Vol 53:  june • juin 2007  Canadian Family Physician • Le Médecin de famille canadien  983 Commentary A terrible beauty A physician’s story of ovarian cancer Linda J. Spano BScN MD MHSc CCFP W hen the fourth member of my 9-person book club was diagnosed with breast cancer, I felt grateful for my own good health and good fortune. We were all baby boomers in our 50s, Western, white, educated, socioeconomically advan- taged women. One in 9 Canadian women will confront breast cancer in her lifetime. We had entered the “at risk” population, but these seemed terrible odds. Then it was me. I was diagnosed with one of the relatives of ovar- ian cancer—a highly aggressive peritoneal tumour with ascites and widespread abdominal metastases. Stage 3. A woman can get this kind of cancer even if she has had a hysterectomy and oophorectomy. It has become important for me to find a way to make my experience useful to my successors in this ill- ness. Few family doctors see many patients with ovar- ian cancer in their practices. In my practice as a family doctor, only 2 women with my diagnosis came to me, both very late in the course of their disease. Risk factors and genetic testing I was unaware until I was researching my own blood- line that 3 of the 6 women in my paternal grandmoth- er’s family had died of either breast or ovarian cancer. I had only 1 other risk factor, never having had children. Few  studies  of  risk  factors  have  focused  specifi- cally  on  ovarian  cancer,  but  we  have  learned  from  the overlap of many studies that have targeted breast  cancer;  age,  familial  predisposition,  and  less  child- bearing  are  shared  risks  with  breast  cancer.  Other  risk  factors  for  ovarian  cancer  include  polycys- tic  ovarian  syndrome  and  more  frequent  menstrual  cycling,  including  early  onset  of  menses  and  late  menopause.  Use  of  oral  contraceptives  substantially  reduces the risk.1  Having  1  first-degree  relative  or  2  or  more  clus- tered  second-degree  relatives  with  breast  or  ovar- ian  cancer,  especially  before  menopause,  increase  a  woman’s  risk  for  breast  and  ovarian  cancer.  Descendants of Ashkenazic Jews are at greater risk of  having the BRCA1 and BRCA2 genes, which are asso- ciated with a lifetime occurrence of breast or ovarian  cancer of up to 40%. Approximately 2% of the general  population  carry  BRCA1  or  BRCA2  gene.  In  general,  known familial factors account for only about 10% of  ovarian cancers.2  Screening and prevention Genetic testing is not something we do for ourselves. We do it to determine choices for our offspring and our sisters and their daughters. Testing is for them. Regular  examinations  and  Papanicolaou  smears  do  not  help  detect  ovarian  cancer  in  its  early  stages.  Serendipitous  testing,  usually  to  investigate  another  problem,  sometimes  uncovers  an  unexpected  early  cancer.  For  those  with  risk  factors,  primarily  family  history  or  having  the  BRCA1  or  BRCA2  genes,  stud- ies  are  under  way  to  determine  whether  biomarkers,  such as the cancer antigen 125 test (CA125) and pelvic  ultrasound, can alert physicians to the need for further  investigations in time.3 For women at high risk, most physicians recommend  annual  assessment  of  CA125  levels,  bimanual  pelvic  examination, and transvaginal ultrasound for screening,  until better measures are developed.4 The  need  for  better  screening  methods  is  clear.  The  critical  question  is,  Will  such  screening  affect  out- comes?  Even  when  family  history  is  compelling,  the  drastic step of surgical removal of breasts, ovaries, and  uterus  is  a  very  difficult  step  to  take  based  only  on  probability.  The  US  Preventive  Services  Task  Force  rec- ommends considering prophylaxis with drugs shown to  reduce breast cancer incidence, such as tamoxifen and  raloxifene.2  Symptoms My own symptoms hit quickly. There was new pain—pain when my bladder filled, especially at night. There was dis- comfort with intercourse and with pressure on my left lower abdomen. Ovarian  cancer  usually  metastasizes  into  the  abdo- men  before  it  causes  symptoms.  While  most  public  education urges early attention to warning symptoms,  only  about  10%  of  ovarian  cancers  are  diagnosed  at  a  curable  stage.5  By  the  time  symptoms  begin—uri- nary  urgency,  abdominal  bloating,  bowel  irritability,  fatigue,  painful  intercourse—the  cancer  is  virtually  always  widespread.  