Gynecology_Novak

Gynecology_Novak. The administration of methotrexate with folinic acid (MTX-FA) in GTN to limit systemic toxicity was first reported in 1964 (71).Subsequently, it has been confirmed that MTX-FA is both effective and safe in the management of GTN.


Gynecology_Novak

Gynecology_Novak. An evaluation of 185 patients treated with MTX-FA revealed that complete remission was achieved in 162 patients (87.6%); of these patients, 132 (81.5%) required only one course of MTX-FA to attain remission (72). MTX-FA induced remission in 147 of 163 patients (90.2%) with stage I GTN and in 15 of 22 patients (68.2%) with low-risk stages II and III GTN. Resistance to therapy was more common in patients with choriocarcinoma, metastasis, and pretreatment serum hCG levels higher than 50,000 mIU/mL. After treatment with MTX-FA, thrombocytopenia, granulocytopenia, and hepatotoxicity developed in 3 (1.6%), 11 (5.9%), and 26 (14.1%) patients, respectively. Thus, MTX-FA achieved an excellent therapeutic outcome with minimal toxicity and attained this goal with limited exposure to chemotherapy. The serum hCG level is measured weekly after each course of chemotherapy. The hCG regression curve serves as the primary basis for determining the need for additional treatment.


Gynecology_Novak

Gynecology_Novak. The serum hCG level is measured weekly after each course of chemotherapy. The hCG regression curve serves as the primary basis for determining the need for additional treatment. After the first treatment: 1. Further chemotherapy is withheld as long as the hCG level is falling progressively. 2. Additional single-agent chemotherapy is not administered at any predetermined or fixed interval. A second course of chemotherapy is administered under the following conditions: 1. If the hCG level plateaus for more than 3 consecutive weeks or begins to rise again. 2. If the hCG level does not decline by 1 log within 18 days after completion of the first treatment. If the patient’s response to the first treatment was adequate and a second course of MTXFA is required, the dosage of MTX is unaltered. An adequate response is defined as a fall in the hCG level by 1 log after a course of chemotherapy.


Gynecology_Novak

Gynecology_Novak. If the response to the first treatment is inadequate, the dosage of MTX is increased from 1.0 mg/kg/day to 1.5 mg/kg/day for each of the 4 treatment days. If the response to two consecutive courses of MTX-FA is inadequate, the patient is considered to be resistant to MTX, and ActD is promptly substituted. If the hCG levels do not decline by 1 log after treatment with ActD, the patient is considered resistant to ActD as a single agent. She must be treated intensively with combination chemotherapy to achieve remission. Management of Refractory GTN


Gynecology_Novak

Gynecology_Novak. Management of Refractory GTN Etoposide induces complete remission in 56 (95%) of 60 patients with nonmetastatic and low-risk metastatic GTN (76). The use of EMA-CO induced an 83% remission rate in patients with metastasis and a high-risk score (77). Another study confirmed that primary EMA-CO induced complete remission in 76% of the patients with metastatic GTN and a high-risk score (78). Another study reported that EMA-CO induced complete sustained remission in 87 (90.6%) of 96 patients with high-risk (score >6) GTN (79). Remission occurred with EMA-CO in 30 (86%) of 35 patients with brain metastasis (65). The EMA-CO regimen is well tolerated, and treatment seldom has to be suspended because of toxicity. The EMA-CO regimen is the preferred primary treatment in patients with metastasis and a high-risk prognostic score (score >6).


Gynecology_Novak

Gynecology_Novak. Patients resistant to EMA-CO can be treated successfully by substituting etoposide and cisplatin on day8 (EMA-EP). EMA-EP induced remission alone or with surgery in 16 (76%) of 21 patients who were resistant to EMA-CO (80).The optimal combination drug protocol will most likely include etoposide, MTX, and ActD and perhaps other agents administered in the most dose-intensive manner.


Gynecology_Novak

Gynecology_Novak. Efforts continue to identify new agents and regimens effective in treating patients who prove resistant to all standard chemotherapy regimens. A combination of cisplatin, vinblastine, and bleomycin (PVB) was used effectively in patients with drug-resistant tumor (74,75,81). Although ifosfamide and paclitaxel were used successfully, further studies are needed to define their potential role in either primary or second-line therapy (82,83). Osborne et al. reported that a novel three-drug doublet regimen consisting of paclitaxel, etoposide, and cisplatin (TE/TP) induced complete remission in two patients with relapsed high-risk GTN (84). Wan et al. demonstrated that ﬂoxuridine (FUDR)-containing regimens induced complete remission in all of 21 patients with drug-resistant GTN (85). Matsui et al. found that 5-ﬂuorouracil (5-FU) in combination with ActD induced remission in 9 of 11 (82%) patients with drug resistance (86). The potential role for autologous bone marrow transplantation or stem


Gynecology_Novak

Gynecology_Novak. found that 5-ﬂuorouracil (5-FU) in combination with ActD induced remission in 9 of 11 (82%) patients with drug resistance (86). The potential role for autologous bone marrow transplantation or stem cell rescue in conjunction with ultra-high-dose chemotherapy has yet to be defined, although complete remissions was reported in patients with refractory GTN (87,88).


Gynecology_Novak

Gynecology_Novak. Duration of Therapy Patients who require combination chemotherapy must be treated intensively to attain remission. Combination chemotherapy should be given as often as toxicity permits until the patient achieves three consecutive normal hCG levels. After normal hCG levels are attained, at least two additional courses of chemotherapy are administered to reduce the risk of relapse.


Gynecology_Novak

Gynecology_Novak. False-Positive hCG Tests The concept of false-positive hCG tests caused by heterophile antibodies is critical to remember when following patients with molar gestation or GTN. Some assay systems used by commercial laboratories are particularly vulnerable to false-positive tests resulting from the presence of heterophilic antibodies in the test kits they were using (89). For the most part this problem was corrected by adding blocking antibodies to the test systems. Since the hCG molecules in GTN are significantly more degraded or heterogeneous than in normal pregnancy, with higher proportions of free B-hCG, nicked hCG, and B-core fragments, it is important to use an assay that detects both intact hCG and its metabolites and fragments in order to accurately assess the tumor burden (90–92). Additionally, cross-reactivity with luteinizing hormone (LH) can cause confusion when dealing with women in the perimenopausal age group whose hCG level may plateau above assay even when there is no


Gynecology_Novak

Gynecology_Novak. Additionally, cross-reactivity with luteinizing hormone (LH) can cause confusion when dealing with women in the perimenopausal age group whose hCG level may plateau above assay even when there is no longer active tumor. The use of hormone suppression will suppress LH and prevent unnecessary treatment. False-positive hCG tests caused by heterophile agglutinins or LH release may cause confusion in the diagnosis of early pregnancy, ectopic pregnancy, and so-called phantom choriocarcinoma. When there is concern about the possibility of a false-positive serum hCG test, a urine sample should be tested, because patients with phantom hCG generally have no measurable hCG in a parallel urine sample.


Gynecology_Novak

Gynecology_Novak. Some patients with molar pregnancy and GTN have persistent (weeks to months) very low levels of real hCG (usually <500 mIU/mL). In these women, extensive radiologic and clinical evaluations fail to reveal any lesions, and chemotherapy is usually not effective. This condition of “real” low-level hCG, where hCG is not hyperglycosylated, is called “quiescent GTN.” These patients should be managed with careful follow-up, because 6% to 10% ultimately will relapse into active disease and rising hCG levels. The risk of relapse to active disease is correlated with the amount of hyperglycosylated hCG. If relapse does occur, chemotherapy usually proves effective (93).


Gynecology_Novak

Gynecology_Novak. Pregnancies After GTN Patients with GTN who are treated successfully with chemotherapy can expect normal reproduction in the future. Patients who were treated with chemotherapy at the NETDC from 1965 to 2007 had 631 subsequent pregnancies that resulted in 422 term live births (66.9%), 42 preterm deliveries (6.7%), 7 ectopic pregnancies (1.1%), 9 stillbirths (1.4%), and 9 repeat molar pregnancies (1.7%) (94). First-and second-trimester spontaneous abortions occurred in 114 (18.1%) pregnancies. Major and minor congenital malformations were detected in 10 infants (2.1%). Primary cesarean delivery was performed in 81 (21.8%) of 371 subsequent term and preterm births from 1979 to 2007. The frequency of congenital anomalies is not increased, although chemotherapeutic agents have teratogenic and mutagenic potential. 1.


Gynecology_Novak

Gynecology_Novak. 1. Berkowitz RS, Goldstein DP. The management of molar pregnancy and gestational trophoblastic tumors. In: Knapp RC, Berkowitz RS, eds. Gynecologic oncology. 2nd ed. New York: McGraw-Hill, 1993:328–338. 2. Bagshawe KD. Risks and prognostic factors in trophoblastic neoplasia. Cancer 1976;38:1373–1385. 3. Palmer JR. Advances in the epidemiology of gestational trophoblastic disease. J Reprod Med 1994;39:155–162. 4. Jeffers MD, O’Dwyer P, Curran B, et al. Partial hydatidiform mole: a common but underdiagnosed condition. Int J Gynecol Pathol 1993;12:315–323. 5. Martin BH, Kim JM. Changes in gestational trophoblastic tumors over four decades: a Korean experience. J Reprod Med 1998;43:60– 68. 6. Parazzini F, La Vecchia C, Mangili G, et al. Dietary factors and risk of trophoblastic disease. Am J Obstet Gynecol 1988;158:93–99. 7.


Gynecology_Novak

Gynecology_Novak. 6. Parazzini F, La Vecchia C, Mangili G, et al. Dietary factors and risk of trophoblastic disease. Am J Obstet Gynecol 1988;158:93–99. 7. Berkowitz RS, Cramer DW, Bernstein MR, et al. Risk factors for complete molar pregnancy from a case-control study. Am J Obstet Gynecol 1985;52:1016–1020. 8. Parazzini F, La Vecchia C, Pampallona S. Parental age and risk of complete and partial hydatidiform mole. Br J Obstet Gynaecol 1986;93:582–585. 9. Sebire NJ, Foskett M, Fisher RA, et al. Risk of partial and complete molar pregnancy in relation to maternal age. Br J Obstet Gynecol 2002;109:99–102. 10. Berkowitz RS, Bernstein MR, Harlow BL, et al. Case-control study of risk factors for partial molar pregnancy. Am J Obstet Gynecol 1995;173:788–794. 11. Acaia B, Parazzini F, La Vecchia C, et al. Increased frequency of complete hydatidiform mole in women with repeated abortion. Gynecol Oncol 1988;31:310–314. 12.


