherapy. Results were analyzed using the Wilcoxon rank sum test and log likelihood ratio to compare toxicities in women age <60 years old to women >/=60 years old. RESULTS: Fifty-three women, 22 of whom were >/=60 years old, were treated with 309 cycles of chemotherapy. Forty-eight patients (92%) completed all six cycles. AUC dosing of carboplatin was equivalent for both groups. Carboplatin dose reduction occurred in 75% of patients for grade 4 neutropenia or thrombocytopenia. No patient required a reduction in the paclitaxel dose. Neutropenia was less frequent in women >/=60 years old than in women <60 years old (P = 0.02). There was no difference between women <60 years old and women >/=60 years old in the incidence of anemia, thrombocytopenia, or the use of growth factors. A 68% complete clinical response rate was observed in women >/=60 years old compared to a 74% complete response rate for women under age 60 (P = 0.22). CONCLUSION: Age is not a barrier to the aggressive treatment of ovarian cancer with this regimen of paclitaxel and carboplatin.