93 Ovaries and Fallopian Tubes Deborah Armstrong S U M M ARY O F K EY P O I N T S Celomic Epithelial Carcinoma the weight of evidence, preferred stable disease, or relapsed during or Basic Characteristics combination being paclitaxel- within 6 months of platinum-based • Ninety percent of the 23,300 new carboplatin: paclitaxel (175 mg/m2 therapy): treatment with drugs that cases and 13,900 deaths annually in the intravenously over 3 hours) followed produce responses (weekly paclitaxel, United States by carboplatin (area under the curve, docetaxel, pegylated liposomal • Derived from celomic epithelium lining 6 to 7.5 intravenously) repeated every doxorubicin, oral etoposide, topotecan, the peritoneal cavity, most commonly 3 weeks for six cycles tamoxifen, gemcitabine, navelbine, from that which invests the ovary • Controversial issues: the roles of new ifosfamide) • Most common route of spread: agents, the role of dose-intense therapy • Offering no proven advantage over dissemination throughout peritoneal supported by marrow reconstitution, intravenous therapy at standard doses cavity the role of intraperitoneal therapy, and to these patients: intraperitoneal • Signiﬁcant prognostic factors: age, the role of maintenance paclitaxel therapy, high-dose therapy with histologic type and grade, extent of Management of Limited marrow reconstitution, radiation disease at diagnosis (Stage I–II) Disease therapy, and biologic agents Screening and Prophylaxis • After careful exploratory laparotomy, Germ Cell Cancers • High-risk individuals: those with one or patients divided into low-risk and Basic Characteristics more ﬁrst-order relatives with ovarian high-risk groups on the basis of the • Germ cell cancers make up 5% of all carcinoma presence of one or more high-risk cancers of the ovary in the United • No proven effective screening tests features: poorly differentiated States available, although transvaginal neoplasm, extracystic tumor, positive • Histologies: dysgerminomas and sonography and serial CA-125 and peritoneal washings, ascites, or nondysgerminomas (endodermal sinus proteomic serum patterns under extraovarian disease tumors, mixed cell tumors, immature evaluation • Those who are at low risk of teratomas, embryonal carcinomas, and • Prophylactic oophorectomy still of no recurrence (no high-risk features): total choriocarcinomas) proven value abdominal hysterectomy, bilateral • Tumor markers are an important salpingo-oophorectomy, and means of detecting early recurrence Initial Evaluation and Management omentectomy followed by observation and monitoring the progress of • Emphasis in initial evaluation placed on • Those who are at high risk of therapy: α-fetoprotein and human the peritoneal cavity, an emphasis recurrence (one or more high-risk chorionic gonadotropin requiring exploratory laparotomy in features): the same surgery as in those • For management purposes, two major those not clearly stage IV who are at low risk followed by groups of patients: (1) stages I to III • Minimum requirements for appropriate adjuvant platinum-based chemotherapy completely resected and (2) laparotomy: surgery through an incision (paclitaxel/carboplatin for three cycles) incompletely resected stage III to IV adequate to inspect the entire Salvage Therapy for Recurrent disease peritoneal surface, multiple peritoneal Disease biopsies in the absence of gross Stages I to III Completely Resected • Patients divided into platinum-sensitive extrapelvic disease, and a maximal • Initial management: complete resection and platinum-resistant groups attempt at surgical cytoreduction, of disease • Platinum-sensitive patients (responded including total abdominal hysterectomy, • Adjuvant therapy: combination to initial platinum-based therapy and bilateral salpingo-oophorectomy, and chemotherapy (either bleomycin/ experienced at least a 6-month omentectomy etoposide/cisplatin or vincristine/ platinum-free interval before relapse): actinomycin/cyclophosphamide) Management of Advanced retreatment with taxane/platinum (Stage III–IV) Disease combination Stages III to IV Incompletely • After surgery, systemic therapy to • Platinum-resistant patients (progressed Resected include at least a platinum compound on platinum-based therapy, best • Systemic therapy: bleomycin/etoposide/ • Combination chemotherapy favored by response to platinum-based therapy cisplatin 1827
1828 Part III: Speciﬁc Malignancies All • Treatment of choice: surgical resection • Pattern of spread similar to that of • Close follow-up after chemotherapy, with little known about the use of celomic epithelial carcinoma of the including monthly assessments of radiation or systemic therapy as either ovary tumor markers, physical examination, adjuvant treatment or management for • Surgical resection the mainstay for and chest radiography advanced or recurrent disease most patients with disease conﬁned to Rare Malignant Ovarian Tumors the fallopian tube • Fewer than 5% of ovarian cancer: Cancer of the Fallopian Tube • Radiation or chemotherapy reserved granulosa cell tumors, thecoma-ﬁbroma • Rare (300 cases annually in the for cases with penetration to or tumors, Sertoli-Leydig cell tumors, United States), with more than 90% beyond the serosa, with evidence gynandroblastomas, and steroid cell of all cases papillary serous favoring management similar to that tumors adenocarcinomas used for advanced ovarian carcinoma INTRODUCTION International Federation of Gynecology and Obstetrics (FIGO) staging system7 (Table 93-1), in which the most common stage at Cancers of the ovary and fallopian tube together account for most presentation is stage III, characterized by spread outside the pelvis to deaths resulting from cancer of the female genital tract. This statistic involve the peritoneal cavity. Because the process is an intra-abdom- relates primarily to the fact that, unlike other common malignant inal disease that produces few symptoms before intraperitoneal dis- gynecologic neoplasms (cancers of the endometrium and cervix), semination and is not amenable to early diagnosis by currently cancers of the ovary and fallopian tube are ﬁrst seen at relatively available screening techniques, essentially 70% to 75% of patients advanced stages of disease because of the lack of an effective early are ﬁrst seen with advanced (stage III or IV) rather than limited (stage diagnostic test. Ovarian cancers are far more common than tubal I or II) disease. malignancies and provide most of the data on which the management Several characteristics of celomic epithelial carcinomas distinguish of both malignancies is based. This chapter ﬁrst addresses cancers of their clinical management from that of the other two common gyne- the ovary extensively, followed by a discussion of cancers of the fal- cologic cancers: endometrial cancer and cervical cancer. First, the lopian tube. primary route of spread, dissemination throughout the peritoneal cavity, opens the possibility for therapy directed toward the perito- CANCER OF THE OVARY neal cavity. Second, unlike the other two common gynecologic cancers, these lesions usually are ﬁrst seen at a relatively advanced Cancer of the ovary will be newly diagnosed in more than 23,300 stage (stage III or IV), which necessitates a larger role for systemic women in the United States each year and will cause the death of more than 13,900 American women annually.1 The lifetime likeli- hood that ovarian cancer will develop in a woman is estimated to be between 1 in 60 and 1 in 70, with a higher frequency associated with certain familial syndromes.2–5 This group of cancers includes three Table 93-1 International Federation major types: celomic epithelial carcinoma of the ovary, germ cell of Gynecology and Obstetrics Staging neoplasms, and stromal tumors. Each of these groups is discussed System for Ovarian Carcinoma separately. Stage Description Celomic Epithelial Carcinoma I Growth limited to the ovaries Almost 90% of cancers of the ovary are celomic epithelial carcinoma, IA One ovary; no ascites; capsule intact; no tumor on external which is one of the three most common gynecologic cancers. Man- surface agement of these lesions evolves from an understanding of certain IB Two ovaries; no ascites; capsule intact; no tumor on external basic aspects