by Dr. C.H. Weaver M.D. Medical Editor, updated 8/2022
Patients who have been diagnosed with ovarian cancer may have persistent, refractory or recurrent cancer following initial treatment. They can benefit from additional systemic treatment with chemotherapy and/or poly ADP-ribose polymerase (PARP) inhibitors or other precision cancer medicines.
- Persistent cancer refers to residual cancer growths or cells that persist during and following initial treatment.
- Patients who have achieved complete remission following initial therapy and who subsequently experience a return of cancer cells after treatment are said to have relapsed or recurrent cancer.
- Patients with ovarian cancer who experience progression or continued growth of the cancer during treatment are said to have refractory cancer.
Many patients with persistent, recurrent or refractory ovarian cancer can benefit from additional treatment with surgery and/or second-line systemic therapy, which is often referred to as salvage therapy. A patient’s treatment options will differ depending on whether the cancer is persistent, recurrent or refractory.
How is Recurrent Ovarian Cancer Detected?
Recurrent or persistent ovarian cancer may be detected by several methods. Some patients will experience abdominal swelling, pain or symptoms related to the spread of cancer cells (metastases) to the bone, liver, or brain. Other patients may simply have an increase or persistent elevation in the CA-125 level, a blood test commonly used to monitor ovarian cancer activity. When an increase in the CA-125 occurs, most patients will undergo ultrasound or CT scanning of the abdomen and pelvis or other diagnostic procedures in order to determine the location of recurrent cancer.
What is the Role of Surgery in Recurrent Ovarian Cancer?
Typically, women who have ovarian cancer are initially treated with surgery, followed by systemic chemotherapy. If the cancer recurs (returns) after treatment, additional systemic therapy is recommended to increase survival time and relieve the symptoms of the cancer. Additional surgery to remove recurrent cancer combined with systemic therapy appears to further improve survival when compared to treatment with systemic therapy alone in certain patients.
Secondary Cytoreduction in Recurrent Ovarian Cancer
Management of recurrent ovarian cancer has often included secondary cytoreduction whereby patients who are usually platinum sensitive with few metastatic lesions are taken back to the operating room to remove any visible cancer.5,6
The results of two clinical trials directly evaluating secondary cytoreduction have been published in 2020 and unfortunately had conflicting results. The GOG-213 trial found no improvement in overall survival when platinum sensitive patients were treated with secondary cytoreduction versus or no additional surgery.
Final results from the second trial DESKTOP III were reported at the American Society of Clinical Oncology 2020 Virtual Meeting.7 This trial was the culmination of two other trials that first defined the optimal patients to receive secondary cytoreduction and used a previously developed AGO (Arbeitsgemeinschaft Gynaekologische Onkologie) predictive score to better identify patients.8,9 The AGO score helps predict those who benefit most from secondary cytoreductive surgery.
In DESKTOP III 407 patients with epithelial ovarian cancer who had their first relapse after a platinum-free interval of at least 6 months, and a positive AGO score were randomly assigned to treatment with either chemotherapy alone or secondary cytoreductive surgery followed by chemotherapy. The study found that in addition to delaying cancer recurrence the average overall survival duration was improved to 53.7 months with secondary cytoreduction compared to 46 months for those treated with chemotherapy without surgery.
DESKTOP III appears to suggest that aggressive surgery in certain patients can improve overall survival compared to treatment with chemotherapy alone. Patients that benefit the most are those in good condition pre-surgery who had complete resection of cancer during 1st line therapy and little ascites. Patients considering secondary cytoreduction should carefully consider whether they are a good candidate for additional surgery in discussion with their treating physician.
Systemic Therapy for Recurrent Ovarian Cancer
Because patients with recurrent ovarian cancer have cancer cells that have spread throughout the body and cannot be completely removed by surgery an effective treatment is needed to find and destroy these cells in order to prolong survival. Systemic therapy is treatment directed at destroying cancer cells throughout the body, and may include chemotherapy, precision cancer medicines, immunotherapy or a combination of these therapies. The effectiveness of additional systemic treatment depends on the kind of chemotherapy previously administered, the duration since last treatment and the extent of recurrent cancer.
