MEDEOS

Introduction
Ovarian cancer is the sixth most common cancer and the
seventh most common cause of cancer-related death in
women. Recent global statistics reports an incidence of
ovarian cancer higher than 200,000/year and mortality
attributable to this disease higher than 125,000/year (1).
Most of women who present ovarian cancer are between 45
and 65 years and the median age on the diagnosis is 60
years.
Ovarian cancer often presents a silent spread and frequently
is diagnosed in advanced stage. Despite advances
of last decades in the combined treatments (surgery and
chemotherapy) many women present disease recurrence,
which is associated with persistent and severe symptoms.
Owing to these reasons, it is important to know the best
possible treatments for symptom control that enables to
establish an adequate support strategy, specific for every
patient.
Natural History of Advanced Ovarian Cancer
After a local growing, usually silent, the ovarian cancer
spreads within pelvis and abdominal cavity. Bilateral tumors
are presented in more than 30% of cases, owing to spread
from one ovary to the other or primary synchronous cancer
development. Ovarian cancer presents a transcoelomic
spread pattern which causes a frequent involvement of
greater omentum in early stages of disease. Later and following
the same pattern of spread, ovarian cancer provokes
a multiple peritoneal seeding which may affect all abdominal
cavity. Peritoneal dissemination is associated with a
rapid production of ascites, which in turn leads to a severe
abdominal distension. The frequent transperitoneal
metastatic infiltration of the umbilicus is known as Sister
Joseph’s nodule. Intra-abdominal spread often provokes
initially episodes of sub-acute bowel obstruction, which
finally may result in a bowel obstruction fully consolidated.
Vaginal bleeding is not a frequent complication in ovarian
carcinoma, except in cases of recurrence in vaginal wall
after surgery or due to hyper-estrogenic production in some
unusual ovarian cancers, as granulosa cell tumor. Lymphonode
involvement is observed initially in pelvic area and
after in para-aortic chain. Those cases who present a
severe local progression, rest of pelvic organs and the lumbosacral
plexus may be infiltrated. Renal failure due to
ureteral tract obstruction is possible but less common than
in other tumors of pelvic growing. The most common extraabdominal
metastatic dissemination is observed in pleura
lung and liver. Pleural effusion is very common and may be
reactive (Meig’s syndrome) or may be due to metastatic
infiltration, transdusate or exudative pleural effusion respectively.
Symptom Complex of Advanced Ovarian
Cancer
The symptom complex in advanced ovarian cancer is the
result of combination of different complications due to natural
spreading of tumor (Table 1). The most common symp-
Palliation of Advanced Ovarian Cancer 108
Albert Tuca, MD
Table 1. Most common complications and related symptoms in
advanced ovarian cancer.
Complication Related symptoms
Intraabdominal
spreading
Extraabdominal
spreading
Other
systemic
related
complications
Abdominal distension
Ascites
Pelvic infiltration
Intestinal dysfunction
Bowel obstruction
Obstructive renal failure
Pleural effusion
Lung metastases
Asthenia
Anorexia-caquexia
Malnutrition
Dehydration
Pre-renal failure
Anemia
Hypercalcemia
Thromboembolic complications
Infections
Fatigue
Anorexia
Functional deterioration
Cognitive failure
Abdominal pain
(continuous and colic)
Neuropathic pain
(lumbosacral plexus)
Nausea-vomiting
Constipation
Dyspnea
toms are: pain, colic pain, neuropathic pain, nausea, vomiting,
constipation, dyspnea, anorexia, weakness, drowsiness
and cognitive failure.
A recent study describe the most common causes of
hospitalization during the last 3 months of life in women presenting
ovarian cancer as (Table 2): bowel obstruction
(28%), pleural effusion and respiratory failure (28%), infectious
diseases (23%), ureteral obstruction and renal failure
(19%) and ascites accumulation (15%) (2).
Pain
Most of ovarian cancer patients, with moderate or severe
cancer-related pain, require treatment with strong opioids
during cancer natural history. There are no specific differences
in pain management compared with other neoplasm.
Most experts recommend applying the guidelines of the
World Health Organization (WHO) for the relief of cancer
pain.
The publication of WHO analgesic ladder represented
an important advance in promoting the principles of good
cancer control for cancer patients (3). Analgesic ladder simplified
pain management strategies and promoted a consensus
about progressive increase of analgesics according
cancer pain severity and analgesic response. The WHO
analgesic ladder emphasises specially on individualized
assessment of pain, continuous analgesia associated with
an adequate design of rescue doses, the oral route as the
more adequate for analgesics administration, progressive
increase of dose and regular review of the analgesia.