Gynecology_Novak

Gynecology_Novak. 11. Acaia B, Parazzini F, La Vecchia C, et al. Increased frequency of complete hydatidiform mole in women with repeated abortion. Gynecol Oncol 1988;31:310–314. 12. Kajii T, Ohama K. Androgenetic origin of hydatidiform mole. Nature 1977;268:633–634. 13. Pattillo RA, Sasaki S, Katayama KP, et al. Genesis of 46XY hydatidiform mole. Am J Obstet Gynecol 1981;141:104–110. 14. Azuma C, Saji F, Tokugawa Y, et al. Application of gene amplification by polymerase chain reaction to genetic analysis of molar mitochondrial DNA: the detection of anuclear empty ovum as the cause of complete mole. Gynecol Oncol 1991;40:29–33. 15. Yamashita K, Wake N, Araki T, et al. Human lymphocyte antigen expression in hydatidiform mole: androgenesis following fertilization by a haploid sperm. Am J Obstet Gynecol 1979;135: 597–600. 16. Szulman AE, Surti U. The syndromes of hydatidiform mole. I. Cytogenetic and morphologic correlations. Am J Obstet Gynecol 1978;131:665–671. 17.


Gynecology_Novak

Gynecology_Novak. 16. Szulman AE, Surti U. The syndromes of hydatidiform mole. I. Cytogenetic and morphologic correlations. Am J Obstet Gynecol 1978;131:665–671. 17. Lawler SD, Fisher RA, Dent J. A prospective genetic study of complete and partial hydatidiform moles. Am J Obstet Gynecol 1991;164:1270–1277. 18. Genest DR, Ruiz RE, Weremowicz S, et al. Do non-triploid partial hydatidiform moles exist?: a histologic and ﬂow cytometric reevaluation of non-triploid specimens. J Reprod Med 2002;47: 363–368. 19. Mosher R, Goldstein DP, Berkowitz RS. Complete hydatidiform mole—comparison of clinicopathologic features, current and past. J Reprod Med 1998;43:21–27. 20. Keep D, Zaragoza MV, Hasold T, et al. Very early complete hydatidiform mole. Hum Pathol 1996;27:708–713. 21. Lage JM, Berkowitz RS, Rice LW, et al. Flow cytometric analysis of DNA content in partial hydatidiform moles with persistent gestational trophoblastic tumors. Obstet Gynecol 1991;77:111. 22.


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Gynecology_Novak. 21. Lage JM, Berkowitz RS, Rice LW, et al. Flow cytometric analysis of DNA content in partial hydatidiform moles with persistent gestational trophoblastic tumors. Obstet Gynecol 1991;77:111. 22. Berkowitz RS, Goldstein DP. Molar pregnancy. N Engl J Med 2009;360:1639–1645. 23. Fisher RA, Hodges MD, Rees HC, et al. The maternally transcribed gene p57 (KIP2) (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles. Hum Mol Genet 2002;11:3267. 24. Soto-Wright V, Bernstein MR, Goldstein DP, et al. The changing clinical presentation of complete molar pregnancy. Obstet Gynecol 1995;86:775–779. 25. Goldstein DP, Berkowitz RS. Current management of complete and partial molar pregnancy. J Reprod Med 1994;39:139–146. 26. Amir SM, Osathanondh R, Berkowitz RS, et al. Human chorionic gonadotropin and thyroid function in patients with hydatidiform mole. Am J Obstet Gynecol 1984;150:723–728. 27.


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Gynecology_Novak. 26. Amir SM, Osathanondh R, Berkowitz RS, et al. Human chorionic gonadotropin and thyroid function in patients with hydatidiform mole. Am J Obstet Gynecol 1984;150:723–728. 27. Berkowitz RS, Goldstein DP. Presentation and management of molar pregnancy. In: Hancock BW, Newlands ES, Berkowitz RS, eds. Gestational trophoblastic disease. London: Chapman and Hall, 1997:127– 142. 28. Osathanondh R, Berkowitz RS, de Cholnoky C, et al. Hormonal measurements in patients with theca lutein cysts and gestational trophoblastic disease. J Reprod Med 1986;31:179–183. 29. Szulman AE, Surti U. The clinicopathologic profile of the partial hydatidiform mole. Obstet Gynecol 1982;59:597–602. 30. Berkowitz RS, Goldstein DP, Bernstein MR. Natural history of partial molar pregnancy. Obstet Gynecol 1985;66:677–681. 31. Elias K, Goldstein DP, Berkowitz RS. Complete hydatidiform mole in women over than age 50. J Reprod Med 2010;55:208–212. 32.


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Gynecology_Novak. 31. Elias K, Goldstein DP, Berkowitz RS. Complete hydatidiform mole in women over than age 50. J Reprod Med 2010;55:208–212. 32. Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic disease. Gynecol Oncol 2009;112:654–662. 33. Rice LW, Berkowitz RS, Lage JM, et al. Persistent gestational trophoblastic tumor after partial hydatidiform mole. Gynecol Oncol 1990;36:358–362. 34. Fine C, Bundy AL, Berkowitz RS, et al. Sonographic diagnosis of partial hydatidiform mole. Obstet Gynecol 1989;73:414–418. 35. Goldstein DP, Berkowitz RS. Prophylactic chemotherapy of complete molar pregnancy. Semin Oncol 1995;22:157–160. 36. Kim DS, Moon H, Kim KT, et al. Effects of prophylactic chemotherapy for persistent trophoblastic disease in patients with complete hydatidiform mole. Obstet Gynecol 1986;67:690–694. 37. Limpongsanurak S. Prophylactic actinomycin D for high-risk complete hydatidiform mole. J Reprod Med 2001;46:110–116. 38.


Gynecology_Novak

Gynecology_Novak. 37. Limpongsanurak S. Prophylactic actinomycin D for high-risk complete hydatidiform mole. J Reprod Med 2001;46:110–116. 38. Uberti EMH, Fajardo Mde C, da Cunha AGV, et al. Prevention of postmolar gestational trophoblastic neoplasia using prophylactic single bolus dose of actinomycin D in high-risk hydatidiform mole: a simple, effective, secure and low cost approach without adverse effects on compliance to general follow-up or subsequent treatment. Gynecol Oncol 2009;114:299–305. 39. Committee on Practice Bulletins-Gynecology. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin 53. Diagnosis and treatment of gestational trophoblastic neoplasms. Obstet Gynecol 2004;103:1365–1373. 40. Genest DR, LaBorde O, Berkowitz RS, et al. A clinicopathologic study of 153 cases of complete hydatidiform mole (1980– 1990): histologic grade lacks prognostic significance. Obstet Gynecol 1991;78:402–409. 41.


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Gynecology_Novak. 41. Wolfberg A, Feltmate C, Goldstein DP, et al. Low risk of relapse after achieving undetectable hCG levels in women with complete molar pregnancy. Obstet Gynecol 2004;104:551–554. 42. Lavie I, Rao G, Castrillon DH, et al. Duration of human chorionic gonadotropin surveillance or partial hydatidiform moles. Am J Obstet Gynecol 2005;192:1362–1364. 43. Sebire NJ, Foskett M, Short D, et al. Shortened duration of human chorionic gonadotropin surveillance following complete or partial hydatidiform mole: evidence for a revised protocol of a regional UK trophoblastic disease unit. Br J Obstet Gynaecol 2007;114:760–762. 44. Stone M, Dent J, Kardana A, et al. Relationship of oral contraception to development of trophoblastic tumour after evacuation of a hydatidiform mole. BJOG 1976;83:913–916. 45. Berkowitz RS, Goldstein DP, Marean AR, et al. Oral contraceptives and postmolar trophoblastic disease. Obstet Gynecol 1981;58:474– 477. 46.


Gynecology_Novak

Gynecology_Novak. 45. Berkowitz RS, Goldstein DP, Marean AR, et al. Oral contraceptives and postmolar trophoblastic disease. Obstet Gynecol 1981;58:474– 477. 46. Curry SL, Schlaerth JB, Kohorn EI, et al. Hormonal contraception and trophoblastic sequelae after hydatidiform mole (a Gynecologic Oncology Group study). Am J Obstet Gynecol 1989;160:805–809. 47. Parrazzini F, Cipriani S, Mangili G, et al. Oral contraceptives and risk of gestational trophoblastic disease. Contraception 2002;65:4257. 48. Feltmate CM, Genest DR, Goldsein DP, et al. Advances in the understanding of placental site trophoblastic tumor. J Reprod Med 2002;47:337–341. 49. Bakri YN, Berkowitz RS, Khan J, et al. Pulmonary metastases of gestational trophoblastic tumor—risk factors for early respiratory failure. J Reprod Med 1994;39:175–178. 50. Bakri YN, Berkowitz RS, Goldstein DP, et al. Brain metastases of gestational trophoblastic tumor. J Reprod Med 1994;39:179–184. 51.


Gynecology_Novak

Gynecology_Novak. 50. Bakri YN, Berkowitz RS, Goldstein DP, et al. Brain metastases of gestational trophoblastic tumor. J Reprod Med 1994;39:179–184. 51. Athanassiou A, Begent RHJ, Newlands ES, et al. Central nervous system metastases of choriocarcinoma: 23 years’ experience at Charing Cross Hospital. Cancer 1983;52:1728–1735. 52. Kohorn EI. Negotiating a staging and risk factor scoring system for gestational trophoblastic neoplasia: a progress report. J Reprod Med 2002;47:445–450. 53. Goldstein DP, Vzanten-Przybysz I, Bernstein MR, et al. Revised FIGO staging system for gestational trophoblastic tumors: recommendations regarding therapy. J Reprod Med 1998;43:37–43. 54. Garner EIO, Garrett A, Goldstein DP, et al. Significance of chest computed tomography findings in the evaluation and treatment of persistent gestational trophoblastic neoplasia. J Reprod Med 2004;49:411–414. 55.


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Gynecology_Novak. 55. Bagshawe KD, Harland S. Immunodiagnosis and monitoring of gonadotropin-producing metastases in the central nervous system. Cancer 1976;38:112–118. 56. Bakri Y, Al-Hawashim N, Berkowitz RS. Cerebrospinal ﬂuid/ serum β-subunit human gonadotropin ratio in patients with brain metastases of gestational trophoblastic tumor. J Reprod Med 2000;45:94–96. 57. Berkowitz RS, Birnholz J, Goldstein DP, et al. Pelvic ultrasonography and the management of gestational trophoblastic disease. Gynecol Oncol 1983;15:403–412. 58. Lurain JR, Singh DK, Schink JC. Role of surgery in the management of high-risk gestational trophoblastic neoplasia. J Reprod Med 2006;51:773–776. 59. Papadopoulos AJ, Foskett M, Seckl MJ, et al. Twenty-five years’ clinical experience with placental site trophoblastic tumors. J Reprod Med 2002;47:460–464. 60. Kohorn EI. Single-agent chemotherapy for nonmetastatic gestational trophoblastic neoplasia. J Reprod Med 1992;36:49. 61.


