Palliative Care of the Patient With Advanced Gynecologic Cancer 

Palliative care of the patient with gynecologic cancer requires attention to many diverse issues and the services of many different specialists. The various gynecologic cancers, although arising from anatomically adjacent organs, have different symptoms and patterns of progression. Palliative strategies are therefore tailored to the complications caused by the particular combination of local invasion and distant spread of tumors arising from a given site of origin.^[1]

As with most incurable cancers, pain control is the dominant issue and must be addressed. Judicious use of narcotics, radiation, and nonnarcotic pain remedies is essential. Bowel obstruction and fistulas remain common problems resulting from progressive gynecologic cancer. Surgical procedures are often used to ameliorate these problems.

Optimal palliative care is provided by a treatment team that may include a gynecologic oncologist, a radiation oncologist, a radiologist, a pain specialist from hospice services, and/or a palliative care physician when available. The skills of the interventional radiologist are also useful for palliation of urinary fistulas and ureteral obstruction. Additionally, early referral to hospice care provides significant support to the patient and family in the home setting.

Cervical cancer tends to spread locally before it metastasizes to distant organs. When confined to the pelvis or regional lymph nodes, it may be cured with radical surgery, chemoradiation, or both. In the presence of distant metastatic disease, the cancer is generally not curable, and treatment is of palliative intent. Patients with advanced or recurrent cervical cancer may have any of the following symptoms:

• Vaginal bleeding or discharge
• Pelvic or back pain
• Urinary or bowel fistulas
• Lower extremity edema
• Deep venous thrombosis (DVT)
• Dyspnea from anemia or pulmonary involvement
• Uremia from ureteral obstruction

Vaginal bleeding

Available interventions to control vaginal bleeding include vaginal packing, radiation therapy, embolization of the uterine arteries, surgical resection, and arterial ligation. Vaginal packing is usually a temporary measure. Gauze, lamb's wool, or calcium alginate packing can be used. Monsel solution (ie, ferric subsulfate) applied to the packing or even formalin applied to only the tip of the packing may enhance this measure.

Other potentially helpful approaches include transvaginal orthovoltage treatment, high-dose fraction teletherapy, or brachytherapy. Type and length of treatment should depend on the patient's Karnofsky performance status (KPS). In the patient with a reasonable KPS, stereotactic radiosurgery may be considered to control bleeding.^[2]

Fulminant hemorrhage might require embolization of the uterine arteries, a procedure performed in the interventional radiology suite. If radiographically directed embolization is not available, laparotomy with ligation of the uterine arteries or the anterior divisions of the hypogastric arteries is another alternative. A measure of this intensity is not appropriate when there is widespread dissemination of disease causing imminent threat to the patient's life, but carefully selected patients may derive benefit. Symptomatic anemia from blood loss can be remedied with blood transfusions once bleeding is stopped.

Pain

Pain is often a very disabling symptom of advanced or recurrent cervical cancer. Regional nerve, muscle, and bone infiltration can cause severe discomfort. Narcotic analgesics are a fundamental component of cancer pain treatment and may be prepared for oral, rectal, vaginal, sublingual, intravenous, intramuscular, epidural, or topical administration. Common adverse effects of narcotics include constipation, pruritus, nausea, drowsiness, and skin rash. Because constipation is almost universal with increasing doses of narcotics, a bowel stimulant should be prescribed simultaneously.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and certain antidepressant medications can often provide a favorable synergistic effect when prescribed concurrently with narcotics, especially for pain thought to be of neuropathic origin.

When pain is directly attributable to specific foci of disease, such as bone metastasis or para-aortic lymph node recurrence, a brief course of palliative radiation therapy yields substantial pain reduction in a high percentage of patients. However, pain relief may not be maximally achieved until 1-2 weeks after palliative radiation therapy.

Transdermal electrical nerve stimulation (TENS), massage therapy, and meditation or other biofeedback techniques are sometimes helpful adjuncts to narcotic therapy. Additionally, epidural analgesia can be particularly beneficial in patients with regional pain and significant side effects from systemic narcotic therapy.

