Palliative Care of the Patient with Advanced Gynecologic Cancer |
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INTRODUCTION |
Cancer of the female genital tract is a significant cause of morbidity and mortality worldwide. In the US, ovarian cancer is the deadliest of gynecologic cancers, ranking fifth among all causes of cancer death in women. In the US and in countries where Papanicolaou (Pap) smear screening and treatment of cervical dysplasia are widely implemented, ovarian cancer is responsible for more cancer deaths each year than cancers of the uterine corpus and cervix combined. Elsewhere, in the absence of effective screening and early intervention programs, cervical cancer is a much more common cause of gynecologic cancer death.
When potentially curative treatment options are unavailable or have proven ineffective, the clinical goal changes from cure to palliation. The various gynecologic cancers, although arising from anatomically adjacent organs, have different natural histories. Symptoms of progressive disease vary depending upon the site of primary tumor origin. Therefore, strategies to palliate disease progression are tailored to the complications caused by the particular combination of local invasion and distant spread encountered with tumors arising from a given site of origin. For this reason, this review is organized by disease site of origin. The description of cervix cancer is subdivided into 3 parts, and information on certain issues of general relevance for all sites can be found in these sections.
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CERVICAL CANCER I: BLEEDING, PAIN, DEPRESSION |
Cervical cancer tends to spread locally before it metastasizes to distant organs. When cervical cancer is confined to the pelvis or regional lymph nodes, it may be cured with radical surgery, chemoradiation, or both. When patients with cervical cancer have distant metastatic disease, the cancer generally is not curable. In this setting, any treatment administered is of palliative intent. As always, palliative treatment should be directed at symptom control. Patients with advanced or recurrent cervical cancer may have any of the following symptoms:
Available interventions to control vaginal bleeding include vaginal packing, radiation therapy, embolization of the uterine arteries, or surgical resection or arterial ligation. Vaginal packing is usually a temporary measure. Monsels solution (ie, ferric subsulfate) applied to the vaginal packing or even formalin applied to only the tip of the vaginal packing may enhance this temporary measure. Gauze, lamb's wool, or calcium alginate packing can be used. Potentially helpful radiation therapy approaches include transvaginal orthovoltage treatment, high dose fraction teletherapy, or brachytherapy (see Radiation Therapy In Gynecology).
Fulminant hemorrhage might require embolization of the uterine arteries, a procedure performed in the interventional radiology suite. If radiographically directed embolization is not available, another emergency alternative is laparotomy with ligation of the uterine arteries or the anterior divisions of the hypogastric arteries. A desperate measure of this intensity is not appropriate when widespread dissemination of disease causing imminent threat to the patient's life exists, but carefully selected patients may derive meaningful benefit. Symptomatic anemia from blood loss can be remedied with blood transfusions once cessation of bleeding is accomplished.
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. Recognizing that narcotics can be delivered via many different routes is important. Agents may be prepared for oral, rectal, vaginal, sublingual, intravenous, intramuscular, epidural, and topical administration. Unfortunately, narcotics are associated with some troublesome common adverse effects that also must be addressed. These 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 analgesics and certain antidepressant medications often can provide a favorable synergistic effect when prescribed concurrently with narcotics, especially for pain suspected 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. Transdermal electrical nerve stimulation (TENS), massage therapy, and meditation or other biofeedback techniques are sometimes helpful adjuncts to narcotic therapy.
Anxiety and depression are common comorbidities in patients with malignancy of any type. Although these responses are not inappropriate in a patient diagnosed with a life-threatening condition, recognizing them and initiating intervention are important. Unless these conditions are treated adequately, patients might be noncompliant with other important therapies. Furthermore, efforts to control pain are particularly compromised. Fortunately, several effective medical therapies are available for both of these conditions. In addition to anxiolytics and antidepressants, supportive counseling, spiritual counseling, and family support can help counter feelings of depression and anxiety.
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CERVICAL CANCER II: FISTULAS, EDEMA, AND VENOUS THROMBOSIS |
Advanced cervical cancer may cause urinary fistulas, vesicovaginal fistulas more commonly, and, less commonly, ureterovaginal fistulas. Constant leakage of urine is extremely disturbing to many patients. Although not necessarily painful, fistulous drainage can have an extremely negative impact on quality of life. Patients with fistulas often may choose to avoid social and family encounters, ultimately becoming housebound.
Palliation of fistulas may be accomplished by either surgery to create an ureterointestinal conduit or by placing bilateral percutaneous nephrostomies and obstructing 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 for these tubes to 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. However, in this author𠏋 experience, unless the patient is confined to bed for other reasons, this is a choice of minimal benefit for most patients.
Occasionally, rectovaginal fistulas occur from primary tumor invasion of the adjacent rectum. More often, these fistulas result from radiation injury or tumor recurrence. Diverting colostomy is the surgical procedure of choice in someone with a limited lifespan. Diverting end colostomy is associated with less long-term complications than loop colostomy.
