- Email: [email protected]
Platinum alone for chemotherapy for ovarian cancer?
COMMENTARY
complete, but that is not long for the GMC to produce coherent and practicable proposals to satisfy sceptical Ministers. Paradoxically, government might have reason to pause before intruding in this episode of medical disarray. The conspicuous lack of energetic support from the chief medical officers of Scotland and England for Irvine’s revalidation plan during the GMC’s debate supports this view. The cost, for example, will be sizeable. How revalidation would sit next to clinical governance4 remains uncertain. And the roles of the National Institute of Clinical Excellence and Commission of Health Improvement have yet to be clarified. In the meantime, a troubling schism has now opened up in the profession. While the royal colleges have given their support to revalidation, the GMC has refused to lend its weight to this principle. But, as Milburn’s letter shows, the GMC is the most politically accountable, and therefore vulnerable, of our medical institutions. It must be seen to be leading this initiative or else government will tire of the GMC’s empty assurances that it is putting the profession’s house in order.
Richard Horton The Lancet, London WC1B 3SL, UK 1 2 3
4
Horton R. How should doctors respond to the GMC’s judgments on Bristol? Lancet 1998; 351: 1900–01. Horton R. UK medicine: what are we to do? Lancet 1998; 352: 1166. Senate of Surgery of Great Britain and Ireland. Response to the GMC determination on the Bristol case. Senate paper 5. London: Senate of Surgery, 1998. A first class service: quality in the new NHS. London: Department of Health, 1998..
Platinum alone for chemotherapy for ovarian cancer? See page 1571 Ovarian cancer represents 5% of cancer deaths in women but is the cause of the greatest number of gynaecological deaths.1 75% of patients present with advanced disease, for which the overall survival is 25%. Since the introduction of cisplatin to treatment regimens in the mid1970s, only the slightest improvements in overall and progression-free survival have been made. Furthermore, an improvement of only 0·2 months per year since 1980 for relapsed or refractory disease was reported at this year’s meeting of the American Society of Clinical Oncology (ASCO). This finding emphasises a need for more effective initial therapies.2 The ideal drug doses and combinations are still debated. Newer drugs are typically compared with the current “standard regimen”, which until 1996 was thought by many to be cisplatin or carboplatin and cyclophosphamide. More recently, because progression-free survival and overall survival were longer in patients treated with cisplatin and paclitaxel than in those treated with cytoxan and cyclophosphamide in a Gynecologic Oncology Group trial (GOG 111), paclitaxel and cisplatin have been accepted as the standard best regimen, at least for suboptimally “debulked” disease.3 However, this view is being questioned. The oncological community throughout the world has been justifiably slow to accept paclitaxel and cisplatin as the new “standard regimen” because of reasons such as cost, concern that the regimen was not compared with a proper control, and toxicity. Also, information derived from two meta-analyses of trials of ovarian cancer chemotherapy suggested that the addition of doxorubicin,4
THE LANCET • Vol 352 • November 14, 1998
and possibly both cyclophosphamide and doxorubicin,5 to cisplatin is important for survival in advanced ovarian cancer. Data from an Intergroup trial6 confirmed the findings of GOG 111 for both optimum and suboptimum disease. The results from both the GOG and the Intergroup trials have now made it increasingly difficult to complete trials not using paclitaxel. They also confound the information derived from trials comparing a non-paclitaxel regimen with a paclitaxel-containing regimen because patients in a trial are commonly given paclitaxel when they do not respond to their assigned regimen. The interpretation of GOG 132, which had three treatment groups (paclitaxel alone, cisplatin alone, and a combination of both) is made more difficult by a high cross-over rate to the other agent in both single-agent groups.7 This trial, which has been presented only in abstract form, did not show a significant difference in overall or progression-free survival between single-agent platinum and its combination with paclitaxel; both of these regimens were more active than paclitaxel alone. ICON2, described in today’s Lancet, is another randomised prospective trial comparing single-agent carboplatin with cyclophosphamide, doxorubicin, and cisplatin (CAP). It was stopped prematurely after accrual of 1526 patients out of an intended 2000, because of clinical interest in paclitaxel and the continuing ICON3 trial, which is comparing carboplatin or CAP against paclitaxel/ carboplatin. ICON2 as designed had adequate power to discover a significant difference and is the largest randomised