Gynecology_Novak

Gynecology_Novak. 60. Kohorn EI. Single-agent chemotherapy for nonmetastatic gestational trophoblastic neoplasia. J Reprod Med 1992;36:49. 61. Tse KY, Chan KKI, Tam KF, Ngan HYS. 20-year experience of managing profuse bleeding in gestational trophoblastic disease. J Reprod Med 2007;52:397–401. 62. Soper JT. Role of surgery and radiation therapy in the management of gestational trophoblastic disease. Clin Obstet Gynecol 2003;17: 943–957. 63. Crawford RAS, Newlands ES, Rustin GJR, et al. Gestational trophoblastic disease with liver metastases: the Charing Cross experience. Br J Obstet Gyaecol 1997;104:105–109. 64. Newlands ES, Holden L, Seckl MJ, et al. Management of brain metastases in patients with high risk gestational trophoblastic tumors. J Reprod Med 2002;47:465–469. 65. Weed JC Jr, Hammond CB. Cerebral metastatic choriocarcinoma: intensive therapy and prognosis. Obstet Gynecol 1980;55:89–94. 66.


Gynecology_Novak

Gynecology_Novak. 65. Weed JC Jr, Hammond CB. Cerebral metastatic choriocarcinoma: intensive therapy and prognosis. Obstet Gynecol 1980;55:89–94. 66. Soper JT, Spillman M, Sampson JH, et al. High-risk gestational trophoblastic neoplasia with brain metastases: individualized multidisciplinary therapy in the management of four patients. Gynecol Oncol 2007;104:691–694. 67. Osborne R, Gerulath A. What is the best regimen for low-risk gestational trophoblastic neoplasia? A review. J Reprod Med 2004;49:602– 616. 68. Osborne R, Filiaci V, Schink J, et al. A randomized phase III trial comparing weekly parental methotrexate and pulsed dactinomycin as primary management of low-risk gestational trophoblastic neoplasia: a Gynecologic Oncology Group study. Gynecol Oncol 2008;108:S2. 69. Yerandi F, Eftekhar Z, Shojaei H, et al. Pulse methotrexate versus pulse actinomycin D in the treatment of low-risk gestational trophoblastic neoplasia. Int J Gynecol Obstet 2008;103:33–39. 70.


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Gynecology_Novak. Yerandi F, Eftekhar Z, Shojaei H, et al. Pulse methotrexate versus pulse actinomycin D in the treatment of low-risk gestational trophoblastic neoplasia. Int J Gynecol Obstet 2008;103:33–39. 70. Osborne R, Filiaci VL, Schink JC, et al. Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a Gynecologic Oncology Group study. J Clin Oncol 2011;29:825–831. 71. Bagshawe KD, Wilde CE. Infusion therapy for pelvic trophoblastic tumors. J Obstet Gynaecol Br Commonw 1964;71:565–570. 72. Berkowitz RS, Goldstein DP, Bernstein MR. Ten years’ experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease. Gynecol Oncol 1986;23:111–118. 73.


Gynecology_Novak

Gynecology_Novak. 72. Berkowitz RS, Goldstein DP, Bernstein MR. Ten years’ experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease. Gynecol Oncol 1986;23:111–118. 73. Curry SL, Blessing JA, DiSaia PJ, et al. A prospective randomized comparison of methotrexate, dactinomycin and chlorambucil versus methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea and vincristine in “poor prognosis” metastatic gestational trophoblastic disease: a Gynecologic Oncology Group study. Obstet Gynecol 1989;73:357–362. 74. Gordon AN, Gershenson DM, Copeland LJ, et al. High-risk metastatic gestational trophoblastic disease: further stratification into clinical entities. Gynecol Oncol 1989;34:54–56. 75. DuBeshter B, Berkowitz RS, Goldstein DP, et al. Metastatic gestational trophoblastic disease: experience at the New England Trophoblastic Disease Center, 1965–1985. Obstet Gynecol 1987;69:390–395. 76.


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Gynecology_Novak. Trophoblastic Disease Center, 1965–1985. Obstet Gynecol 1987;69:390–395. 76. Wong LC, Choo YC, Ma HK. Primary oral etoposide therapy in gestational trophoblastic disease: an update. Cancer 1986;58: 14–17. 77. Bagshawe KD. Treatment of high-risk choriocarcinoma. J Reprod Med 1984;29:813–820. 78. Bolis G, Bonazzi C, Landoni F, et al. EMA-CO regimen in high-risk gestational trophoblastic tumor (GTT). Gynecol Oncol 1988;31:439– 444. 79. Kim SJ, Bae SN, Kim JH, et al. Risk factors for the prediction of treatment failure in gestational trophoblastic tumors treated with EMA/CO regimen. Gynecol Oncol 1998;71:247–251. 80. Bower M, Newlands ES, Holden L, et al. EMA-CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients. J Clin Oncol 1997;15:2636–2643. 81. Azab M, Droz JP, Theodore C, et al. Cisplatin, vincristine and bleomycin combination in the treatment of resistant high-risk gestational trophoblastic tumors. Cancer 1989;64:1829–1832. 82.


Gynecology_Novak

Gynecology_Novak. 81. Azab M, Droz JP, Theodore C, et al. Cisplatin, vincristine and bleomycin combination in the treatment of resistant high-risk gestational trophoblastic tumors. Cancer 1989;64:1829–1832. 82. Sutton GP, Soper JT, Blessing JA, et al. Ifosfamide alone and in combination in the treatment of refractory malignant gestational trophoblastic disease. Am J Obstet Gynecol 1992;167:489–495. 83. Jones WB, Schneider J, Shapiro F, et al. Treatment of resistant gestational choriocarcinoma with Taxol: a report of two cases. Gynecol Oncol1996;61:126–130. 84. Osborne R, Covens A, Merchandani DE, et al. Successful salvage of relapsed high-risk gestational trophoblastic neoplasia patients using a novel paclitaxel-containing doublet. J Reprod Med 2004;49:655– 661. 85. Wan X, Yang Y, Wu Y, et al. Floxuridine-containing regimens in the treatment of gestational trophoblastic tumor. J Reprod Med 2004;49:453–456. 86.


Gynecology_Novak

Gynecology_Novak. 85. Wan X, Yang Y, Wu Y, et al. Floxuridine-containing regimens in the treatment of gestational trophoblastic tumor. J Reprod Med 2004;49:453–456. 86. Matsui H, Iitsuka Y, Suzuka K, et al. Salvage chemotherapy for high-risk gestational trophoblastic tumor. J Reprod Med 2004;49:438– 442. 87. Giacalone PL, Benos P, Donnadio D, et al. High dose chemotherapy with autologous bone marrow transplantation for refractory metastatic gestational trophoblastic disease. Gynecol Oncol 1999;5:38–45. 88. VanBesien K, Verschraegen C, Mehta R, et al. Complete remission of refractory gestational trophoblastic disease with brain metastases treated with multicycle ifosfamide, carboplatin, and etoposide (ICE) and stem cell rescue. Gynecol Oncol 1997;65:366–369. 89. Khanlian SA, Cole LA. Management of gestational trophoblastic disease and other cases with low serum levels of human chorionic gonadotropin. J Reprod Med 2006;51:812–818. 90.


Gynecology_Novak

Gynecology_Novak. 89. Khanlian SA, Cole LA. Management of gestational trophoblastic disease and other cases with low serum levels of human chorionic gonadotropin. J Reprod Med 2006;51:812–818. 90. Hancock BW. hCG measurement in gestational trophoblastic neoplasia: a critical appraisal. J Reprod Med 2006;51:859–860. 91. Mitchell H, Bagshawe KD, Newlands ES, et al. Importance of accurate human chorionic gonadotropin measurement in the treatment of gestational trophoblastic disease and testicular cancer. J Reprod Med 2006;51:868–870. 92. Cole LA, Kohorn EI. The need for an hCG assay that appropriately detects trophoblastic disease and other hCG-producing tumors. J Reprod Med 2006;51:793–811. 93. Kohorn EI. What we know about low-level hCG: definition, classification and management. J Reprod Med 2004;49:433–437. 94.


Gynecology_Novak

Gynecology_Novak. 93. Kohorn EI. What we know about low-level hCG: definition, classification and management. J Reprod Med 2004;49:433–437. 94. Garrett LA, Garner EO, Feltmate CM, et al. Subsequent pregnancy outcomes in patients with molar pregnancy and persistent gestational trophoblastic neoplasia. J Reprod Med 2008;53:481–486. 95. Tuncer ZS, Bernstein MR, Wang J, et al. Repetitive hydatidiform mole with different male partners. Gynecol Oncol 1999;75:224–226. Junko Ozao-Choy Armando E. Giuliano Breast cancer accounts for one-third of cancers in women. The risk of breast cancer increases with a positive family history and the use of hormone therapy. Breast cancer may be either in situ (ductal carcinoma in situ or lobular carcinoma in situ) or invasive (infiltrating ductal carcinoma, infiltrating lobular carcinoma). The standard screening modalities for detection of breast cancer include yearly mammography and physical examination.


Gynecology_Novak

Gynecology_Novak. The standard screening modalities for detection of breast cancer include yearly mammography and physical examination. Tissue diagnosis is achieved using fine-needle aspiration cytology (FNAC) or core needle biopsy (CNB). Open biopsy is performed if FNAC or CNB results are equivocal or discordant with the clinical findings. The combination of segmental mastectomy (with negative surgical margins), axillary lymph node dissection, and postoperative radiation therapy has the same overall survival compared to modified radical mastectomy for the management of patients with stages I and II breast cancer. Axillary lymph node status and the number of involved nodes are the most important prognostic indicators in primary breast cancer. Sentinel lymph node dissection alone can replace axillary lymph node dissection if the sentinel lymph node is found to be negative on pathology.


Gynecology_Novak

Gynecology_Novak. Sentinel lymph node dissection alone can replace axillary lymph node dissection if the sentinel lymph node is found to be negative on pathology. Adjuvant systemic therapy prolongs survival and is recommended for women with a greater than 10% chance of relapse within 10 years.


Gynecology_Novak

Gynecology_Novak. Adjuvant systemic therapy prolongs survival and is recommended for women with a greater than 10% chance of relapse within 10 years. Breast cancer accounts for approximately one-third of all cancers in women and is second only to lung cancer as the leading cause of cancer deaths among women. Breast cancer has the highest incidence rate of all cancers. According to statistics from the American Cancer Society (ACS), over 230,000 new cases of invasive breast cancer will be diagnosed in women during 2011 in the United States as well as over 55,000 patients of in situ cancers, with almost 40,000 women succumbing to the disease during the same period (1). Over the past 50 years, the incidence of breast cancer in the United States increased significantly; one in every seven women will develop the disease during her lifetime. Fortunately, the mortality rate has declined since 1990.


Gynecology_Novak

Gynecology_Novak. Less than 1% of breast cancers occur in women younger than 25 years of age. After age 30, there is a sharp increase in the incidence of breast cancer. Except for a short plateau between the ages of 45 and 50 years, the incidence increases steadily with age (2). Family History Of women who develop breast cancer, 20% to 30% have a family history of the disease. Although any family history of breast cancer increases the overall relative risk, this risk is not significantly increased if the disease was diagnosed postmenopausally in a first-degree or more distant relative (3). If a woman’s mother or sister had unilateral breast cancer premenopausally, her lifetime risk of developing the disease approaches 30%, whereas a woman whose mother or sister had bilateral breast cancers premenopausally has at least a 40% to 50% lifetime risk. The increased incidence in these women is probably the result of inherited oncogenes.