Weight  loss,  breathlessness,  ane- mia,  early  satiety,  and  abdominal  pain  are  symptoms  that come later.6 Diagnosis Most of the women I have come to know experienced the frustration of not having their symptoms recognized 984  Canadian Family Physician • Le Médecin de famille canadien  Vol 53:  june • juin 2007 Commentary as serious. As a result, several weeks or months passed before appropriate investigations were undertaken. One  study  indicates  that  most  women  have  symp- toms  for  at  least  6  months  before  diagnosis.4  Doctors  often initiate investigation with gastrointestinal or bowel  studies  in  light  of  the  symptoms,  but  these  studies  are  generally  not  helpful.  Despite  its  vague  presentation,  it  is  the  persistence or escalation  of  symptoms  in  ovarian  cancer that is serious.6  Investigation  of  suspicious  symptoms  should  include  a  pelvic  examination,  assessment  of  CA125  levels,  and  transvaginal  ultrasound.  On  pelvic  examination,  an  adnexal  mass  is  usually  evident,  but  the  ovary  is  not  always  enlarged.  Computed  tomography  scanning  is  often  necessary.  Pelvic  fluid  should  not  be  dismissed  as  “normal,” particularly in postmenopausal women.4  The  CA125  test  is  the  best  single  tool  we  have  to  identify  and  follow  a  tumour.  Levels,  however,  are  not  numerically  correlated  to  extent  of  disease,  except  within  a  given  individual.  Although  more  than  80%  of  women  with  ovarian  tumours  have  elevated  CA125  lev- els  when  diagnosed,  levels  are  often  not  elevated  until  the cancer has spread. False-positive and false-negative  results (early in the disease) can occur.7 Treatment It is not uncommon to think that, faced with this illness, a person might decide not to accept treatment; however, this rarely happens. Meeting women who have been through surgery and chemotherapy, who are finding meaningful life not only during the glorious remission, but also during the treatment process itself, will kindle the weakest hope and strengthen the remotest resolve. Most of the interven- tions do not add to the quantity of time we live, but rather to the quality. During  the  past  10  to  15  years,  most  women  with  ovarian cancer have had initial surgery to reduce tumour  bulk, ideally to microscopic size. Almost 80% of women  are  candidates  for  surgery  either  before  or  after  ini- tial  chemotherapy.  They  might  require  an  ostomy  from  bowel or bladder structures to achieve the best possible  results.8  Surgery  is  followed  by  chemotherapy,  which  usually  entails  6  to  8  cycles  of  platinum  and  taxane  drugs, each lasting 3 to 4 weeks. Women with “platinum- sensitive” tumours generally go into a remission lasting  at least 6 months.9,10 Recently,  intraperitoneal  chemotherapy  as  a  treat- ment  option  has  been  reexamined.  A  major  US  study  found  that  a  combination  of  intravenous  and  intraperi- toneal  chemotherapy  after  primary  surgery  increased  time  to  recurrence  by  a  median  of  12  months  and  sur- vival  by  16  months.11  Although  this  study  demonstrates  the first major improvement in survival in many years, it  is  associated  with  more  severe  side  effects  in  the  short- term  and  can  be  performed  only  with  optimal  surgical  results and in patients free of other illness.  Many women I know have sought the advice of thera- pists in the “wellness” or naturopathic movement to try to maximize nutritional and immunologic strengths. Other  commonly  accessed  resources  include  ther- apeutic  touch,  relaxation,  massage,  neurolinguistics,  healing  workshops,  and  spiritual  guidance.  There  is  lit- tle study data available to evaluate these therapies with  regard  to  objective  benefits  in  cancer  care,  but  they  are  regarded  as  very  helpful  by  women  struggling  to  cope  with the disease. Prognosis Living under the spectre of a short life expectancy is shocking, confusing, depressing, unnerving, and—some- times—has a terrible beauty. Every moment becomes precious. I have had my remission. Now I have my own “appointment in Samarra.”12 More  than  80%  of  those  diagnosed  with  epithelial  ovarian  cancer  are  already  in  advanced  metastatic  stages. Fewer than 10% of these women will live 5 years.  