of the disease process. surface Basic Characteristics IC One or both ovaries with either surface tumor; ruptured capsule; or ascites or peritoneal washings with malignant CLINICALLY RELEVANT DISEASE FEATURES. Celomic cells epithelial carcinomas may arise in any part of the peritoneal cavity, although most appear to arise from the celomic epithelium that II Pelvic extension invests the ovary during embryonic development. The reasons for the IIA Involvement of uterus and/or tubes preference for ovarian celomic epithelium are not entirely clear. It IIB Involvement of other pelvic tissues has been speculated that repeated rupture and repair of this portion IIC Stage IIA or IIB with factors as in stage IC of the celomic epithelium with the process of ovulation afford a greater opportunity for mutations that lead to malignancy. Such III Peritoneal implants outside pelvis and/or positive speculation is supported by observations that associate multiple preg- retroperitoneal or inguinal nodes nancies and the use of birth control pills, which suppress ovulation, IIIA Grossly limited to true pelvis; negative nodes; microscopic with a decreased risk for ovarian carcinoma.6 seeding of abdominal peritoneum Furthermore, most of these lesions arise in invaginated epithelium IIIB Implants of abdominal peritoneum ≤2 cm; nodes negative in areas of repair after ovulation, developing as though within a cyst. The process eventually penetrates the capsule of the ovary, forms IIIC Abdominal implants >2 cm and/or positive retroperitoneal tumor excrescences on the surface of the ovary, and then disseminates or inguinal nodes primarily by direct spread throughout the peritoneal cavity. Subse- IV Distant metastases quent spread via lymphatic and hematogenous dissemination also occurs. This pattern of evolution of the disease is reﬂected in the Data from the New FIGO stage grouping.7
Ovaries and Fallopian Tubes • CHAPTER 93 1829 Table 93-2 Impact of Volume of Residual Disease Table 93-4 Prognostic Factors in Ovarian on Pathologic Complete Response Carcinoma to Combination Chemotherapy in Patients with Advanced Ovarian Factor Description Carcinoma Age Older patients have poorer survival. Grade Poorly differentiated lesions are associated with Regimen Minimal Bulky poorer survival. PAC (GOG)8,9 45/137 (33%) 13/107 (12%) Histologic type Clear cell and mucinous histologies are PAC (Ehrlich et al.)10 5/17 (30%) 5/39 (13%) associated with poorer survival. Tumors of low malignant potential imply a much better survival. HCAP (Greco et al.)11 18/21 (86%) 3/29 (10%) Stage More extensive disease, as reﬂected in the FIGO CHEX-UP (Young et al.)12 5/14 (36%) 5/37 (14%) staging system, produces poorer survival. CHEX-UP, cyclophosphamide + hexamethylmelamine + 5-ﬂuoruracil + cisplatin; Volume of disease In patients with stage III disease, larger volume ofHCAP, hexamethylmelamine + cyclophosphamide + doxorubicin + cisplatin; PAC, residual disease leads to poorer survival.cisplatin + doxorubicin + cyclophosphamide.therapy in the management of these cases. Finally, the volume of behave in a more aggressive fashion. At that point, chemotherapyresidual disease at initiation of systemic therapy inﬂuences the sub- may be used, although its efﬁcacy in this setting is not clear.sequent response to chemotherapy and survival. The smaller thelargest residual nodule, the more likely it is that the disease will regress EXTRAOVARIAN PERITONEAL SEROUS PAPILLARYwith drug therapy8–11 (Table 93-2) and the more likely it is that the CARCINOMA. It has long been recognized that celomic epithelialpatient will live longer12–14 (Table 93-3). carcinomas can arise in portions of the peritoneal cavity other than Other disease characteristics have been observed to inﬂuence the surface of the ovaries. The Gynecologic Oncology Group (GOG)outcome (Table 93-4). Shortened survival is associated with older undertook a study of these extraovarian peritoneal papillary serousage15 and more poorly differentiated disease. These factors do not, carcinomas to determine whether they responded in a fashion similarhowever, affect therapeutic decisions except for the role of histologic to that of standard treatment for celomic epithelial carcinomas of thegrade in limited disease, a role that is discussed later in the chapter. ovary.23 The study of 47 women with these extraovarian celomicHistologic subtype also affects survival: Patients who have clear cell epithelial carcinomas showed that when the data are compared withor mucinous carcinomas have shorter survival, whereas those with results of treatment of ovarian carcinomas with the same chemo-tumors of low malignant potential (“borderline carcinomas”) have a therapy, similar response rates, surgical complete response rates, andmarkedly better survival. These subtypes constitute fewer than 10% survivals are observed. This is the basis on which these lesions areof all celomic epithelial tumors. Because no alternative therapeutic now included in trials of chemotherapy for ovarian carcinoma.choice offers greater beneﬁt for mucinous or clear cell carcinomas,these histologic types do not currently inﬂuence therapeutic deci- INTERNATIONAL FEDERATION OF GYNECOLOGYsions. Conversely, tumors of low malignant potential do inﬂuence AND OBSTETRICS STAGE. The factor that most inﬂuencestherapeutic choices, as will be discussed. management is the extent of disease at diagnosis (stage). This discus- sion is organized accordingly: A general approach to initial evaluationTUMORS OF LOW MALIGNANT POTENTIAL. Celomic and surgical management is followed by a discussion of the role ofepithelial tumors of low malignant potential account for approxi- chemotherapy both in previously untreated patients with advancedmately 15% of ovarian carcinomas.16 Patients with these lesions tend disease and in patients with recurrent or persistent disease. The man-to be younger than those with invasive ovarian carcinoma (average agement of patients with limited lesions is then considered.age at onset: 49 years).17 The sine qua non of the diagnosis is theabsence of invasion of the stroma.18 The vast majority of cases display Initial Evaluation and Managementserous or mucinous histology with bilaterality in roughly one third Patients with celomic epithelial carcinomas generally are ﬁrst seenof serous tumors. with complaints of a full or heavy sensation in the pelvis or with Recognition of these tumors is important because both prognosis increasing abdominal girth. Unfortunately, these symptoms usuallyand management differ greatly, in comparison to standard manage- reﬂect the presence of advanced disease. Efforts directed to earlierment of invasive ovarian carcinomas.19–21 In general, management diagnosis have largely been unsuccessful, with the possible exceptionshould begin with an exploratory laparotomy and resection of as of the application of certain tools to patient populations that are atmuch disease as possible. Pathology should be reviewed carefully to high risk for the development of ovarian carcinoma.ensure that no areas of invasive carcinoma are present.22 After surgery,patients should be observed until such time as the disease begins to HIGH-RISK PATIENTS, SCREENING, AND GENETIC TESTING. Within the past decade, interest in using family history to identify patients who are at high risk of developing ovarian carci- Table 93-3 Impact of Volume of Residual Disease noma has escalated.2,24–26 Data now suggest that women with one on Survival in Patients with Advanced ﬁrst-order relative with ovarian carcinoma have a 3.6-fold higher risk than that of the general population. For those who have two or more Ovarian Carcinoma relatives with ovarian carcinoma, at least one of whom is a ﬁrst-order Regimen Minimal (months) Bulky (months) relative, risk is considerably higher, with estimates as great as 50% or better reported but not necessarily substantiated. PAC (GOG)8,9 42 19 Certain hereditary syndromes have been described.3,25 These L-PAM (GOG) 13,14 33 13 include hereditary breast and ovarian cancer syndromes associated with changes at chromosome 17q (BRCA1) and at chromosome 13q L-PAM, melphalan; PAC, cisplatin + doxorubicin + cyclophosphamide. (BRCA2) and hereditary nonpolyposis colon cancer syndromes