Gynecology_Novak

Gynecology_Novak. Approximately 5% to 10% of breast cancers have an inherited basis. All inherited genes are autosomal dominant but have variable penetrance. Men carry the gene 50% of the time. The most common mutations are the BRCA1 (chromosome 17q21) and BRCA2 (chromosome 13q12-13) gene deletions. Carriers of these germline mutations have up to a 4% per year risk of developing breast cancer and a lifetime risk that ranges from 35% to 85% (4). These individuals have up to a 65% risk of developing a contralateral breast cancer. The BRCA1 mutation is associated with an increased risk of ovarian and prostate cancer, whereas BRCA2 carriers, although less common, demonstrate increased risks of male breast and prostate cancers. Both mutations are rare in the general public (0.1%) but are more commonly identified in Jews of Ashkenazi descent (1% to 2.3%) (5). Genetic testing is available and should be considered if there is a high likelihood that results will be positive and will be used to inﬂuence


Gynecology_Novak

Gynecology_Novak. in Jews of Ashkenazi descent (1% to 2.3%) (5). Genetic testing is available and should be considered if there is a high likelihood that results will be positive and will be used to inﬂuence decisions regarding the clinical management of the care of the patient and her family. Patients with three of more relatives with breast or ovarian cancer with one of the relatives being diagnosed before the age of 50, two first-or second-degree relatives with breast or ovarian cancer, any relative with male breast cancer, patients whose cancer has been diagnosed before the age of 50, and any patients with both breast and ovarian cancer in their family should undergo genetic counseling for BRCA testing. Ashkenazi Jewish patients should undergo genetic counseling if any first-degree relative, or two second-degree relatives on the same side have breast or ovarian cancer (6). Genetic testing is increasingly important given the evidence that prophylactic surgery may prevent new cancers from occurring,


Gynecology_Novak

Gynecology_Novak. relatives on the same side have breast or ovarian cancer (6). Genetic testing is increasingly important given the evidence that prophylactic surgery may prevent new cancers from occurring, as well as prolong survival, in some cases. A prospective multicenter cohort study of 2,482 women with BRCA1 and BRCA2 mutations between 1974 and 2008 showed risk-reducing mastectomy was associated with a decreased risk of breast cancer. Risk-reducing salpingooophorectomy was associated with decreased risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality (7).


Gynecology_Novak

Gynecology_Novak. Diet, Obesity, and Alcohol There are marked geographic differences in the incidence of breast cancer that may be related to diet. A meta-analysis demonstrated an association between a healthy diet and lower risk of breast cancer (8). Although a definitive relationship between total alcohol consumption and increased risk of breast cancer has yet to be determined, high wine intake was associated with elevated risk (8,9). The risk of breast cancer increases with the length of a woman’s reproductive phase (10). Although early menarche was reported among breast cancer patients, early menopause appears to protect against the development of the disease, with artificial menopause from oophorectomy lowering the risk more than early natural menopause (11). There is no clear association between the risk of breast cancer and menstrual irregularity or the duration of menses.


Gynecology_Novak

Gynecology_Novak. Although lactation does not affect the incidence of breast cancer, women who were never pregnant have a higher risk of breast cancer than those who are multiparous. Women who give birth to their first child later in life have a higher incidence of breast cancer than do younger primigravida women (12). A historic well-controlled study from the Centers for Disease Control and Prevention showed that oral contraceptive use does not increase the risk of breast cancer, regardless of duration of use, family history, or coexistence of benign breast disease (13). A pooled analysis from 54 epidemiologic studies showed current users of oral contraceptives had a small but significant increased risk when compared with nonusers. Ten years after discontinuation, the risk of past users declined to that of the normal population (14).


Gynecology_Novak

Gynecology_Novak. It was reported that short-term estrogen treatment for menopausal symptoms did not increase the risk of breast cancer, but this belief was refuted by the results of the Women’s Health Initiative randomized trial. This prospective trial, involving 16,000 postmenopausal women randomly assigned to receive estrogen plus progesterone or placebo, revealed an association between hormone therapy use and the development of breast cancer. When invasive breast cancer developed, it was diagnosed at a more advanced stage compared with tumors that developed among placebo users. Based on interim analysis, the trial was stopped early and the investigators concluded that even relatively short-term use of combined estrogen–progesterone therapy increases the development of invasive breast cancer (15). The risk demonstrated by this study must be considered when postmenopausal hormone therapy is used to treat conditions such as hot ﬂashes and osteoporosis.


Gynecology_Novak

Gynecology_Novak. History of Cancer Women with a history of breast cancer have a 50% risk of developing microscopic cancer and a 20% to 25% risk of developing clinically apparent cancer in the contralateral breast, which occurs at a rate of 1% to 2% per year (16). Lobular carcinoma has a higher incidence of bilaterality than does ductal carcinoma. A history of endometrial, ovarian, or colon cancer is associated with an increased risk of subsequent breast cancer, as is a history of radiation therapy for Hodgkin’s lymphoma, even if the patient is BRCA1 and BRCA2 negative.


Gynecology_Novak

Gynecology_Novak. Breast cancer commonly arises in the upper outer quadrant, where there is proportionally more breast tissue. Masses are often discovered by the patient and less frequently by the physician during routine breast examination. The increasing use of screening mammography has enhanced the ability to detect nonpalpable breast abnormalities. Metastatic breast cancer is found as an axillary mass without obvious malignancy in less the 1% of cases.


Gynecology_Novak

Gynecology_Novak. The standard screening modalities of mammography and physical examination are complementary. Approximately 10% to 50% of cancers detected mammographically are not palpable, whereas physical examination detects 10% to 20% of cancers not seen radiographically (17). The purpose of screening is to detect tumors when they are small (<1 cm) and have the highest potential for surgical cure. Most trials show a 20% to 30% reduction in breast cancer mortality for women age 50 and older who undergo annual screening mammography. Data on screening women younger than 40 years are more controversial. Results from the Gothenburg screening trial showed a 45% reduction in mortality for women screened between the ages of 40 and 49 (18). Because of these findings, it is recommended that all women undergo yearly screening mammography starting at age 40, along with clinical breast examination at least every 3 years (19). Monthly breast self-examination (BSE) is no longer recommended because there is little


Gynecology_Novak

Gynecology_Novak. screening mammography starting at age 40, along with clinical breast examination at least every 3 years (19). Monthly breast self-examination (BSE) is no longer recommended because there is little evidence to show that BSE is superior to heightened breast awareness such that any new symptoms related to the breast in daily activities would be reported promptly when noticed. BSE was not shown to improve survival. Women should be informed about the benefits and limitations of monthly BSE, mainly the risk of a false-positive result. Women who would still prefer to perform BSE should be instructed in the technique and occasionally have their technique reviewed. No other tests, including ultrasonography, computed tomography (CT) scans, sestamibi scans, positron emission tomography (PET) scans, or serum blood markers, have been shown to be effective screening modalities. Screening guidelines recommended by the American College of Radiology and the American Cancer Society are presented in


Gynecology_Novak

Gynecology_Novak. or serum blood markers, have been shown to be effective screening modalities. Screening guidelines recommended by the American College of Radiology and the American Cancer Society are presented in Table 40.1. In 2010, the ACS recommended annual screening mammography and magnetic resonance imaging (MRI) starting at age 30 for women with a known BRCA mutation and other high-risk genetic syndromes, women who are untested with a first-degree relative with the BRCA mutation and women with an approximately 20% to 25% or greater lifetime risk of breast cancer, or women who have been treated with radiation for Hodgkin’s lymphoma (19). Although breast MRI may prove to be advantageous for other women with an elevated risk of breast cancer, there


Gynecology_Novak

Gynecology_Novak. Table 40.1 Screening Recommendations Beginning at age 40 yearly mammograms, which should continue as long as the patient is in good health. Is an option for women starting in their 20s. Women should be counseled on the benefits and limitation of breast self-examination and should be told to report any changes in their breasts to their health professional right away. Age 20–40 examination by physician every 3 years, annually if positive history (May do annually if there is a positive family history) Age ≥ 40 examination by physician every year Medium risk women (15%–20% lifetime risk) should talk to their health care professional about the benefits and limitations of adding MRI to their yearly mammographic screening. Low risk women (less than 15% lifetime risk) are not recommended to undergo additional MRI screening.


Gynecology_Novak

Gynecology_Novak. Low risk women (less than 15% lifetime risk) are not recommended to undergo additional MRI screening. From American Cancer Society Screening Guidelines. Smith RA, Cokkinides V, Brooks D, et al. Cancer screening in the United States, 2010: a review of current American Cancer Society Guidelines and Issues in Cancer Screening. CA Cancer J Clin 2010;60:99–119. is currently insufficient evidence to make recommendations for women with lower than a 20% lifetime risk of breast cancer (19). Masses are easier to palpate in older women with fatty breasts than in younger women with dense, nodular breasts. An area of thickening amid normal nodularity may be the only clue to an underlying malignancy. Skin dimpling, nipple retraction, or skin erosion, while obvious, are later-stage disease signs. Algorithms for the evaluation of breast masses in premenopausal and postmenopausal women are presented in Chapter 21.


Gynecology_Novak

Gynecology_Novak. When a dominant breast mass is identified, the presence of a carcinoma must be considered, and biopsy should be performed to establish a tissue diagnosis. About 30% to 40% of lesions clinically believed to be malignant will be benign on histologic examination (20). Conversely, 25% of clinically benign-appearing lesions will be malignant when biopsied (21). Biopsy Techniques It is preferable for the patient to be involved in planning her therapy. In most instances, initial biopsy can be followed by definitive treatment at a later date. This approach allows the physician to discuss alternative forms of surgical therapy with the patient who has a malignancy. It gives the patient an opportunity to obtain a second opinion before undergoing definitive treatment.


Gynecology_Novak

Gynecology_Novak. Fine-needle aspiration cytology (FNAC) is usually performed on palpable lesions or under ultrasound guidance using a 20-or 22-gauge needle. The technique has a high level of diagnostic accuracy, with low false-negative rates and rare, but persistent, false-positive results (20,22). In most reported series, false-negative rates range from 10% to 15%, and false-positive rates are generally less than 1%, whereas insufficient specimens account for about 15% of samples (23). If a mass appears malignant on physical examination, mammography, or both, FNAC cytology results can be used for definitive diagnosis, although in these circumstances a core biopsy is usually the biopsy of choice. Negative FNAC results do not exclude malignancy and should be evaluated by either a core needle or traditional excisional biopsy for suspicious lesions. In younger women, it is prudent to monitor a benign-appearing mass for one or two menstrual cycles. Confirmation of a clinically apparent fibroadenoma with


Gynecology_Novak

Gynecology_Novak. excisional biopsy for suspicious lesions. In younger women, it is prudent to monitor a benign-appearing mass for one or two menstrual cycles. Confirmation of a clinically apparent fibroadenoma with FNAC can serve as the basis for observational follow-up without excision. FNAC may be used in cystic lesions to aspirate ﬂuid, especially in benign-appearing cystic lesions. For benign cysts, cytologic examination is not necessary if the ﬂuid is nonbloody and the cyst resolves after aspiration.