They  will  be  “long-term  survivors”  and  will  typically  have  had  several  rounds  of  chemotherapy  with  shorter  and  shorter  remissions.  More  than  half  of  those  who  respond  to  platinum  chemotherapy  relapse  by  12  to  18  months.  Median  survival  ranges  from  28  to  40  months.  While there are other less lethal types of ovarian cancer,  they constitute less than 20% of cases.5 Relapsed ovarian cancer is currently incurable. While  ovarian  cancer  in  Canada  affects  only  one  tenth  of  the  number  of  women  affected  by  breast  cancer,  it  will  claim  more  life  years.  The  profile  of  survival  has  barely  changed in more than 30 years. Reactions to diagnosis At some point in our cancer stories, most of us ask “Why me?” I am saddened to hear a great deal of misinformation when I listen to answers to that question. Resources Information about clinical trials •  US National Institutes of Health:   www.clinicaltrials.gov •  National Cancer Institute: www.cancer.gov •  National Ovarian Cancer Association (Canadian):  http://ovariancanada.org or   www.ovairecanada.org (en français) Information for patients and families •  Ovarian Cancer Canada:   www.ovariancancercanada.ca •  National Ovarian Cancer Association (Canadian):  http://ovariancanada.org or   www.ovairecanada.org (en français) •  Canadian Cancer Society: www.cancer.ca Vol 53:  june • juin 2007  Canadian Family Physician • Le Médecin de famille canadien  985 Commentary Having  cancer  is  often  the  subject  of  shame,  blame,  or  remorse.  In  addition  to  their  grief,  anger,  and  angst,  women  often  feel  a  sense  of  failure.  There  is  very  little  evidence  that  women  who  develop  ovarian  cancer  are  different from other women except for their genetic pre- dispositions and reproductive histories.  There  is  no  evidence  that  “bad  feelings”  cause  can- cer or that “good feelings” cure cancer. Feelings are just  feelings.  Professionals  need  to  help  patients  to  iden- tify  and  express  their  feelings  before  rushing  to  explain,  suppress,  or  deny  them.  Hope  should  never  be  discour- aged. People do unexpectedly defy the odds.13  Support The stress of living with cancer is enormous. The expecta- tion that we can all emerge hopeful, positive, and coura- geous is an additional burden. Added to this, many of the afflicted women I know have no partners and no children. When  asked  what  is  most  helpful  in  coping  with  the  distress  of  this  disease,  almost  all  women  with  ovarian  cancer  name  family,  professional  caregivers,  and  other  women  who  have  walked  the  same  path  before  them.  Understandable  information  is  another  key  element  in  coping  with  cancer.  The  wealth  of  information  on  ovar- ian  cancer  available  on  the  Internet  can  be  overwhelm- ing at times. Clinical trials Many of us, knowing that our lives will be limited, would be willing to risk the potential consequences of being involved in clinical studies. We offer a good testing model because outcomes become evident within a fairly short interval, and our lives are already compromised. We are long overdue for a national cancer strategy* to  help  inform  the  public  and  coordinate  services  so  that  patients know what resources are available and can par- ticipate in studies that are trying to answer key questions. Vaccines,  monoclonal  antibodies,  angiostatins  (inhib- itors  of  neovascularization)  and  stem-cell  transplants  are  among  the  promising  treatments  of  the  future.5,14,15  Most  cancers,  including  ovarian  cancer,  occur  partly  because  growth  factors  are  “turned  on”  without  normal  control  mechanisms.  Much  current  research  is  focusing  on ways to block this overactive process.16  Studies  are  looking  at  drugs  that  target  human  epi- thelial  receptor  factors  because  approximately  30%  of  women with ovarian cancer have positive test results for  this factor.14,17,18 Other epithelial growth factor receptors  are also common in women with ovarian cancer. Some  tumours  trigger  a  native  immune  response,  and  studies  are looking at how to enhance this defence.16,19  At  the  cutting  edge  of  future  technologies  is  nanotech- nology, where tiny particles with attachments pass through  leaky blood vessels into the tumour and deliver drugs lethal  only  to  the  tumour  or  deliver  metallic  particles  that  can  then  