1830 Part III: Speciﬁc Malignancies (Lynch syndrome II with an association with colon and endometrial ated with inheritance of an autosomal dominant genetic mutation cancers as well), which exhibit hMLH1, hMSH2, and hPMS2 muta- and a resultant strong family history of ovarian carcinoma and certain tions. These familial ovarian cancers typically appear at a younger age other associated cancers, such as breast cancer.38 These cases fall into than does sporadic ovarian carcinoma and, despite pathologic factors two broad categories. The ﬁrst is commonly called the breast and that should portend a poor survival, predict a signiﬁcantly better ovarian cancer syndrome and is associated with mutations at two loci: survival than that associated with sporadic ovarian cancer of the same BRCA1 on chromosome 17q21 (75% to 90% of breast and ovarian stage.4,5,25–29 Both hereditary breast/ovarian syndrome and hereditary cancer syndrome) and BRCA2 on chromosome 13q12 (10% to 25% nonpolyposis colon cancer syndromes appear to be vertically trans- of breast and ovarian cancer syndrome). In published series, these mitted by an autosomal dominant mode, with incomplete pene- mutations account for approximately 7% of ovarian carcinoma. The trance. Familial ovarian cancer registries have now identiﬁed a second is commonly called the hereditary nonpolyposis colorectal number of women who either ﬁt one of these syndromes or have at carcinoma (HNPCC) syndrome and is associated with mutations least one ﬁrst-order relative with ovarian cancer. that include three known genes: hMSH1 (45% to 50% of cases of These observations raise at least four signiﬁcant questions with HNPCC syndrome), hMLH1 (45% to 50% of cases of HNPCC regard to management. First, should prophylactic oophorectomy be syndrome), and hPMS2 (fewer than 5% of cases of HNPCC syn- recommended to women who are at high risk? The largest experience drome). These lesions account for approximately 3% of ovarian with prophylactic oophorectomy comes from the Gilda Radner carcinoma. Familial Ovarian Cancer Registry. To date, 324 women with at least Although the risk of inheriting a mutation from a parent carrier one ﬁrst-order relative with ovarian cancer have undergone prophy- is 50%, the actual risk of developing a cancer varies from as high as lactic oophorectomy. The relatively short follow-up evaluation of 80% to 85% to as low as 16% for different mutations.38 This vari- most of these women shows that in six, celomic epithelial carcinomas ability of risk and the previously discussed controversy about the of the peritoneal cavity have developed, for an overall rate of 1.8%.30 efﬁcacy of prophylactic oophorectomy raise questions about the role Although this rate is low, it exceeds the rate of ovarian carcinoma in of genetic testing in individuals with family histories of ovarian car- the general population. Other reports have documented the occur- cinoma. The American Society of Clinical Oncology recently issued rence of primary peritoneal neoplasms in women who have previously an updated policy statement about genetic testing and cited three undergone oophorectomy.31 This ﬁnding raises questions about the criteria for determining when genetic testing should be offered (Table value of prophylactic oophorectomy in preventing the development 93-5).39 Such testing should be done only if counseling before and of celomic epithelial carcinomas. No prospective trials have been after the test is available to discuss such issues as the risks and ben- conducted to examine this question. The weight of evidence suggests eﬁts of genetic testing as well as the efﬁcacy, or lack thereof, of that the procedure should not be routinely recommended until interventions that are prompted by the tests. further follow-up is available to determine whether a further signiﬁ- Fourth, might interventions other than prophylactic oophorec- cant increase in the incidence of peritoneal malignancies will occur. tomy be efﬁcacious in high-risk women? Oral contraceptives have The exception to this might be women who have a true hereditary been reported to reduce the risk of ovarian carcinoma by as much as syndrome with a very high risk of developing ovarian carcinoma, 50% after prolonged (>10 years) use.40–42 At least some reports suggest although no clinical trial documents the value of prophylactic oopho- that the effects of such oral contraceptive use on cancer incidence rectomy even in this population.32,33 differ between women with positive family histories and those with Second, how should patients who are at high risk be monitored? a true hereditary syndrome associated with BRCA1 or BRCA2,43,44 More simply put, do we have valid screening tests? Family history with an actual increase in breast cancer risk among those BRCA1 or clearly identiﬁes a high-risk population. Logic dictates that screening BRCA2 women who take tamoxifen for chemoprevention.45 Although leading to early diagnosis would result in a higher cure rate. The this implies a need for caution, at least one study reports that pro- problem is the lack of evidence that any monitoring technique yields longed oral contraceptive use reduces the risk of ovarian cancer in early diagnosis at a reasonable rate. Both CA-125 and transvaginal women with pathogenic mutations in the BRCA1 or BRCA2 gene,46 sonography have been recommended for screening. Evidence is whereas another study shows no impact, negative or positive, of oral lacking that CA-125 leads to early diagnosis.4 By contrast, trans- contraceptives on ovarian cancer risk.47 In the absence of clear-cut vaginal sonography has proved capable of identifying ovarian carci- evidence for a beneﬁt, the role of oral contraceptives to prevent noma at a limited stage in two series.5,30 The drawback of the ovarian cancer is not established; hence, they should not be used for technique is that 15 to 40 laparotomies have to be done to diagnose such a purpose at present. one case of limited ovarian carcinoma. At least for the present, neither Use of other hormones also has been evaluated. At least some approach can be recommended for routine screening, although reports show a direct correlation between postmenopausal estrogen- selected high-risk patients, with a clear understanding of the atten- replacement therapy and risk for development of ovarian carcinoma dant difﬁculties, can be screened with transvaginal sonography.34,35 with a relative risk ranging from 1.59 to 2.81.48–50 This correlation More recently, new technology has offered some hope of an effec- tive approach to screening for ovarian carcinoma. Investigators at the U.S. National Cancer Institute reported the use of proteomic patterns Table 93-5 Criteria for Offering Genetic Testing* in serum to identify patients with ovarian cancer.36 In a population of 50 patients with ovarian cancer and 66 patients with nonmalignant • Individual has personal or family history features suggestive of a disease, the test reportedly had a sensitivity of 100%, a speciﬁcity of genetic cancer susceptibility condition. 95%, and a positive predictive value of 94% for correctly identifying • Test can be adequately interpreted. those with or without ovarian cancer. Unfortunately, the calculation of the positive predictive value did not take into account the preva- • Results will aid in diagnosis or inﬂuence the medical or surgical lence of the disease in the target population. When this deﬁciency is management of the patient or family members at hereditary risk corrected, the true positive predictive value is 1%, not 94%. This is of cancer. less than the positive predictive value that has been reported for the use of CA-125 alone.37 Before proteomic patterns can be recom- *Genetic testing must include pretest and post-test counseling, including a discussion of the risks and beneﬁts of testing and the interventions prompted by the mended to screen for ovarian carcinoma, further retrospective and testing. prospective studies are required. Data from ASCO Working Group on Genetic Testing for Cancer Susceptibility: Third, should patients with positive family histories be offered American Society of Clinical Oncology policy statement update: genetic testing for genetic testing? Approximately 10% of ovarian carcinoma is associ- cancer susceptibility. J Clin Oncol 2003;21:2397–2406.