Gynecology_Novak

Gynecology_Novak. Core Needle Biopsy Core needle biopsy (CNB) can be performed on both palpable and nonpalpable breast masses. Performing a core biopsy instead of FNAC on a palpable lesion has the advantage of obtaining more tissue for diagnostic purposes, including tests for estrogen and progesterone receptors and Her-2/neu, and has generally replaced FNAC unless aspiration of a cystic mass is being performed. Core biopsy of nonpalpable breast lesions usually is performed using mammographic or ultrasonographic guidance. MRI-detected lesions that cannot be seen with mammography or ultrasonography may be biopsied under MRI guidance. Mammographic units with computerized stereotactic modifications can be used to localize abnormalities and perform CNB without surgery. Under imaging guidance, a biopsy needle is inserted into the lesion and a core of tissue is removed for histologic examination. Devices with suction assistance often are used to increase the volume of tissue removed for evaluation. A titanium


Gynecology_Novak

Gynecology_Novak. inserted into the lesion and a core of tissue is removed for histologic examination. Devices with suction assistance often are used to increase the volume of tissue removed for evaluation. A titanium clip often is used to mark the biopsy site and serve as a guide should further excision be required. Ultrasonography may be used to perform core biopsy on a nonpalpable lesion. Because it is less invasive and less expensive than open mammographic localization biopsy, CNB is preferred for accessible lesions. If a definitive diagnosis is not established, these procedures must be followed by open biopsy.


Gynecology_Novak

Gynecology_Novak. Open Biopsy Open biopsy may be performed if the lesion cannot be successfully biopsied with a needle, or if FNAC or CNB has shown a lesion that may be associated with malignancy, such as atypical ductal hyperplasia (ADH) or lobular carcinoma in situ (LCIS). Excision must be performed if the results with needle biopsy are equivocal or discordant with the clinical findings. An unequivocal histologic diagnosis of cancer should be obtained before treatment of breast cancer is undertaken. Cytologic diagnosis may be relied on if the mass clinically or mammographically appears to be malignant. Open biopsy can be performed in the outpatient setting with local anesthesia in the following manner (although this technique largely is replaced by core biopsy and usually is not necessary): 1. The patient is positioned and the location of the mass confirmed. 2. Local anesthesia is used to infiltrate the skin and subcutaneous tissue surrounding the palpable mass. 3.


Gynecology_Novak

Gynecology_Novak. The patient is positioned and the location of the mass confirmed. 2. Local anesthesia is used to infiltrate the skin and subcutaneous tissue surrounding the palpable mass. 3. The skin in incised directly over the mass. Placement of this incision is critical. It should be situated in such a way that it can be excised with an ellipse of skin should the patient require a subsequent mastectomy, or placed cosmetically so that partial mastectomy can be performed successfully through it. Para-areolar incisions are appropriate only for lesions in proximity to the nipple–areolar complex. 4. The mass is gently grasped with Allis forceps or with a stay suture and moved into the operative field. 5.


Gynecology_Novak

Gynecology_Novak. 4. The mass is gently grasped with Allis forceps or with a stay suture and moved into the operative field. 5. The mass should be excised completely whenever possible. Larger lesions that are difficult to totally excise can be incised for diagnostic purposes only. When an incisional biopsy is performed, a frozen section should be obtained to confirm that appropriate tissue for diagnosis is present. Such masses are preferably sampled with FNAC or CNB, with incisional biopsy rarely, if ever, indicated. 6. Once the mass is removed, hemostasis is achieved and the incision is closed. A cosmetically superior result will be achieved if the deep breast parenchyma is not reapproximated. The most superficial subcutaneous fat can be reapproximated with fine absorbable sutures, and the skin can be closed with a subcuticular suture and adhesive strips.


Gynecology_Novak

Gynecology_Novak. Biopsy of nonpalpable lesions is a potentially difficult procedure that requires close cooperation between the surgeon and radiologist. Using ultrasonographic, mammographic, or MRI guidance, a needle or specialized wire is placed into the breast parenchyma at or near the site of the suspected abnormality. Some mammographers will inject a biologic dye into the breast parenchyma to assist localization. The surgeon reviews the films and localizes the abnormality with respect to the tip of the wire or needle. Alternatively, the surgeon will perform ultrasonography intraoperatively to directly localize the lesion. An incision is made directly over the abnormality, and a small portion of the breast tissue suspected of containing the abnormality is excised. For mammographically detected lesions, a specimen radiograph is obtained to ensure that the abnormality has been recovered. Often, the radiologist can place a needle in the specimen at the site of the abnormality to facilitate histologic


Gynecology_Novak

Gynecology_Novak. a specimen radiograph is obtained to ensure that the abnormality has been recovered. Often, the radiologist can place a needle in the specimen at the site of the abnormality to facilitate histologic evaluation and ensure that the pathologist examines the site of the abnormality. Image-guided biopsy should be performed only for lesions inaccessible to needle biopsy or those lesions that may be associated with malignancy such as ADH.


Gynecology_Novak

Gynecology_Novak. Breast cancer may arise in the intermediate-size ducts, terminal ducts, or lobules. In most cases, the diagnosis of lobular and intraductal carcinoma is based more on histologic appearance than site of origin. The cancer may be either in situ (ductal carcinoma in situ or lobular carcinoma in situ) or invasive (infiltrating ductal carcinoma, infiltrating lobular carcinoma). Morphologic subtypes of infiltrating ductal carcinoma include scirrhous, tubular, medullary, and mucinous carcinoma.


Gynecology_Novak

Gynecology_Novak. True invasive ductal carcinoma accounts for 80% of all invasive tumors, with the final 20% split evenly between lobular carcinoma and special variants of infiltrating ductal carcinoma (24). Mammographically, invasive ductal cancers are characterized by a stellate density or microcalcifications. Macroscopically, gritty, chalky streaks are present within the tumor that most likely represent a desmoplastic response. Invasion of the surrounding stroma and fat, with a fibrotic, desmoplastic reaction surrounding the invasive carcinoma, generally is present.


Gynecology_Novak

Gynecology_Novak. Special types of infiltrating ductal carcinoma are uncommon and typically account for nearly 10% of all invasive cancers. Medullary carcinoma, which accounts for 5% to 8% of breast carcinomas, arises from larger ducts within the breast and has a dense lymphocytic infiltrate. The tumor appears to be a slower growing and less-aggressive malignancy than other forms of carcinoma. Even when axillary disease is present, the prognosis with medullary carcinoma is better than that of other variants of invasive ductal carcinoma. Mucinous (colloid) carcinoma accounts for 5% of all breast cancers. Grossly, areas of the tumor may appear mucinous or gelatinous, whereas microscopically they are relatively acellular. Infiltrating comedo carcinoma accounts for less than 1% of all breast malignancies and is an invasive cancer characterized by foci of necrosis that exude a comedonecrosis-like substance when biopsied. Usually, comedocarcinomas are in situ malignancies. Papillary carcinoma is


Gynecology_Novak

Gynecology_Novak. and is an invasive cancer characterized by foci of necrosis that exude a comedonecrosis-like substance when biopsied. Usually, comedocarcinomas are in situ malignancies. Papillary carcinoma is predominantly a noninvasive ductal carcinoma; when invasive components are present, it should be specified as invasive papillary carcinoma. Tubular carcinoma, a well-differentiated breast cancer that accounts for 1% to 2% of all malignant breast neoplasms, rarely metastasizes to axillary lymph nodes and tends to have a better prognosis than infiltrating ductal carcinoma. Adenoid cystic carcinomas are extremely rare breast tumors that histologically are similar to those seen in the salivary glands. They are well-differentiated cancers that are slow to metastasize.


Gynecology_Novak

Gynecology_Novak. Growth Patterns The growth potential of breast cancer and the patient’s resistance to malignancy vary widely with the individual and the stage of disease. The doubling time of breast cancer ranges from several weeks for rapidly growing tumors to months or years for slowly growing lesions. If the doubling time of a breast tumor were constant and a tumor originated from one cell, a doubling time of 100 days would result in a 1-cm tumor in about 8 years (Fig. 40.1) (25). During the preclinical phase, tumor cells may be circulating throughout the body. Because of the long preclinical tumor growth phase and the tendency of infiltrating lesions to metastasize early, many clinicians view breast cancer as a systemic disease at the time of diagnosis. Although cancer cells may be released from the tumor before diagnosis, variations in the tumor’s ability to grow in other organs and the host’s response to tumor cells may inhibit dissemination of the disease. Many women with breast cancer can be


Gynecology_Novak

Gynecology_Novak. tumor before diagnosis, variations in the tumor’s ability to grow in other organs and the host’s response to tumor cells may inhibit dissemination of the disease. Many women with breast cancer can be treated successfully with surgery alone, and some patients have been cured even in the presence of palpable axillary disease. A pessimistic attitude that breast cancer is systemic and incurable at diagnosis is unwarranted.


Gynecology_Novak

Gynecology_Novak. 13121110987654321 1 mm 1 cm 1 kg 40302010 Number of cell doublings Diameter (cm) 0.5 1 2 8 Premammographic Preclinical Years of growth Figure 40.1 Growth rate of breast cancer indicating long preclinical phase. (From Gullino PM. Natural history of breast cancer: progression from hyperplasia to neoplasia as predicted by angiogenesis. Cancer 1977;39:2699.) A more realistic approach may be to view breast cancer as a two-component disease involving the breast and the body as a whole. Although the primary breast tumor and issues of local control must be managed, the possibility of systemic metastases with their life-threatening consequences should not be overlooked. Breast cancer can metastasize to any organ, and involvement of bone, lungs, or liver occurs in up to 85% of women who develop distant disease (26,27). In addition to these sites, invasive lobular carcinoma is known to disseminate to the abdominal viscera, uterus, ovaries, and peritoneal surfaces. Number of cells


Gynecology_Novak

Gynecology_Novak. Number of cells Staging After the diagnosis of breast cancer is definitively established, the clinical stage of the disease should be determined. The Columbia Clinical Staging System was used historically but is replaced by the tumor-node-metastases (TNM) system of the American Joint Committee on Cancer (28,29). The TNM system allows both preoperative clinical staging and postoperative pathologic staging to be determined (Tables 40.2 and 40.3). Table 40.2 Tumor-Node-Metastasis (TNM) System for Staging of Breast Cancer T4 Tumor of any size with direct extension to chest wall and/or skin (ulceration or skin nodules) T4a Extension to chest wall, not including only pectoralis muscle adherence/invasion T4b Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d’orange) of the skin which do not meet the criteria for inﬂammatory carcinoma NX Regional lymph nodes cannot be assessed (e.g., previously removed)