In first step the recommendation is to use a non opioid
analgesic drug, as paracetamol or nonsteroidal anti-inflamatory
drugs, associated to adjuvant drugs if it is necessary.
The second step of WHO analgesic ladder proposes the
addition of weak opioids to drugs used in first step. In third
step, the weak opioid is substituted by a strong opioid, combined
with nonopioid drugs and adjuvants if it is considered
necessary (Figure 1) (3).
The effectiveness of analgesic ladder strategy, based
on three analgesic steps, is widely validated in clinical setting,
and accepted by most of specialist as the best way to
assure adequate pain control. In fact, there are a lot of studies
published, which demonstrate a satisfactory pain relief
in more than 80% of cancer patients treated according to
WHO analgesic ladder (4-8). A working definition of refractory
pain, who present in 20% of patients, is the inadequate
pain relief with a strong opioid administered in a dose
enough to cause intolerable side-effects despite the best
measures to its control. It’s well accepted that treatment
options in those cases of refractory pain are: opioid rotation
(20%); intravenous or subcutaneous opioids (5%); nerve
blocks or epidural or intratechal analgesia (5%).
Ascites (9)
Ascites due to peritoneal carcinomatosis is a very common
complication of advanced ovarian cancer. The persistent
abdominal distension may cause abdominal pain, nausea,
fatigue, constipation, dyspnea, umbilical hernia and oedemas
in lower extremities.
The diet low in sodium is rarely an effective measure in
ascites caused by peritoneal carcinomatosis. Diuretics may
reduce ascites in more than 30% of patients during some
weeks. It’s recommended to use the adjusted dose of a
combination of potassium-sparing diuretic (espironolactona)
and loop diuretic (furosemide). However, most
patients may present with dehydration or electrolyte disturbances,
fact that reduces diuretic efficacy and prevents
their use during long periods of time.
Paracentesis for ascitis evacuation is alternatively frequently
used to reduce symptoms due to abdominal distension.
An evacuation of ascites of no more than 5 litres is
usually recommended. Dehydration, hypovolemia and renal
failure are common complications of repeated paracentesis,
albumin infusion may be considered in some cases to avoid
these complications. The repeated paracentesis may also
cause loculation of ascites, which in turn may reduce the
success at subsequent evacuation paracentesis. When the
frequency of paracentesis necessary for a satisfactory
2 Palliation of Advanced Ovarian Cancer
Table 2. Hospitalization causes during last 3 months of life of
women presenting advanced ovarian cancer.2
Hospitalization cause Prevalence (%)
Bowel obstruction
Infection diseases
Pleural effusion
Ascites accumulation
Urinary obstruction
Dehydration
Pain (no controlled pain)
Nervous system disorders
Congestive heart failure
Respiratory failure no related with pleural effusion
Anemia
Deep venous thrombosis
Renal failure
28
23
21
15
15
13
8
8
8
6
6
6
4
Figure 1. WHO analgesic ladder and measures in refractory pain
reduction of abdominal distension is higher than one every
8-10 days can be considered the insertion of a silicone
catheter internal-external. This technique can avoid the
inconvenience of repeated abdominal puncture and in some
cases can be made by the patient or his family at home.
The main complications of an abdominal catheter internextern
are infection, peritonitis and lumen obstruction which
may be prevented by means of carefully catheter manipulation
and training the patient or family. Peritoneovenous
shunts (LeVeen and Denver shunts) are multi-perforated
catheters inserted into the abdominal cavity and connected
to a unidirectional valve implanted in the subcutaneous tissue.
A subcutaneous tunneled catheter, communicates
abdominal cavity with the jugular vein. The current use of
peritoneovenous shunt in ascites due to carcinomatosis is
rare because they present frequent complications such as
thrombosis, coagulopathy, infection or obstruction.
Dyspnea and pleural effusion (10)
Dyspnea is a common symptom in patients presenting
advanced ovarian cancer and may be the result of a pleural
effusion or severe ascites. When etiologic treatment is not
possible the palliative management of dyspnea is based on
opioids, corticosteroids and oxygen therapy.
The primary site of action of opioids for reducing the
sensation of breathlessness is the medulla oblongata. The
specific mechanism of opioids acting in respiratory centre
still is not well known. Clinical effects can be summarized
as: reduction of response to hypercapnia, reduction of anxiety,
reduction of cardiac pre-load, reduction of oxygen consumption,
increase of tolerance to the effort. A systematic
review of Cochrane Fundation published in 2001 confirmed
that opioids are effective in breathlessness relief in
advanced cancer patients without significant modifications
in pO2 or pCO2 levels.
