Top Ten Tips Palliative Care Clinicians Should Know About Caring for Patients with Cervical Cancer

Abstract

Cervical cancer is the most common gynecologic cancer worldwide. Almost all are related to human papillomavirus exposure. Cervical cancer treatment is associated with significant morbidity that is likely to require support from palliative care teams. In these pearls on cervical cancer, we hope to inform providers about the common treatments and issues for cervical cancer patients. Treatment modalities include surgery for early-stage disease, radiation therapy for locally advanced disease, and pelvic exenteration, chemotherapy, or immunotherapy for recurrent disease. Cervical cancer causes pain and bleeding. Radiation can affect ovarian, urinary, and bowel function. Chemotherapy and immunotherapy are associated with fatigue and nausea. Fistulas between the vagina and bowel or bladder can occur due to cancer or to cancer treatments. Physical and emotional supportive care is important for women with cervical cancer.

Introduction

In 2019, >13,000 women were diagnosed with cervical cancer in the United States.¹ Screening with cytology and human papillomavirus (HPV) has decreased mortality in high-resource countries by allowing treatment of preinvasive disease. In the future, increased uptake of the HPV vaccine may lead to a decline in cervical cancer cases across the globe.²

Despite being a preventable disease, worldwide, cervical cancer is the most lethal cancer for women. Many patients present with advanced disease that is heavily symptomatic, particularly with pain and vaginal bleeding. Treatments such as radical hysterectomy and/or chemoradiation are associated with an 80% and 60% cure rates in stage I–II and stage III disease, respectively.³ Unfortunately, these treatments are associated with morbidity, including lymphedema, vesicovaginal fistula, and menopausal symptoms.

Palliative care (PC) clinicians can provide needed support for cervical cancer patients. An understanding of the unique aspects of the diagnosis, treatment, and surveillance of cervical cancer can inform counseling between patients and PC practitioners. In this review, we highlight key concepts of the diagnosis and treatment of cervical cancer that are relevant to the supportive care of women with cervical cancer.

Tip 1: Most Cervical Cancers Are Treated the Same, Regardless of Histology Subtype

About 80% of cervical cancers are squamous cell carcinoma, whereas the remaining 20% adenocarcinoma or adenosquamous carcinoma. These are associated with HPV infection and have precursor lesions (squamous intraepithelial lesions and adenocarcinoma in situ) that can be detected with pap smear cytology screening protocols. More recently, screening guidelines have focused on HPV tests, since a negative HPV screen makes dysplasia and cancer unlikely.⁴ Early cancers can be treated surgically, but any locally advanced or distant disease is treated with radiation, chemotherapy, or both.

Other rare histologies (<1%) include adenoma malignum (gastric type adenocarcinoma, or minimal deviation adenocarcinoma) and neuroendocrine carcinoma of the cervix. These are not associated with HPV exposure or precursor lesions on pap smears. Gastric type adenocarcinoma is a low-grade subset of adenocarcinoma. It can easily be missed on biopsies due to the bland nature of the pathology. It does have a poor prognosis, however, and is treated aggressively even at an early stage. Neuroendocrine carcinoma is also aggressive and has a high likelihood of nodal and distant involvement, even with a small primary tumor. Multimodal therapy includes surgery, radiation, and chemotherapy.⁵

Tip 2: The Primary Treatments for Cervical Cancer Include Surgery and/or Chemoradiation

Surgery is the treatment of choice only for early cervical cancers. These include cancers <4 cm with no parametrial involvement and no or minimal upper vaginal involvement. Microscopic cancers can be treated with a cold knife cone, removing only a portion of the cervix, as long as there are negative margins. Macroscopic disease is treated with a radical hysterectomy, which involves removal of the uterus and cervix with wide parametrial and vaginal margins. The fertility-sparing option of radical trachelectomy (see Tip 3) can be considered for women with tumors <2 cm in size. Patients with high risk features on postoperative pathology then undergo external beam pelvic radiation. Patients who have both surgery and external beam radiation have the highest rate of complications, in particular urological complications.⁶

A combination of radiation and chemotherapy (chemoradiation) is used for cervical cancers >4 cm, cancers with high-risk features, and women with positive lymph nodes. Cisplatin is given concurrently with external beam pelvic radiation (teletherapy) followed by local radiation (brachytherapy), delivered with tandem and ovoids or interstitial needles placed into the cervical tumor. The weekly chemotherapy is low dose and generally well tolerated; it is used as a radiosensitizer and significantly improves survival.⁷

Women with distant metastases at diagnosis are incurable. They are treated with palliative chemotherapy, most frequently carboplatin, paclitaxel, ±bevacizumab. Often, they also receive palliative pelvic radiation to control pain and bleeding.