prospective ovarian cancer trial. Because of the substantial neurotoxicity from cisplatin reported by both GOG and Intergroup, carboplatin is commonly used instead, despite lack of solid evidence that these two agents are equivalent, especially when combined with paclitaxel. The rationale is that many studies have shown similar efficacy, in terms of survival for at least the first 4 years of follow-up,8 for both platinum drugs when combined with cyclophosphamide but with less neurotoxicity for the combination with carboplatin. Trials addressing the issue of platinum equivalence when used with paclitaxel are in progress. Early data from one trial presented at ASCO this year confirmed the lower incidence of grade 3 neurotoxicity (three-fold lower) and similar progression-free survival, but follow-up time was short.9 Although still debated, intensification of the dose of the platinum drugs within a standard range seems to affect long-term survival in ovarian cancer very little but, clearly, the higher the dose of cisplatin or carboplatin, the greater the toxicity, especially neurotoxicity (for cisplatin) and thrombocytopenia (for carboplatin).10–12 The current recommended dose of cisplatin (75 mg/m 2) was settled upon as a comfortable compromise between toxicity and response.10 ICON2 did not show a survival advantage for CAP over carboplatin alone in women with ovarian cancer. Median progression-free and overall survival were similar to those reported in other trials for advanced disease. The trial design arose from conclusions derived from a metaanalysis revealing that carboplatin and cisplatin are interchangeable,8 that cisplatin combinations might be more effective than single-agent platinum,8 and that CAP has a 7% survival advantage at 6 years over cisplatin plus cyclophosphamide.8 The ICON2 investigators are to be commended for their rapid accrual of a large number of patients from 132 centres in nine countries. Although a mix of stages, of bulk of residual disease, of tumour 1567
COMMENTARY
grades, and of surgical approaches were included, and many of these factors have different survival potentials based on historical controls, the treatment groups were well balanced. 77% of patients in each treatment group had advanced disease. As the investigators point out, this mix is probably representative of the overall population that is treated for ovarian cancer. The results of this study and of GOG 132 are interesting because they suggest, that, despite new drugs and many trials, no definitive advances in treatment have been made since platinum was introduced, and that future trials should include a group receiving single-agent platinum. However, the question remains—at what dose? A plea could also be made for international cooperation within the gynaecological oncology community to accrue the large numbers of patients required for decisive trials and to avoid redundancy in trial design.
Carolyn Johnston Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA 1
Boring CC, Squires TS, Tong T, et al. Cancer statistics. 1994. CA Cancer J Clin 1994; 44: 7–26. 2 Knopf K, Brown M, Kohn EC. Lack of improvement in survival in patients with relapsed or refractory epithelial ovarian cancer, 1980–1997. Proc ASCO 1998; 17: 359 (abstr). 3 McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage 3 and stage 4 ovarian cancer. N Engl J Med 1996; 334: 1–6. 4 A’hern PR, Gore ME. Impact of doxorubicin on survival in advanced ovarian cancer. J Clin Oncol 1995; 13: 726–32. 5 Ovarian Cancer Meta-Analysis Project. Cyclophosphamide plus cisplatin versus cyclophosphamide, doxorubicin, and cisplatin chemotherapy of ovarian carcinoma: a meta-analysis. J Clin Oncol 1991; 9: 168–74. 6 Stuart G, Bertelsen K, Mangioni C, et al. Updated analysis shows a highly significant improved overall survival (OS) for cisplatin-paclitaxel as first line treatment of advanced ovarian cancer: mature results of the EORTC-GCCG, NO-COVA, NCIC CTG and Scottish Intergroup trial. Proc ASCO 1998; 17: 361 (abstr). 7 Muggia FM, Braly PS, Brady MF, et al. Phase 3 of cisplatin or paclitaxel, versus their combination in suboptimal stage 3 and 4 epithelial ovarian cancer (EOC): Gynecologic Oncology Group (GOG) study #132. Proc ASCO 1997; 16: 352 (abstr). 8 Advanced Ovarian Cancer Trialists Group. Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. BMJ 1991; 303: 884–93. 9 duBois A, Richter B, Warm M, et al. Cisplatin/paclitaxel vs carboplatin/paclitaxel as first line treatment in ovarian cancer. Proc ASCO 1998; 17: 361 (abstr). 10 Kaye SB, Paul J, Cassidy J, et al. Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. J Clin Oncol 1996; 14: 2113–19. 11 McGuire WP, Hoskins WJ, Brady MF, et al. Assessment of doseintensive therapy in suboptimally debulked ovarian cancer: a GOG study group. J Clin Oncol 1995; 13: 1589–99. 12 Jakobsen A, Bertelsen K, Andersen JE, et al. Dose effect study of carboplatin in ovarian cancer: a Danish ovarian cancer group study. J Clin Oncol 1997; 15: 193–98.