Ovaries and Fallopian Tubes • CHAPTER 93 1831appears to hold only for patients who take estrogen only and not for support for this view.14 Operative notes on the population in thethose who take a combined estrogen/progesterone regimen. Other database were reviewed to separate the patients into two groups: thosestudies have failed to ﬁnd such a correlation.51 In women who are who had stage IIIA or IIIB disease and those who had stage IIICsurvivors of ovarian cancer, no evidence has been found that estrogen disease that was successfully surgically cytoreduced to small-volumeuse increases the likelihood of relapse or shortens survival.52 residual disease. Patients who required surgical cytoreduction had an Finally, one report assessed the relationship between raloxifene inferior survival in comparison with those who already had small-and risk for ovarian carcinoma.53 This study was actually a meta- volume disease at the time the abdomen was opened. Although thisanalysis of seven randomized placebo-controlled trials of raloxifene investigation shows a difference between these two patient groups, itinvolving a total of 9837 women. The relative risk associated with does not prove that surgical cytoreduction has no value, in the absencethe use of raloxifene was 0.50. This suggests that there is no adverse of a population for comparison in which chemotherapy was startedeffect, but it does not prove a beneﬁcial effect. with large-volume disease. In summary, no scientiﬁcally proven screening approach exists for The only way to address the question of the value of cytoreductiveovarian carcinoma. In addition, no clear role is seen for the use of surgery is to conduct a randomized trial in which all patients areinterventions in the high-risk patient, although the ovarian consensus randomized to surgical cytoreduction or no surgical cytoreductionstatement recommends the use of screening with transvaginal sonog- and are then analyzed by intent to treat. No such study assessingraphy and prophylactic oophorectomy in women with true hereditary initial surgical cytoreduction has been successfully completed.syndromes. The basis for this recommendation is expert opinion and However, two prospective randomized phase III trials have evaluatednot appropriate deﬁnitive trials. the role of interval cytoreduction55,56 (Table 93-6). In a European trial by the European Organization for ResearchINITIAL EVALUATION. The initial evaluation of patients with and Treatment of Cancer,55 patients with advanced disease receivedsuspected ovarian carcinoma, after the usual history, physical exami- three courses of cisplatin plus cyclophosphamide and were then ran-nation, laboratory testing, and CA-125, should be directed toward a domized to receive either three more courses of the same chemo-detailed assessment of the abdominal cavity. Although a variety of therapy or interval cytoreductive surgery, followed by three moreimaging techniques for the abdominal cavity are now available, cycles of cisplatin plus cyclophosphamide. The group that receivedincluding sonography, computed tomography (CT), magnetic reso- interval cytoreductive surgery demonstrated a statistically signiﬁ-nance imaging (MRI), and special isotopic scanning techniques, none cantly superior progression-free and overall survival.provides the level of detailed study necessary for accurate staging of A GOG study56 took patients with stage IIIC disease who hadovarian carcinoma. At the very least, CT scanning of the abdominal undergone an aggressive attempt at initial surgical cytoreduction andcavity, chest radiography, and bone scanning should be done. still had large-volume disease remaining and randomized them to Unless this evaluation demonstrates evidence of disease outside either six cycles of paclitaxel plus cisplatin or three cycles of paclitaxelthe abdominal cavity, exploratory laparotomy is an essential part of plus cisplatin followed by interval surgical cytoreduction and thenthe initial evaluation of the patient. The laparotomy should be done three more cycles of paclitaxel plus cisplatin. This trial showed nothrough an incision that is adequate to evaluate the entire peritoneal difference between the two study arms.surface, including the undersurface of the diaphragm and the right The most rational interpretation of these two studies rests on anparacolic gutter, as well as the para-aortic lymph nodes. If no evidence understanding of the differences in study execution. In the Europeanof gross disease is found outside the pelvis, multiple biopsies of the trial, initial surgery was performed by surgeons with varied trainingperitoneal surface should be obtained. Many patients in whom the backgrounds and, in many instances, probably did not represent truedisease is apparently conﬁned to the pelvis will have evidence of aggressive attempts at surgical cytoreduction. In the GOG study,microscopic seeding of the abdominal peritoneum in one or more conversely, virtually every patient underwent an initial attempt atbiopsies. At the conclusion of this procedure, accurate staging of the aggressive surgical cytoreduction by a trained gynecologic oncologist.disease will have been accomplished and will serve to direct further What the two trials show is that patients with a less than optimalmanagement. initial attempt at surgical cytoreduction beneﬁt from interval bulk reduction, whereas those who undergo an aggressive initial surgeryTherapeutic Role of SurgeryThe volume of residual disease is related both to response to chemo-therapy and to survival. As a result, the standard of care of patientswith ovarian carcinoma with disease that is conﬁned to the abdomi- Table 93-6 Results of Two Studies of Intervalnal cavity is to resect as much disease as possible at initial laparotomy. Surgical CytoreductionThis approach applies to patients with limited disease that can becompletely removed as well as to patients with advanced disease that Parameter All IDS No IDScan be only partially resected. Data on which this approach has beenbased are retrospective analyses showing that patients who initiate EORTC STUDY55chemotherapy with small-volume disease (no nodule larger than 2 cm Patients 408 150 149in diameter remaining in the abdominal cavity) have both a higher Response after three cyclesfrequency of pathologic complete response and a superior survival Complete response rate 17%with chemotherapy8,10–14,54 (see Tables 93-2 and 93-3). Several major questions have been raised about the value of cyto- Partial response rate 55%reductive surgery in patients with advanced disease that is not ame- Progression-free survival 15 months 12.5 monthsnable to a “curative” resection. First and foremost, detractors have Survival 27 months 19 monthspointed out that approximately one half of the population of patientswith small-volume disease consists of patients with stage IIIA or IIIB GOG STUDY56disease—patients who already have small-volume disease at the time Patients 425 216 209the abdomen was opened without any surgical cytoreduction. Accord-ing to this line of reasoning, the improved results in small-volume Progression-free survival 10.5 months 10.8 monthsdisease relate entirely to this portion of the patients who presumably Survival 32 months 33 monthshave biologically less aggressive disease. A retrospective analysis of aGOG database of patients with small-volume disease provided some IDS, interval debulking surgery.
