PatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
Ovarian cancer is a malignancy arising from the ovary. It is the leading cause of death from gynaecological cancer in the UK. Early symptoms may be subtle and presentation is often late. The vast majority of ovarian cancers are classified as epithelial, as they arise from the epithelial surface of the ovary. Malignant ovarian tumours may be solid or cystic.
There are many different types of ovarian cancer, and the age group affected, management and prognosis vary widely between them. Classification varies across the literature, but can be broadly broken down as follows.
- Epithelial ovarian tumours:
- The most common type, accounting for 85-90% of all ovarian cancers.
- Arise from the epithelial surface of the ovary.
- Occur most commonly in women aged over 50 years.
- There are a number of subtypes of epithelial tumours. These include:
- Serous. The most common subtype, accounting for more than half of epithelial tumours. Most occur in women between 40-60 years of age.
- Endometrioid. 10-20% of epithelial tumours. Most common between ages 50-70.
- Clear cell tumours. 5-6% of epithelial tumours. Affect ages 40-80. Often associated with endometriosis.
- Mucinous tumours. 10% of epithelial tumours. Most commonly affect ages 30-50.
- Brenner (transitional cell) tumours. Rare.
- Undifferentiated tumours. Do not fit into any of the above categories. 15% of epithelial tumours.
- Germ cell tumours:
- Derived from primitive germ cells of embryonic gonad.
- Account for 2-10% of all ovarian tumours.
- Most common in younger women under the age of 35.
- Often curable with high survival rates.
- Usually present as a rapidly enlarging abdominal mass, which causes considerable pain.
- They often rupture or undergo torsion.
- Dysgerminoma is the most common type and has an excellent prognosis for Stage I tumours.
- Types of germ cell tumours are:
- Endodermal sinus tumours.
- Embryonal carcinoma.
- Sex cord-stromal tumours:
- Derive from connective tissue cells.
- Less than 5% of all ovarian tumours.
- Sertoli-Leydig tumours.
- Granulosa cell tumours.
- Borderline tumours (tumours of low malignant potential):
- These do not fit into the category of benign or malignant.
- 10-15% of ovarian tumours
- Managed primarily by surgery and do not respond well to chemotherapy.
- Types are:
- Borderline serous - the most common.
- Borderline mucinous.
- Borderline endometrioid.
- Metastatic tumours. Ovarian secondary tumours may arise from the breast, gastroentestinal tract, haemopoietic system, uterus or cervix.
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Ovarian cancer is the fifth most common cancer in women. It has a lifetime risk of around 2% for women in England and Wales. It is the leading cause of death from gynaecological cancer.
Incidence rate in England in 2009 was 17.1 per 100,000 women. There were 5,861 cases in England in 2009, and 3,478 deaths.
In the UK as a whole, there were 7,011 new cases in 2010, and 4,295 deaths.
Age-specific Incidence rates rise with age, and the peak is in the 70s-80s; however, the number of cases is highest in the 60-70 age range. Median age at diagnosis is 61 years, peaking at 75-79 years but it can occur at any age. Elderly women are more likely than younger women to be in an advanced stage of disease at initial diagnosis.
- Increasing age.
- Lifestyle. It has been estimated that 21% of ovarian cancer can be attributable to lifestyle.Factors which increase the risk include:
- Smoking. It is estimated that 2% of cases may be caused by smoking.
- Obesity. There is evidence of increased risk in postmenopausal women who are overweight.
- Lack of exercise. There is some evidence that regular physical exercise protects against some forms of ovarian cancer.
- Talcum powder use (pre-1975, after which regulation was introduced to prevent the contamination of talcum powder with asbestos).
- History of infertility and use of fertility drugs - eg, clomifene.
- Nulliparous women are more likely to develop an ovarian malignancy than women who have been pregnant three or more times.
- Early menarche and late menopause.
- Family history of ovarian cancer. Women with a first-degree relative with ovarian cancer have 3-4 times the risk of developing the disease. However, only 10% of cases arise in women with a positive family history.
