- Email: [email protected]
All, none, or some?
Available online at www.sciencedirect.com R
Gynecologic Oncology 89 (2003) 341–342
www.elsevier.com/locate/ygyno
Editorial
All, None, or Some? Are you a lumper or a splitter? Cancer staging systems are contrived to impose a semblance of order and predictability on biologic phenomena whose heterogeneity and complexity would otherwise overwhelm our vocabulary and understanding. Patients are grouped together based on clinical characteristics most easily measured: tumor size and anatomic extent. By this means, we gain the ability to create statistical forecasts for collections of superficially similar individuals and to study their response to various therapeutic interventions. In an effort to optimize outcomes, cooperative groups conduct prospective randomized trials. The fruit of such endeavor is designated level I evidence, and it carries the highest endorsement of the scientific community. Ideally, results obtained from a clinical trial will then be extrapolated to the treatment of the larger population of patients from whom the study subjects were selected, based on the assumption that study participants are broadly representative of a group of patients sharing common characteristics. From these efforts, rational treatment policies and useful clinical algorithms are thought to derive. In this issue of the journal, such a trial is published [1]. It is the product of diligent, conscientious efforts by many investigators. It also embodies the courage of study patients willing to have a major medical management decision (on which the duration and quality of their lives might well depend) assigned by random chance. It therefore merits our serious and respectful scrutiny. But it should not earn our uncritical acceptance. Arguably, this trial also constitutes level I evidence regarding what can be expected when clinical acumen is abdicated in deference to scientific method. Briefly summarized, this study prospectively randomized 256 patients with “bulky” FIGO IB cervical cancer between treatment with radiation alone (80 Gray) and treatment with preoperative radiation (75 Gray) followed by routine adjunctive extrafascial hysterectomy. Compared to radiation alone, combined modality therapy resulted in modest improvement in pelvic control (15% pelvic relapse versus 27% pelvic relapse at 5 years) and statistically borderline (P ⫽ 0.09) improvement in progression-free survival (62% versus 53% at 5 years), but no statistical improvement in overall survival. In order to potentially benefit one patient
with respect to freedom from progression, we would, on average, need to operate on 11 patients. What ought we to conclude from such evidence? How should we extrapolate these findings to routine clinical practice? Curiously, this article concludes without a strong, unequivocal recommendation. The successor study of the Gynecologic Oncology Group (GOG 123) incorporated hysterectomy in all patients because preliminary analysis suggested lower pelvic progression rates with hysterectomy [2]. Should this now remain the standard of care absent demonstrated survival benefit? Or should this practice be abandoned in the context of improved results reported for synchronous cytotoxic chemotherapy and radiation (chemoradiation)? Should all patients with bulky IB cervical cancer continue to be offered adjunctive hysterectomy, or none? How will I advise the next such patient I see in my consulting room? Regrettably, this study will have little impact on how I practice. In the light of current knowledge regarding the design of radiation ports (target volume definition), the radiation dose, and the significance of elapsed time required to complete treatment, it is possible that the results this article reports for radiation alone underestimate the results that can be accomplished when radiation alone is optimally applied. For example, only 49% of the patients in this trial who were randomized to radiation alone completed treatment in 60 days or less employing a radiation regimen that might well be completed in 40 elapsed days. In centers known for excellence in the radiotherapeutic management of cervical cancer, radiation is generally applied in higher dose delivered over shorter periods of elapsed time than specified in this protocol. In the era of widespread use of synchronous radiopotentiating chemotherapy, it is unclear whether the modest improvement in freedom from pelvic progression achieved by supplemental surgery compared to radiation alone would still obtain if compared to optimal contemporary chemoradiation. However, the decision to perform adjunctive hysterectomy need not be an “all or none” controversy. Nor need the ultimate treatment program for an individual patient be assigned prior to initiation of therapy. Flexibility in the face of changing clinical circumstance is often preferable to doctrinal rigidity. Decisions are best taken when all of the
0090-8258/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0090-8258(03)00260-9
342
Editorial / Gynecologic Oncology 89 (2003) 341–342