1832 Part III: Speciﬁc Malignancies and still have large-volume disease do not beneﬁt from interval surgery. Table 93-7 Active Single Agents in Celomic On the basis of the weight of current evidence, patients, except Epithelial Carcinoma of the Ovary* for those with obvious stage IV disease, should undergo an initial laparotomy with intent to carry out maximal surgical cytoreduction. PATIENTS This should improve response to chemotherapy as well as survival. Drug N Percent† Those who have a less aggressive initial operation should be consid- Alkylating agents57 1371 33 ered for interval surgical cytoreduction. 57,213–215 Ifosfamide 98 15 Management of Advanced Disease Cisplatin57–59 190 32 Patients with stage III or IV disease, on completion of initial Carboplatin57,60,61 82 24 surgery, should receive systemic therapy for control of disease. For- Oxaliplatin243 45 16 tunately, celomic epithelial carcinoma is a chemosensitive disease— 63–66 hence the signiﬁcant therapeutic options for patients with advanced Paclitaxel 157 35 disease. Docetaxel67–71 423 29 Doxorubicin57 102 33 ACTIVE AGENTS. A number of cytotoxic agents as well as bio- logic and hormonal agents have activity against celomic epithelial 5-Fluorouracil57 126 29 neoplasms6–8,10–15,24–26,54 (Table 93-7). Response rates that have been Methotrexate 57 34 18 reported for each of the active agents vary as a result of several factors: Mitomycin57 49 16 (1) volume of residual disease in the patient population at the initia- Hexamethylmelamine175–182 296 23 tion of therapy, (2) dose and schedule of the agent under study, and (3) whether the patient population has received prior cytotoxic Topotecan121,122,183–185 352 17 therapy to which the neoplasm has become clinically resistant, as Irinotecan 186 29 17 evidenced by clinical progression during therapy. With the reserva- Pegylated liposomal doxorubicin119,120,187–190 557 18 tion that these factors cannot be sorted out in many of the single- agent studies that have been reported, it is possible to point to certain Oral etoposide118,191–194 193 28 active cytotoxic drugs of major interest: the platinum compounds, Gemcitabine123–125 109 16 the taxanes, the mustard-type alkylating agents, the anthracyclines Vinorelbine 195–199 156 22 (including pegylated liposomal encapsulated doxorubicin), the topoi- somerase I inhibitors, oral etoposide, gemcitabine, vinorelbine, and Dihydroxybusulfan57 26 27 hexamethylmelamine. In addition, among hormonal and biologic Galactitol57 39 15 agents, interferon-α, interferon-γ, and tamoxifen display activity. 5-Fluorouracil/leucovorin200 44 14 Among these, the platinum compounds and paclitaxel deserve spe- 201 Mitoxantrone 33 15 ciﬁc comment because of their current major relevance to front-line therapy for newly diagnosed disease. Treosulfan202 80 19 Oral trofosfamide203 31 16 Platinum Analogs. The platinum analogs are the most system- Progestins57 176 12 atically evaluated and active cytotoxic drugs. Cisplatin demonstrates 204–206 clear-cut activity in patients with no prior chemotherapy, as well as Tamoxifen 141 14 in those who are refractory to prior alkylating agents.57–61 Carbopla- Prednimustine57 36 28 tin produces less neurotoxicity and nephrotoxicity than does cispla- Mifepristone207 34 26 tin, in exchange for thrombocytopenia as the dose-limiting adverse effect, and exhibits activity similar to that seen with cisplatin.61 Interferon-α57 21 19 57 Interferon-γ 14 29 Taxanes. Paclitaxel, a diterpenoid extracted from the bark of Taxus Trastuzumab127 41 7 brevifolia (the Western yew tree), acts to enhance tubulin polymeriza- tion and microtubule stability and hence to produce microtubule *Response rate >15%. bundling throughout the cell.62 This stability leads to inhibition of † Response rate percentage. the dynamic reorganization of the microtubular structure of the cell Data from references 48–71, 120–125, 175–200, 213–215, and 243. before cell division. This unique mechanism of action accounts for the apparent lack of cross-resistance between this drug and the plat- inum analogs. The other taxane, docetaxel, has been less extensively Paclitaxel demonstrated signiﬁcant activity in four phase II trials evaluated.67–71 Activity appears to be similar to that of paclitaxel. in patients who had received prior platinum-based combination che- Whether toxicity differs signiﬁcantly awaits publication of random- motherapy63–66 (Table 93-8). In two of the four trials, responses were ized trials that have evaluated this, but on the basis of data available to documented in both platinum-sensitive and platinum-resistant date, docetaxel could be less neurotoxic but more myelosuppressive. patients. Adverse effects, including myelosuppression, hypersensitiv- In summary, a variety of drugs have activity against ovarian car- ity reactions, and signiﬁcant arrhythmias requiring continuous cardiac cinoma. The most important of these are the platinum compounds monitoring during therapy, were frequent and severe but manageable and the taxanes. Other agents of particular interest exhibit the ability and resulted in no deaths attributable to toxicity. The occurrence of to obtain responses in patients who have progressed on paclitaxel- signiﬁcant anaphylactic episodes in the initial experience with the platinum front-line therapy and include oral etoposide, topotecan, drug led to the use of premedication with steroids and H1 and H2 tamoxifen, gemcitabine, navelbine, ifosfamide, and possibly doxil. blockers in the phase II trials, with the resultant virtual elimination of signiﬁcant hypersensitivity reactions. The dose-limiting toxicity is COMBINATION CHEMOTHERAPY. An extensive series of myelosuppression, which, with 24-hour infusions, is severe but questions had to be addressed to evolve effective regimens for the brief. treatment of advanced ovarian carcinoma after surgical cytoreduc-
Ovaries and Fallopian Tubes • CHAPTER 93 1833 clinical complete response rate in the patients who were treated Table 93-8 Phase II Trials of Taxol as Salvage with doxorubicin plus cyclophosphamide, as compared with those Therapy in Patients with Ovarian who received melphalan alone. This was the basis for selection of the Carcinoma two-drug combination as the control arm of the second trial (GOG Protocol 47), which compared doxorubicin plus cyclophos- Investigators No. of Patients Response Rate (%) phamide with the same two drugs plus cisplatin.8 Results showed a McGuire et al. 65 40 30 statistically signiﬁcant improvement in clinical complete response Sensitive 15 40 rate, overall response rate, progression-free interval, and survival in the patients who were treated with the three-drug cisplatin-based Resistant 25 24 combination. GOG (Thigpen et al.)63 43 35 The third critical study (GOG Protocol 52), in patients with Sensitive 16 44 minimal residual disease (deﬁned as patients with stage III disease and no nodules larger than 1 cm in diameter), compared the three- Resistant 27 30 drug combination with cisplatin plus cyclophosphamide9 (Table Einzig et al.64 30 20 93-10). The pathologic complete response rates, as documented at Kohn et al.66 44 48 second-look laparotomy, were not signiﬁcantly different, nor were any differences noted in progression-free interval or survival. By the late 1980s, these three trials made a strong case for the combination of cisplatin plus cyclophosphamide as the standard che-tion. Over the last two decades, the major themes that have keyed motherapy for advanced or recurrent ovarian carcinoma. Four otherthe development of current therapy include the evolution of plati- studies focusing on the substitution of carboplatin for cisplatinnum-based combination chemotherapy, assessment of the value of expanded somewhat the meaning of standard chemotherapy.73–76dose intensity, the deﬁning of the role of paclitaxel, the determination These studies compared the relative efﬁcacy of cisplatin-based versusof which platinum compound to use, and the ascertainment of the carboplatin-based regimens (Table 93-11). The trial of the Southwestrole, if any, of maintenance or consolidation therapy for those who Oncology Group compared cyclophosphamide (600 mg/m2) plusrespond to front-line therapy. Each of these issues is discussed, and either cisplatin (100 