Tip 3: Cervical Cancer Is a Disease of Young Women Requiring Complex Conversations About Fertility Concerns and Premature Menopause

Up to 40% of cervical cancer patients are under the age of 45.⁸ Many have not completed their family, and some may be candidates for fertility-sparing surgery. Microinvasive squamous cancers can be treated with a cold-knife cone. Patients with localized macroscopic tumors 2 cm or smaller may be candidates for radical trachelectomy, which involves removing the cervix and parametria and suturing the lower uterine segment to the upper vagina. Pregnancy after radical trachelectomy is high risk for preterm delivery and miscarriage, with second trimester losses as high as 12%.⁹ However, up to a 64% live birth rate has been reported.^9,10

Premature menopause is another concern for many younger women undergoing treatment. Because the risk of metastasis to the ovaries is <2%,⁸ ovaries can be left in place during radical hysterectomy. Before radiation, premenopausal women can be offered the option of surgically transposing the ovaries out of the field of radiation (oophoropexy). Unfortunately, ovarian failure still occurs in about 50% of women who undergo ovarian transposition.⁹ Hormone replacement therapy (HRT) does not appear to impact recurrence or overall survival⁸ and should be considered for all cervical cancer patients with premature menopause. HRT should include a progestin for endometrial protection, even after radiation.⁸

Finally, many young women will have unique psychological needs in coping with a cancer diagnosis. Adequate family-oriented psychosocial support must be provided for these patients.

Tip 4: Pelvic Radiation Has both Short-Term and Long-Term Side Effects, Which Can Be Severe

Pelvic radiation is recommended for 58% of patients with cervical cancer.¹¹ In the primary setting, chemoradiation for locally advanced cancer has high cure rates, with five-year survival ranging from 40% to 75%.¹² Despite successful outcomes, the treatment has short-term side effects that include fatigue, anorexia, nausea, vomiting, diarrhea, cystitis, and tinnitus. Although most of the acute side effects resolve, persistent and delayed changes are particularly notable in bowel and bladder function.

Long-term genitourinary (GU) and gastrointestinal (GI) side effects are those that occur after three months, and although most common in the first three years, they can present many years after cancer treatment. Smoking, prior surgery, vascular disorders, and inflammatory bowel disease increase the risk of serious side effects from pelvic radiation. Late GU and GI problems are the results of obliterative endarteritis that causes radiation fibrosis and necrosis. This can lead to diminished bladder capacity, hemorrhagic cystitis, chronic diarrhea, malabsorption, enteritis, colitis, bowel obstruction, and GU or GI fistulas. The rate of severe GU and GI toxicity in one of the seminal studies establishing the use of primary chemoradiation for cervical cancer is 3% and 20%, respectively.^13,14

In addition, vaginal dryness and vaginal agglutination can diminish sexual health and make it difficult to obtain a pap smear after radiation. The use of vaginal dilators is recommended to reduce the risk of vaginal stenosis and improve sexual function.

Tip 5: There Is No Routine Imaging to Monitor for Cervical Cancer Recurrence, but Surveillance with Physical Examination Is Performed

The Society of Gynecologic Oncology recommends that patients with cervical cancer undergo surveillance for disease recurrence every three to six months for the first two years and then every 6–12 months until five years have elapsed.¹⁵ Pelvic examination is a well-accepted approach for surveillance and has the highest detection rate when compared with pap smear and imaging studies. Evidence is lacking for surveillance with cytology with low detection rates and false positives related to atypical cells from prior radiation, but it may help to detect other lower genital tract disease. HPV is never cleared from the body and may reactivate after several years of negative HPV tests without a new exposure. Detection of HPV reactivation is a risk factor for recurrence.