Anxiety and depression

Anxiety and depression are common comorbidities in patients with malignancy of any type and must be promptly recognized and treated. If they are not, pain control and patient compliance with other important therapies may be compromised. Effective therapies include anxiolytics, antidepressants, supportive counseling, spiritual counseling, and family support.

Fistulas

Advanced cervical cancer may cause urinary fistulas, vesicovaginal more commonly than ureterovaginal fistulas. Although not necessarily painful, fistulous drainage can have an extremely negative impact on quality of life. Because of constant odor, patients with fistulas may often choose to avoid social and family encounters, ultimately becoming housebound.

Palliation of fistulas may be surgically accomplished by creation of a ureterointestinal conduit or by placement of bilateral percutaneous nephrostomies to decompress the ureters. Both procedures require an external appliance and maintenance. Functional status and operative risk should guide the selection of the means of palliation.

Although placement of nephrostomy tubes is a simpler procedure than surgical diversion of ureteral outflow, it is not necessarily a better choice for patients with a life expectancy of more than a few months. One disadvantage of percutaneous nephrostomies is the relative ease with which these tubes become kinked or dislodged. The tubes can be a source of infection and must be exchanged every few months. The use of external pads (diapers) to absorb drainage is the simplest option of all but, unless the patient is confined to bed for other reasons, is highly undesirable for most patients.

Occasionally, rectovaginal fistulas occur from primary tumor invasion of the adjacent rectum. These more often result from radiation injury or tumor recurrence. A diverting colostomy is the surgical procedure of choice in someone with a limited lifespan. Diverting end colostomy is associated with fewer long-term complications than loop colostomy.^[3]

Edema

Edema may be generalized anasarca caused by protein depletion and malnutrition or may be localized to the legs as a consequence of lymphatic and/or venous obstruction due to a large tumor burden in pelvic lymph nodes. Symptomatic relief of edema and leg discomfort may be achieved by the use of graded compression stockings, elevation of the legs, and administration of diuretics. Physical therapists with training and expertise in lymphedema management can facilitate fluid drainage with external massage maneuvers and appropriate placement of compression bandages.

Deep venous thrombosis

DVT may cause secondary edema. Anticoagulation is standard treatment for DVT unless medically contraindicated. Conventional or low-molecular-weight heparin is usually followed by oral warfarin. Prolonged anticoagulation is typically necessary, because DVT often recurs in terminally ill patients with recurrent cancer. Anticoagulation prevents further extension of the thrombus and promotes gradual recanalization of the vessel as the thrombus is resorbed. At the same time, collateral vessels enlarge to accommodate more flow, and the net result is relief of extremity swelling and improved comfort for the patient.

Because anticoagulation might exacerbate hemorrhage from recurrent cancer in the pelvis or elsewhere, vena caval filters are sometimes preferable to prevent pulmonary emboli and can be used when anticoagulation is contraindicated.

Pulmonary complications of cervical cancer

In the patient with end-stage cancer, dyspnea may be caused by anemia, pleural effusion, infection, heart failure, or lymphangitic spread of cancer. Blood transfusions rapidly ameliorate the dyspnea of anemia.

Stem cell support using erythropoietin may provide a delayed benefit in this set of patients. Thoracentesis with pleurodesis can improve the symptoms of a malignant pleural effusion. Drainage of fluid is followed by pleural instillation of talc or doxycycline to sclerose the pleural lining. Video-assisted thorascopic sclerosis (VATS) may also be considered to achieve higher sclerosis efficacy with shorter inpatient admission time.

Pneumonia and heart failure should be treated as in the patient without cancer. Lymphangitic spread of cancer can cause hypoxia and dyspnea. Both oxygen and narcotics ameliorate this symptom.

Uremia

Progressive or recurrent cervical cancer may cause uremia secondary to ureteral obstruction. Uremia may induce nausea, vomiting, somnolence, confusion, and seizures. Untreated uremia is eventually fatal.