mg/m2) or carboplatin (300 mg/m2) in patientsa brief look at other signiﬁcant issues follows. with bulky stage III or IV disease.73 The study showed no signiﬁcant differences between the two regimens with regard to response rate,Evolution of Platinum-based Combination Chemo- progression-free interval, or survival. The toxicities of the two regi-therapy. A multitude of trials have made a ﬁrm case for the value mens was different, the cisplatin regimen producing greater adverseof combination chemotherapy compared with treatment with single effects. The National Cancer Institute of Canada trial comparedagents. The most signiﬁcant of these studies were three large, rando- essentially the same regimens, except for a slightly lower cisplatin dosemized trials.8,9,54 The conclusions from these three GOG studies, of 75 mg/m2, with similar results.75supported by other trials of systemic therapy, formed the basis for The study conducted by the Gynaecological Cancer Cooperativepractice at the end of the 1980s.72 Group for the European Organization for Research and Treatment The ﬁrst two GOG trials were successive studies in patients with of Cancer compared two four-drug combinations consisting of cyclo-bulky advanced disease8,54 (Table 93-9). The ﬁrst of these (GOG phosphamide, doxorubicin, and hexamethylmelamine with eitherProtocol 22) compared melphalan alone with either melphalan plus cisplatin or carboplatin.74 No signiﬁcant differences were noted withhexamethylmelamine or doxorubicin plus cyclophosphamide.54 The regard to response rate, progression-free interval, or survival.only statistically signiﬁcant difference that was observed was a greater The trial that was conducted by investigators at the Mayo Clinic is ﬂawed by a major design problem.76 The dose intensity of carbo- platin is well below that of cisplatin in the other arm, making it Table 93-9 Results of Two GOG Studies difﬁcult to determine whether the differences in progression-free of Combination Chemotherapy interval and survival favoring the cisplatin regimen were related to a different platinum compound or to a lower dose intensity of the in Large-Volume Advanced Ovarian carboplatin. This study has two other features that distinguish it from Carcinoma the other three trials. The number of patients in the trial is consider- GOG PROTOCOL 22 GOG PROTOCOL 47 ably smaller and included 65% with small-volume disease. Parameter L-PAM AC AC PAC Patients 64 72 120 107 CRR 20% 32% 26% 51% Table 93-10 Results of a GOG Study of Minimal Residual Stage III Ovarian Carcinoma Total response 37% 49% 48% 76% (CRR + PRR) Parameter PAC PC CRR 4/23 13/39 Patients 173 176 PCR/total 3% 12% Early recurrence 19 30 Duration 8 months 10 months 9 months 15 months Refused second look 36 37 Median survival 12 months 14 months 16 months 20 months Residual disease 73 67 2 2 AC, doxorubicin (50 mg/m ) plus cyclophosphamide (500 mg/m ), both Pathologic complete response (%) 45 (26%) 42 (24%)intravenous, every 3 weeks, for eight courses; CRR, complete response rate; L-PAM,melphalan (0.2 mg/kg/day orally), for 5 days every 4 to 6 weeks, for 10 courses or 18 PAC, cisplatin (50 mg/m2) plus doxorubicin (50 mg/m2) plus cyclophosphamidemonths; PAC, cisplatin (50 mg/m2) plus doxorubicin and cyclophosphamide as in AC, (500 mg/m2), all intravenous every 3 weeks, for eight cycles; PC, cisplatin (50 mg/m2)all intravenous, every 3 weeks, for eight courses; PCRR, pathologic complete response plus cyclophosphamide (1000 mg/m2), both intravenous, every 3 weeks, for eightrate; PRR, partial response rate. cycles. Data from references 8 and 54. Data from reference 9.
1834 Part III: Speciﬁc Malignancies development of combinations of a platinum compound and pacli- Table 93-11 Randomized Trials Comparing taxel, and the choice of platinum compound. Cisplatin-based with Carboplatin- based Combination Chemotherapy Dose Intensity. Although debated to some extent, the concept of in Advanced, Predominantly Large- the importance of dose intensity to the success of chemotherapy in Volume Ovarian Carcinoma the management of celomic epithelial carcinomas of the ovary has been generally well accepted among oncologists. In vitro data support Response the efﬁcacy of increasing drug levels in enhancing cell kill in cultures Study and Regimen Rate (%) Survival of ovarian cancer cells.77 In patients who have experienced recurrence 73 ALBERTS ET AL (342 PATIENTS) after prior platinum-based chemotherapy for ovarian carcinoma, responses to higher doses of the same platinum compound78 or to Carboplatin (300 mg/m2), every 4 weeks CCR, 34 20 months greater exposure as a result of intraperitoneal administration79 have 2 Cyclophosphamide (600 mg/m ), every 4 PCR, 12 been cited as evidence that enhanced dose can result in response when weeks lower doses have failed. The use of hypertonic saline to permit esca- Cisplatin (100 mg/m2), every 4 weeks CCR, 27 17 months lation of cisplatin dose to 200 mg/m2 per course in combination with 2 cyclophosphamide has been reported to yield high response rates that Cyclophosphamide (600 mg/m ), every 4 PCR, 7 are superior to those achieved with lower-dose regimens.80 Finally, weeks meta-analyses have been reported to show a correlation between dose TEN BOKKEL HUININK ET AL74 (339 PATIENTS) intensity of platinum and response.81,82 These kinds of evidence have Cyclophosphamide (100 mg/m2 PO), days CCR, 24 107 weeks provided strong support for the value of dose intensity in the treat- 14–28 ment of ovarian carcinoma. At ﬁrst glance, the case for dose intensity would appear to be very Hexamethylmelamine (150 mg/m2 PO), solid. However, several signiﬁcant questions remain. First, with days 14–28 regard to reported responses of “refractory” ovarian carcinoma to Doxorubicin (35 mg/m2 IV), day 1 higher doses of drug, it is becoming increasingly apparent that such Carboplatin 350 mg/m2 IV), day 1 responses occur not in patients whose disease progresses with the Cyclophosphamide (100 mg/m2 PO), days CCR, 23 108 weeks lower-dose therapy but rather in patients in whom recurrent disease 14–28 develops some time after they have completed prior therapy. For example, Ozols and colleagues83 reported a series of 30 patients with Hexamethylmelamine (150 mg/m2 PO), “refractory” ovarian carcinoma who were treated with high-dose car- days 14–28 boplatin (800 mg/m2 per 35 day cycle). Although eight responses were Doxorubicin (35 mg/m2 IV), day 1 observed, Ozols and colleagues also noted that “no responses were Cisplatin (20 mg/m2 IV), days 1–5 observed from high-dose carboplatin in  patients who had progres- sive disease during prior therapy with a cisplatin-based regimen.” PATER ET AL75 (447 PATIENTS) Similar observations emerge from second-line phase II studies of Carboplatin (300 mg/m2), every 4 weeks PCR, 13 24 months intraperitoneal chemotherapy. In other words, patients whose tumors 2 Cyclophosphamide (600 mg/m ), every 4 are clinically resistant to platinum-based chemotherapy do not beneﬁt weeks from treatment with higher doses of the same or similar drugs. Second, the reported improvement in response rate that was seen Cisplatin (75 mg/m2), every 4 weeks PCR, 18 23 months with high-dose cisplatin regimens has been reappraised in light of the Cyclophosphamide (600 mg/m2), every 4 signiﬁcant neurotoxicity that emerged from these studies.80 Although weeks this is not a randomized comparison, it is instructive to compare the EDMONDSON ET AL76 (103 PATIENTS) results of GOG studies with regimens using 50 mg/m2 of cisplatin in the combination regimen with results of using high-dose cisplatin. Carboplatin (150 mg/m2), every 4 weeks 20 months In patients with minimal residual stage III disease (no nodule >2 cm Cyclophosphamide (1000 mg/m2), every remaining), the high-dose regimen (cisplatin 200 mg/m2 plus cyclo- 4 weeks phosphamide 1000 mg/m2 repeated every 4 weeks) yielded a patho- Cisplatin (60 mg/m2), every 4 weeks 27 months logic complete response rate of 38%,80 whereas the GOG regimen (cisplatin 50 mg/m2 plus cyclophosphamide 1000 mg/m2 every 3 Cyclophosphamide (1000 mg/m2), every weeks) yielded a pathologic complete response rate of 30%.9 In 4 weeks patients with bulky stage III or stage IV disease, the high-dose regimen (the same as was noted earlier) yielded a