relevant information becomes available. Tumor response to teletherapy [3] and anatomic feasibility for aggressive intracavitary brachytherapy are parameters that are not known at the time of initial consultation. The observations of the eyes and the fingers may not qualify as level I evidence, but they do constitute valuable evidence. Should they not play a significant role in the individualized treatment programs we associate with excellence in clinical care? Determination of the final treatment strategy can be delayed pending an evaluation of tumor response to teletherapy and the adequacy of brachytherapy dose distribution. It is almost certainly superfluous to surgically remove a cervix and uterus in which there has been complete histologic clearance of cancer by radiation alone. This was the case with 48% of the 123 patients undergoing hysterectomy in this trial. It may not be helpful to remove the cervixes from a group of patients with only microscopic tumor persistence after preoperative radiotherapy (40% of the operated patients in this trial) if there is generally acknowledged tolerance for substantial additional brachytherapy in such patients. Similarly, it does not seem sensible to leave, in situ, a cervix suspicious for persistent cancer because the routine use of adjunctive hysterectomy has not demonstrated a statistically significant impact on the overall survival statistics for the aggregate population of patients diagnosed with this initial extent of disease. If there has been substantial tumor shrinkage in response to teletherapy, and if “favorable geometry” (practically defined as a ratio of brachytherapy dose to Points A compared to dose to urinary bladder outlet or anterior rectal wall equal to or exceeding 1.6) obtains at the time of intracavitary insertion, it would seem reasonable to complete treatment by radical radiation. Brachytherapy should be administered sufficiently to complete an aggressive cumulative dose (teletherapy plus brachytherapy) comprising 85–90 Gy to Points A with low-dose-rate brachytherapy technique. The somewhat subjective clinical impression of tumor shrinkage can be objectively quantified by volumetric comparison of pretreatment magnetic resonance imaging with repeat imaging after completion of a preoperative dose of teletherapy (45–50.4 Gy). Such measurements have been shown to correlate with the likelihood of durable local control and progression-free survival [4]. Conversely, if minimal tumor shrinkage is achieved by teletherapy and/or unsatisfactory geometry is encountered at the time of intracavitary insertion, the eventualities of tumor persistence and late radiation complications become somewhat more predictable. It seems prudent under those conditions to truncate the brachytherapy dose and to proceed with extrafascial hysterectomy. This strategy should limit the additional efforts, discomfort, and expense of surgery to selected patients who are most likely to benefit and for whom more complex therapy can therefore be justified. Such a strategy is predicated on clinical judgment and the willingness of both patient and physician to defer the
fourth-quarter game plan until the results of the first three quarters of play have been posted on the scoreboard. How treatment will be completed will depend on whether the home team appears to be ahead or behind at that point. Such an approach implicitly recognizes the biodiversity of the patient population being treated, and divides patients within a defined stage, in part, based on their response to a complex therapeutic intervention. Can we then compare outcomes of patients treated with and without hysterectomy? No, for we will have selected patients for surgery based on poor tolerance for, or response to, a form of therapy successful for most other patients. Such patients conceivably are burdened with an inherently worse prognosis than the group managed with radiation or chemoradiation without surgery. But that observation is more likely to reflect the behavior of the cancer rather than the comparative efficacy of differing treatment strategies. This is the approach I have used in my practice for many years. Patients with FIGO IB2 cancer of the cervix are counseled that they may, or may not, be advised to undergo adjunctive hysterectomy. That decision will be taken jointly with their attending gynecologic oncologist at such time when all of the pertinent information is available and when the decision needs to be made. The majority of my FIGO IB2 patients do not undergo adjunctive hysterectomy after radiation-based therapy. Some still do. So lump me with the splitters.
References [1] Keys HM, Bundy BN, Stehman FB, et al. Radiation therapy with and without extrafascial hysterectomy for bulky stage Ib cervical carcinoma: a randomized trial of the Gynecologic Oncology Group. Gynecol Onco. [2] Keys HM, Bundy BN, Stehman FB, et al. Weekly cisplatin chemotherapy during irradiation improves survival and reduces relapses for patients with bulky stage IB cervical cancer treated with irradiation and adjuvant hysterectomy: results of a randomized Gynecologic Oncology Group trial. N Engl J Med 1999;340:1154 –1161. [3] Thoms WW, Eifel PJ, Smith TL, et al. Bulky endocervical carcinoma: a 23-year experience. Int J Radiat Oncol Biol Phys 1992;23:491– 499. [4] Mayr NA, Taoka T, Yuh WT, et al. Method and timing of tumor volume measurement for outcome prediction in cervical cancer using magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2002;52: 14 –22.