Persistent Ovarian Cancer
Patients with persistent ovarian cancer have cancer cells that are detected after initial surgery and first-line systemic therapy. Persistent ovarian cancer is detected either by an elevated CA-125 blood level, abnormal x-rays and CT scans, or with a biopsy performed during second-look laparotomy.
Individuals with persistent ovarian cancer have a number of treatment options. Additional debulking surgery to remove as much persistent cancer as possible should be considered before resuming additional systemic treatment. Even with additional surgery additional systemic treatment is still necessary since undetectable microscopic deposits of cancer still exist and cause recurrences even after successful debulking surgery. Patients should consider participation in a clinical trial evaluating new systemic treatment approaches.
- Continued Standard Chemotherapy: The standard course of initial chemotherapy is approximately 6 cycles, or about 4 months of treatment. If, after 6 cycles, there is a small amount of persistent cancer, some doctors feel further chemotherapy treatment for 10 or 12 cycles may continue to cause shrinkage of the cancer. Some patients may achieve a complete remission with continued standard chemotherapy.
- Second-Line Therapy: Not all patients are able to undergo secondary debulking surgery or are expected to improve with continued treatment with their first-line treatment. Salvage or second-line systemic therapy with other anti-cancer drugs that destroy cancer cells by a different mechanism may provide additional benefit over the continuation of first-line Second line systemic therapy may consist of precision cancer medicines, immunotherapy, and/or chemotherapy medications not previously used or participation in a clinical trial evaluating altogether new medications and combinations.
Recurrent Ovarian Cancer
Patients with recurrent ovarian cancer have experienced a period of “remission” following initial surgery and first-line systemic therapy, but have subsequently developed a cancer recurrence. Both the effectiveness and type of available therapy depends on the first-line systemic therapy received, the length of time since finishing treatment and the extent of recurrent cancer.
Checkpoint Inhibitors + Avastin for Recurrent Ovarian Cancer
Anit-angiogenic - immunotherapy combination represents new treatment option for recurrent ovarian cancer.
In general, additional systemic therapy treatment is used to improve a patient’s quality of life by reducing symptoms of recurrent cancer and prolong survival.
The length of time between the completion of first-line chemotherapy and the development of recurrent cancer affects treatment options. Patients who develop recurrent cancer more than 6 months after first-line chemotherapy can experience another remission following treatment with the identical first-line chemotherapy that was previously used. Patients who develop recurrent cancer within 6 months from first-line chemotherapy are less likely to improve with the same anti-cancer drugs and should consider treatment with a different chemotherapy regimen. All patients with recurrent cancer should also consider participating in clinical trials.
Recurrence after 6 Months from Therapy
Patients who develop recurrent ovarian cancer more than 6 months after first-line platinum based chemotherapy are referred to as “platinum sensitive” and have a good chance of improving with continued use of chemotherapy or maintenance therapy. Additional "secondary" debulking surgery to remove as much cancer as possible may also be considered before resuming chemotherapy treatment. Over half of patients who develop a recurrence longer than 12 months from initial treatment are likely to improve with further chemotherapy, compared with less than half of patients who develop a recurrence between 6 and 12 months from initial treatment.
In addition to retreatment with a platinum based treatment regimen, other treatment options are available and include:
- Carboplatin plus liposomal doxorubicin and Avastin (bevacizumab) is an NCCN preferred regimen) that has been shown to improve survival compared to carboplatin, Gemzar (gemcitabine) + Avastin.4
- Camptosar (irinotecan) plus cisplatin (useful in certain circumstances, for clear cell carcinoma)
- Fulvestrant (useful in certain circumstances, for low-grade serous carcinoma).2
Recurrence within 6 Months from Therapy
Patients who develop recurrent cancer within 6 months from first-line systemic therapy are referred to as “platinum resistant” and less likely to improve with additional treatment that utilizes the same first-line chemotherapy drugs. Patients can derive significant benefit from additional treatment with additional systemic therapy or from participation in a clinical trial designed to evaluate promising new treatment strategies.
