/The symptoms, diagnosis and treatment of ovarian cancer

The symptoms, diagnosis and treatment of ovarian cancer

The symptoms, diagnosis and treatment of ovarian cancer2018-09-23T16:17:09+00:00

Summary

Ovarian cancer forms in tissues of the ovary.  Most ovarian cancers are either ovarian epithelial carcinomas (cancer that begins in the cells on the surface of the ovary) or malignant germ cell tumours (cancer that begins in egg cells).

Causes

Predisposing factors seem to include a long lifetime of unopposed oestrogens circulating in that the disease is more common in those who had an early menarche, a late menopause and never been pregnant.

The fact that the disease is less common in those who have had multiple pregnancies fits in well with this thesis and the oral contraceptive pill (low oestrogen) is thought to be protective.

There is unquestionably a genetic predisposition to this disease in some patients and there has been much fruitful research recently on this topic. Where a woman has one affected first degree relative with the disease, there is a 2.5% risk (twice background) that she will contract the disease. Where there are two first degree relatives with the illness there is a 25% chance that she will contract ovarian cancer also. In families such as the latter instance there are commonly other cancers represented within the family and particularly breast and colorectal cancers. The predisposition oncogene BRCA, which has already been mentioned in connection with breast cancer, is also one the best worked out familial predisposition genes for ovarian cancer.

Incidence

The lifetime risk of a woman in the UK developing cancer of the ovary is 1.4%. Currently in the UK this is a higher incidence than cancer of the cervix (lifetime risk: 1.25%) and uterine/endometrial cancer (lifetime risk: 1.1%) but not as frequent as breast cancer (lifetime risk: 7%).

With regard to the time of occurrence of the disease, the disease is very rare in early life and slowly increases in incidence to peak in the age range 50-70 years.

Symptoms & diagnosis: Ovarian cancer

During the early stages of ovarian cancer, symptoms are often vague and ill-defined. Symptoms may include pelvic or abdominal discomfort, bloating, difficulty eating or feeling full, increased abdominal size, or urinary symptoms (urgency and frequency).

In some women, ovarian cancer is initially suspected when a mass or lump is felt during a routine pelvic examination. However, a mass is not always detectable in the early stages of ovarian cancer. Even when a mass is detected, it does not necessarily mean that the woman has ovarian cancer. A number of other non-cancerous conditions can cause masses.

Because the initial symptoms are vague and nonspecific, the majority of women have advanced stage disease by the time the diagnosis is made. At this point, the woman may have more prominent symptoms such as abdominal distention (swelling), nausea, or a significant loss of appetite.

Diagnosis

If ovarian cancer is suspected because of symptoms and/or an abnormal physical examination, imaging tests of the abdomen and pelvis (such as a CT scan) are usually recommended initially. In the presence of ascites (fluid in the peritoneal cavity,) a procedure to remove some fluid can be undertaken to confirm the diagnosis. Most women who are suspected of having ovarian cancer undergo a blood test to measure the level of a protein tumour marker called CA 125. If this is very high a diagnosis of ovarian cancer may be made with additional information from imaging and analysis of fluid from the abdomen.

The only way to diagnose ovarian cancer with certainty in the majority of patients is with an operation. This may involve an open operation (exploratory laparotomy) or using a small incision and a laparoscope (diagnostic laparotomy).

Stages

Based upon the findings during exploratory surgery, the tumour is formally “staged” according to the size, extent, and location of the cancer. Accurate staging during surgery is very important in determining a woman’s long-term outcome (prognosis) and choosing the appropriate treatment regimen after surgery.

In general, the stages I, II, III, and IV refer to the location of tumour involvement, while the subdivisions A, B, and C define the extent of tumour involvement. A higher stage of disease indicates more extensive tumour involvement. Worldwide, 23 to 33 percent of women have stage I disease at diagnosis, 9 to 13 percent of women have stage II, 46 to 47 percent have stage III, and 12 to 16 percent have stage IV.

Recommendations for postsurgical treatment vary according to disease stage. While a course of chemotherapy is recommended after surgery for all women with stage III or IV ovarian cancer, it may or may not be recommended for women who have stage I or II disease.

Treatment & outcomes: Ovarian cancer

The most important first procedure in the therapy of early ovarian cancer is surgery performed through a large abdominal excision, allowing the surgeon to inspect and stage the abdomen as well as the pelvis.

Where the disease is confined to the ovaries, Stage 1 disease, this may be curative on its own, but for higher risk patients in stage 1 (e.g. tumour rupturing through the capsule of the ovary) and all stage 2 cases, adjuvant chemotherapy is recommended. The term adjuvant therapy is used in cancer medicine to describe the administration of therapy, usually in the post-operative setting, to patients with no overt evidence of disease left following the operation, but who from risk factors are at high risk of later relapse. It has been demonstrated convincingly, for many cancers including ovarian cancer, that such therapy reduces this later relapse rate and that by giving the therapy early in the post-operative period rather than waiting for overt relapse to occur, the overall cure chance is increased.