Imaging for surveillance is not recommended but is used to investigate new symptoms. The most common sites of recurrence are the vagina, pelvic sidewall, and distant metastatic sites. Symptoms that raise concern are vaginal bleeding and pelvic pain as well as changes in urinary and/or bowel patterns. Imaging with computed tomography (CT), positron emission tomography (PET) or PET/CT combined is the mainstay of evaluation. PET/CT is a sensitive and specific method of detecting metastases in cervical cancer, and many perform a PET/CT scan during initial assessment. Although not routinely recommended for surveillance, most utilize this modality for follow-up of high-risk patients because of its ability to detect asymptomatic central pelvic recurrence that can be cured.¹⁶

Tip 6: Cervical Cancer Itself or Prior Treatment with Radiation and/or Bevacizumab May Cause GI or GU Fistulas

The development of a fistulous connection involving the bowel or bladder is a rare but serious event.¹⁷ These fistulas can happen as a result of prior radiation and/or be caused by cancer growth that destroys the natural barrier between organs. Fistulas are most often seen in cases that require high-dose radiation to control gross tumor in the vagina or in cases with cancer invading the bladder or rectum. In some cases, a GI or GU fistula is the presenting symptom for an advanced cervical cancer. The communication usually occurs between the vagina and the bladder (vesicovaginal) or rectum (rectovaginal), but it can involve the small bowel. GU or GI fistulas to the skin or vagina are managed by nonemergent palliative diverting procedures so that the urine or stool is contained.

An additional reason that a fistula may develop is treatment with bevacizumab. Bevacizumab is an antiangiogenic agent that is given concurrently with platinum-based chemotherapy for the treatment of recurrent or metastatic cervical cancer.³ In women with advanced cervical cancer and prior pelvic radiation, a 15% fistula rate was noted with the use of bevacizumab compared with 1% in women who did not receive bevacizumab.¹⁸ Fistulas are not an emergency; however, bevacizumab is also associated with bowel perforation, which is a surgical emergency. Surgery for GU/GI fistula or bowel perforation is complex and often necessitates the expertise of a gynecologic oncologist in addition to general surgeons and/or urologists.

Tip 7: Lymphedema Can Be Caused by Cervical Cancer Treatments or Pelvic Recurrence and May Be Treated with Physical/Occupational Therapy and Fitted Garments

Lymphedema can occur as a swelling of the legs, pubic area, and lower abdomen that results from disrupted lymph vascular transport from surgical and radiation treatment. The differential diagnosis for lower extremity edema (LEE) includes venous thromboembolism and pelvic compression from recurrent tumor; therefore, these diagnoses should be ruled out by imaging before proceeding with therapy for lymphedema. Although prospective studies of LEE have employed measurement standards that require substantial training, there is no established criteria for diagnosing LEE.^19,20 Because bilateral involvement is common, comparing measurements between legs may not be helpful for making the diagnosis. However, patient-reported questionnaires have been shown to correlate with measurements²¹ and could be used as a surrogate.

Lymphedema resulting from cervical cancer therapy usually develops within one year of treatment and may cause chronic heaviness, pain, limited mobility, or depression and anxiety from altered body image.²⁰ The largest prospective study of lymphedema in gynecologic cancer found the postoperative prevalence in cervical cancer patients to be 22.5% mild, 10.5% moderate, and 1.5% severe.¹⁹ Postoperative radiation may be associated with a higher risk for lymphedema due to fibrosis that prevents lymphatic reconstruction.²² There is also increased risk in women with more than eight lymph nodes removed, which is why sentinel lymph nodes are removed whenever feasible to avoid a full lymphadenectomy.

Lymphedema resulting from cancer treatment is chronic, but early treatment may improve outcomes.²³ Complex physical/occupational therapy consisting of skin care, manual massage, exercise to increase muscle mass and stimulate lymphatic flow, and compression garments have demonstrated the most improvement in limb volumes.²⁴ Although diuretics may provide temporary initial relief from lymphedema, the resulting increased tissue protein concentration may ultimately lead to worse lymphedema and, therefore, should be avoided. Surgical lymphovascular reconstruction may be employed in highly selected cases.²⁴

Tip 8: Recurrent Cancer Is Treated with Chemotherapy or Radiation and Is Incurable, but, If Localized, Cancer Can Be Cured with Extensive Surgery

The vast majority of women who develop recurrent cervical cancer will not be cured and will ultimately die of the disease. However, recurrence in the central pelvis or within an isolated para-aortic node can potentially be cured with either chemoradiation or extensive surgery. For women with vaginal recurrence after hysterectomy without pelvic side wall extension, pelvic radiation yields a favorable five-year survival approaching 50%–70%.^25–27

