by Dr. C.H. Weaver M.D. Updated 3/2022
Cervical cancer diagnosed as stage IV disease is commonly detected from an abnormal pelvic examination or symptoms produced by the patient’s cancer. Following a staging evaluation of cervical cancer, a stage IV cancer is said to exist if the cancer has extended beyond the cervix into adjacent organs, such as the rectum or bladder (stage IVA), or the cancer has spread to distant locations in the body which may include the bones, lungs or liver (stage IVB). Cervical cancer diagnosed in this stage is often difficult to treat, however a small minority of patients are cured of disease.
The following is an overview of the treatment of stage IV cervical cancer. The information is intended to help educate you about treatment options and to facilitate a shared decision-making process with your treating physician.
Patients diagnosed with stage IV cervical cancer can be broadly divided into two groups. Patients with disease that is locally confined, but involves adjacent organs in the pelvis, such as the rectum and bladder, have localized stage IVA cervical cancer. Other patients have disease that has spread to distant organs, most commonly the bones, lungs or liver, and have metastatic stage IVB cervical cancer. Management of patients with metastatic stage IVB disease is aimed at control of symptoms and pain. After undergoing treatment for cervical cancer, your doctor will continue to follow you to check to see that the cancer has not returned or is not progressing.
Treatment of Localized Stage IVA Cervical Cancer
Stage IVA cervical cancer is currently best managed by a combination of radiation therapy and chemotherapy. Radiation therapy is treatment with high energy x-rays that have the ability to kill cancer cells. Radiation therapy can be administered by a machine that aims x-rays at the body (external beam radiation) or by placing small capsules of radioactive material directly near the cervix (internal or implant radiation). Most patients will receive both kinds of radiation therapy during their course of treatment. External beam radiation therapy for cervical cancer is administered on an outpatient basis for approximately 4 to 6 weeks.1,2
During or immediately following the external beam portion of radiation therapy, patients may also undergo an implant radiation procedure. Placing the radiation within the cervix allows a high dose of radiation to be delivered to the cancer, while reducing the radiation to the surrounding normal tissues and organs. During a procedure in the operating room, a small device is placed into the cervix and vagina and later is “loaded” with radioactive material. The radioactive material is left in place while the patient stays in the hospital for 1-3 days. This process may be performed once or twice during the course of treatment.
The addition of chemotherapy (anti-cancer drugs) has improved long-term outcomes in patients with cervical cancer.. Chemotherapy has the ability to kill cancer cells and make radiation therapy more effective at killing cancer cells. The strategy of administering chemotherapy concurrently with radiation treatment is appealing because chemotherapy and radiation therapy may act together to increase the killing of cancer cells. Chemotherapy may also destroy cells independently of radiation therapy. Clinical studies performed in patients with locally advanced cervical cancer utilizing concurrent chemotherapy and radiation therapy have improved remission rates and prolonged survival.1
Radiation therapy plus concomitant chemotherapy appears superior to radiation therapy alone. The 5-year survival rate of patients with stage IB, IIA, or IIB cervical cancer was 77% for patients treated with concurrent radiation therapy and chemotherapy, compared to only 50% for patients treated with radiation therapy alone. Concurrent chemotherapy and radiation therapy were well tolerated except for minor gastrointestinal and hematologic side effects, which were reversible. Other clinical studies have confirmed that treatment of locally advanced cervical cancer with concurrent Platinol®-based chemotherapy and radiation therapy is superior to radiation therapy alone.1,2
Even with combination chemotherapy and radiation treatment, approximately 20-40% of patients with stage II cervical cancer experience recurrence of their cancer because cancer cells may have survived near the cancer despite the radiation therapy or small amounts of cancer may have spread outside the cervix and were not treated by the chemotherapy. These cancer cells cannot be detected and are referred to as micrometastases. The presence of these microscopic areas of cancer or surviving cancer cells can cause the relapses that follow treatment.
Treatment of Stage IVB and Recurrent Cervical Cancer
Cervical cancer that has spread to distant organs and bones is difficult to treat and the main goal of treatment is to reduce symptoms and prolong survival. Some patients are offered treatment with chemotherapy for the purpose of prolonging their duration of survival and alleviating symptoms from progressive cancer. Other patients are managed with efforts to reduce pain or bleeding, including local radiation therapy to affected parts of the body.
There is no good single chemotherapy approach that can improve the length of survival in patients with metastatic cervical cancer. Treatment with Platinol® can produce shrinkage in 15-25% of patients with metastatic cervical cancer. Many clinical trials have combined Platinol® with other chemotherapy drugs in hopes of improving cancer shrinkage and survival. Although these combination regimens can have more side effects, length of survival has not been improved over Platinol® alone. Unfortunately, these chemotherapies typically work for only a few months before the cervical cancer begins to grow again. Better treatment strategies are clearly needed.
Avastin (bevacizumab) is a targeted therapy that blocks a protein—VEGF—that plays a key role in the development of new blood vessels. This deprives the cancer of nutrients and oxygen and inhibits its growth. One pivotal clinical trial has demonstrated that the addition of Avastin to chemotherapy increases tumor shrinkage and improves survival among women with advanced cervical cancer.3
Since October 2021 patients with PD‑L1–positive disease or a combined positive score of ≥1 are eligible to receive Keytruda (pembrolizumab) plus platinum-based chemotherapy and Avastin based on results of the KEYNOTE-826 clinical trial.
