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Drug therapy of ovarian and fallopian tube cancer

The goal of chemotherapy is to treat macroscopic and microscopic metastasis. 

Ovarian cancer

Epithelial ovarian cancer

For epithelial ovarian cancer in stage I, randomized studies have shown that postoperative chemotherapy can reduce the risk for recurrence and improve survival in patients having a significant risk for recurrence. Clear-cell tumors and moderately differentiated tumors have a high risk for recurrence. Aneuploid tumors also have a significantly higher risk for recurrence. The difference in frequency of recurrence related to stage Ia, Ib, and Ic is modest, however, especially compared to ploidy analysis.

The patient is evaluated according to a low/high risk group:

  • Low risk: Stage 1a–c, grade 1–2, non clear-cell type and diploid
  • High risk: All grade 3, all clear-cell, all aneuploid

Low risk patients are not given postoperative chemotherapy if they are staged correctly and operated radically. All patients in the high risk group are offered adjuvant chemotherapy. Standard treatment is currently carboplatin and paclitaxel combination therapy, and is given over 3–6 cycles. In a randomized study where the effect of 3 versus 6 cycles was assessed, no difference in survival was found between 3 and 6 cycles.

Patients with stage II-IV ovarian cancer are offered chemotherapy. Standard treatment is carboplatin and paclitaxel given over 6 cycles. No data are available supporting more than 6 cycles, dose escalation, or addition of a third drug. Patients with reduced general health condition and/or elderly may be offered treatment with carboplatin alone. Patients with significantly reduced kidney function may be offered paclitaxel or liposomal doxorubicin (Caelyx®) alone.

A phase III study of neoadjuvant chemotherapy of patients in stage IV or stage III with uncertain resectability of the tumor was recently published. This study  set up by EORTC concluded that neoadjuvant chemotherapy followed by interval debulking was no worse than primary debulking surgery followed by chemotherapy treatment in "bulky" in stage IIIc and IV patients. Complete resection of all macroscopic tumor disease was, regardless of neoadjuvant chemotherapy or primary surgery, the most important prognostic factor. Patients in stage IIIa, IIIb, IIIc and IV that are considered to be radically operable should undergo primary surgery. For patients with reduced general health condition, neoadjuvant chemotherapy can be offered.

Two prospective randomized studies, GOG-218 and ICON7, also recently published, investigated whether the angiogenesis inhibitor Avastin® combined with standard treatment with carboplatin and paclitaxel, improved progression-free survival. PFS was one of the endpoints. Addition of Avastin® gave a significantly better median PFS of 3.8 months and 1.8 months respectively. However, it is still too early to evaluate the effect on long-term survival. The side effects of Avastin® combined with carboplatin and paclitaxel were tolerable. At present, it cannot be predicted whether the combination of carboplatin, paclitaxel, and Avastin® will be the new standard treatment for advanced ovarian cancer. A decision will not be made until long-term surival and cost-benefit analyses are published.

Intraperitoneal chemotherapy (IP) may be appropriate for patients with no macroscopic tumor or only minimal changes remaining after surgery. A Cochran review concluded that with IP, a significantly prolonged long-term survival and progression-free survival was achieved in patients with optimal tumor-reducing surgery in stage I. Toxicity, especially neurotoxicity, and the risk for complications are significant. 

Chemotherapy generally has little effect on borderline tumors and adjuvant chemotherapy is not offered. In selected cases, it may be appropriate to try treatment with carboplatin and paclitaxel. 

The following chemotherapies are recommended by Oslo University Hospital for advanced ovarian cancer:

  • Combination regimen of carboplatin and paclitaxel in 6 cycles. The recommended dose for carboplatin AUC = 5-6 and paclitaxel 175mg/m² body surface area given over 3 hours every 3 weeks.
  • In cases where the patient does not tolerate this combination, carboplatin alone is given (AUC=5-6)
  • Patients hypersensitive to paclitaxel can alternatively be given docetaxel (Taxotere®), gemcitabine or liposomal doxorubicin (Caelyx®)  
  • Fit patients, adequately operated in stage III may be considered for IP with cisplatin or paclitaxel. 

We strive to include as many patients as possible in clinical studies.

Non-epithelial ovarian cancer

Types:

  • Rare germ cell tumors (endodermal sinus tumor, embryonal carcinoma, polyembryoma, choriocarcinoma, immature teratoma grade 3, mixed types, dysgerminomas, and immature teratoma grade 1-2)
  • Sex cord thecomas/fibromas (granulosa cell tumors, Sertoli-Leydig cell tumor and thecoma)

Non-epithelial ovarian cancer is generally more sensitive to chemotherapy than epithelial ovarian cancer, with the exception of granulosa cell tumors. 

For non-epithelial stage 1a, the preferred treatment is adjuvant chemotherapy with BEP (bleomycin, etoposide, cisplatin) appropriate for:

  • endodermal sinus tumor
  • embryonal carcinoma
  • polyembryoma
  • choriocarcinoma
  • immature teratoma grade 3 
  • mixed types

Adjuvant treatment is usually not given for:

  • dysgerminoma
  • immature teratoma grade 1–2 ,
  • granulosa cell tumor
  • Sertoli-Leydig cell tumor 
  • thecoma 

In advanced stages with remaining tumor after surgery, 3 cycles of BEP are given (cisplatin, etoposide, bleomycin), followed by 1 to 3 cycles of EP.

Fallopian tube cancer

Fallopian tube cancer is treated the same way as epithelial ovarian cancer.

Treatment of recurrence

Recurrence of epithelial ovarian cancer is separated into early and late recurrence.

Early recurrence occurs within the first 6 months after finished primary treatment and is considered resistant to platinum based chemotherapy. Further treatment of these patients will be palliative. Treatment with other types of chemotherapy than those used for primary treatment may be appropriate. 

Liposomal doxorubicin (Caelyx®) and topotecan are the two best documented chemotherapy drugs for this type of situation. In phase II studies, gemcitabine has shown response rates and progression-free survival equivalent to liposomal doxorubicin (Caelyx®) and topotecan. Weekly paclitaxel has also shown an equivalent effect in phase II studies, and has a favorable side effect profile. Hormonal treatment with tamoxifen appears to have a certain stabilizing effect.  

Late recurrence occurs after 6 months subsequent to finished primary treatment and is considered platinol-sensitive. There is a high likelihood for response to re-treatment with carboplatin combination treatment.

The best treatment is liposomal doxorubicin and carboplatin (CD). A prospective randomized study compared CD to carboplatin and paclitaxel (CP) and showed an improved median PFS of 11.3 months compared to 9.4 months (p = 0.005). It is still too early to draw conclusions regarding long-term survival. The most significant side effects for CD were hand and foot syndrome, nausea, and mucositis, while for CP, side effects were alopecia and neuropathy.

The second alternative to CD and CP is carboplatin with gemcitabin and liposomal doxorubicin with trabectedin.

If combination treatment is not tolerable, carboplatin alone is given.

Patients with non-epithelial ovarian cancer who have not been given chemotherapy as primary treatment are treated with BEP. In the case of BEP resistance, the patient can be offered treatment with POMB-ACE. High-dose treatment may be appropriate in some cases. 

Recurrence of fallopian tube cancer is treated the same way as recurrence of epthelial ovarian cancer.

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