Gynecology_Novak

Gynecology_Novak. NX Regional lymph nodes cannot be assessed (e.g., previously removed) N1 Metastases to movable ipsilateral level I, II axillary lymph node(s) N2 Metastases in ipsilateral level I, II axillary lymph node(s) that are clinically fixed or matted, or in clinically detected ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases N2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures N2b Metastases only in clinically detected ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph node metastases


Gynecology_Novak

Gynecology_Novak. N2b Metastases only in clinically detected ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph node metastases N3 Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement; or in clinically detected ipsilateral internal mammary lymph nodes and with clinically evident level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement


Gynecology_Novak

Gynecology_Novak. Table 40.2 Continued pNX Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study) pN0 No regional lymph node metastasis identified histologically pN0(i−) No regional lymph node metastases histologically, negative IHC pN0(i+) Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by H&E or IHC including ITC) pN0(mol−) No regional lymph node metastases histologically, negative molecular findings (RT-PCR) pN0(mol+) Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC pN1 Micrometastases; or metastases in 1 to 3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected pN1mi Micrometastasis (>0.2 mm and/or more than 200 cells, but none >2.0 mm) pN1a Metastases in 1 to 3 axillary lymph nodes, at least one metastasis >2.0 mm pN1b Metastases in internal mammary nodes with micrometastases or


Gynecology_Novak

Gynecology_Novak. mm and/or more than 200 cells, but none >2.0 mm) pN1a Metastases in 1 to 3 axillary lymph nodes, at least one metastasis >2.0 mm pN1b Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically apparent pN1c Metastases in 1 to 3 axillary lymph nodes, and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected pN2 Metastases in 4 to 9 axillary lymph nodes; or in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases pN2a Metastases in 4 to 9 axillary lymph nodes (at least one tumor deposit >2.0 mm) pN2b Metastases in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases pN3 Metastases in ten or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or in clinically detected ipsilateral internal mammary lymph nodes in


Gynecology_Novak

Gynecology_Novak. lymph node metastases pN3 Metastases in ten or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or in clinically detected ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected; or in ipsilateral supraclavicular lymph nodes pN3a Metastases in ten or more axillary lymph nodes (at least one tumor deposit greater than 2.0 mm); or metastasis to the infraclavicular (level III axillary lymph) nodes pN3b Metastases in clinically detected ipsilateral internal mammary nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected


Gynecology_Novak

Gynecology_Novak. M0 No clinical or radiologic evidence of distant metastasis cM0(i+) No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastases M1 Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven larger than 0.2 mm From Edge SB, Byrd DB, Compton CC, et al., eds. Breast. In AJCC cancer staging manual. 7th ed. New York: Springer, 2010:419–460, with permission. Table 40.3 Staging of Breast Carcinoma Anatomic Stage/Prognostic Groups ∗T1 includes T1mi ∗∗T0 and T1 tumors with nodal micrometastases only are excluded from stage IIA and are classified stage IB. From Edge SB, Byrd DB, Compton CC, et al., eds. Breast. In AJCC cancer staging manual. 7th ed. New York: Springer, 2010:419–460, with permission.


Gynecology_Novak

Gynecology_Novak. Preoperative Evaluation The extent of the preoperative workup varies with the initial stage of the disease (30). For most patients with small tumors, clinically negative lymph nodes, and no evidence of metastasis (TNM stage I), the preoperative evaluation should consist of bilateral mammography, chest radiography, complete blood count, and screening blood chemistry tests. Bone, CT, and MRI scanning are unnecessary unless there are symptoms or abnormal blood chemistry levels to suggest the existence of bone or intra-abdominal involvement. For patients with clinical stage II, node-positive disease, a bone scan is recommended, but CT scan of the abdomen is not necessary unless symptoms or laboratory results suggest liver disease. Patients with clinical stage III or stage IV disease should undergo both bone and liver scanning. PET scanning is becoming a popular means of total body scanning for breast cancer, but there have been concerns that this modality may miss some bony metastasis. A


Gynecology_Novak

Gynecology_Novak. both bone and liver scanning. PET scanning is becoming a popular means of total body scanning for breast cancer, but there have been concerns that this modality may miss some bony metastasis. A study found that PET scan is highly concordant (81%) with bone scan in a study of 132 paired studies of breast cancer patients (31). Of 31 (19%) discordant pairs, 12 patients had pathology proven metastatic disease. Nine of these 12 patients had a positive PET scan but negative bone scan, supporting the use of PET scan in detecting osseous metastasis in breast cancer, although further studies are needed to ascertain whether this modality should supplant the use of bone scan in this setting.


Gynecology_Novak

Gynecology_Novak. Figure 40.2 Appearance of breast after radical mastectomy (A) versus modified mastectomy (B). (From Kruper L, Giuliano AE. Breast disease. In: Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:636.)


Gynecology_Novak

Gynecology_Novak. Radical Mastectomy Traditionally, the treatment of breast cancer has been surgical, but the type of procedure has remained a controversial and highly emotional issue. During the 19th century, surgical treatment of breast cancer was haphazard, varying from local excision alone to total mastectomy. The radical mastectomy was based on the principle that breast carcinoma was a locally infiltrative process that spread in a stepwise fashion from breast, to nodes, to distant sites (32). Thus, radical mastectomy removes the entire breast, the underlying pectoral muscles, and the contiguous axillary lymph nodes in continuity (33) (Fig. 40.2A). A report of 51 years of experience with radical mastectomy, which included 1,036 patients with a follow-up of 47 years, is unequaled in evaluating any single method of treating breast cancer (34).


Gynecology_Novak

Gynecology_Novak. During the 20th century, extensions and modifications of the radical mastectomy were devised that involved removal of more local and regional tissue. At one time, supraclavicular lymph node dissections were considered a routine component of surgical treatment (35). Supraclavicular, mediastinal, and internal mammary lymph node dissections were performed (36).


Gynecology_Novak

Gynecology_Novak. An en bloc internal mammary lymph node dissection was added to the standard radical mastectomy in the 1960s (37). This technique became popular and is the operation commonly referred to as the extended radical mastectomy. Extended radical mastectomy did not enhance overall survival rates, because only 3% to 5% of patients with negative axillary nodes will have involvement of internal mammary nodes (38). Locally destructive surgery is not justified, based on current understanding of the biologic behavior of breast cancer. Radical mastectomy is no longer an indicated procedure, except in the most unusual circumstances, with extensive pectoralis involvement by direct tumor extension.


Gynecology_Novak

Gynecology_Novak. In contrast to radical mastectomy, modified radical mastectomy preserves the pectoralis major muscle (39,40) (Fig. 40.2B). The breast is removed in a manner similar to that of radical mastectomy, but neither the axillary lymph node dissection nor the skin excision is as extensive. Consequently, there is no need for skin grafting. There are no differences in survival rates between radical and modified radical mastectomy, but the latter procedure has a better functional outcome and a superior cosmetic result (41). Modified radical mastectomy has replaced radical mastectomy in the United States and is an alternative to breast conserving surgery and axillary dissection for some patients.


Gynecology_Novak

Gynecology_Novak. Total Mastectomy Total mastectomy involves removal of the entire breast, nipple, and areolar complex without resection of the underlying muscles or intentional excision of axillary lymph nodes. Low-lying lymph nodes in the upper outer portion of the breast and low axilla often are excised. Total mastectomy has local control rates comparable with those of radical or modified radical mastectomy but has a higher risk of axillary recurrence. In the past, regional recurrence would occur in at least 15% to 20% of patients treated with total mastectomy alone. With the addition of sentinel lymph node biopsy, which selects patients who are lymph node negative, local recurrence rates should be lowered in patients with total mastectomy and node negative disease compared to those in the past with unknown axillary status.


Gynecology_Novak

Gynecology_Novak. More patients have early small cancers and others are undergoing prophylactic mastectomy for genetic mutations and for other high-risk lesions. Patients may elect to undergo a skin-sparing mastectomy (SSM) with nipple–areolar complex (NAC) removal that leaves a skin envelope to accommodate the breast reconstruction, as well as providing a nipple-sparing mastectomy (NSM) with preservation of the NAC. Both of these procedures are being studied for their potential utility and safety in various clinical situations. Retrospective series show that performing NSM does not impact survival, although a prospective randomized trial has not been performed (42).


Gynecology_Novak

Gynecology_Novak. McWhirter developed the combination of total mastectomy followed by radiation (43). Many advocated adjuvant radiation therapy used in combination with various operative procedures. Studies claiming improvements in overall survival usually are ﬂawed by the use of historical controls and inaccurate preoperative staging. Classic trials, both prospective randomized and historical control studies, showed that adjuvant radiation therapy improves local control but not overall survival rates (44–47). In a prospective randomized trial performed by the National Surgical Adjuvant Breast Project (NSABP), the roles of postoperative radiation therapy and axillary treatment were examined. Patients were randomly assigned to either total mastectomy, radical mastectomy, or total mastectomy with radiation therapy. This trial showed no difference in survival among the three treatment arms, whereas radiation therapy and axillary treatment improved local and regional control. Twenty-five-year follow-up


Gynecology_Novak

Gynecology_Novak. therapy. This trial showed no difference in survival among the three treatment arms, whereas radiation therapy and axillary treatment improved local and regional control. Twenty-five-year follow-up data continue to support these conclusions (48).


Gynecology_Novak

Gynecology_Novak. Three randomized control studies from the 1990s showed that postmastectomy radiation therapy reduced the risk of local–regional failure by 20% and produced an absolute sur


Gynecology_Novak

Gynecology_Novak. Breast Conservation Therapy with or without Radiation Therapy vival benefit of 10% at 10 years among women with stage II to III breast cancer, regardless of menopausal status (49–51). Additional trials challenged the need for postmastectomy radiation among women with only one to three involved axillary nodes and T1 or T2 primary tumors. These studies showed adequate local–regional control rates with mastectomy and chemotherapy alone (52–54). In a large meta-analysis, an absolute risk reduction in local recurrence was found in women with radiation therapy after both breast conservation and mastectomy. One breast cancer death is avoided for every four local recurrences, reducing the 15-year mortality among patients with a greater than 10% risk of local recurrence (55). Guidelines from the American Society of Clinical Oncology recommend postmastectomy radiation therapy for women with T3 (>5 cm) primary tumors and four or more positive axillary lymph nodes (56).


Gynecology_Novak

Gynecology_Novak. Radiation therapy alone, without excision of the tumor, is associated with a high local failure rate, as is local excision without radiation (57–60). Throughout the last quarter of the 20th century, a paradigm shift occurred in the surgical management of breast cancer. Data from the NSABP B-04 trial, for which 25-year follow-up exists, established the equivalency of radical versus total mastectomy with regard to overall survival. Shortly after initiation of the B-04 trial, a number of studies were designed to evaluate the efficacy of breast preservation among women with early-stage breast cancers. The Milan trial, a major prospective randomized trial that began accruing patients in 1973, compared treatment with either radical mastectomy or a combination of quadrantectomy, axillary lymph node dissection, and postoperative radiation therapy. In total, 701 clinically node-negative patients with noncentrally located, small tumors (<2 cm) (T1 N0 M0) were enrolled. After 25 years of


Gynecology_Novak

Gynecology_Novak. lymph node dissection, and postoperative radiation therapy. In total, 701 clinically node-negative patients with noncentrally located, small tumors (<2 cm) (T1 N0 M0) were enrolled. After 25 years of follow-up, there continues to be no statistically significant difference between the two groups in either local control or overall survival rates (61).