Strategies to Improve Treatment
Currently, there are several areas of active exploration aimed at improving the treatment of advanced cervical cancer.
Precision Cancer Medicines: Precision cancer medicine and immunotherapy utilize molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Patients should ask their doctor about participating in clinical trials evaluating precision medicines and whether testing is appropriate.
Checkpoint Inhibitors + Avastin for Recurrent Ovarian Cancer
Anit-angiogenic - immunotherapy combination represents new treatment option for recurrent ovarian cancer.
Tisotumab vedotin is an investigational antibody-drug conjugate (ADC) composed of a human monoclonal antibody specific for tissue factor and a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody and releases it upon internalization, inducing target cell death. In cancer biology, tissue factor is a protein that can promote tumor growth, angiogenesis and metastases.8
The immune system is also part of the body’s innate disease-fighting capability to treat cancer. With cancer, part of the problem is an ineffective immune system. The immune system recognizes cancer cells as foreign and up to a point can get rid of them or keep them in check. Cancer cells are very good at finding ways to hide from, suppress, or wear out the immune system and avoid immune destruction. The immune system may not attack cancer cells because it fails to recognize them as foreign and harmful.
The use of PD-1 "checkpoint inhibitor" immunotherapy appears promising for the treatment of advanced cervical cancer. The U.S. Food and Drug Administration (FDA) approved Keytruda for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 in 2018. Keytruda was the first "checkpoint inhibitor" anti-PD-1 immunotherapy approved for patients with advanced cervical cancer. Reports also suggest the checkpoint inhibitor Opdivo (nivolumab) produces similar responses.6,7
The combination of two immunotherapy agents may be ever more effective. Researchers tested the combination of a PD-1 inhibitor with a CTLA-4 inhibitor (another type of immunotherapy) in women with recurrent/metastatic cervical cancer and report an overall response rate of 26% including 8% of patients who experienced a complete response and a 33% response rate in patients whose tumors were PD-L1 positive. The trial was conducted 155 women between the ages of 24 and 76 in the trial. All had previously been treated with at least one prior line of platinum-based chemotherapy.11
Tumor-infiltrating lymphocytes (TILS) show promising overall response rates for the treatment of advanced cervical cancer. Initial data show that investigational therapy with LN-145 had a 44% overall response rate among patients with advanced cervical cancer. TILS are a type of adoptive cellular therapy (ACT) in which T cells are isolated based on their tumor-specific antigen recognition and then expanded outside the body and infused back into the patient.9.10
Adoptive T-cell therapy (ACT) uses a patient’s own type of immune cell (T-cell) that is engineered through laboratory processes to identify and attack cancer cells when infused back into the patient’s body. An initial trial using T-cells from patients selected based upon their ability to fight certain strains of HPV associated with cervical cancer produced a complete response in some patients. Clinical trials are ongoing.4,5
The phase II SKYSCRAPER-04 trial is evaluating the safety and efficacy of combining tiragolumab, a TIGIT inhibitor, and Tecentriq (atezolizumab) as a second-line therapy in patients with metastatic and/or recurrent PD-L1–positive cervical cancer.
Tiragolumab is another precision cancer immunotherapy human monoclonal antibody that targets TIGIT, an inhibitory immune checkpoint that like PD-L1 is expressed on tumor-infiltrating immune cells like T cells and NK cells. TIGIT expression appears to correlate with PD-1 expression on T cells in lung cancer and in pre-clinical models when combined with the PD-L1 antibody Tecentriq resulted in more tumor control and better survival than with either antibody alone.
Phase I Trials: New chemotherapy or immunotherapy drugs continue to be developed and evaluated in patients with recurrent cancers in phase I clinical trials. The purpose of phase I trials is to evaluate new anti-cancer medications in order to determine the safety and tolerability of a drug and the best way of administering the drug to patients.
- Duenas-Gonzalez A, Zarba JJ, Alcedo JC, et al. A phase III study comparing concurrent gemcitabine (Gem) plus cisplatin (Cis) and radiation followed by adjuvant Gem plus Cis versus concurrent Cis and radiation in patients with stage IIB to IVA carcinoma of the cervix. Presented at the 2009 annual meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL. Abstract CRA5507.
- Tewari KS, Sill M, Long III HJ. Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: a Phase III randomized trial of the Gynecologic Oncology Group. Presented at the 49thAnnual Meeting of the American Society of Clinical Oncology. May 31-June 4, 2013; Chicago, IL. Abstract 3.
- Takeuchi S, Shoji T, Kagabu M, et al. Phase 2 studies of multiple peptides cocktail vaccine for treatment-resistant cervical and ovarian cancer. Journal of Clinical Oncology. 2015; 33 (suppl; abstract 5567).
- Stevanovic S, Draper L, Langhan M, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. Journal of Clinical Oncology, 2015; 10:33(4): 1543-1550. Doi: 10.1200/JCO.2014.58.9093.
- FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for Previously Treated Patients with Recurrent or Metastatic Cervical Cancer Whose Tumors Express PD-L1 (CPS Greater Than or Equal to 1)
- J Clin Oncol. 2019;37:2825-2834
- Seattle Genetics Announces Positive Topline Results from Phase 2 Clinical Trial of Tisotumab Vedotin in Recurrent or Metastatic Cervical Cancer
- Sarnaik A, et al. Abstract 2518. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
- Jazaeri AA, et al. Abstract 2538. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.