pathologic complete CCR, clinical complete response; PCR, pathologic complete response. response rate of 12%,80 whereas the GOG regimen (cisplatin 50 mg/ m2 plus doxorubicin 50 mg/m2 plus cyclophosphamide 500 mg/m2 repeated every 3 weeks) yielded a pathologic complete response rate In summary, these seven randomized trials8,9,54,73–76 deﬁned four of 11%.8 Thus, no evidence exists that the high-dose cisplatin regimen major concepts about standard chemotherapy for advanced ovarian yielded a superior result, even though the dose intensity of the plat- carcinoma as of 1990. First, combination chemotherapy is superior inum compound as a function of dose and time was 3 times as to single-agent therapy. Second, platinum-based combination che- high. motherapy offers signiﬁcant advantages over non-platinum-based Third, although a dose-intensity meta-analysis conducted by regimens. Third, carboplatin offers certain advantages over cisplatin Levin and Hryniuk81 indeed documented a dose-response relation for in terms of altered and more tolerable toxicity with no diminution cisplatin, this relation held only over the range of 0.4 to 0.8. For in efﬁcacy. Finally, two-drug combinations of a platinum compound purposes of this meta-analysis, the “standard” regimen used a cispla- and an alkylating agent offer beneﬁts that are equivalent to those that tin dose equivalent to 15 mg/m2 per week. The dose-response rela- are achieved with more complex regimens. Three major themes tion for cisplatin thus held over a range of 6 mg/m2 per week to dominated clinical research in the 1990s in attempts to improve 12 mg/m2 per week. This equates to a highest dose of 36 mg/m2 every further on systemic therapy for advanced disease: dose intensity, the 3 weeks. This meta-analysis thus supplied no support for the use of
Ovaries and Fallopian Tubes • CHAPTER 93 1835doses higher than those used by the GOG in their relatively low-dose as having nodules larger than 1 cm or stage IV disease to receive eithercisplatin regimens. eight cycles of cisplatin (50 mg/m2) plus cyclophosphamide (500 mg/ An extended meta-analysis by the same investigators82 included m2) every 3 weeks or four cycles of cisplatin (100 mg/m2) plusmore studies in the higher dose range. This study demonstrated the cyclophosphamide (1000 mg/m2) every 3 weeks. A total of 458superiority of combination chemotherapy over single agents and also eligible patients was randomized, of whom 130 had measurablenoted a correlation between response and cisplatin dose up to a level disease. Prognostic features were evenly distributed between the twoof 25 mg/m2/week (or 75 mg/m2 every 3 weeks). In this analysis, the treatment arms. If the prescribed low dose is assigned a dose intensityinvestigators also suggested that total dose delivered might be as of 1.0, the actual received dose intensity for the low-dose regimenimportant as dose intensity. Neither meta-analysis, however, offered was 0.95, and that for the high-dose regimen was 1.90. A twofoldany evidence supporting the importance of total dose nor of a cor- difference in dose intensity was thus achieved. No difference in totalrelation between response and dose intensity for any drug other than dose received was noted between the two arms as planned.cisplatin; nor was either meta-analysis able to support the importance With regard to response, of 60 patients assigned to the high-doseof cisplatin dose intensity beyond 25 mg/m2/week. arm, 19 (32%) achieved a clinical complete response, 16 (27%) These considerations raise serious questions about the value of achieved a partial response, 18 (30%) had stable disease, and 7 (12%)dose-intense regimens in the treatment of ovarian carcinoma. Address- experienced increasing disease. The overall response rate for the high-ing these issues appropriately requires randomized prospective trials. dose arm was thus 59%. Of 70 patients assigned to the low-dose arm,Eight such studies have been reported (Table 93-12).84–91 27 (39%) achieved a clinical complete response, 18 (26%) achieved a partial response, 24 (34%) had stable disease, and 1 (1%) experi-Studies Showing No Advantage from Dose Intensity. GOG enced increasing disease. The overall response rate for the low-doseProtocol 9784 randomized patients with large-volume disease deﬁned arm was thus 65%. No statistically signiﬁcant differences were noted between the two arms with regard to response. With regard to progression-free interval and survival, all 458 patients were included in the analysis. Median progression-free inter- Table 93-12 Eight Randomized Trials of Platinum vals for the low-dose and high-dose regimens were 12 and 13 months, Dose Intensity in Advanced Ovarian respectively, whereas median survivals were 24 and 21 months, Carcinoma respectively. No signiﬁcant differences were observed in either parameter. Response The high-dose regimen was associated with more severe or life- Trial Platinum DI Rate (%) Survival threatening (grade III or IV) toxicity, which included more leukope- SHOWING NO DIFFERENCE nia (82% versus 40%), more thrombocytopenia (22% versus 1%), more anemia (9% versus 2%), more nausea and vomiting (16% GOG84 Cisplatin, 16.7 mg/m2/ 65 21 months versus 3%), and more nephrotoxicity (5% versus 1%). Very few cases week of grade III or IV neurotoxicity were seen. Cisplatin, 33.3 mg/m2/ 59 24 months This GOG study was designed as a pure dose-intensity study only week in patients with large-volume disease. No evidence exists that a GICOG86 Cisplatin, 25 mg/m2/ 61 33 months twofold increase in dose intensity yields any greater patient beneﬁt week over the range of doses used in this trial for patients with large- Cisplatin, 50 mg/m2/ 66 36 months volume disease, but it is clear that the higher-dose regimen was more week toxic. A Gruppo Interregionale Collaborativo in Ginecologia Onco- GONO87 Cisplatin, 12.5 mg/ 61 24 months logica trial86 randomized 306 patients with advanced disease to either m2/week cisplatin 75 mg/m2 every 3 weeks for six cycles or cisplatin 50 mg/m2 Cisplatin, 25 mg/m2/ 58 29 months weekly for 9 weeks. The actual received dose intensity of the high- week dose regimen was twice that of the low-dose regimen, and no differ- London88 Carboplatin, AUC 6 57 HR: 0.91 ences existed in the total dose delivered in either arm of the trial. In contrast to the GOG study, 45% of the patients in this study had Carboplatin, AUC 12 63 small-volume advanced disease. No signiﬁcant differences were Danish89 Carboplatin, AUC 8 33% 3 years observed between the arms with regard to pathologic complete Carboplatin, AUC 4 30% 3 years response (24% high-dose versus 28% low-dose), progression-free Austrian90 Cisplatin, 25 mg/m2/ 42 38 months interval (21 versus 18 months), and survival (36 versus 33 months). week Like the GOG study, this was a trial of pure dose intensity, because each regimen delivered the same total dose of drug. Also like the Cis, 25 mg/m2 + Carbo 39 42 months GOG trial, this study provides no support for the importance of dose 75 mg/m2/week intensity over the range of cisplatin dose intensity from 25 mg/m2/ SHOWING A DIFFERENCE week to 50 mg/m2/week. Scottish85 Cisplatin, 16.7 mg/ 34 27% 4 years A North-West Oncology Group trial87 randomized 145 patients m2/week with large-volume advanced disease to receive cyclophosphamide 600 mg/m2 plus epirubicin 60 mg/m2 plus either cisplatin 50 mg/m2 Cisplatin, 33.3 mg/ 61 32% 4 years or cisplatin 100 mg/m2 every 4 weeks for six cycles. In contrast to m2/week the GOG and Gruppo Interregionale Collaborativo in Ginecologia Hong Kong91 Cisplatin, 15–20 mg/ 30 30% 3 years Oncologica trials, this study called for the delivery of twice as much m2/week total dose of cisplatin in the high-dose regimen. Actual received dose Cisplatin, 30–40 mg/ 55 60% 3 years intensity achieved a 2 : 1 ratio between the high-dose and low-dose m2/week regimens and evaluated the range of cisplatin dose intensity from 12.5 mg/m2/week to 25 mg/m2/week. No signiﬁcant differences were DI, dose intensity; HR, hazard ratio. noted with regard to clinical response (57.5% high-dose versus 61.1% Data from references 84–91. low-dose), pathologic complete response (9.6% high-dose versus