Anthony H. Russell, M.D.* Department of Radiation Oncology, Cox 305, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114, USA E-mail address: [email protected] * Fax: ⫹1-617-726-3603 doi:10.1016/S0090-8258(03)00260-9
Gynecologic Oncology 89 (2003) 341–342
www.elsevier.com/locate/ygyno
Editorial
All, None, or Some? Are you a lumper or a splitter? Cancer staging systems are contrived to impose a semblance of order and predictability on biologic phenomena whose heterogeneity and complexity would otherwise overwhelm our vocabulary and understanding. Patients are grouped together based on clinical characteristics most easily measured: tumor size and anatomic extent. By this means, we gain the ability to create statistical forecasts for collections of superficially similar individuals and to study their response to various therapeutic interventions. In an effort to optimize outcomes, cooperative groups conduct prospective randomized trials. The fruit of such endeavor is designated level I evidence, and it carries the highest endorsement of the scientific community. Ideally, results obtained from a clinical trial will then be extrapolated to the treatment of the larger population of patients from whom the study subjects were selected, based on the assumption that study participants are broadly representative of a group of patients sharing common characteristics. From these efforts, rational treatment policies and useful clinical algorithms are thought to derive. In this issue of the journal, such a trial is published [1]. It is the product of diligent, conscientious efforts by many investigators. It also embodies the courage of study patients willing to have a major medical management decision (on which the duration and quality of their lives might well depend) assigned by random chance. It therefore merits our serious and respectful scrutiny. But it should not earn our uncritical acceptance. Arguably, this trial also constitutes level I evidence regarding what can be expected when clinical acumen is abdicated in deference to scientific method. Briefly summarized, this study prospectively randomized 256 patients with “bulky” FIGO IB cervical cancer between treatment with radiation alone (80 Gray) and treatment with preoperative radiation (75 Gray) followed by routine adjunctive extrafascial hysterectomy. Compared to radiation alone, combined modality therapy resulted in modest improvement in pelvic control (15% pelvic relapse versus 27% pelvic relapse at 5 years) and statistically borderline (P ⫽ 0.09) improvement in progression-free survival (62% versus 53% at 5 years), but no statistical improvement in overall survival. In order to potentially benefit one patient
with respect to freedom from progression, we would, on average, need to operate on 11 patients. What ought we to conclude from such evidence? How should we extrapolate these findings to routine clinical practice? Curiously, this article concludes without a strong, unequivocal recommendation. The successor study of the Gynecologic Oncology Group (GOG 123) incorporated hysterectomy in all patients because preliminary analysis suggested lower pelvic progression rates with hysterectomy [2]. Should this now remain the standard of care absent demonstrated survival benefit? Or should this practice be abandoned in the context of improved results reported for synchronous cytotoxic chemotherapy and radiation (chemoradiation)? Should all patients with bulky IB cervical cancer continue to be offered adjunctive hysterectomy, or none? How will I advise the next such patient I see in my consulting room? Regrettably, this study will have little impact on how I practice. In the light of current knowledge regarding the design of radiation ports (target volume definition), the radiation dose, and the significance of elapsed time required to complete treatment, it is possible that the results this article reports for radiation alone underestimate the results that can be accomplished when radiation alone is optimally applied. For example, only 49% of the patients in this trial who were randomized to radiation alone completed treatment in 60 days or less employing a radiation regimen that might well be completed in 40 elapsed days. In centers known for excellence in the radiotherapeutic management of cervical cancer, radiation is generally applied in higher dose delivered over shorter periods of elapsed time than specified in this protocol. In the era of widespread use of synchronous radiopotentiating chemotherapy, it is unclear whether the modest improvement in freedom from pelvic progression achieved by supplemental surgery compared to radiation alone would still obtain if compared to optimal contemporary chemoradiation. However, the decision to perform adjunctive hysterectomy need not be an “all or none” controversy. Nor need the ultimate treatment program for an individual patient be assigned prior to initiation of therapy. Flexibility in the face of changing clinical circumstance is often preferable to doctrinal rigidity. Decisions are best taken when all of the
0090-8258/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0090-8258(03)00260-9
342
Editorial / Gynecologic Oncology 89 (2003) 341–342