Edema may result from generalized anasarca from protein depletion and malnutrition. Alternatively, edema may be localized to the lower extremities as a consequence of lymphatic and/or venous obstruction due to a large tumor burden in the lymph nodes. Symptomatic relief of edema and leg discomfort may be obtained by the use of graded compression stockings, elevation of the extremities, and diuretics. Physical therapists with training and expertise in lymphedema management can facilitate fluid drainage with external massage maneuvers.
Deep venous thrombosis (DVT) may cause secondary edema. For DVT developing for any other reason, anticoagulation is standard treatment unless medically contraindicated. Conventional or low molecular heparin usually is followed by oral warfarin. Prolonged anticoagulation is usually 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, in some cases, vena caval filters are preferable to prevent pulmonary emboli.
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CERVICAL CANCER III: PULMONARY, METABOLIC, AND GASTROINTESTINAL COMPLICATIONS |
Dyspnea may be a symptom of anemia, pleural effusion, infection, heart failure, or lymphangitic spread of cancer. Blood transfusions rapidly ameliorate the dyspnea of anemia. Thoracentesis with pleurodesis should 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. 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.
Progressive or recurrent cervical cancer may cause uremia secondary to ureteral obstruction. Nausea, vomiting, somnolence, confusion, and seizures may result from uremia. Untreated uremia eventually is fatal. Death may be delayed if ureteral obstruction is relieved, either by percutaneous nephrostomy or ureteral stents.
Patients often request life-prolonging interventions as long as quality of life can be maintained through adequate pain control and other symptom relief. 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 can occur as a result of mechanical obstruction of the small or large bowel. Metabolic derangements, such as uremia, infection, or central nervous system metastases, also can cause nausea. Vomiting from small bowel obstruction either can be relieved by small bowel resection and reanastomosis, bowel bypass, ileostomy, placement of a percutaneous gastrostomy tube, or nasogastric tube. Colonic obstruction usually occurs at the rectum or sigmoid. Transverse loop colostomy is a fast and relatively easy way to circumvent vomiting from 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. 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 by the use of radiation therapy and steroids.
Diarrhea also can accompany advanced or recurrent cervical cancer. While loose bowel movements are a frequent 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, Kaopectate, paregoric, cholestyramine, and Donnatal.
Occasionally, diarrhea remains a long-term adverse effect following successful treatment of cervix cancer. Especially when patients experience exacerbation with intake of fatty foods, a suspected contributing influence is chronic mucosal change within the terminal ileum, where bile acid reabsorption can be impaired. Dietary modification can be particularly helpful in this regard.
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OVARIAN CANCER |
Recurrent ovarian cancer seldom is curable. Second-, third-, or even fourth-line chemotherapy often is administered in a palliative fashion, both to diminish symptoms and prolong life. When chemotherapeutic options are exhausted or the 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 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 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.
Small bowel obstruction is more challenging. Commonly, there are multiple areas of partial small bowel obstruction 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 with a percutaneous gastrostomy tube draining by gravity or a nasogastric tube on suction is used.
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. 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 seldom exists without a component of 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 may be an adverse effect of narcotic analgesics or colonic dysmotility from tumor involvement. Treatment options range from behavioral changes to medicinal agents. Increasing fluid intake and exercise when possible help, as does 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 if 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 distention and reflex peristalsis. Saline laxatives include magnesium sulfate, milk of magnesia, magnesium citrate, phospho-soda, and sodium phospate. Prolonged use of these agents may cause fluid and electrolyte imbalance.
Stimulant laxatives include senna, bisacodyl, cascara, castor oil, phenolphthalein, and danthron. These drugs ultimately may contribute to a loss of normal bowel function and cause laxative dependence, but this issue is often not important 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 and 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 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 and require at least weekly injections.
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ENDOMETRIAL CANCER |
Endometrial cancer may recur regionally within the pelvis or in distant sites including the lung, bone, and liver. Complications from pelvic or intra-abdominal disease progression are managed according to the general principles outlined above for cervical or ovarian cancer. Recurrence in other sites warrants symptom-driven intervention.
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 temporarily may improve the pulmonary symptoms. For recurrent effusions, thoracostomy tube drainage and subsequent pleurodesis relieve the symptoms of pleural effusion.
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 then is applied to prevent dislocation of the implanted devices as a result of continued tumor cell proliferation within the remaining bone.
Hypercalcemia may accompany bone metastases, either as a direct consequence of bone destruction or an indirect paraneoplastic phenomenon. Common symptoms of hypercalcemia include malaise and fatigue as well as 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; however, the quality of life preserved should be reasonable. Prolonging dying by extending a period of suffering usually is not in the patient's or family's best interest, especially when the alternative may be a relatively painless way to die.