Oxygen therapy improves alveolar pressure of oxygen
and reduces the respiratory work. In hypoxemic patients the
oxygen saturation improves after oxygen administration.
However oxygen therapy can reduce the sensation of
breathlessness in hypoxemic patients and in patients with
normal levels of oxygen. The general recommendations
would be to use oxygen therapy in hypoxemic patients and
to establish a subjective test about effect of oxygen in
patients who show no significant hypoxia. In patients who
present chronic obstructive pulmonary present with associated
and increased levels of pCO2 is not recommendable oxygen
use with fluxes higher than 28% because it may block
the hypoxemic stimulus and increase respiratory failure.
Approximately 40% of patients treated with corticosteroids
show an improvement of dyspnea, due to reduction
of inflammatory component and edema associated with
tumor spreading.
Pleural effusion is a very common complication in
advanced ovarian cancer. May be reactive (Meig’s
Syndrome) or due to pleural metastatic infiltration. The use
of corticosteroids and diuretics may improve dyspnea associated
with pleural effusion in some cases during a short
period of time. Most patients need pleural drainage by
means of thoracocentesis. Drainage of pleural effusion,
between 500 and 1500 mL, usually achieves a fast reduction
of dysnea. A pneumothorax by accidental lung perforation
is the most common complication of thoracocentesis. If
the technique is performed carefully the probability to provoke
a pneumothorax is low and if it occurs it is usually not
clinically serious. The hemotorax is not a common complication
of thoracocentesis, except in excessively vascularized
tumors in patients with severe coagulopathy. Tumor
seeding in the path of the thoracic puncture and in the skin
after thoracocentesis is possible but rare. Pleural instillation
of sclerosing substances with the aim of provoking a pleural
fibrosis and preventing reproduction of a pleural effusion,
is known as pleurodesis. Many chemical agents can be
used, including talc, bleomycin, tetracycline, doxorubicin
and quinacrine. Chemical pleurodesis can be done using
closed technique (thoracostomy tube) or open technique
(video-assisted thoracoscopic surgery). Pleurodesis is indicated
when patients need repeated thoracocentesis, their
life expectancy is higher than 2 months and there is possibility
for the lung re-expansion. The success of pleurodesis
in dyspnea control is between 70-90% of patients if they
accomplish the above mentioned conditions.
Inoperable malignant bowel obstruction (11-12)
Malignant bowel obstruction (MBO) is a common complication
in advanced cancer, especially in patients with abdominal
or pelvic tumors. MBO can be defined as a clinical syndrome
in which a patient presents digestive obstructive
symptoms caused by the presence of intra-abdominal cancer.
The criteria of MBO diagnosis, defined by a recent consensus
conference, are: a) clinical evidence of bowel
obstruction (clinical history, physical and radiographic
explorations); b) bowel obstruction beyond the ligament of
Treitz; c) intra-abdominal primary cancer with incurable disease
or no-intra-abdominal primary cancer with clear
intraperitoneal disease. Although the MBO may occur at
any time of natural history of cancer, it’s observed more
often in advance stages. The overall frequency of MBO in
advanced cancer patients has been estimated between 3%
and 15%. This frequency can reach more than 40% in
patients presenting ovarian cancer, and necropsy studies
demonstrated that 50% of patients presented this complication.
MBO causes severe symptoms, which are often difficult
to control, and are associated with an overall median life
expectancy of three months. Palliative surgery is the only
alternative to restore the continuity of the bowel lumen.
Many patients with advanced cancer are not eligible for surgery
because of technical difficulties that preclude restoring
Palliation of Advanced Ovarian Cancer 3
intestinal transit or due to a poor general status. The transcelomic
pattern of spreading of ovarian cancer causes an
intense peritoneal seeding (peritoneal carcinomatosis). For
this reason most of patients presenting MBO, show multiple
intestinal levels of obstruction, fact that precludes any surgical
intend. Standard conservative medical treatment in
inoperable MBO includes gastric venting, through nasogastric
or gastrostomy tube, no oral intake, intravenous hydration,
and antiemetic drugs administered by parenteral route.
The objective is redressing the electrolyte imbalance,
reduction of intestinal distension, controlling symptoms, and
in some cases facilitation of spontaneous resolution of
occlusive process. Adequate control of nausea and vomiting
can be achieved in more than 80% of the cases, when
gastric aspiration tube is maintained together with no-oral
intake. In about 30% of cases, a spontaneous resolution of
occlusion is observed within a period of between five and
eight days from the start of conservative treatment, especially
if the condition is a sub-occlusive crisis. Nevertheless,
in those cases of spontaneous resolution, the re-obstruction
rate is higher than 50%.