Prenatal ultrasonography: first do no harm? See page 1577 Ultrasonographic imaging during pregnancy is widely viewed as a safe, invaluable tool for obtaining important information about the growing fetus. This attitude has led to its wide use as a universal screening tool. In this issue of The Lancet, P A Boyd and colleagues report their 6-year experience of antenatal ultrasonography as a screening tool for the detection of fetal malformations, a major cause of perinatal mortality. Although not a randomised trial, the endeavour is a huge one. A register of congenital malformations was
1568
established for the Oxford region in 1991 for all cases diagnosed clinically or pathologically in livebirths, neonatal deaths, stillbirths, and induced and spontaneous abortions. Approximately 90% of the 33 376 pregnancies were scanned antenatally for the detection of anomalies. All screening was done at a prenatal-diagnosis unit in a tertiary referral centre, so the examination was likely to be uniform and of high quality. Over the 6-year study, the investigators found a substantial increase in the sensitivity for prenatal detection of congenital anomalies. By the end of the study period, the detection rate of anomalies confirmed at birth was 68%, a rate higher than has been reported by other large studies.1,2 Although this high rate is encouraging, ultrasonography did not pick up many infants with anomalies. Have the limits with current ultrasound technology been reached? This study and others have shown that the type of anomaly is important to successful diagnosis.2 For instance, sensitivity was extremely high (over 90%) for the identification of external structural abnormalities, such as neural-tube and abdominal-wall defects. By contrast, this study and others indicate that the rate of detection of serious internal structural abnormalities, such as congenital heart disease or congenital diaphragmatic hernia, remains at or below 50%.3,4 Continued efforts to improve detection of these anomalies may lead to improved survival through delivery at a tertiary-care centre, or eventually through prenatal therapy. Although anomalies are an important cause of perinatal mortality, the diagnosis of a lethal anomaly does not change the eventual outcome. A lethal anomaly will be lethal whether the death occurs after early termination in utero or after birth. Nonetheless, for both lethal and less serious anomalies, antenatal diagnosis offers parents and health-care providers the important benefit of being able to consider options about whether to proceed to delivery, whether to deliver at a high-risk centre, and what therapies to consider subsequently. Equally important, additional information can be obtained and decisions thought out before the medical and emotional crisis brought on by having a critically ill newborn infant. In the study at Oxford, improvement in sensitivity of detection was accompanied by worsening of specificity, which emerged in the later years of the study period as the investigators began to identify and register “soft markers”, including choroid plexus cysts, nuchal thickening, and echogenic bowel. Little improvement in sensitivity of detection of serious anomalies could be attributed to the use of soft markers. Instead, the most striking finding in the Oxford report is that 174 pregnancies in which there was a suspicion of an anomaly resulted in the birth of a normal infant. Over 90% of these pregnancies were registered because of the presence of soft markers. Two normal pregnancies were terminated against the recommendations of the caregivers, because of parental concern about fetal anomalies based on sonographic findings. The investigators’ thoughtful discussion about the serious harm that can result from the provision of information to parents is commendable. Even large studies have not shown that antenatal ultrasonography improves the outcome of pregnancy when that outcome is defined as the birth of a healthy infant.5 However, the Oxford study shows that ultrasonography is increasingly sensitive for the detection of many serious anomalies, and therefore capable of providing good
THE LANCET • Vol 352 • November 14, 1998
complete, but that is not long for the GMC to produce coherent and practicable proposals to satisfy sceptical Ministers. Paradoxically, government might have reason to pause before intruding in this episode of medical disarray. The conspicuous lack of energetic support from the chief medical officers of Scotland and England for Irvine’s revalidation plan during the GMC’s debate supports this view. The cost, for example, will be sizeable. How revalidation would sit next to clinical governance4 remains uncertain. And the roles of the National Institute of Clinical Excellence and Commission of Health Improvement have yet to be clarified. In the meantime, a troubling schism has now opened up in the profession. While the royal colleges have given their support to revalidation, the GMC has refused to lend its weight to this principle. But, as Milburn’s letter shows, the GMC is the most politically accountable, and therefore vulnerable, of our medical institutions. It must be seen to be leading this initiative or else government will tire of the GMC’s empty assurances that it is putting the profession’s house in order.