1836 Part III: Speciﬁc Malignancies 18.1% low-dose), progression-free interval (18 months high-dose This trial has major problems. First, 49 (31%) of the 159 patients versus 13 months low-dose), and survival (29 months high-dose had stage IC or II disease. The heterogeneous patient population versus 24 months low-dose). The high-dose regimen was clearly more resulting from the inclusion of these limited-disease patients makes toxic. The trial provides no support for the importance of either dose interpretation of results very difﬁcult, especially when one considers intensity or total dose over the range of cisplatin dose intensity that the relatively small total number of patients in the study. Second, the was tested (12.5 mg/m2/week to 25 mg/m2/week). actual difference in 4-year survival of less than 6% is not impressive; A London GOG trial88 randomized 241 patients with either and the relative death rate of the higher-dose regimen versus the small-volume or large-volume advanced disease to single-agent car- lower-dose regimen after the ﬁrst 2 years is 1.30. The overall advan- boplatin dosed to an area under the curve (AUC) of either 6 for six tage for the higher-dose regimen is signiﬁcant only at P = 0.061. courses or 12 for four courses at 4-week intervals. In the high-dose Finally, the choice of 75 mg/m2 every 3 weeks as the optimal dose of arm, dose intensity was doubled, and total dose increased by 22%. cisplatin does not follow from the results of the study, which did not No signiﬁcant differences were noted with respect to response (63% deal with the recommended dose. high-dose versus 57% low-dose), progression-free interval (hazard A Hong Kong trial91 is the smallest of the randomized studies, ratio, 0.98), and survival (hazard ratio: 0.91). This trial also provides with only 50 patients entered. The patient population is not well no support for the importance of dose intensity or total dose over the characterized. Cisplatin doses on the two regimens were 60 mg/m2 range that was tested. and 120 mg/m2, respectively. The higher-dose regimen yielded a In a Danish Ovarian Cancer Group trial,89 Danish investigators response rate of 55% and a 3-year survival rate of 60% as compared randomized 222 patients with advanced ovarian carcinoma to carbo- with lower-dose results of a response rate of 30% and a 3-year survival platin dosed to an AUC of either 4 or 8 every 4 weeks for six cycles. rate of 30%. Even though these results suggest that the higher-dose No differences were observed with respect to pathologic complete regimen offered an advantage, the size of the trial and the poor char- response or survival. acterization of the patient population make the conclusions less An Austrian trial90 approached the problem of platinum dose convincing. intensity by combining cisplatin and carboplatin. A total of 253 patients with stages IC to IV disease were randomized either to cis- Conclusions Regarding Dose Intensity. In conclusion, the case for platin 100 mg/m2 plus carboplatin 300 mg/m2 or to cisplatin 100 mg/ the use of regimens with greater dose intensity, especially greater dose m2 plus cyclophosphamide 600 mg/m2 monthly for six cycles. Actual intensity of the platinum compound, is unclear at best. To understand received dose intensity for platinum was 1.6-fold greater with the the apparent contradiction between in vitro data and clinical results, cisplatin/carboplatin regimen. The platinum-intensiﬁed regimen one must look to certain basic principles on which the concept of the produced more myelosuppression, ototoxicity, and gastrointestinal value of dose intensity is based. By using a somatic mutation theory toxicity. The cisplatin/carboplatin regimen produced a response rate for drug resistance, Coldman and Goldie92 postulated that the failure of 39%, a complete response rate of 26%, a progression-free median to cure a patient of malignancy results from either the failure to survival of 22 months, and an overall median survival of 42 months. eradicate all drug-sensitive cells because of insufﬁcient drug dose These results were not signiﬁcantly different from those that were intensity or the emergence of cells that were resistant to the drug seen with the cisplatin/cyclophosphamide regimen: 42% response regimen. Enhanced dose intensity functions in two ways to improve rate, 26% complete response rate, 25-month median progression-free the likelihood of cure: (1) eradicating all sensitive cells and (2) survival, and 38-month median overall survival. This trial thus failed eliminating cells that are likely to mutate to resistance before such to conﬁrm an advantage for a 1.6-fold increase in platinum dose mutations take place. No evidence exists that drug resistance can be intensity. overcome in vivo by enhancement of dose intensity over the range These observations contradict the dogma that higher-dose sched- that can be clinically achieved. ules yield better results. Several possible explanations may be found. If these considerations are translated into simple terms, increasing First, total dose instead of dose intensity could be important. At least dose intensity yields increasing clinical response rates up to the point four of the six studies, however, used differences in both dose inten- at which all sensitive cells have been eradicated. Further increase in sity and total dose and showed no advantage. Second, dose intensity dose intensity cannot be expected to yield further improvement in may be relatively ineffective in large-volume disease and still yield results over the currently achievable range. The only basis on which better results in patients with small-volume disease. All but the GOG an increased cure rate can be expected from dose escalation is that trial, however, included patients with small-volume disease, with no the drugs are started before the emergence of resistant cells, an advantage noted in the small-volume subset. Third, a twofold increase unlikely circumstance in patients with advanced disease. in dose intensity may be too small to permit observation of differ- ences. Finally, and perhaps most devastatingly, once a certain thresh- Role of Paclitaxel old has been reached, further escalation in dose intensity may yield Paclitaxel, a new agent with a unique mechanism of action, has sig- no further beneﬁt. niﬁcant activity in ovarian carcinoma as second-line therapy with a response rate in excess of 20% in patients, regardless of prior response Studies Showing an Advantage for Dose Intensity. A study from to platinum-based chemotherapy. These results marked paclitaxel as the Scottish Gynaecology Cancer Trials Group85 randomized 159 probably non-cross-resistant with the platinum compounds and patients with stages IC to IV disease to cyclophosphamide 750 mg/ alkylating agents and suggested a major role for the drug in ﬁrst-line m2 plus either cisplatin 50 mg/m2 or cisplatin 100 mg/m2 every 3 treatment of ovarian carcinoma. These data prompted four major weeks. Actual received dose intensity for the higher-dose regimen randomized trials testing paclitaxel in front-line combination versus the lower-dose regimen was 1.8 to 1. The lower-dose regimen chemotherapy. produced signiﬁcantly less neurotoxicity. At 4 years of follow-up, GOG Protocol 11193 randomized 386 newly diagnosed patients 32% of those receiving the higher-dose regimen were alive compared with large-volume advanced ovarian carcinoma to six cycles of cis- to 27% of those on the lower-dose regimen. The ratio of deaths platin 75 mg/m2 plus either cyclophosphamide 750 mg/m2 or pacli- among those receiving the higher-dose regimen versus that of those taxel 135 mg/m2 over a 24-hour period preceding the cisplatin. The receiving the lower-dose regimen was 0.52 at 2 years and 0.68 at 4.75 paclitaxel-based regimen proved superior in regard to overall response years. These results suggest that in contrast to results in the previous rate (73% versus 60%, P = 0.01), clinical complete response rate ﬁve studies, an advantage that diminished with time occurred for the (51% versus 31%, P = 0.01), percentage grossly disease free at higher-dose regimen. The investigators’ conclusion was that the second-look laparotomy (40% versus 24%, P = 0.001), progression- optimal dose of cisplatin would be 75 mg/m2 every 3 weeks. free survival (median, 18 versus 13 months, P < 0.001), and overall