Treatment of hypercalcemia with subsequent reversal of symptoms rests in restoration of volume, increasing calcium excretion, and inhibiting osteoclastic release of calcium. Intravenous fluids administration is the first step. Once volume has been restored, treatment with loop diuretics increases calcium excretion. One must be careful not to recreate a dehydrated state with overly aggressive diuretics. In the palliative setting, a significant decrease in tumor burden is unlikely; therefore, other agents need to 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.
Liver metastases are usually asymptomatic and frequently are detected only after other sites of disease have become manifest. A potential role exists for systemic chemotherapy for treatment of pulmonary or hepatic spread of disease, but response rates are generally low. No consensus standard regimen exists for metastatic endometrial cancer. 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.
Hepatic metastases occasionally can enlarge and cause pain from liver capsule distention. Analgesics, regional nerve block, and whole liver radiotherapy can provide palliative benefit. Brain metastases may cause a wide range of cognitive or behavioral abnormalities. Systemic corticosteroids and radiation usually are employed 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.
Clinical case
The following case report documents the clinical history of a patient whose endometrial cancer exhibited unusually aggressive behavior, prompting consideration of a broad range of palliative interventions.
A 46-year old female, G3 P2 A1, presented with a chief complaint of severe low back pain worsening over the preceding few months. She had associated irregular menstrual periods. Physical exam revealed an enlarged uterus, and an endometrial biopsy proved the presence of high-grade carcinoma.
At the time of abdominal hysterectomy in September 1999, operative findings included not only the irregularly shaped uterus and adnexal involvement by tumor but also a partly necrotic mass of unresectable matted adenopathy in the para-aortic region near the renal vessels.
Narcotic analgesics were prescribed to reduce pain from the retroperitoneal adenopathy. Postoperative pelvic and para-aortic radiotherapy was given and completed in October 1999.
In November 1999, the patient began to experience bladder incontinence. An MRI of the lumbar spine revealed direct invasion of the L3 vertebral body and an adjacent soft tissue mass but no definite compression of the spinal cord or cauda equina. A neurosurgical consultation was obtained, but no surgery was recommended initially in view of the lack of radiographic evidence of compromised neurological structures. The patient was fitted with a removable body cast to provide lumbar support.
Unfortunately, in early January 2000, the patient suffered a sudden onset lower extremity paralysis. Repeat imaging studies indicated a compression fracture at L3 with bone fragments protruding posterior and compressing the lower spinal cord and cauda equina. An emergency surgical decompression and spinal stabilization procedure was performed, but the neurological deficits proved to be irreversible despite the presence of implanted metal rods to support and realign the lumbar spine.
The patient thereafter required a wheelchair and a chronic, in-dwelling Foley catheter. She proceeded to have a trial of chemotherapy once her condition stabilized, but in November 2000 died as a result of progressive intra-abdominal disease causing bowel perforation and sepsis.
Two aspects of the case are particularly noteworthy. First, although patients with resectable para-aortic nodal disease are classified as stage IIIC and have a chance for long-term, disease-free survival with surgery and adjuvant postoperative radiotherapy, the patient's unresectable disease rendered her incurable at the time of diagnosis. Surgical debulking was impossible in view of the invasion of adjacent large vessels and bone, and it is not possible to administer potentially curative doses of external beam radiotherapy to that region of the body without excessive dose to the nearby small bowel.
Second, treating patients with metastatic disease threatening to destabilize the spine can be difficult. The placement of rods to augment the structure of lumbar vertebral bodies is a major procedure with some risk of causing paralysis. However, the consequences of progressive disease causing paralysis constitute a major negative influence on quality of life.
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VULVAR AND VAGINAL CANCER |
Vulvar and vaginal cancer, like cervical cancer, tends to spread locally before widespread metastases occur. Accordingly, vulvar and vaginal cancers can cause many of the same problems of pelvic and systemic disease progression as the other cancers mentioned above. Palliative treatment strategies are similar to those outlined above. Additionally, because of their relatively more superficial site of origin, complications may arise as a result of disease involvement of the perineal region and inguinofemoral nodal chains (Picture ).
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 sometimes can 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.
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SUMMARY |
Palliative care of the patient with gynecologic cancer requires attention to many diverse issues. As with most incurable cancers, pain control is the dominant issue. Patients fear dying with uncontrolled pain most of all. Health care providers must adequately address pain needs. 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 often are used to ameliorate these problems. The skills of the interventional radiologist are also useful for palliation of urinary fistulas and ureteral obstruction.
Palliative care of the gynecologic oncology patient requires the services of many different specialists. Optimal palliative care of the patient with gynecologic cancer is provided by a treatment team that may include a gynecologic oncologist, a radiation oncologist, a radiologist, and a pain specialist from hospice services and/or a palliative care physician when available.
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BIBLIOGRAPHY |
Section 11 of 11 
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