Women whose cancers were treated with primary chemoradiation who subsequently develop recurrence confined to the cervix may be candidates for surgery, provided there is no evidence of distant disease. Most isolated central recurrences after primary chemoradiation treatment will require pelvic exenteration with urinary and/or fecal diversion to achieve complete resection. Pelvic exenteration involves removal of the uterus, cervix, and vagina en bloc with the bladder and/or rectum, with formation of urostomy and/or colostomy, depending on the location of the recurrence. Vaginal reconstruction may be performed using rectus abdominis or gracilis myocutaneous flaps and may allow for sexual activity.^28–30 Five-year survival after pelvic exenteration is ∼50%, and improved five-year survival is associated with initially long disease-free interval, small tumor size, and negative margins.^27,30,31

Para-aortic lymph node recurrence is usually associated with systemic recurrence; however, women with isolated para-aortic node recurrence may achieve long-term survival after concurrent chemoradiation, especially if associated with squamous histology and longer disease-free interval.³²

Tip 9: Palliative Chemotherapy and/or Immunotherapy Are Recommended for Regional and Distant Recurrence, but Life Expectancy Is Short

Patients with recurrent metastatic cervical cancer are considered incurable, with a life expectancy of ∼12 months. The combination of cisplatin or carboplatin with paclitaxel and bevacizumab is the preferred chemotherapy for recurrence with distant metastases.³ A pivotal Gynecologic Oncology Group trial demonstrated that the addition of bevacizumab to cisplatin and paclitaxel improved overall survival by 3.7 months.³³ Although the addition of bevacizumab is associated with more toxicity, it has not been associated with decreased patient reported quality of life. However, not all patients are able to tolerate this multidrug regimen due to poor performance status and many providers substitute carboplatin for cisplatin to reduce toxicity. Other options include combinations of these drugs with topotecan or use of single agent cisplatin, carboplatin, or paclitaxel.

A newer approach to care with immunotherapy has emerged with favorable results and a low toxicity profile. Patients whose tumors are programmed death ligand 1 (PD-L1) positive, have high microsatellite instability, or a high tumor mutational burden are eligible to receive pembrolizumab. Another marker, PD-1, is a T cell receptor that under normal conditions functions in an immunoregulatory manner and plays a role in cancer by contributing to the ability of a tumor to avoid immunosurveillance. Pembrolizumab is a monoclonal antibody that prevents interaction between PD-1 and its ligands, and has demonstrated response rates in the 20%–30% range, with some impressive long-term responses.³⁴

Tip 10: Recurrent Cervical Cancer Is Often Associated with Severe Prolonged Pelvic Pain and Vaginal Bleeding, Before Affecting Vital Organs

Recurrent cervical cancer is infrequently diagnosed at routine surveillance. More commonly, patients present with symptoms such as vaginal bleeding, low back pain radiating to the leg, and unexplained weight loss.³⁵ Recurrence in the pelvic and para-aortic lymph nodes can be associated with pain from nerve root involvement. Bulky pelvic disease and lymphadenopathy can involve the ureter and cause hydronephrosis. It is important to have a high level of suspicion for recurrence for patients presenting with pain and a history of cervical cancer.

After life-prolonging treatment has been attempted, patients will need support at end-of-life. Anecdotally, compared with other gynecologic cancers, recurrent cervical cancer is associated with more severe pain, requiring escalation of pain medication. The classic approach of treating pain with medication is useful for these patients, but many will also benefit from regional approaches to pelvic pain with nerve blocks. Although many patients have metastatic disease along with progression in the central pelvis, vital organs are rarely impacted and it is their severe pelvic pain and vaginal bleeding that are difficult to manage. Vaginal recurrence is common and the associated bleeding can range from minor episodes to severe hemorrhage necessitating vaginal packing and urgent intervention with uterine artery embolization.

Conclusion

Cervical cancer and its treatments, such as radical surgery and/or pelvic radiation, can be associated with long-lasting morbidity in a relatively young patient population. Although there is hope that the incidence of cervical cancer will diminish with increased HPV vaccination, uptake is not universal and many countries do not have access to vaccination. Women with cervical cancer have many supportive care needs and PC teams are likely to be involved due to the substantial symptoms associated with these cancers and treatments. As many cervical cancer patients also tend to be young, they may require family-oriented support as well. We hope that this review of cervical cancer tips can provide context for the expected course of cervical cancer and management of the most common side effects of treatment.

Footnotes

Funding Information

No funding was provided for this article.

Author Disclosure Statement

No competing financial interests exist.

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