- Presence of BRCA1 and 2 genes increases susceptibility. Women with a prior history of ovarian cancer or breast cancer have an increased risk of ovarian cancer. BRCA1 gene confers familial susceptibility for the breast-ovarian cancer syndrome.
- History of endometriosis confers a significant increased risk.Studies suggest a link between ovarian endometriosis and clear-cell ovarian cancer, possibly linked to mutation of the ARID1A gene.
- Asbestos exposure.
- Hormone replacement therapy (HRT):[12, 13]
- Further studies are needed to ascertain the exact risk. There does appear to be a small increased risk of ovarian cancer associated with the use of HRT for more than five years. This is present for both oestrogen-only and combined HRT. Risk of serous and endometrioid tumours is increased, although risks of some other types may be reduced.
- Past users of HRT are not at an increased risk of developing or dying from ovarian cancer.
Any factor which prevents or inhibits ovulation appears to protect against ovarian cancer. Protective factors therefore include:
- Early menopause
- The oral contraceptive pill
- No screening method has been shown to affect mortality significantly. Screening may result in unnecessary surgery. A large trial in the USA in 2011 based on CA 125 (cancer antigen 125) levels and ultrasound scan confirmed there was no benefit to screening the general population.A UK-based study is expected to report in 2015.
- 2013 Scottish Intercollegiate Guidelines Network (SIGN) guidelines advise that women with a family history that appears to increase their risk of developing ovarian cancer should be referred to a clinical genetics service for full assessment of risk. Any of the following criteria would signify an increased risk:
- The woman is a known carrier of BRCA1, BRCA2, or any other known relevant cancer gene mutations.
- She has a first-degree or second-degree relative who carries a known relevant gene mutation.
- Two family members who are first-degree relatives of each other have ovarian cancer.
- A family member who has ovarian cancer at any age and is a first-degree relative of someone who developed breast cancer under the age of 50, or of two who developed it under the age of 60.
- Three or more family members with colon cancer; or two with colon cancer and one with stomach, ovarian, endometrial, small bowel or urinary tract cancer in two generations. (One must be diagnosed under the age of 50 and they should be first-degree relatives of each other.)
- One family member with both breast and ovarian cancer.
- These high-risk women should be offered genetic screening and counselling. They may be offered referral for prophylactic salpingo-oophorectomy.
- Women diagnosed with ovarian cancer should be offered genetic screening for the relevant gene mutations.
75% of patients present with advanced (Stage III or IV) disease:
- Onset of symptoms is insidious. Early symptoms are often vague, such as abdominal discomfort, abdominal distension or bloating, urinary frequency or dyspepsia.Constitutional symptoms include fatigue, weight loss, anorexia and depression.
- It most commonly presents with a pelvic or abdominal mass that may be associated with pain. Abdominal, pelvic or back pain is usually a late sign and seen only with early disease that is complicated by torsion, rupture, or infection.
- It may cause abnormal uterine bleeding.
- Often associated with ascites. One third of patients with ascites also have a pleural effusion.
- Ovarian cancers metastasise to pelvic and peri-aortic lymph nodes, as well as over the pelvic and abdominal peritoneum.
- Benign ovarian tumour or cyst.
- Uterine or tubal mass.
- Bowel mass or primary peritoneal carcinoma.
- Secondary carcinoma: breast, gastrointestinal tract, lymphomas and pelvic-organ tumours may all metastasise to ovary.
In primary care
- Refer urgently any woman with ascites and/or a pelvic or abdominal mass not obviously fibroids.
- Consider tests for ovarian cancer in women (especially over the age of 50) who present frequently (particularly more than twelve times a year) with the following symptoms:
- Abdominal distension (often described as 'bloating').
- Early feeling of fullness whilst eating (satiety) and/or loss of appetite.
- Pelvic or abdominal pain.
- Urinary frequency or urgency.
- Consider ovarian cancer tests for women of 50 or over who have a 12-month history of irritable bowel syndrome (this rarely presents for the first time at this age).
- Also consider testing women who present with unexplained fatigue, weight loss or change in bowel habit.