Death may be delayed if ureteral obstruction is relieved by percutaneous nephrostomy or ureteral stents. If other, intercurrent complications of disease progression have proven refractory to medical or surgical intervention, then relieving ureteral obstruction to provide transiently improved excretion of uric acid and other waste products only prolongs the patient's pain and suffering. Patient and family counseling are necessary to identify the point at which further medical intervention is inappropriate in this setting.

Nausea and vomiting

Nausea and vomiting can occur as a result of mechanical obstruction of the small or large bowel. Infection, central nervous system metastases, and metabolic derangements, such as uremia, can also cause nausea.

Vomiting from small bowel obstruction can be relieved by small bowel resection and reanastomosis, bowel bypass, ileostomy, percutaneous gastrostomy tube, or nasogastric tube. Colonic obstruction usually occurs at the rectum or sigmoid. Transverse loop colostomy, or cecostomy tube, is a fast and relatively easy way to circumvent vomiting caused by this problem.

Metabolic causes of nausea and vomiting can be relieved by correcting the metabolic imbalance. Hypercalcemia is an uncommon paraneoplastic manifestation of metastatic gynecologic cancer for which hydration, diuretics, steroids, calcium-binding agents, and bisphosphonates should be considered.

Immediate symptomatic relief of nausea may be obtained with the use of phenothiazines, antihistamines, steroids, or 5HT-3 antagonists. Nausea and vomiting caused by brain metastases can be improved through the use of radiation therapy and steroids.

Diarrhea

Diarrhea can also accompany advanced or recurrent cervical cancer. While loose bowel movements are a frequent result of acute lower gastrointestinal toxicity from pelvic radiotherapy, this effect nearly always resolves within a few weeks after treatment is completed. Agents that reduce diarrhea include anticholinergics and opiate derivatives, such as loperamide, codeine, diphenoxylate sodium with atropine, bismuth subsalicylate , paregoric, cholestyramine, and belladonna alkaloids/phenobarbital.

Occasionally, diarrhea remains a long-term adverse effect following successful treatment of cervical cancer. A suspected contributing influence is chronic mucosal change within the terminal ileum (where bile acid reabsorption can be impaired) from radiation therapy, especially when patients experience exacerbation with intake of fatty foods. Dietary modification can be particularly helpful in this regard. Ultimately some patients will require small bowel resection or bypass.

Recurrent ovarian cancer is seldom curable. Second-, third-, or even fourth-line chemotherapy is often administered in a palliative fashion, as a means of diminishing symptoms and prolonging life. When chemotherapy is considered for patients with good performance status, it is most appropriate to offer enrollment in formal clinical studies, such as those coordinated by the Gynecologic Oncology Group.

Oral thalidomide has shown activity in heavily pretreated patients with ovarian cancer when compared with traditional intravenous chemotherapy.^[4]

When chemotherapeutic options are exhausted or their adverse effects are not worth the small potential for benefit, other means of palliating symptoms of progressive ovarian cancer are necessary.

Ovarian cancer spreads regionally in the form of scattered deposits of tumor on all surfaces in the peritoneal cavity. Morbidity and mortality as a direct result of this process are far more common than symptoms related to recurrence, specifically at the primary tumor site or in distant extra-abdominal sites.

Bowel obstruction

Bowel obstruction is a common terminal effect of progressive ovarian cancer. Rectosigmoid obstruction in the face of progressive disease is best palliated with a transverse loop colostomy. Often, a small incision at the stoma site is all that is necessary to identify the dilated proximal colon and to elevate it through the anterior abdominal wall. The stoma starts to function immediately, and patients can eat and return to their baseline functional status soon.^[5]

Cecostomy tube placement can be used to vent the large intestine in colonic obstruction. However, cecostomy sites are prone to recurrent obstruction from solid stool, and tube placement is most appropriate in those patients with extremely short life expectancies.

