Recurrent

Cervical Cancer

When cervical cancer has been detected or has returned following initial treatment with surgery, radiation therapy and/or chemotherapy, it is said to be recurrent or relapsed. The course of treatment for relapsed cervical cancer depends on what treatment a patient has previously received and where the recurrence is located. Some patients who have recurrence of cervical cancer within the pelvis can be treated with additional surgery or with radiation therapy, if no radiation therapy was given previously. Recurrence of cervical cancer outside the pelvis is difficult to treat.

The following is an overview of the treatment of recurrent 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.

Treatment depends on many factors, including what treatment the patient had before, the location of the recurrence and the overall condition of the patient. If the patient had surgery to remove the cervix and the cancer comes back only in a small area near the operation, radiation therapy may be administered. If the patient already received radiation therapy to the pelvis, radiation therapy cannot be administered again to the same part of the body. Some patients with recurrent cervical cancer in the pelvis can undergo an extensive surgical procedure that removes the cancer and many pelvic organs. Other patients have recurrent cervical cancer outside the pelvis and may receive chemotherapy or radiation therapy to alleviate symptoms.

Recurrent Cervical Cancer After Surgery

A radical hysterectomy is a very effective therapy if the cancer has not spread beyond the cervix. At times, a small area of cancer has spread beyond the cervix and cancer cells may be present at the edge of the surgical specimen. Usually, this can be determined only after the surgery when the specimen is examined under the microscope. Other times, the region of the operation may be contaminated with microscopic cancer cells. The presence of microscopic areas of cancer cells can cause the cancer to return some time after the surgery. This situation occurs more frequently in patients with large stage IB or stage II cervical cancer.

Patients with a small amount of cancer recurrence in the area of previous surgery can be treated in an attempt to rid the cancer again. If the patient has not received radiation therapy to the pelvis, external beam radiation therapy to the area of the recurrence can kill cancer cells after the surgery. Patients who have received prior radiation therapy may be able to undergo a pelvic exenteration, which is an extensive surgical procedure that removes the cancer and many pelvic organs. A pelvic exenteration is only performed if cancer cannot be detected elsewhere in the body and all of the cancer can be removed by the surgery. Approximately one-third of patients with recurrent cancer will survive free of cancer after treatment with radiation therapy or pelvic exenteration.

Other patients already have small amounts of cancer that have spread outside the pelvis and were not removed by surgery. These cancer cells cannot be detected with any of the currently available tests. Undetectable areas of cancer outside the pelvis are referred to as micrometastases. The presence of microscopic areas of cancer cells can cause the cancer to return outside the pelvis some time after the surgery. Please see the section below for more information.

Recurrent Cervical Cancer After Radiation Therapy

Depending on the features of the cervical cancer, some patients will experience a recurrence of the cervical cancer after radiation therapy. In these patients, cancer cells may have survived despite the radiation therapy. Other patients already have small amounts of cancer that have spread outside the pelvis and were not treated by the radiation. These cancer cells cannot be detected with any of the currently available tests. Undetectable areas of cancer outside the pelvis are referred to as micrometastases. The presence of these microscopic areas of cancer or surviving cancer cells can cause the relapses that follow treatment with radiation therapy.

Once a patient has received radiation therapy to the pelvis, more radiation therapy cannot safely be administered to the same area. Patients who have received prior radiation therapy may be able to undergo a pelvic exenteration, which is an extensive surgical procedure that removes the cancer and many pelvic organs. A pelvic exenteration is only performed if cancer cannot be detected elsewhere in the body and all of the cancer can be removed by the surgery. Approximately one-third of patients with recurrent cancer will survive free of cancer after treatment with radiation therapy or pelvic exenteration.

Recurrent Cervical Cancer Outside the Pelvis

Cervical cancer that has spread to distant organs and bones is difficult to treat. Historically, patients with metastatic cervical cancer have been considered incurable. 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. Most patients ultimately succumb to cancer and better treatment strategies are clearly needed.1

Strategies to Improve Treatment

The progress that has been made in the treatment of cervical cancer has resulted from improved development of treatments in patients with more advanced stages of cancer and participation in clinical trials. Future progress in the treatment of cervical cancer will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of stage II cervical cancer.

Precision Cancer Medicines:  The purpose of precision cancer medicine is not to categorize or classify cancers solely by site of origin, but to define the genomic alterations in the cancers DNA that are driving that specific cancer.  Precision cancer medicine utilizes 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. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Precision medicines are being developed for the treatment of cervical cancer and patients should ask their doctor about participating in clinical trials evaluating precision medicines and whether testing is appropriate.

Immunotherapy:  The immune system is an elaborate network of cells and organs that protect the body from infection.  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 goal of immunotherapy is to help the immune system recognize and eliminate cancer cells by either activating the immune system directly, or by inhibiting mechanisms of suppression of the cancer.

General types of immunotherapy include interferon, interleukin, and colony stimulating factors (cytokines), which generally activate the immune system to attack the cancer. These general immunotherapies however are not specific and their activation of the immune system can cause severe side effects by attacking normal cells along with cancer cells.  Immunotherapy treatment of cancer has progressed considerably over the past 30 years and has evolved from a general to more precisely targeted immunotherapy treatment. Examples of precision immunotherapy include checkpoint inhibitors, CAR T cells, and vaccines.

In an attempt to improve the chance of cure, immunotherapies are being tested alone or in combination with chemotherapy in clinical trials.

Adoptive T-cell therapy (ACT) appears to provide anti-cancer responses among some patients with advanced cervical cancer for whom standard therapy has stopped working. The treatment includes the collection of a patient’s own type of immune cell (T-cell), that are 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.2,3

Vaccines designed to stimulate the immune system against several different biologic pathways associated with incurable cervical can produce anti-cancer responses.  Researchers from Japan have conducted some studies to evaluate the effectiveness of using a “cocktail” vaccine, in which the patient’s immune system was stimulated to identify several different markers commonly found on cancer cells. In clinical trials evaluating 21 patients with cervical cancer some patients achieved a response to the vaccine and patients who demonstrated high levels of skin sensitivity to a pre test with the vaccine did significantly better.  Clinical trials are ongoing to evaluate this approach.

New Chemotherapy Regimens: Several newer chemotherapeutic drugs have demonstrated ability to kill cervical cancer cells in patients with advanced cancer. One area of active investigation is the development and exploration of single or multi-agent chemotherapy regimens as a treatment approach for patients with widespread cervical cancer. In particular, drugs such as paclitaxel, ifosfamide, Taxotere®, Navelbine®, Camptosar®, and Avastin appear to have promising activity against cervical cancer cells and are being tested alone or in combination with radiation and other anticancer agents in clinical trials.

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.

Newer Radiation Techniques: External beam radiation therapy can be delivered more precisely to the cervix by using a special CT scan and targeting computer. This capability is known as three-dimensional conformal radiation therapy, or 3D-CRT. The use of 3D-CRT appears to reduce the chance of injury to nearby body structures, such as the bladder or rectum.

Next: Surgery for Cervical Cancer

References

1 https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site

2 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).

3 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.