The surgery usually involves the removal of the ovaries, the womb and the oviducts, as well as that covering membrane of abdominal contents, the omentum. Before the major surgery is carried out, the surgeon inspects the upper abdomen and samples the peritoneal surfaces at several sites to rule out stage 3.

Some patients who present with advanced disease will be advantaged in having ‘upfront (neo-adjuvant) chemotherapy and then the surgery when the disease has been shrunk to minimal proportions.

Adjuvant chemotherapy (i.e. chemotherapy after definitive surgery) is delivered to all but the earliest stage 1 patients –  in the post-operative setting and six courses of a regime of at least two drugs (e.g. carboplatin and paclitaxel) would be typical: the courses being three weeks apart. Most oncologists now divide early/stage 1 disease into low and higher risk stage 1 cases. Patients whose disease is low grade (or well differentiated – a histology term referring to the fact that the tumour’s appearance down the microscope is to resemble the normal ovarian epithelium) have a very good prognosis, with a five year survival rate in excess of 90%. On the other hand, patient’s whose disease is of higher grade fare worse, with those with intermediate grade histology (grade 2) having a five year survival of 77% and those with poorly differentiated disease (grade 3 histology) having a 55% five year survival. Obviously, this subdivision of stage 1 disease by histological grade has influenced oncologists as to whom they recommend chemotherapy.

Thus, for patients with low risk, early stage disease, including stages 1A and 1B (intact capsule, no tumour excrescences and no malignant ascites or positive peritoneal cytology) surgery alone is recommended. However, for patients with higher risk disease: stage 1C (ruptured capsule, tumour excrescences, positive peritoneal cytology or malignant ascites) or high grade histology, adjuvant chemotherapy is now recommended.

In patients presenting with advanced stage 3 disease or stage 4 disease, there is no point in primary surgery and all to be gained by reducing the tumour ‘burden’ first by ‘cytoreductive’ chemotherapy. Chemotherapy (nowadays the first line drugs being a combination of taxol and a platinum plus the smart durg : Bevacizumab/avastin* can usually shrink the cancer down and make the ascites disappear and then, when the tumour has been shrunk right down, the surgeon resects any residual disease and removes those organs listed above.

It has been shown that the addition of bevacizumab* (a molecularly targeting drug aimed at the VEGF pathway) enhances the efficacy of chemotherapy and this drug has found its way routinely into first line chemotherapy regimes for more advanced cases.

Particularly in patients with the BRCA mutaion, the use of a new ‘smart’ drug therapy: PARP – poly (ADP ribose) polymerase –  inhibitors ( e.g Olaparib) has added considerably to the response rates/duration in this disease. The rationale here is of interest: Ovarian cancer is driven by DNA repair faults and PARP inhibitors accentuate DNA repair incapacity and hence make them a lethal treatment for this disease. That they accentuate the effects of chemotherapy, such as platinum compounds, should lead to a greater effect when they are used in combination with platins rather than as single agents but toxicity to the bone marrow (particularly in BRCA mutation patients who are even more prone to DNA repair faults) is a side effect. Nevertheless, a maintenance therapy in higher risk cases, this is recommended and has proved to increase the remission period. This applies to sporadic and BRCA related cases.

What to do if the patient has proven resistant to all the foregoing therapies?

In the chemo-refractory patient, it is worthwhile performing next generation genomics on either a fresh specimen of the cancer by new tissue biopsy, or, a cell-free (cfDNA) specimen from a blood draw (as most advanced ovarian cancers release sufficient DNA degradation products into the circulation for this to be analysed – and it has the advantage that it does not represent one clone – as does a tissue biopsy – but the ‘mean’ of the tumour in the body quae genomics).

If the NGS demonstrates an ‘actionable’ (the Americans call it ‘druggable’) mutation, then the quest is on to find an inhibitor to the downstream effector pathway from the mutated gene. As time goes by we are developing more and more such inhibitors – often tyrosine kinase inhibitors – and this is certainly a path to be explored in the resistant cancer patient. That ovarian cancer seems to most often ‘driven’ by DNA repair faults, so there may be a pattern to be discovered in the type of mutations that drive this cancer and hopefully an opportunity for inhibitors.

The fact that there are so many DNA repair faults in this disease suggests that it will be antigenic (in the sense that the may  mutations that accrue from DNA repair deficiency lead to the transcription/translation of abnormal proteins that are recognised as foreign antigens by the immune system, which can be induced to attack the cancer (in a similar way to the rejection of a kidney transplant – that bears foreign antigens from another person).

The field is developing but the check-point inhibitors (such as pembrolizumab and nivolumab) represent a method of tearing down the smokescreen by which cancers hide their ‘foreign’ identity – by presenting PDL1 ligands, which silence the lymphocytes (PD receptors – one of the checkpoints that determine attack or not to the immune system) that would otherwise attack/reject them. It should be noted that, in foetal life, this is one method by which normal tissues record their normality to the immune system to prevent attack on themselves in later life. The realisation that cancers can mimic this self-tolerance mechanism has been a major breakthrough in Oncology in the last decade.