- Women who do not warrant testing at the time should be advised to return if they have any symptoms which persist or become more frequent
If the woman comes into a category that warrants investigation:
- Organise a CA 125 test.
- If this is reported as raised (35 IU/mL or greater) arrange pelvic and abdominal ultrasound scans.
- If the scan is suggestive of ovarian cancer, refer the patient urgently.
- Consider investigating women for other causes if they have a normal or raised CA 125 but a normal scan.
In the absence of any definitive diagnosis, advise the woman to return if her symptoms become more frequent or persistent.
In secondary care
- CA 125, pelvic and abdominal ultrasound, if not already done in primary care.
- Consider CT scan of the pelvis and abdomen if CA 125, ultrasound and clinical status suggest malignancy, to establish the extent of disease (may also need CT scan of the thorax if clinically appropriate).
- CT or MRI scan can be used for pre-operative staging.CT is the investigation of choice in the UK, though MRI may be useful for imaging other pelvic tumours, or if contrast-enhanced CT cannot be used.
- National Institute for Health and Care Excellence (NICE) and SIGN guidelines both advise using the Risk Malignancy Index 1 to assess the likelihood of malignancy, and if >250 (NICE) or >200 (SIGN), refer to a specialised multidisciplinary team.
This score is calculated as ultrasound score x menopausal score (where 1 = premenopausal, and 3 = postmenopausal) x CA 125 level in U/mL. The ultrasound score is the number of the following findings on scan: multilocular cyst, solid areas, bilateral lesions, ascites, intra-abdominal metastases. (0 = no abnormalities, 1 = one abnormality, 3 = two or more).
- In women under 40, exclude endodermal sinus tumours by arranging alpha-fetoprotein (AFP). Also check beta human chorionic gonadotrophin (beta-hCG) to identify women who may have dysgerminomas, embryonal carcinomas or choriocarcinomas.
- If cytotoxic therapy is to be offered, discuss risks and benefits of obtaining tissue confirmation first. This may be done at laparotomy, or via percutaneous image-guided biopsy
- Occasionally, chemotherapy may be offered without tissue confirmation.
Three different familial syndromes of cancer have been identified:
- Site-specific: at risk of development of ovarian cancer only.
- Breast-ovarian: increased risk of either cancer alone or in combination. BRCA1 and BRCA2 susceptibility genes are responsible for at least 90% of hereditary breast-ovarian cancer and site-specific ovarian cancer cases.
- Nonpolyposis colon carcinoma families: increased risk of ovarian, endometrial and breast cancer.
The Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) staging system remains the best indicator of prognosis and guides management strategy.
- Stage I ovarian cancer is limited to the ovaries:
- Stage IA: tumour is limited to one ovary, the capsule is intact, no tumour on ovarian surface and no malignant cells in ascites or peritoneal washings.
- Stage IB: tumour is limited to both ovaries, capsules intact, no tumour on ovarian surface and no malignant cells in ascites or peritoneal washings.
- Stage IC: tumour is limited to one or both ovaries with any of the following: capsule ruptured, tumour on ovarian surface, malignant cells in ascites or peritoneal washings.
- Stage II ovarian cancer is tumour involving one or both ovaries with pelvic extension and/or implants:
- Stage IIA: extension and/or implants on the uterus and/or Fallopian tubes. No malignant cells in ascites or peritoneal washings.
- Stage IIB: extension to and/or implants on other pelvic tissues. No malignant cells in ascites or peritoneal washings.
- Stage IIC: pelvic extension and/or implants (Stage IIA or Stage IIB) with malignant cells in ascites or peritoneal washings.
- Stage III ovarian cancer is tumour involving one or both ovaries with microscopically confirmed peritoneal implants outside the pelvis:
- Superficial liver metastasis equals Stage III.
- Stage IIIA: microscopic peritoneal metastasis beyond pelvis (no macroscopic tumour).
- Stage IIIB: macroscopic peritoneal metastasis beyond pelvis less than 2 cm in greatest dimension.