Gynecology_Novak

Gynecology_Novak. At nearly the same time, in the NSABP B-06 trial, patients with early breast cancer (stage I or stage II, T1 or T2, and N0 or N1) were randomized to modified radical mastectomy, segmental mastectomy (lumpectomy) and axillary lymph node dissection, or segmental mastectomy, axillary lymph node dissection and postoperative radiation therapy. Unlike the quadrantectomy performed in the Milan study, segmental mastectomy consists of removing only the tumor and a small rim of normal surrounding tissue, yielding cosmetically superior results (Fig. 40.3). A total of 1,843 women were enrolled, with the lowest local recurrence rate


Gynecology_Novak

Gynecology_Novak. Figure 40.3 Appearance of breast after lumpectomy, axillary dissection, and radiation therapy. (From Kruper L, Giuliano AE. Breast disease. In: Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Williams & Wilkins, 2010:638.) seen among patients treated with segmental mastectomy and postoperative radiation therapy. The addition of radiation improved the local control rate, but no significant differences in overall survival or disease-free survival rates were detected among the three treatment arms; there was a trend, however, in favor of patients who had received radiation. This NSABP study established, now with 25-year follow-up, that the combination of segmental mastectomy (with negative surgical margins), axillary lymph node dissection, and postoperative radiation therapy is as effective as modified radical mastectomy for the management of patients with stages I and II breast cancer (62). A number of additional prospective randomized studies also


Gynecology_Novak

Gynecology_Novak. radiation therapy is as effective as modified radical mastectomy for the management of patients with stages I and II breast cancer (62). A number of additional prospective randomized studies also demonstrated no decrease in overall survival among women being treated with breast preservation therapy (63–65).


Gynecology_Novak

Gynecology_Novak. Axillary lymph node status and the number of involved nodes are the most important prognostic indicators for patients with primary breast cancer (66). Axillary lymphadenectomy traditionally was used to detect and quantify the extent of nodal metastasis (67). Before the introduction of sentinel lymph node dissection in the 1990s, axillary lymph node dissection was performed routinely on all patients with early breast cancer. Although axillary dissection is associated with a very low risk of regional recurrence (1% to 3%), the rate of acute complications is as high as 30% (68). Similarly, the risk of chronic lymphedema ranges from 6% to as high 30% (69). Limiting the dissection to level I nodes or random sampling is associated with unacceptably high false-negative rates and should not be done (70). Only one-third of patients with a clinically negative axilla will have nodal metastasis after histopathologic examination of all harvested lymph nodes (71). This means that two-thirds of


Gynecology_Novak

Gynecology_Novak. done (70). Only one-third of patients with a clinically negative axilla will have nodal metastasis after histopathologic examination of all harvested lymph nodes (71). This means that two-thirds of patients will be exposed to the morbidity of axillary lymph node dissection without proven benefit when performed routinely in the presence of invasive breast cancer.


Gynecology_Novak

Gynecology_Novak. In 1991 intraoperative lymphatic mapping and sentinel lymph node dissection were introduced to address these problems (72). The concept behind sentinel lymph node dissection is best described by the definition of a sentinel node. The sentinel node is the lymph node that has the greatest potential to harbor metastasis if axillary disease is present. Examination of the sentinel lymph node dissection can accurately predict the status of the entire nodal basin. Removing only one or two lymph nodes can accurately stage the axilla with minimal morbidity. Numerous investigators have demonstrated that, with proper training, sentinel lymph node dissection identification rates range from 90% to 99%, with false-negative rates of less than 5% found in most large studies (73). In one study of 107 patients with T1 and T2 breast cancer who underwent sentinel lymph node dissection followed by axillary lymph node dissection, the sentinel node was successfully identified in 100 patients (93.5%) (73).


Gynecology_Novak

Gynecology_Novak. with T1 and T2 breast cancer who underwent sentinel lymph node dissection followed by axillary lymph node dissection, the sentinel node was successfully identified in 100 patients (93.5%) (73). There were no false-negative results, and the sentinel node accurately predicted axillary status in all 100 patients.


Gynecology_Novak

Gynecology_Novak. The technique of sentinel lymph node dissection is validated by a number of authors using a variety of techniques (74,75). The information obtained from sentinel lymph node dissection appears to be equivalent to that of axillary lymph node dissection. One prospective study demonstrated that in node-negative patients undergoing only sentinel lymph node dissection, the recurrence rate in the axilla was zero at a median follow-up of 39 months (76). Overall survival for patients who undergo sentinel lymph node dissection without axillary dissection appears to be excellent. In a randomized controlled trial, Veronesi et al. showed that the long-term breast cancer–related event-free survival among patients in the sentinel node biopsy arm (89.9%) was similar to that in the axillary lymph node dissection arm (88.8%), affirming not only that sentinel lymph node biopsy is as good as complete axillary dissection at staging the axilla, but that it is as safe as the once standard method of complete


Gynecology_Novak

Gynecology_Novak. arm (88.8%), affirming not only that sentinel lymph node biopsy is as good as complete axillary dissection at staging the axilla, but that it is as safe as the once standard method of complete axillary dissection (77). Sentinel node biopsy alone without complete axillary lymph node dissection may have value in patients with micrometastatic and macrometastatic disease given low recurrence rates after sentinel lymph node biopsy. In a randomized controlled trial, in patients with hematoxylin and eosin (H&E) positive sentinel lymph nodes, there was no statistically significant difference in overall survival between patients randomized to complete axillary lymph node dissection and sentinel lymph node biopsy alone (78). The degree of accuracy in predicting axillary metastasis, combined with its very low morbidity rate, makes sentinel lymph node dissection the preferred procedure for staging the axilla in breast cancer.


Gynecology_Novak

Gynecology_Novak. Adjuvant Systemic For many patients, local and regional control of breast cancer is achieved with a combination Therapy of surgery and radiation therapy. About 90% of patients will never experience an in-breast recurrence; these patients may develop metastatic disease. The goal of adjuvant systemic therapy is to eliminate occult metastases during the early postoperative period and thus reduce the risk of local and distant recurrence (79).


Gynecology_Novak

Gynecology_Novak. Adjuvant systemic therapy will prolong survival in selected breast cancer patients. In patients with favorable tumors and a low risk of recurrence and subsequent death, such as those with node-negative cancers smaller than 1 cm and favorable biology, this benefit is small and may not justify the risks of systemic therapy. Adjuvant systemic therapy reduces the odds of death by 25% per year in both node-negative and node-positive patients (80). Because this risk reduction is relatively constant, patients with favorable, node-negative disease have a much smaller absolute benefit compared with patients who have higher-risk, node-positive disease and/or patients with unfavorable biologic markers such as patients with triple negative disease or Her-2/neu positive disease. For patients with node-negative disease, the absolute benefit may be minimal versus 10% to 20% for those with nodal involvement.


Gynecology_Novak

Gynecology_Novak. Cytotoxic chemotherapy and hormonal therapy have inherent risks that must be considered when treatment decisions are made. There are many known acute side effects with standard regimens, and there is growing evidence that patients who undergo chemotherapy report more frequent chronic neurocognitive deficits than do untreated controls (81). The impact of these deficits remains undefined. Systemic therapy with tamoxifen is associated with an increased incidence of uterine cancer, vaginal dryness, and hot ﬂashes, whereas aromatase inhibitors are linked to osteoporosis and musculoskeletal symptoms. Choosing those patients who should receive adjuvant therapy can be a difficult decision that often entails analyzing a variety of prognostic and predictive factors, identifying patients at risk for recurrence, and quantifying that risk. Based on available data, adjuvant chemotherapy is recommended for women with greater than a 10% chance of relapse within 10 years. The choice of therapy depends


Gynecology_Novak

Gynecology_Novak. recurrence, and quantifying that risk. Based on available data, adjuvant chemotherapy is recommended for women with greater than a 10% chance of relapse within 10 years. The choice of therapy depends on an evaluation of specific risk factors. Two multigene assays such as the Oncotype DX and the Mammaprint have been introduced to help identify those estrogen receptor–positive, lymph node–negative patients who will benefit most from systemic chemotherapy. These tests, which calculate a recurrence risk score for each individual based on a 21-gene assay and 70-gene signature, respectively, allow the treating physician to determine the average rate of distant disease at 10 years and make treatment recommendations based on this risk (82).


Gynecology_Novak

Gynecology_Novak. Prognostic Indicators Factors that determine each patient’s risk of recurrence include nodal involvement, tumor size, estrogen and progesterone receptor status, nuclear grade, histologic type, proliferative rate, and biologic markers such as Her-2/neu status. These prognostic factors and their effects on recurrence are summarized in Table 40.4. Patients with high-risk prognostic factors are more likely to benefit from adjuvant cytotoxic or hormonal therapy and usually are offered such treatment. Table 40.4 Prognostic Factors in Node-Negative Breast Carcinoma From Giuliano AE, Hurvitz SA. Breast Disorders. In: McPhee SJ, Papadakis MA, eds. 2011 current medical diagnosis and treatment. New York: McGraw Hill, 2011;710, with permission. Table 40.5 Year Survival According to Stage of Breast Cancer


Gynecology_Novak

Gynecology_Novak. Table 40.5 Year Survival According to Stage of Breast Cancer AJCC, American Joint Committee on Cancer. From Giuliano AE, Hurvitz SA. Breast disorders. In: McPhee SJ, Papadakis MA, eds. 2011 current medical diagnosis and treatment. New York: McGraw Hill, 2011;716, with permission. Patients with lymph node metastasis have a higher risk of recurrence than patients with node-negative disease. The 10-year survival rate for women with palpable metastatic axillary lymph nodes who fail to receive systemic therapy is about 50% to 60%. The number of lymph nodes involved and the presence of extracapsular invasion are important indicators of poor prognosis.


Gynecology_Novak

Gynecology_Novak. Another prognostic indicator of relapse is primary tumor size. In an evaluation of 767 patients with node-negative disease who underwent radical or modified radical mastectomy without adjuvant chemotherapy, the relapse rate in patients with tumors larger than 1 cm or special tumor types larger than 3 cm (tubular, mucinous, or papillary) was 27% at 10 years, compared with 9% for tumors smaller than 1 cm (83).