When palliative surgery is not possible, and a spontaneous
resolution is not seen, the condition of persistent
intestinal obstruction provokes a fast and progressive
impairment of general status and very severe symptoms.
Baines et al. demonstrated in 1985 that palliative treatment
based on the rational use of analgesics, antiemetics, antisecretory
drugs, and corticoids can control the persistent
symptoms, many times without nasogastric tube drainage,
and in some cases, with a continuation of minimum food
intake.
The abdominal pain (continuous and colic) caused by
inoperable MBO is very severe and usually the patients
need be treated with strong opioids. It’s well known that
strong opioids reduce intestinal peristalsis. However, pain
relief is a priority in advanced disease and there is no clinical
evidence that use of strong opioids causes a significant
reduction of rate of spontaneous resolution in the specific
situation of inoperable MBO. Fentanyl is the strong opioid
with less influence in intestinal motility and some authors
suggest that this drug would be the opioid of first choice in
this complication.
The majority of investigators accept that haloperidol is
the first-choice antiemetic drug because of the potent central
anti-dopaminergic action. Prokinetic drugs, such as
metoclopramide, are useful but may paradoxically increase
colic pain. A recent phase II clinical trial has demonstrated
that antagonists of 5-HT3 receptor (granisetron) are highly
efficacious in vomiting control due to MBO, even in those
cases in whom other standard antiemetics did not achieve
an adequate control of nausea-vomiting. Antisecretory
drugs reduce endoluminal flow of water and sodium, assisting
in the control of nausea, abdominal distension, and colic
pain. The anticholinergics (hyoscine butylbromide and
hydrobromide) have been traditionally used as first choice
anti-secretory drugs.
Octreotide, a synthetic analogue of somatostatin, also
possess a potent antisecretory effect and can be used as a
second-line treatment, in combination or not, with an anticholinergic
agent. Octreotide has greater potency than anticholinergics,
and according to the results of some clinical
trials, can be effective when there is no adequate response
to hyoscine. The use of corticosteroids also is particularly
recommended given their antiemetic action and their antiinflammatory
effect with reduction of intestinal oedema. In
addition, corticosteroids are the unique class of drugs,
according to the data from clinical trials evaluated in metaanalyses,
which can improve the index of spontaneous resolution
of MBO.
Probability of adequate symptom control with conservative-
palliative treatment in inoperable MBO is higher than
75%, and overall probability of spontaneous resolution is
between 68% and 30%. The mean survival of MBO patients
is between 20 and 75 days and the life expectancy for 3
months is lower than 25%.
Multidimensional approach
The symptoms perception and also the response to symptomatic
treatment may be influenced by thought (cognitive
area), mood (affective area) and behavior, in addition to the
psychological impact.
Many times, a multidimensional evaluation and multidisciplinary
intervention is needed in order to assist patients
suffering in advanced stage of cancer.
Summary of key points
Pain
• Most of advanced ovarian cancer patients suffer severe
abdominal pain and they need analgesia with strong
opioids
• Analgesia in advanced cancer must be based on WHO
analgesic ladder (adequate control of pain 80%)
• If patient presents refractory pain (20% of cases) consider
consulting with palliative care or pain specialist, to
assess indication of opioid rotation or interventional
analgesia (nerve block, epidural or intratechal analgesia)
Ascites
• Ascites due to peritoneal carcinomatosis is a very common
symptom in advanced ovarian cancer
• Combination of potassium-sparring diuretic (espironolactone)
and a loop diuretic (furosemide) may reduce
ascites in some cases (30%) during a short period of
time
• Paracentesis may be an alternative to reduce ascites
and relieve symptoms related with abdominal distension
• Dehydration, hypovolemia, pre-renal failure and ascites
4 Palliation of Advanced Ovarian Cancer
loculation are the more common complications of
repeated paracentesis
• When the need of repeated paracentesis is higher than
one per 8-10 days and life expectancy are weeksmonths,
consider implantation of a drainage silicone
catheter. This technique may avoid repeated abdominal
puncture and it is possible to be made at home by
patient/family with an adequate training.
Dyspnea
• An accurate etiologic diagnosis is mandatory. When etiologic
treatment is not possible the basic palliative treatment
is based on oxygen-therapy, strong opioids and
corticosteroids
• Oxygen-therapy is efficacious in hypoxemic patients
and can assist in subjective experience of breathlessness
in patients with normal levels of oxygen. For this
reason, oxygen-therapy may be recommendable in: a)
hypoxemic patients; b) end-of-life situation (life
expectancy weeks to days) if patient reports subjective
improvement.