Small bowel obstruction is more challenging. Multiple areas of partial small bowel obstruction are typically not amenable to surgical correction. Tumor implants on the bowel surface and mesentery cause adhesions and impede peristalsis. Infrequently, an isolated small bowel obstruction can be managed with bowel resection and reanastomosis. More commonly, palliation is achieved with a percutaneous gastrostomy tube draining by gravity or with a nasogastric tube on suction. It may also be beneficial to decrease gastrointestinal secretions with somatostatin combined with erythromycin to improve motility in the management of small bowel obstruction.

Ascites

Ascites can result from widespread microscopic and macroscopic tumor infiltration over the peritoneum, preventing absorption of peritoneal fluid. This symptom can become quite troubling when progressive disease is unresponsive to chemotherapy. Patients complain of pain, early satiety, vomiting, fatigue, and shortness of breath. Diuretics are of limited efficacy in relieving malignant ascites, and relief is best obtained by repetitive paracentesis. Placement of a semipermanent drainage tube, Pleurx, has been FDA-approved for symptomatic relief in patients with recurrent ascites. The eventual metabolic impact is depletion of albumin. However, the immediate, temporary improvement in patient comfort usually takes precedence over long-term nutritional status for a patient who is terminally ill.

Anorexia

Anorexia seldom occurs without bowel obstruction or ascites. For anorexia without associated bowel obstruction, treatment with megestrol acetate or steroids can stimulate appetite and lead to an increased sense of well-being. Parenteral nutritional support might be appropriate as a short-term measure perioperatively following relief of bowel obstruction or other intervention. However, long-term parenteral nutritional support is seldom an appropriate measure in a patient with incurable malignant impairment of bowel function.

Constipation

Constipation may be an adverse effect of narcotic analgesics or colonic dysmotility from tumor involvement. Treatment options range from behavioral changes to medicinal agents. When possible, an increase in fluid intake and exercise can be of benefit, as can close attention to bodily signals of defecation. More useful to the patient with cancer is the addition of fiber, colonic stimulants, and laxatives to their regimen.

For narcotic-induced constipation, stool softeners should be combined with stimulant laxatives, such as docusate sodium tablets and senna or bisacodyl tablets. Cascara, a liquid cathartic derived from tree bark, is also useful. For patients with obstipation or for those in whom the above measures are inadequate, enemas and suppositories are helpful. Enema choices include warm tap water, phosphate/biphosphate, soapsuds, milk and molasses, and mineral oil. Bisacodyl or glycerin suppositories are also useful. Saline laxatives draw fluid into the intestine, causing distension and reflex peristalsis. Saline laxatives include magnesium sulfate, milk of magnesia, magnesium citrate, and sodium phosphate. Prolonged use of these agents may cause fluid and electrolyte imbalance and should be avoided in malnourished patients.

Stimulant laxatives include senna, bisacodyl, cascara, castor oil, phenolphthalein, polyethylene glycol, and danthron. These drugs may ultimately contribute to a loss of normal bowel function and cause laxative dependence, but this issue is often unimportant in the palliative care setting.

Lubricating agents include oral ingestion of mineral oil. Prolonged use of mineral oil may lead to malabsorption of fat-soluble vitamins. Lactulose draws water into the intestinal lumen, softens stools, and increases defecation frequency. Excessive use can lead to fluid and electrolyte imbalance. Polyethylene glycol electrolyte solution is useful for stimulating defecation with minimal fluid or electrolyte imbalance.

Fatigue and dyspnea

Fatigue or dyspnea secondary to anemia can be treated with blood transfusions or erythropoietin. Transfusions provide immediate improvement, whereas erythropoietin injections may take weeks to improve fatigue.

Endometrial cancer may recur regionally within the pelvis or in distant sites, including the lung, bone, liver, and brain. Complications from pelvic or intra-abdominal disease progression are managed according to the general principles previously outlined for cervical or ovarian cancer. Recurrence in other sites warrants symptom-driven intervention.