Richard Horton The Lancet, London WC1B 3SL, UK 1 2 3
4
Horton R. How should doctors respond to the GMC’s judgments on Bristol? Lancet 1998; 351: 1900–01. Horton R. UK medicine: what are we to do? Lancet 1998; 352: 1166. Senate of Surgery of Great Britain and Ireland. Response to the GMC determination on the Bristol case. Senate paper 5. London: Senate of Surgery, 1998. A first class service: quality in the new NHS. London: Department of Health, 1998..
Platinum alone for chemotherapy for ovarian cancer? See page 1571 Ovarian cancer represents 5% of cancer deaths in women but is the cause of the greatest number of gynaecological deaths.1 75% of patients present with advanced disease, for which the overall survival is 25%. Since the introduction of cisplatin to treatment regimens in the mid1970s, only the slightest improvements in overall and progression-free survival have been made. Furthermore, an improvement of only 0·2 months per year since 1980 for relapsed or refractory disease was reported at this year’s meeting of the American Society of Clinical Oncology (ASCO). This finding emphasises a need for more effective initial therapies.2 The ideal drug doses and combinations are still debated. Newer drugs are typically compared with the current “standard regimen”, which until 1996 was thought by many to be cisplatin or carboplatin and cyclophosphamide. More recently, because progression-free survival and overall survival were longer in patients treated with cisplatin and paclitaxel than in those treated with cytoxan and cyclophosphamide in a Gynecologic Oncology Group trial (GOG 111), paclitaxel and cisplatin have been accepted as the standard best regimen, at least for suboptimally “debulked” disease.3 However, this view is being questioned. The oncological community throughout the world has been justifiably slow to accept paclitaxel and cisplatin as the new “standard regimen” because of reasons such as cost, concern that the regimen was not compared with a proper control, and toxicity. Also, information derived from two meta-analyses of trials of ovarian cancer chemotherapy suggested that the addition of doxorubicin,4
THE LANCET • Vol 352 • November 14, 1998
and possibly both cyclophosphamide and doxorubicin,5 to cisplatin is important for survival in advanced ovarian cancer. Data from an Intergroup trial6 confirmed the findings of GOG 111 for both optimum and suboptimum disease. The results from both the GOG and the Intergroup trials have now made it increasingly difficult to complete trials not using paclitaxel. They also confound the information derived from trials comparing a non-paclitaxel regimen with a paclitaxel-containing regimen because patients in a trial are commonly given paclitaxel when they do not respond to their assigned regimen. The interpretation of GOG 132, which had three treatment groups (paclitaxel alone, cisplatin alone, and a combination of both) is made more difficult by a high cross-over rate to the other agent in both single-agent groups.7 This trial, which has been presented only in abstract form, did not show a significant difference in overall or progression-free survival between single-agent platinum and its combination with paclitaxel; both of these regimens were more active than paclitaxel alone. ICON2, described in today’s Lancet, is another randomised prospective trial comparing single-agent carboplatin with cyclophosphamide, doxorubicin, and cisplatin (CAP). It was stopped prematurely after accrual of 1526 patients out of an intended 2000, because of clinical interest in paclitaxel and the continuing ICON3 trial, which is comparing carboplatin or CAP against paclitaxel/ carboplatin. ICON2 as designed had adequate power to discover a significant difference and is the largest randomised prospective ovarian cancer trial. Because of the substantial neurotoxicity from cisplatin reported by both GOG and Intergroup, carboplatin is commonly used instead, despite lack of solid evidence that these two agents are equivalent, especially when combined with paclitaxel. The rationale is that many studies have shown similar efficacy, in terms of survival for at least the first 4 years of follow-up,8 for both platinum drugs when combined with cyclophosphamide but with less neurotoxicity for the combination with carboplatin. Trials addressing the issue of platinum equivalence when used with paclitaxel are in progress. Early