• Strong opioids improve dyspnea at rest and tolerance to
effort, without significant modifications of pO2. Oral
morphine dose suggested in opiod naive patients: 2,5
mg PO every 4 hours
• Benzodiazepines can assist in dyspnea relief especially
if patient shows anxiety.
• Cortocosteroids may improve dyspnea in 40% of
patients. Consider therapeutic trial.
• Most of patients presenting pleural effusion need
repeated pleural drainage (thoracocentesis). Chemical
pleurodesis is recommendable if patient has a life
expectancy higher to 2 months, need repeated thoracocentesis
and ilung reexpansion is possible.
Inoperable malignant bowel obstruction
• Inoperable MBO causes severe symptoms and a short
life-expectancy.
• Palliative treatment is based on analgesics, antiemetics,
anti-secretory drugs and corticosteroids. Oral medications
must be avoided, use transdermal, subcutaneous
or intravenous routes of drug administration.
• Usually strong opiods are needed for pain relief.
Fentanyl is the opioid with less influence in intestinal
motility.
• Haloperidol is a butyrophenone with a strong antiemetic
action and is the antiemetic of first choice in MBO.
Pro-kinetic drugs such as metoclopramide are useful
but can increase colic pain. Antagonist of 5HT3 receptors
(granisteron, ondansetron) may be useful even
when other antiemetics have failed.
• Anticholinergics (hyoscine, scopolamine) and somatostatin
analogues (octreotide) are anti-secretory drugs of
first choice in MBO and can be used in combination.
Dose of octreotide suggested by subcutaneous route
(intermittent or continuous infusion): start 100 mcg
every 12 hours and increase to 300 mcg every 8 hours.
• Nasogastric tube drainage is uncomfortable and
increases risk of bronchial aspiration. Consider use of
gastric aspiration only if other measures fail to reduce
vomiting and pain.
Suggested References For Further Reading:
1. Parkin DM et al. Global cancer statistics, 2002. Cancer J Clin,
2005: 55: 74-108
2. Von Gruenigen V, Frasure HE, Reidy AM, Gil KM. Clinical disease
course during last year in ovarian cancer. Gynecologyc
Oncology, 2003 90: 619-624.
3. World Health Organization. Cancer Pain Relief- Second
Ediction- Geneva. Switzerland: World Health Organization,
1996: 1-69
4. Ventafridda V, Tamburini M, Caraceni A, De Conno F, Naldi F.
A validation study of the WHO method for cancer pain relief.
Cancer. 1987 Feb 15;59(4):850-6.
5. Zech DF, Grond S, Lynch J, Hertel D, Lehmann KA. Validation
of World Health Organization Guidelines for cancer pain relief:
a 10-year prospective study. Pain. 1995 Oct;63(1):65-76.
6. Mercadante S. Pain treatment and outcomes for patients with
advanced cancer who receive follow-up care at home. Cancer.
1999 Apr 15;85(8):1849-58.
7. Hanks GW, Conno F, Cherny N, Hanna M, Kalso E, McQuay
HJ, Mercadante S, Meynadier J, Poulain P, Ripamonti C,
Radbruch L, Casas JR, Sawe J, Twycross RG, Ventafridda V;
Expert Working Group of the Research Network of the
European Association for Palliative Care. Morphine and alternative
opioids in cancer pain: the EAPC recommendations. Br
J Cancer. 2001 Mar 2;84(5):587-93.
8. Ross JR, Riley J, Quigley C, Welsh KI. Clinical Pharmacology
and Phramacotherapy of Opioid Switching in Cancer Pain. The
Oncologist. 2006; 11:765-773.
9. Pawlik T, Sherwood T. Pleural and peritoneal catheters. In
Declan Walsh et al (eds) Palliative Medicine, pp 550-4.
Saunders Elsevier Inc, Philadelphia, 2009.
10. Ahmedzai S. Palliation of respiratory symptoms. In Doyle D et
al (eds) Oxford Textbook of Palliative Medicine, second edition,
pp 583-616. Oxford Medical Publications 1998.
11. Mercadante S, Casuccio A, Mangione S. Medical treatment for
inoperable malignant bowel obstruction: a qualitative systematic
review. J Pain Symptom Manage. 2007 Feb;33(2):217-23
12. Tuca A, Roca R, Sala C, Porta J, Serrano G, González-
Barboteo J, Gómez-Batiste X. Efficacy of Granisetron in the
Antiemetic Control of Nonsurgical Intestinal Obstruction in
Advanced Cancer: A Phase II Clinical Trial. J Pain Symptom
Manage. 2009 Feb;37(2):259-70.
Palliation of Advanced Ovarian Cancer 5

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