- Stage IIIC: peritoneal metastasis beyond pelvis greater than 2 cm in greatest dimension and/or regional lymph node metastasis.
Stage IV ovarian cancer is tumour involving one or both ovaries with distant metastasis. Parenchymal liver metastasis equals Stage IV.
If epithelial ovarian cancer is suspected on the basis of physical examination and imaging, an exploratory laparotomy is usually done for histological confirmation, staging and tumour debulking. The standard comprehensive surgical staging approach consists of a total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH and BSO) along with examination of all peritoneal surfaces, an infracolic omentectomy, biopsies of pelvic and para-aortic lymph nodes and clinically uninvolved areas and peritoneal washings.
Further management is then determined by the stage and histology of the tumour. Adjuvant therapy to surgery for epithelial ovarian cancer varies according to the stage of the disease but, in most cases, will consist of chemotherapy. Because of late diagnosis, much of the appropriate management is often directed towards palliative care.
A clinical nurse specialist should be present when the diagnosis of ovarian cancer is given.
- Standard treatment is surgery (staging and optimal debulking) followed by adjuvant chemotherapy in most cases. Even if optimal surgery is not possible, removing as much tumour as possible will provide significant palliation of symptoms.
- Borderline lesions may be treated with conservative surgery.
- In early disease, assessment of peritoneal cytology, hysterectomy, removal of ovaries and Fallopian tubes and infracolic omentectomy should be performed.
- Management of early ovarian cancer in young women who desire future childbearing may be more conservative, ie a unilateral salpingo-oophorectomy and staging but the long-term safety is uncertain. Treatment choice will depend on type of tumour and stage, and in partnership with the patient, who will need to be fully informed about prognosis.
- In advanced disease, debulking is recommended. Interval debulking is recommended if there is evidence of a response to chemotherapy as determined by CA 125 and imaging. There is evidence that complete clearance of all visible disease at the time of surgery is associated with a better prognosis.
- The value of surgery for relapse and palliation remains unclear.
- Adjuvant platinum-based chemotherapy improves survival in early (Stage I/IIa) epithelial ovarian cancers.
- Chemotherapy is advised for all women with Stage II-IV disease following surgery. The standard regime is paclitaxel and carboplatin given intravenously every three weeks for six cycles.
- Intraperitoneal chemotherapy may be used as an alternative, and evidence suggests it may be more effective, but as it is more difficult to deliver and associated with more risks, is not standard treatment.
- New biological therapies are being developed and undergoing trials as understanding of the molecular biology of the types of ovarian cancer has advanced. These targeted treatments include:
- Bavacizumab. This is a monoclonal antibody against vascular epithelial growth factor (VEGF). This helps to prevent angiogenesis (the formation of new blood vessels), which is an important part of cancer growth. This is not currently approved for use by NICE or the Scottish Medicines Consortium, (reviewed in 2013.)[16, 23, 24]
- Poly (ADP-ribose) polymerase (PARP) Inhibitors - eg, olaparib. These are able to target cancer cells whilst sparing normal cells.
- CA 125 may be used to monitor efficacy of treatment, and to monitor for recurrence. The need to test it in follow-up, however, can be guided by the presence of symptoms.
- Advanced epithelial ovarian cancer is very sensitive to chemotherapy, with responses in the range of 70-80% to first-line chemotherapy. The majority (70-75%), however, relapse and ultimately die of chemotherapy-resistant disease. Second-line chemotherapy to date is disappointing in all forms of epithelial ovarian cancer, with virtually no chance of successful second-line treatment following failure of initial regime.
- Germ cell tumours are treated with surgery and multi-agent chemotherapy in most cases.
- The less common types and subtypes of ovarian cancer behave in different ways, and need different treatment, but there is not the evidence available to guide strategy to the same extent. Guidelines mainly apply to epithelial cancers.
- NICE guidelines for the use of chemotherapy:
- It is recommended that paclitaxel in combination with a platinum-based compound or platinum-based therapy alone (cisplatin or carboplatin) be offered as alternatives for first-line chemotherapy (usually following surgery) in the treatment of ovarian cancer.