relevant information becomes available. Tumor response to teletherapy [3] and anatomic feasibility for aggressive intracavitary brachytherapy are parameters that are not known at the time of initial consultation. The observations of the eyes and the fingers may not qualify as level I evidence, but they do constitute valuable evidence. Should they not play a significant role in the individualized treatment programs we associate with excellence in clinical care? Determination of the final treatment strategy can be delayed pending an evaluation of tumor response to teletherapy and the adequacy of brachytherapy dose distribution. It is almost certainly superfluous to surgically remove a cervix and uterus in which there has been complete histologic clearance of cancer by radiation alone. This was the case with 48% of the 123 patients undergoing hysterectomy in this trial. It may not be helpful to remove the cervixes from a group of patients with only microscopic tumor persistence after preoperative radiotherapy (40% of the operated patients in this trial) if there is generally acknowledged tolerance for substantial additional brachytherapy in such patients. Similarly, it does not seem sensible to leave, in situ, a cervix suspicious for persistent cancer because the routine use of adjunctive hysterectomy has not demonstrated a statistically significant impact on the overall survival statistics for the aggregate population of patients diagnosed with this initial extent of disease. If there has been substantial tumor shrinkage in response to teletherapy, and if “favorable geometry” (practically defined as a ratio of brachytherapy dose to Points A compared to dose to urinary bladder outlet or anterior rectal wall equal to or exceeding 1.6) obtains at the time of intracavitary insertion, it would seem reasonable to complete treatment by radical radiation. Brachytherapy should be administered sufficiently to complete an aggressive cumulative dose (teletherapy plus brachytherapy) comprising 85–90 Gy to Points A with low-dose-rate brachytherapy technique. The somewhat subjective clinical impression of tumor shrinkage can be objectively quantified by volumetric comparison of pretreatment magnetic resonance imaging with repeat imaging after completion of a preoperative dose of teletherapy (45–50.4 Gy). Such measurements have been shown to correlate with the likelihood of durable local control and progression-free survival [4]. Conversely, if minimal tumor shrinkage is achieved by teletherapy and/or unsatisfactory geometry is encountered at the time of intracavitary insertion, the eventualities of tumor persistence and late radiation complications become somewhat more predictable. It seems prudent under those conditions to truncate the brachytherapy dose and to proceed with extrafascial hysterectomy. This strategy should limit the additional efforts, discomfort, and expense of surgery to selected patients who are most likely to benefit and for whom more complex therapy can therefore be justified. Such a strategy is predicated on clinical judgment and the willingness of both patient and physician to defer the
fourth-quarter game plan until the results of the first three quarters of play have been posted on the scoreboard. How treatment will be completed will depend on whether the home team appears to be ahead or behind at that point. Such an approach implicitly recognizes the biodiversity of the patient population being treated, and divides patients within a defined stage, in part, based on their response to a complex therapeutic intervention. Can we then compare outcomes of patients treated with and without hysterectomy? No, for we will have selected patients for surgery based on poor tolerance for, or response to, a form of therapy successful for most other patients. Such patients conceivably are burdened with an inherently worse prognosis than the group managed with radiation or chemoradiation without surgery. But that observation is more likely to reflect the behavior of the cancer rather than the comparative efficacy of differing treatment strategies. This is the approach I have used in my practice for many years. Patients with FIGO IB2 cancer of the cervix are counseled that they may, or may not, be advised to undergo adjunctive hysterectomy. That decision will be taken jointly with their attending gynecologic oncologist at such time when all of the pertinent information is available and when the decision needs to be made. The majority of my FIGO IB2 patients do not undergo adjunctive hysterectomy after radiation-based therapy. Some still do. So lump me with the splitters.
References [1] Keys HM, Bundy BN, Stehman FB, et al. Radiation therapy with and without extrafascial hysterectomy for bulky stage Ib cervical carcinoma: a randomized trial of the Gynecologic Oncology Group. Gynecol Onco. [2] Keys HM, Bundy BN, Stehman FB, et al. Weekly cisplatin chemotherapy during irradiation improves survival and reduces relapses for patients with bulky stage IB cervical cancer treated with irradiation and adjuvant hysterectomy: results of a randomized Gynecologic Oncology Group trial. N Engl J Med 1999;340:1154 –1161. [3] Thoms WW, Eifel PJ, Smith TL, et al. Bulky endocervical carcinoma: a 23-year experience. Int J Radiat Oncol Biol Phys 1992;23:491– 499. [4] Mayr NA, Taoka T, Yuh WT, et al. Method and timing of tumor volume measurement for outcome prediction in cervical cancer using magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2002;52: 14 –22.
Anthony H. Russell, M.D.* Department of Radiation Oncology, Cox 305, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114, USA E-mail address: [email protected] * Fax: ⫹1-617-726-3603 doi:10.1016/S0090-8258(03)00260-9