Pulmonary metastases

Parenchymal lung metastases are often asymptomatic until erosion into a bronchus or blood vessel occurs. Centrally located recurrence in the mediastinum or hilar regions can cause superior vena cava syndrome or large airway compromise. Palliative radiotherapy and endobronchial stents are available therapeutic options. Metastases to the pleural cavity may cause effusions and subsequent dyspnea. Thoracentesis may temporarily improve the pulmonary symptoms. For recurrent effusions, thoracostomy tube drainage and subsequent pleurodesis or VATS will most likely relieve the symptoms of pleural effusion.

Bone metastases

Bone metastasis can cause severe pain, jeopardize the spinal column or nerve roots, lead to fracture, and contribute to hypercalcemia. Focal external beam radiation directed at metastasis can prevent and alleviate impending spinal or nerve root injury. Fractures or impending fractures of the femur require orthopedic surgical fixation to stabilize the weight-bearing structure. Postoperative radiotherapy is then applied to prevent dislocation of the implanted devices as a result of continued tumor cell proliferation within the remaining bone.

Hypercalcemia

Hypercalcemia may accompany bone metastases, either as a direct consequence of bone destruction or as an indirect paraneoplastic phenomenon. Common symptoms of hypercalcemia include malaise, fatigue, obtundation, anorexia, pain, polyuria, polydipsia, dehydration, constipation, nausea, and vomiting. Cardiac dysrhythmias and cardiac arrest may result. Untreated hypercalcemia may progress to loss of consciousness and coma. As with correcting uremia by relieving bilateral ureteral obstruction, correcting hypercalcemia can prolong life and relieve symptoms.

Treatment of hypercalcemia with subsequent reversal of symptoms rests in restoring volume, increasing calcium excretion, and inhibiting osteoclastic release of calcium. Administration of intravenous fluids is the first step. Once volume has been restored, treatment with loop diuretics increases calcium excretion. Avoid re-creation of a dehydrated state with overly aggressive diuretics. In the palliative setting, a significant decrease in tumor burden is unlikely; therefore, other agents must be used to correct hypercalcemia. Administering bisphosphonates, calcitonin, mithramycin, or gallium nitrate inhibits osteoclastic activity. Bisphosphonates are the most popular agent because of their ease of administration, relatively long duration of action, and effectiveness throughout multiple treatments.

Hepatic metastases

Liver metastases are usually asymptomatic and are frequently detected only after other sites of disease have become manifest. There is a potential role for systemic chemotherapy for pulmonary or hepatic spread of disease, but response rates are generally low. Hepatic metastases can occasionally enlarge and cause pain from liver capsule distention. Analgesics, regional nerve block, and whole-liver radiotherapy can provide palliative benefit.

Brain metastases

Brain metastases may cause a wide range of cognitive or behavioral abnormalities. Systemic corticosteroids and radiation are usually used to lessen the effects of brain metastasis. Neurosurgical resection followed by whole-brain radiotherapy is appropriate for patients with a solitary solid-tumor brain metastasis, good performance status, and minimal disease outside the central nervous system.

Vulvar cancer and vaginal cancer, as with cervical cancer, tend to spread locally before widespread metastases occur. Accordingly, they can cause many of the same problems that are associated with pelvic and systemic disease progression that the other gynecologic cancers do; vulvar and vaginal cancer therefore call for similar palliative treatment strategies. Additionally, because of their relatively more superficial sites of origin, complications may arise as a result of disease involvement of the perineal region and inguinofemoral nodal chains. Local groin progression (seen in the image below) may provide a challenge in terms of odor and hygiene, which is amenable to dressing with activated charcoal.

Rectal fistulas or anal sphincter involvement might warrant consideration of diverting colostomy. Groin node involvement may compress the femoral vessels and cause lower extremity edema. Vascular stents can sometimes relieve obstruction and improve edema. Ulceration of the skin by infiltrative tumor can be treated with radiotherapy if the region has not been pretreated too heavily with radiotherapy during an initial attempted curative treatment. Other topical treatments for localized ulcers include zinc oxide and gel-based wound dressings.