data from one trial presented at ASCO this year confirmed the lower incidence of grade 3 neurotoxicity (three-fold lower) and similar progression-free survival, but follow-up time was short.9 Although still debated, intensification of the dose of the platinum drugs within a standard range seems to affect long-term survival in ovarian cancer very little but, clearly, the higher the dose of cisplatin or carboplatin, the greater the toxicity, especially neurotoxicity (for cisplatin) and thrombocytopenia (for carboplatin).10–12 The current recommended dose of cisplatin (75 mg/m 2) was settled upon as a comfortable compromise between toxicity and response.10 ICON2 did not show a survival advantage for CAP over carboplatin alone in women with ovarian cancer. Median progression-free and overall survival were similar to those reported in other trials for advanced disease. The trial design arose from conclusions derived from a metaanalysis revealing that carboplatin and cisplatin are interchangeable,8 that cisplatin combinations might be more effective than single-agent platinum,8 and that CAP has a 7% survival advantage at 6 years over cisplatin plus cyclophosphamide.8 The ICON2 investigators are to be commended for their rapid accrual of a large number of patients from 132 centres in nine countries. Although a mix of stages, of bulk of residual disease, of tumour 1567
COMMENTARY
grades, and of surgical approaches were included, and many of these factors have different survival potentials based on historical controls, the treatment groups were well balanced. 77% of patients in each treatment group had advanced disease. As the investigators point out, this mix is probably representative of the overall population that is treated for ovarian cancer. The results of this study and of GOG 132 are interesting because they suggest, that, despite new drugs and many trials, no definitive advances in treatment have been made since platinum was introduced, and that future trials should include a group receiving single-agent platinum. However, the question remains—at what dose? A plea could also be made for international cooperation within the gynaecological oncology community to accrue the large numbers of patients required for decisive trials and to avoid redundancy in trial design.
Carolyn Johnston Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA 1
Boring CC, Squires TS, Tong T, et al. Cancer statistics. 1994. CA Cancer J Clin 1994; 44: 7–26. 2 Knopf K, Brown M, Kohn EC. Lack of improvement in survival in patients with relapsed or refractory epithelial ovarian cancer, 1980–1997. Proc ASCO 1998; 17: 359 (abstr). 3 McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage 3 and stage 4 ovarian cancer. N Engl J Med 1996; 334: 1–6. 4 A’hern PR, Gore ME. Impact of doxorubicin on survival in advanced ovarian cancer. J Clin Oncol 1995; 13: 726–32. 5 Ovarian Cancer Meta-Analysis Project. Cyclophosphamide plus cisplatin versus cyclophosphamide, doxorubicin, and cisplatin chemotherapy of ovarian carcinoma: a meta-analysis. J Clin Oncol 1991; 9: 168–74. 6 Stuart G, Bertelsen K, Mangioni C, et al. Updated analysis shows a highly significant improved overall survival (OS) for cisplatin-paclitaxel as first line treatment of advanced ovarian cancer: mature results of the EORTC-GCCG, NO-COVA, NCIC CTG and Scottish Intergroup trial. Proc ASCO 1998; 17: 361 (abstr). 7 Muggia FM, Braly PS, Brady MF, et al. Phase 3 of cisplatin or paclitaxel, versus their combination in suboptimal stage 3 and 4 epithelial ovarian cancer (EOC): Gynecologic Oncology Group (GOG) study #132. Proc ASCO 1997; 16: 352 (abstr). 8 Advanced Ovarian Cancer Trialists Group. Chemotherapy in advanced ovarian cancer: an overview of randomised clinical trials. BMJ 1991; 303: 884–93. 9 duBois A, Richter B, Warm M, et al. Cisplatin/paclitaxel vs carboplatin/paclitaxel as first line treatment in ovarian cancer. Proc ASCO 1998; 17: 361 (abstr). 10 Kaye SB, Paul J, Cassidy J, et al. Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. J Clin Oncol 1996; 14: 2113–19. 11 McGuire WP, Hoskins WJ, Brady MF, et al. Assessment of doseintensive therapy in suboptimally debulked ovarian cancer: a GOG study group. J Clin Oncol 1995; 13: 1589–99. 12 Jakobsen A, Bertelsen K, Andersen JE, et al. Dose effect study of carboplatin in ovarian cancer: a Danish ovarian cancer group study. J Clin Oncol 1997; 15: 193–98.