Interestingly and, from the foregoing not surprisingly, one side effect of this check-point inhiobitor therapy is that the patient may develop autoimmune disease – e.g. Hashimoto’s disease, Systemic Lupus Erythematosis etc.

Rarely are ovarian cancers susceptible to endocrine manipulation, such as tamoxifen therapy.

The old fashioned oral, chemotherapy, alkylating agent: chlorambucil has limited palliative roles.

P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics). Tel: +44-207-631-1632

Outcomes

A number of factors influence the success of treatment for ovarian cancer. Treatment tends to be more successful when the cancer is diagnosed at an early stage, and in younger women.

One of the most important factors influencing the outcome of treatment is the amount of tumour that remains after the initial surgery (i.e. the success of the initial debulking procedure). This is the reason that the surgeon aims to remove as much of the cancerous tissue as possible during the initial surgery – or consider neo-adjuvant chemotherapy.

The patients who relapse are regrettably many for only 25% of the total ovarian population present with the highly curable stage 1 disease. The decision for repeating chemotherapy would be made on prior response, the duration of remission and drugs used. Treatment at relapse is palliative, some drugs can be reused. The choice of drugs are varied and should be offered with a view to optimise quality of life.

Screening

The topic of screening for ovarian cancer is currently evoking a high level of interest, particularly in the families where there appears to be a genetic predisposition. Annual pelvic ultrasound examinations and serum CA-125 levels are performed in these patients but on a population wide basis, ovarian screening has not established itself as producing the ‘pick-up’ rates that would justify its widespread adoption.

Patients with a BRCA mutation, who may well elect to undergo bilateral mastectomies to forestall the 85% risk of developing breast cancer, should also consider prophylactic bilateral oophorectomy, once they have had t heir families – after genetic counselling.

Questions & answers about ovarian cancer

Question

The ovaries were removed because of genetic reasons.

In 2009, the patient was diagnosed with ovarian cancer in the abdominal cavity.

In 2010 the patient received chemotherapy with Taxotere every 3 weeks in total 6 times.

In 2011, the patient received chemotherapy with Caelyx and Carboplatin every 4 weeks, in total six times, completed in July 2011. The patient received infusion two times weekly with Magnesium until august 2011.

A. Can the patient acquire more targeted treatment types with and without chemotherapy?
B. It is possible to get Tailor-made treatments in relation to her cell configuration.
C. Can you recommend other kind of treatments?
D. Are there other methods to treat the magnesium deficiency?

Answer

The first point of interest to the oncologist is that this 56 year old lady has been counselled to have her ovaries removed on genetic grounds. This only occurs in patients with a strong likelihood of genetic risk of subsequent ovarian cancer – such a BRCA family members and I wonder if this is the case with this lady. Secondly, the origin of the cancer is said to be cervix but then we are told that she was diagnosed as ovarian cancer in 2009. I suspect that it is ovarian cancer all the way through.

We are told that she had an abdominal operation, which must have been for extensive disease if she has been left with an ileostomy and I note that there is currently a suspicion of a liver metastasis. We are told that she has had carboplatin, taxotere and caelyx chemotherapy (all of which again suggest that the origin was ovary as these are the drugs that are active against ovarian cancer). I strongly suspect that the low magnesium level was due to the platinum drug as this is a well recognised side effect of these drugs. The treatment is magnesium suppplements usually orally although they can be given intravenously in cases where the level is very low.

Targeted/’tailor-made’ therapies have been explored but currently are not having success. Research drug regimens might be worth exploring and there is a Sarah Cannon centre in London (93 Harley Street London W1) which may be able to give you advice (e.g. PARP inhibitors if she is a BRCA gene carrier case). Other chemotherapy regimens containing drugs might include cyclophosphamide exist, but, by themselves, are unlikely to be durably effective in a patient who has relapsed through the regimens that are listed above.

Question

A 70 year-old lady is suffering from primary Ovarian cancer which has spread to stomach and pelvis. The liver, Pancreas, Spleen and Kidneys appear normal.

She has received 3 sessions of chemotherapy to date.

Can an operation be performed to remove the Ovary which is the primary affected site?

What is the best prevention for spread?

Answer

In general, for fit patients, with metastatic ovarian carcinoma and primary peritoneal carcinoma there is a role for cyto-reductive or debulking surgery where the affected sites of disease can be removed. In the UK this is carried out by specialist surgeons who have an interest in this area. The level of expertise required to perform a complete operation in a fit patient is high and if a patient has responded to chemotherapy such surgery should be considered. If an ovary has been confirmed as a primary site then its removal in addition to other sites of disease would be advised.
Following on from chemotherapy and if surgery is undertaken, most specialists would advise surveillance. There are no known medications presently which would be absolutely effective in preventing recurrence. There is also no strong evidence that measurement of serum tumour markers (CA125) can prevent the natural history of this disease.