Gynecology_Novak

Gynecology_Novak. Hormone receptor status is an important predictor not only of long-term prognosis but also of response to endocrine therapy. Several studies demonstrated that patients with positive estrogen and progesterone receptor status have improved overall survival (84,85). Receptor status should be known when determining the need for and choice of adjuvant therapy. Histologic grade appears to predict overall survival. Patients with well-differentiated tumors tend to have more favorable outcomes than those with poorly differentiated ones (Table 40.5). In a British study of 1,168 women, histologic grade, along with tumor size and lymph node status, was an independent predictor of overall survival at 10 years (86).


Gynecology_Novak

Gynecology_Novak. Two multigene assays were rapidly developed and are commercially available including the 21-gene assay (Oncotype DX) and the 70-gene signature (Mammaprint). Oncotype DX was developed for identifying patients who have a high risk of recurrence distantly and for patients with node negative ER+ breast cancer. Large-scale phase III trials are under way in the United States and in Europe to test the clinical utility of these multigene assays, which will assist in determining the use of adjuvant systemic therapy.


Gynecology_Novak

Gynecology_Novak. The possible roles of specific tumor markers in predicting which patients will respond to chemotherapy regimens were investigated. The most thoroughly researched of these markers is HER-2/neu. In an NSABP study, patients with HER-2/neu overexpression who were not treated with anthracycline-based regimens fared worse (87). Another study showed that the addition of trastuzumab (Herceptin), an antibody directed against the HER-2/neu receptor, significantly increased the response rate to therapy over standard chemotherapy alone in the presence of metastatic disease (88). Reports from trials investigating the adjuvant use of trastuzumab for women with early-stage Her-2/neu breast cancers show significant improvements in disease-free survival for women receiving trastuzumab; trastuzumab is used as systemic adjuvant therapy for patients with Her-2/neu positive breast cancer, and the standard length of treatment is one full year (89–91).


Gynecology_Novak

Gynecology_Novak. description of the more commonly used regimens. Initially, trials involved a single perioperative course of chemotherapy aimed at eradicating circulating tumor cells. The Nissen-Meyer study from Norway showed that a single course of cyclophosphamide improved overall survival rates (92). Numerous trials demonstrated the benefit of adjuvant chemotherapy for certain subgroups of patients (93). In the initial NSABP adjuvant trial, a 2-year course of melphalan was superior to no treatment, and further trials demonstrated enhanced beneficial effect with the use of multiple drugs as well as with the combination of hormonal manipulation with chemotherapy (94,95).


Gynecology_Novak

Gynecology_Novak. Historically, the most frequently used adjuvant combination chemotherapy was CMF: cyclophosphamide (C), methotrexate (M), and 5-ﬂuorouracil (5-FU). In the original study by Bonadonna et al., patients with positive axillary lymph nodes were randomized to receive either 12 monthly cycles of CMF or no therapy after radical mastectomy (96). A statistically significant benefit was found with CMF treatment for premenopausal patients, especially those with one to three positive nodes. A subsequent study showed six cycles of CMF to be as effective as 12 cycles (97). No significant effect was seen for postmenopausal women, which may result from the fact that these women were less likely to tolerate the full course of therapy (98). After 20 years of follow-up, this trial demonstrated a persistent survival advantage for premenopausal women receiving CMF adjuvant therapy (99). In a later study involving node-negative, estrogen receptor–negative breast cancer patients, after 12 years of follow-up,


Gynecology_Novak

Gynecology_Novak. advantage for premenopausal women receiving CMF adjuvant therapy (99). In a later study involving node-negative, estrogen receptor–negative breast cancer patients, after 12 years of follow-up, 71% of patients treated with adjuvant CMF remained disease free compared with 48% in the control group, regardless of menopausal status (100).


Gynecology_Novak

Gynecology_Novak. Anthracylines (A) were more commonly used in the adjuvant and metastatic treatment of breast cancer than any other agents. A large randomized NSABP study compared CMF with AC regimens in node-positive patients and found similar treatment outcomes among both groups. The AC regimen was preferred because of its shorter duration (four cycles for 3 months vs. six cycles for 6 months) and better tolerance (101).


Gynecology_Novak

Gynecology_Novak. Several landmark trials showed that taxanes such as paclitaxel and docetaxel in combination with anthracyclines have significant efficacy and are the new standard adjuvant therapy for node-positive breast cancer. The Cancer and Leukemia Group B was the first to show a 17% improvement in the rate of recurrence and 18% reduction in the rate of death with the addition of paclitaxel to cyclophosphamide (102). Given concerns over the cardiotoxicity of anthracyclines as well as the 0.21% risk of leukemia after the AC regimen at 5 years, a US oncology trial randomized stage I, II, and III patients to AC or docetaxel and cyclophosphamide (TC) every 3 weeks for four cycles and found that after 7 years’ follow-up disease-free survival and overall survival statistically favored the TC group (103). This was the first trial to compare a taxane-based regimen to an anthracycline-based regimen. Concerns remain because multiple trials demonstrate that the duration of therapy is significant and the TC


Gynecology_Novak

Gynecology_Novak. was the first trial to compare a taxane-based regimen to an anthracycline-based regimen. Concerns remain because multiple trials demonstrate that the duration of therapy is significant and the TC regimen used was a short-duration treatment of four cycles (104). Until results of an ongoing US oncology trial designed to assess whether an incremental benefit exists for adding an anthracycline to TC-based therapy for six cycles on a 3-week dosing schedule for Her-2/neu negative patients, oncologists will need to decide whether to add anthracycline to taxane-based chemotherapy guided by their clinical judgment.


Gynecology_Novak

Gynecology_Novak. The use of neoadjuvant chemotherapy traditionally was limited to those individuals with either inoperable locally advanced or inﬂammatory breast cancers. The goal of preoperative systemic therapy was to convert inoperable patients into resectable candidates on the basis of pathologic and clinical responses (105). Indications for neoadjuvant chemotherapy were broadened to include individuals presenting with large operable tumors and wanting to undergo breast preservation instead of mastectomy. Reports indicate that breast conservation therapy is possible and that low rates of in-breast or local–regional recurrences occur when neoadjuvant chemotherapy results in clinical and pathological tumor downstaging (106). In addition to large, operable tumors, neoadjuvant therapy continues to have a role in the treatment of inﬂammatory breast cancers and those presenting in a locally advanced state.


Gynecology_Novak

Gynecology_Novak. Hormonal Therapy Hormonal manipulation with tamoxifen or an aromatase inhibitor, used alone or in combination with a cytotoxic regimen, is beneficial in select groups of women. Tamoxifen,an estrogen analogue, offers substantial benefits in both premenopausal and postmenopausal women. Taken at a dose of 20 mg per day for 5 years, tamoxifen reduces the annual risk of recurrence by about 50% and the annual risk of death by about 25%. These benefits occur in women with estrogen receptor–positive disease regardless of chemotherapy treatment (107).


Gynecology_Novak

Gynecology_Novak. Tamoxifen, when used in combination with cytotoxic chemotherapy, improves survival in women with positive axillary lymph nodes and tumor estrogen receptor expression (108). In patients with node-negative, estrogen receptor–positive disease, the addition of tamoxifen to chemotherapy improved disease-free survival rates after 5 years of follow-up (109). In NSABP study B-14, 2,644 patients with estrogen receptor–positive tumors and no axillary metastases were randomized to either tamoxifen (10 mg orally twice daily for 5 years) or a placebo control. After a 4-year median follow-up, the disease-free survival rate for the 1,318 patients treated with tamoxifen was 82% compared with 77% for the 1,326 patients treated with placebo (p = .00001), again regardless of menopausal status.


Gynecology_Novak

Gynecology_Novak. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) performed a meta-analysis of adjuvant systemic therapy for breast cancer. They analyzed randomized trials involving adjuvant systemic hormonal, cytotoxic, or immune therapy administered to more than 75,000 women with stage I or II carcinoma. The investigators concluded that for post-menopausal women with estrogen receptor–positive tumors, tamoxifen daily for at least 2 years had a significant beneficial effect on disease-free survival rates, with these effects lasting up to 10 years. The incidence of both carcinoma in the contralateral breast and death rate from heart disease decreased.


Gynecology_Novak

Gynecology_Novak. In addition to tamoxifen, aromatase inhibitors have been approved for use in the adjuvant treatment of patients with estrogen receptor–positive cancers. Aromatase inhibitors act by inhibiting the aromatase enzyme, thus blocking the conversion of androgens into estrogens. These drugs should be used only in postmenopausal patients or premenopausal women who have undergone chemical ovarian suppression or oophorectomy. Although aromatase inhibitors cause fewer episodes of thrombotic events, hot ﬂashes, and endometrial cancers, musculoskeletal symptoms and osteoporosis are more commonly encountered among aromatase inhibitor users than those taking tamoxifen. Results from the anastrozole (Arimidex), tamoxifen, Alone or in Combination (ATAC) trial showed overall lower recurrence rates, as well as fewer contralateral tumors, among women treated with anastrozole alone after 68 months of follow-up (110). A meta-analysis confirmed that aromatase inhibitor therapy alone conferred a 2.9% absolute


Gynecology_Novak

Gynecology_Novak. fewer contralateral tumors, among women treated with anastrozole alone after 68 months of follow-up (110). A meta-analysis confirmed that aromatase inhibitor therapy alone conferred a 2.9% absolute decrease in recurrence; aromatase inhibitor therapy after 2 to 3 years of tamoxifen conferred a 3.1% reduction in recurrence, as well as a 0.7% decrease in mortality at 5-year follow-up, although additional long-term follow-up is needed (111). Based on these results, aromatase inhibitors are now often offered as a first-line treatment option for adjuvant therapy. Research suggests that conversion of patients from tamoxifen to an aromatase inhibitor, such as letrozole (Femara), after 2.5 or 5 years may improve survival, although concurrent use of the two agents offers no benefit (110,112).


Gynecology_Novak

Gynecology_Novak. Adjuvant systemic therapy lowers the incidence of recurrence by 25% to 30%. It is important to understand that the proportional reduction in risk of relapse is relatively constant regardless of absolute risk (113). The EBCTCG meta-analysis showed that the risk reduction of recurrence and breast cancer–specific mortality from polychemotherapy occurs in all women, but the most benefit occurs in women under the age of 50 (Table 40.6). A meta-analysis from the EBCTCG assessing the effect of polychemotherapy and tamoxifen on estrogen receptor–poor breast cancer found that women under the age of 50 or between the ages of 50 and 69 had statistically significant decreases in 10-year risks of recurrence and mortality, with more benefit in women under the age of 50, confirming the results of the earlier study in patients with estrogen receptor–poor breast cancer (114). Tamoxifen did not add any benefit in patients with estrogen receptor–poor tumors. Adjuvant cytotoxic chemotherapy appears to


Gynecology_Novak

Gynecology_Novak. earlier study in patients with estrogen receptor–poor breast cancer (114). Tamoxifen did not add any benefit in patients with estrogen receptor–poor tumors. Adjuvant cytotoxic chemotherapy appears to affect the natural history of patients with either axillary node–negative or node–positive breast cancer. All high-risk patients with node-negative disease are considered candidates for adjuvant cytotoxic therapy.