Prenatal ultrasonography: first do no harm? See page 1577 Ultrasonographic imaging during pregnancy is widely viewed as a safe, invaluable tool for obtaining important information about the growing fetus. This attitude has led to its wide use as a universal screening tool. In this issue of The Lancet, P A Boyd and colleagues report their 6-year experience of antenatal ultrasonography as a screening tool for the detection of fetal malformations, a major cause of perinatal mortality. Although not a randomised trial, the endeavour is a huge one. A register of congenital malformations was
1568
established for the Oxford region in 1991 for all cases diagnosed clinically or pathologically in livebirths, neonatal deaths, stillbirths, and induced and spontaneous abortions. Approximately 90% of the 33 376 pregnancies were scanned antenatally for the detection of anomalies. All screening was done at a prenatal-diagnosis unit in a tertiary referral centre, so the examination was likely to be uniform and of high quality. Over the 6-year study, the investigators found a substantial increase in the sensitivity for prenatal detection of congenital anomalies. By the end of the study period, the detection rate of anomalies confirmed at birth was 68%, a rate higher than has been reported by other large studies.1,2 Although this high rate is encouraging, ultrasonography did not pick up many infants with anomalies. Have the limits with current ultrasound technology been reached? This study and others have shown that the type of anomaly is important to successful diagnosis.2 For instance, sensitivity was extremely high (over 90%) for the identification of external structural abnormalities, such as neural-tube and abdominal-wall defects. By contrast, this study and others indicate that the rate of detection of serious internal structural abnormalities, such as congenital heart disease or congenital diaphragmatic hernia, remains at or below 50%.3,4 Continued efforts to improve detection of these anomalies may lead to improved survival through delivery at a tertiary-care centre, or eventually through prenatal therapy. Although anomalies are an important cause of perinatal mortality, the diagnosis of a lethal anomaly does not change the eventual outcome. A lethal anomaly will be lethal whether the death occurs after early termination in utero or after birth. Nonetheless, for both lethal and less serious anomalies, antenatal diagnosis offers parents and health-care providers the important benefit of being able to consider options about whether to proceed to delivery, whether to deliver at a high-risk centre, and what therapies to consider subsequently. Equally important, additional information can be obtained and decisions thought out before the medical and emotional crisis brought on by having a critically ill newborn infant. In the study at Oxford, improvement in sensitivity of detection was accompanied by worsening of specificity, which emerged in the later years of the study period as the investigators began to identify and register “soft markers”, including choroid plexus cysts, nuchal thickening, and echogenic bowel. Little improvement in sensitivity of detection of serious anomalies could be attributed to the use of soft markers. Instead, the most striking finding in the Oxford report is that 174 pregnancies in which there was a suspicion of an anomaly resulted in the birth of a normal infant. Over 90% of these pregnancies were registered because of the presence of soft markers. Two normal pregnancies were terminated against the recommendations of the caregivers, because of parental concern about fetal anomalies based on sonographic findings. The investigators’ thoughtful discussion about the serious harm that can result from the provision of information to parents is commendable. Even large studies have not shown that antenatal ultrasonography improves the outcome of pregnancy when that outcome is defined as the birth of a healthy infant.5 However, the Oxford study shows that ultrasonography is increasingly sensitive for the detection of many serious anomalies, and therefore capable of providing good
THE LANCET • Vol 352 • November 14, 1998