- Oral cyclophosphamide plus Avastin (preferred regimen)
- Sorafenib plus topotecan.
- Fulvestrant (useful in certain circumstances, for low-grade serous carcinoma).
Avastin Plus Chemotherapy in Platinum-Resistant Recurrent Ovarian Cancer
Avastin is a targeted therapy that blocks a protein known as VEGF. VEGF plays a key role in the development of new blood vessels. By blocking VEGF, Avastin deprives the cancer of nutrients and oxygen and inhibits its growth. The addition of Avastin® to standard chemotherapy significantly improves progression-free survival and objective response rate among women with platinum-resistant recurrent ovarian cancer.1
The PARP inhibitor Zejula (niraparib) has been approved for use as maintenance therapy in patients with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy. Zejula unlike other PARP inhibitors is active both in patients with and those without BRCA mutations.
In patients with ovarian, fallopian tube, or primary peritoneal cancer who had received at least two prior treatments of platinum-based chemotherapy and were in a complete or partial response to the most recent chemotherapy treatment Zejula significantly delayed cancer progression in both patients with and without a germline BRCA mutation.3
The NCCN has defined other acceptable maintenance regimens.
- Lynparza (olaparib) after complete or partial clinical remission following primary therapy – with or without Avastin for BRCA1/2 mutations
- Avastin can be used as maintenance therapy option for stable disease following treatment with Avastin.2
Strategies to Improve Treatment
Development of Precision Cancer Medicines: Research is ongoing to develop new medications that specifically target cancer cells in clinical trials. These trials typically require a sample of the cancer to be available in order to evaluate for biomarkers. Patients should learn about options to participate in these trials prior to surgery in order to ensure that cancer tissue is obtained correctly. Learn more about development of precision cancer medicines for treatment of ovarian cancer.
- Pujade-Lauraine E, Hilpert F, Weber B, et al: Bevacizumab Combined With Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: The AURELIA Open-Label Randomized Phase III Trial. Journal of Clinical Oncology. Published early online March 17, 2014. doi: 10.1200/JCO.2013.51.4489.
- NCCN Updates Clinical Practice Guideline for Ovarian Cancer
- Mansoor R. Mirza, M.D et. al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer N Engl J Med 2016; 375:2154-2164.
- Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial
- Margul D, Coleman RL, Herzog TJ; The Current Status of Secondary Cytoreduction in Ovarian Cancer: A Systematic Review; Clinical Advances in Hematology & Oncology June 2020 - Volume 18, Issue 6
- Coleman RL, Spirtos NM, Enserro D, Herzog TJ, Sabbatini P, Armstrong DK, Kim JW, Park SY, Kim BG, Nam JH, Fujiwara K, Walker JL, Casey AC, Alvarez Secord A, Rubin S, Chan JK, DiSilvestro P, Davidson SA, Cohn DE, Tewari KS, Basen-Engquist K, Huang HQ, Brady MF, Mannel RS. N Engl J Med. 2019 Nov 14;381(20):1929-1939. doi: 10.1056/NEJMoa1902626.
- Bois AD, Vergote I, Ferron G, et al. Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: AGO DESKTOP III/ENGOT ov20. Journal of Clinical Oncology. 2020 ASCO Abstracts.
- Harter P, du Bois A, Hahmann M, et al. Surgery in recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR trial. Ann Surg Oncol. 2006;13(12):1702-1710.
- Harter P, Sehouli J, Reuss A, et al. Prospective validation study of a predictive score for operability of recurrent ovarian cancer: the Multicenter Intergroup Study DESKTOP II. A project of the AGO Kommission OVAR, AGO Study Group, NOGGO, AGO-Austria, and MITO. Int J Gynecol Cancer. 2011;21(2):289-295.