- When relapse occurs after an initial (or subsequent) course of first-line chemotherapy, additional courses of treatment should be considered, using different treatment options.
- Paclitaxel in combination with a platinum-based compound (carboplatin or cisplatin) is recommended as an option for the second-line (or subsequent) treatment of women with platinum-sensitive or partially platinum-sensitive advanced ovarian cancer, except in women who are allergic to platinum-based compounds.
- Single-agent paclitaxel is recommended as an option for the second-line (or subsequent) treatment of women with platinum-refractory or platinum-resistant advanced ovarian cancer and for women who are allergic to platinum-based compounds.
- Pegylated liposomal doxorubicin hydrochloride (PLDH) is recommended as an option for the second-line (or subsequent) treatment of women with partially platinum-sensitive, platinum-resistant or platinum-refractory advanced ovarian cancer and for women who are allergic to platinum-based compounds.
- Topotecan is recommended as an option for second-line (or subsequent) treatment only for those women with platinum-refractory or platinum-resistant advanced ovarian cancer, or those who are allergic to platinum-based compounds, for whom PLDH and single-agent paclitaxel are considered inappropriate.
- The following definitions are used by NICE:
- Platinum-sensitive ovarian cancer: disease that responds to first-line platinum-based therapy but relapses 12 months or more after completion of initial platinum-based chemotherapy.
- Partially platinum-sensitive ovarian cancer: disease that responds to first-line platinum-based therapy but relapses between 6 and 12 months after completion of initial platinum-based chemotherapy.
- Platinum-resistant ovarian cancer: disease that relapses within six months of completion of initial platinum-based chemotherapy.
- Platinum-refractory ovarian cancer: disease that does not respond to initial platinum-based chemotherapy.
- There is little evidence that radiotherapy is superior to chemotherapy for advanced Stage III and IV disease.
- Radiotherapy can be used in earlier disease with small residual tumour bulk. There are few studies comparing radiotherapy and chemotherapy in Stage I and II disease.
- Complications of the tumour: torsion, rupture, infection.
- Complications of treatment: bone marrow depression, infection, neurotoxicity, nephrotoxicity, ototoxicity.
- Complications of advanced disease: malnutrition, electrolyte imbalance, small and large bowel obstruction, infection, ascites, pleural effusion.
- Overall, five-year survival in ovarian epithelial carcinoma is 35%.This low rate occurs because of the preponderance of late-stage disease at diagnosis. Five-year survival rates drop as follows with stage:
- Stage I: 92%
- Stage II: 55%
- Stage III: 21.9%
- Stage IV: 5.6%
- Patients under the age of 50 in all stages have considerably better five-year survival than older patients (40% compared with 15%). In 2005-2009, five-year survival ranged from 87% of 15- to 39-year-olds to 16% of 80- to 99-year-olds.
- Survival rates have doubled in a 30-year period. This is thought to have resulted from advances in surgery, better chemotherapy agents such as platinum-based drugs and the more co-ordinated care offered by specialised centres.
- The subtypes of epithelial cancers differ prognostically.
- Dysgerminomas treated by surgery and radiation have an excellent cure rate in both early- and late-stage disease.
- Endodermal sinus tumour has poor prognosis.
Further reading & references
- Jacobs IJ, Menon U, Ryan A, et al; Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2015 Dec 16. pii: S0140-6736(15)01224-6. doi: 10.1016/S0140-6736(15)01224-6.
- Fertility Sparing Treatments in Gynaecological Cancers: Scientific Impact Paper; Royal College of Obstetricians and Gynaecologists, 2013
- Partridge E, Kreimer AR, Greenlee RT, et al; Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol. 2009 Apr;113(4):775-82.