be  exposed  to  infrared  light  to  attack  the  cancer.20  Dr Linda Spano died on September 10, 2006, of ovar- ian cancer. Dr Michael Brennan and Dr Linda Spano, together with their families and many friends, have estab- lished The Brennan/Spano Family Foundation, which has a major interest in supporting research dedicated to the early detection and treatment of ovarian can- cer. For more information, contact The Brennan/Spano Family Foundation within the Victoria Foundation, 109-645 Fort St, Victoria, BC V8W 1G2, or visit www.victoriafoundation.bc.ca. The opinions expressed in commentaries are those of the authors. Publication does not imply endorsement by the College of Family Physicians of Canada. References 1. Abenhaim HA, Titus-Ernstoff L, Cramer DW. Ovarian cancer risk in relation  to medical visits, pelvic examinations and type of health care provider. CMAJ 2007;176(7):941-7. DOI:10.1503/cmaj.060697. 2. US Preventive Services Task Force. Genetic risk assessment and BRCA mutation  testing for breast and ovarian cancer susceptibility: recommendation statement.  Ann Intern Med 2005;143(5):355-61. Erratum in: Ann Intern Med 2005;143(7):547. 3. National Institutes of Health. Prospective study of risk-reducing salpingo-oophorectomy and longitudinal CA-125 screening among women at increased genetic risk of ovarian cancer. Protocol 02-C-0268. Bethesda, Md:  National Institutes of Health; 2007. Available from: http://clinicalstudies.info. nih.gov/cgi/detail.cgi?A_2002-C-0268.html. Accessed 2007 Apr 2. 4. Smith LH, Morris CR, Yasmeen S, Parikh-Patel A, Cress RD, Romano PS. Ovarian  cancer: can we make the diagnosis earlier? Cancer 2005;104(7):1398-407. 5. Berkenblit A, Cannistra SA. Advances in the management of epithelial ovarian  cancer. J Reprod Med 2005;50(6):426-38. 6. Goff BA, Mandel LS, Melancon CH, Muntz HG. Frequency of symptoms of ovarian  cancer in women presenting to primary care clinics. JAMA 2004;291(22):2705-12. 7. Buys SS, Partridge E, Greene MH, Prorok PC, Reding D, Riley TL, et al. Ovarian  cancer screening in the prostate, lung, colorectal and ovarian (PLCO) cancer  screening trial: findings from the initial screen of a randomized trial. Am J Obstet Gynecol 2005;193(5):1630-9. 8. Morice P, Dubernard G, Rey A, Atallah D, Pautier P, Pomel C, et al. Results  of interval debulking surgery compared with primary debulking surgery in  advanced stage ovarian cancer. J Am Coll Surg 2003:197(6):955-63. 9. Bookman MA, Greer BE, Ozols RF. Optimal therapy of advanced ovarian cancer:  carboplatin and paclitaxel vs. cisplatin and paclitaxel (GOG 158) and an update  on GOG0 182-ICON5. Int J Gynecol Cancer 2003;13(6):735-40. 10. Moss C, Kaye SB. Ovarian cancer: progress and continuing controversies in  management. Eur J Cancer 2002;38(13):1701-7. 11. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen, Lele S, et al.  Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med  2006;354(1):34-43. 12. Maugham WS. Sheppey. London, Engl: William Heinemann; 1933. 13. Hirshberg C, Barasch I. Remarkable recovery. New York, NY: Riverhead  Books; 1995. 14. Paley PJ. Angiogenesis in ovarian cancer: molecular pathology and therapeutic  strategies. Curr Oncol Rep 2002;4(2):165-74. 15. Hortobagyi GN. Trastuzumab in the treatment of breast cancer. N Engl J Med  2005;353(16):1734-6. 16. See HT, Kavanagh JJ, Hu W, Bast RC. Targeted therapy for ovarian cancer: cur- rent status and future prospects. Int J Gynecol Cancer 2003;13(6):701-34. 17. Hasan J, Ton N, Mullamitha S, Clamp A, McNeilly A, Marshall E, et al. Phase II  trial of tamoxifen and goserlin in recurrent epithelial ovarian cancer. Br J Cancer  2005;93(6):647-51. 18. Angus DB, Gordon MS, Taylor C, Natale RB, Karlan B, Mendelson DS, et al.  Phase 1 clinical study of pertuzumab, a novel HER dimerization inhibitor, in  patients with advanced cancer. J Clin Oncol 2005;23(11):2534-43. 19. Blank SV, Chang R, Muggia F. Epidermal growth factor receptor inhibitors for  the treatment of epithelial ovarian cancer. Oncology 2005;19(4):553-9. 20. Halder J, Kamat AA, Landen CN Jr, Han LY, Lutgendorf SK, Lin Yg, et al. Focal  adhesion kinase targeting using in vivo short interfering RNA delivery in neutral  liposomes for ovarian carcinoma therapy. Clin Cancer Res 2006:12(16):4916-24. *Editor’s note: The Canadian Partnership Against Cancer  was  announced  in  November  2006  by  the  Government  of  Canada.  See  www.partnershipagainstcancer.ca  for  more details.