- CancerHelp UK
- Macmillan Cancer Support
- Ultra-radical (extensive) surgery for advanced ovarian cancer, NICE Interventional Procedure guidance (Nov 2013)
- Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for treating recurrent ovarian cancer; NICE Technology Appraisal Guidance, April 2016
- A profile of ovarian cancer in England; Ovarian Cancer Resources, National Cancer Intelligence Network (NCIN)
- Guide to types and stages of ovarian cancer: Dr Sarah Blacklidge; Ovarian cancer action, 2012
- Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2013)
- Ovarian cancer - the recognition and initial management of ovarian cancer; NICE Clinical Guideline (April 2011)
- Overview of Ovarian Cancer in England: Incidence, Mortality and Survival; National Cancer Intelligence Network (NCIN)/Trent Cancer Registry report, November 2012
- Ovarian cancer statistics; Cancer Research UK
- Parkin DM, Boyd L, Walker LC; 16. The fraction of cancer attributable to lifestyle and environmental factors in Br J Cancer. 2011 Dec 6;105 Suppl 2:S77-81. doi: 10.1038/bjc.2011.489.
- Parkin DM; 2. Tobacco-attributable cancer burden in the UK in 2010. Br J Cancer. 2011 Dec 6;105 Suppl 2:S6-S13. doi: 10.1038/bjc.2011.475.
- Gayther SA, Pharoah PD; The inherited genetics of ovarian and endometrial cancer. Curr Opin Genet Dev. 2010 Jun;20(3):231-8. doi: 10.1016/j.gde.2010.03.001. Epub 2010 Apr 24.
- Melin A, Sparen P, Bergqvist A; The risk of cancer and the role of parity among women with endometriosis. Hum Reprod. 2007 Nov;22(11):3021-6. Epub 2007 Sep 13.
- Wiegand KC, Shah SP, Al-Agha OM, et al; ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010 Oct 14;363(16):1532-43. Epub 2010 Sep 8.
- Morch LS, Lokkegaard E, Andreasen AH, et al; Hormone therapy and different ovarian cancers: a national cohort study. Am J Epidemiol. 2012 Jun 15;175(12):1234-42. doi: 10.1093/aje/kwr446. Epub 2012 Apr 19.
- MHRA statement: Hormone replacement therapy (HRT) - latest data from the Million Women Study and Women's Health Initiative trial; Medicines and Healthcare products Regulatory Agency, 19 April 2007
- Buys SS, Partridge E, Black A, et al; Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011 Jun 8;305(22):2295-303. doi: 10.1001/jama.2011.766.
- UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)
- Management of epithelial ovarian cancer; Scottish Intercollegiate Guidelines Network - SIGN (Nov 2013)
- Hennessy BT, Coleman RL, Markman M; Ovarian cancer. Lancet. 2009 Oct 17;374(9698):1371-82. Epub 2009 Sep 28.
- Bankhead CR, Collins C, Stokes-Lampard H, et al; Identifying symptoms of ovarian cancer: a qualitative and quantitative study. BJOG. 2008 Jul;115(8):1008-14.
- Jelovac D, Armstrong DK; Recent progress in the diagnosis and treatment of ovarian cancer. CA Cancer J Clin. 2011 May-Jun;61(3):183-203. Epub 2011 Apr 26.
- Winter-Roach BA, Kitchener HC, Lawrie TA; Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database Syst Rev. 2012 Mar 14;3:CD004706. doi: 10.1002/14651858.CD004706.pub4.
- Jaaback K, Johnson N, Lawrie TA; Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev. 2011 Nov 9;(11):CD005340. doi: 10.1002/14651858.CD005340.pub3.
- Targeted Therapies for the Management of Ovarian Cancer; Royal College of Obstetricians and Gynaecologists Scientific Impact Paper, Sept 2013
- Bevacizumab in combination with paclitaxel and carboplatin for first-line treatment of advanced ovarian cancer; NICE Technology Appraisal, May 2013
- Bevacizumab in combination with gemcitabine and carboplatin for treating the first recurrence of platinum-sensitive advanced ovarian cancer; NICE Technology Appraisal, May 2013
- Ovarian cancer (advanced) - paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan; NICE Technology Appraisal, 2005
Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but makes no warranty as to its accuracy. Consult a doctor or other healthcare professional for diagnosis and treatment of medical conditions. For details see our conditions.
Dr Colin Tidy
Dr Mary Harding
Dr John Cox