High dose rate versus low dose rate brachytherapy for gynecological cancer

High Dose Rate Versus Low Dose Rate Brachytherapy for Gynecological Cancer Colin G. Orton

High dose rate (HDR) remote afterloading for the treatment of gynecologic cancers began about 30 years ago. The promising clinical results obtained have led to the establishment of hundreds of HDR facilities worldwide with tens of thousands of patients treated. Unfortu. nately, there has never been a randomized prospective clinical trial with sufficient patients to adequately compare results obtained with HDR and conventional low dose rate (LDR). However, there have been several dozen nonrandomized studies. For cervical cancer, with over 10,000 patients treated with each modality, these studies show that mean 5-year survival rates obtained with HDR are slightly better (61.1%) than with LDR (56.4%), and that these HDR results compare favorably with the best 5-year survival rates reported for LDR

(61,6%). P values for these comparisons are not appropriate because of the nonrandomized nature of these studies. As far as severe complications are concerned, HDR appears to be significantly better than LDR (2.6% v 6.2%). Nonrandomized studies to compare HDR with LDR for endometrial cancer have been fewer; with over 1,000 patients treated by each technique, 5-year survival rates for HDR are better than for LDR (81% v 73%), and severe complication rates are slightly lower (1.0% v 1.4%). Because radiobiological principles would seem to favor LDR over HDR, unless a large number of HDR fractions are used, it is postulated that it is the "physics" of HDR that makes it work, not the "biology." Copyright �9 1993 by W.B. Saunders Company

F or almost a century, low dose rate (LDR) brachytherapy has been successfully applied to the

t reatment of gynecologic cancers) There can be no doubt that LDR intracavitary radiotherapy, either alone or in combination with external beam telether- apy or, when appropriate, surgery, has been an essential component of the t reatment of these dis- eases. Indeed, it would have bordered on clinical malpractice not to have used LDR brachytherapy in most cases. Therefore, it is not surprising to find that there has been a reluctance on the part of radiation oncologists and gynecologists to give up such a firmly established t reatment modality in favor of high dose rate (HDR) remote afterloading, a technique that has been around for only a fraction of this time. 1 However, what is even more surprising is that over the past 5 years there has been a sudden, dramatic reversal of this reluctance, especially in North Amer- ica. However, is this a wise move or are the risks too high, as claimed in a recent editorial by Eifel. 2 Can this switch to HDR be justified and, if so, on what grounds?

This article presents arguments and, wherever possible, evidence for or against the use of HDR for the t reatment of gynecologic cancers. Factors pre-

From the Gershenson Radiation Oncology Center, Wayne State Univer- sit); and the Detroit Medical Center, Detroit, MIi

Address reprint requests to Colin G. Orton, PhD, Gershenson Radiation Oneology Center, Harper Hospital, 3990John R. St, Detroit, MI48201.

Copyright �9 1993 by W.B. Saunders Company 1053-4296/93/0304-0002505.00/0

sented include clinical results, as well as physical, radiobiological, and even economic considerations.

Clinical Results

Clearly, the most important consideration has to be clinical results obtained with HDR. Do these compare favorably with LDR with respect to local control and survival? What about complications? Are all the data anecdotal or have there been carefully designed and analyzed clinical trials? Were these prospective or retrospective, randomized or nonrandomized? All these considerations will now be addressed.

Anecdota l Data

The HDR treatment of gynecologic cancers was first introduced by Henschke et aP ,4 in the early 1960s and, within just a few years, H D R facilities began to be established worldwide 1 using HDR remote afterloading machines such as the Cervitron, 5 Cathetron, 6 Ralstron] Gammamed , ~ Brachytron, 9 Decatron, ~~ and Buchler. H

Early- results were equivocal. Good local control and survival rates were almost always achieved, but occasionally at the expense of increased late complications.~2 It was probably the few reports of increased morbidity that most limited enthusiasm for HDR in these early days. Only when it was realized that this increased risk of complications could be controlled by reducing the dose per fraction, 12 did H D R begin to attract new devotees in significant numbers. Publica-

2,3 2, Seminars in Radiation Oncology, Vol 3, No 4 (October), 1993:pp 232-239

HDR Versus LDR for GYN Cancer 233

tions citing good control without increased morbidity in the mid-to-late 1970s and early 1980s were especially influential, these being primarily the works of Joslin] 20 'Conne l l et al l ~ Ward et al, 14 Snelling et al, 15 and Newman et a116 in the United Kingdom, Rotte 17 and Glase? 8 in Germany, Utley et aP 9 in the United States, and Arai et al, 2~ Shigematsu et al,21 and Sato et a122 in Japan. Of special importance were these latter results from Japan because it has been from there that a great deal of our clinical data has been obtained: by 1985, 150 HDR facilities had been established in Japan where about 80% of all cervical cancer brachytherapy was practiced. 23

However, despite all this enthusiasm elsewhere, skepticism in North America continued, probably because most of the early data were anecdotal and from abroad. It is only since 1980 that studies comparing HDR and LDR for the treatment of gynecologic cancer have been published.

Comparative Studies: HDR Versus LDR

In the past decade or so, several dozen studies have been published comparing HDR and LDR results. With very few exceptions, 21'24 these have been nonran-

domized comparisons, using either historical or con- comitant LDR data on patients treated at the same institution, usually by the same physician(s). For cervical cancer treatments there have also been three surveys published of multifacility data deter- mined by either literature search 25 or questionnaire surveys. 96,27 All these data for cervix and endometrial treatments are presented in the tables.

Cervix Data

Table 1 lists published comparisons of HDR and LDR survival data from 21 institutions treating 4,283 patients with HDR and 5,100 with LDR. For simplic- ity of presentation, data for all stages have been combined, although most of the original reports gave survival rates for each stage separately. All are crude 5-year survival rates except where noted otherwise.

The overall crude 5-year survival rates are 61.2% and 55.5% for HDR and LDR, respectively. For the calculation of these values, the 2- and 3-year survival data have been omitted, and all the actuarial survival rates have been reduced to crude statistics for consis- tency by dividing by an actuarial-to-crude conversion factor of 1.12. This factor was derived from an

Table 1. Published Comparisons of HDR and LDR Crude Survival Data for Cervical Cancer Treatments

No. of Patients Survival Rate (%)

Study Stages HDR LDR HDR LDR

Arai 28 I-IV 1,015 251 58 52 Kauppila 29 I-IV 78 237 761- 72t Uzel 3~ I-IV 199 139 43~: 36:~ Loh 31 I-Ill 350 165 55* 59* Akine 32 IIB/UIB 57 295 50* 39* Sato 2~ I-IV 87 147 53* 46* Chen 33 I1B/I]/B 297 43 54* 50* Glaser 34 I-II/ 493 288 59* 33* Cikaric 35 I-If] 140 187 53 49 Himmelmann 36 IB/IIA 107 484 88 77 Vahrson 37 I-IV 97 557 68 52 Djordjevic 3~ I-IV 228 310 64 51 Yamashita 39 III-IV 86 160 33 41 Cai Shu-Mo 4~ I-IV 489 1,202 77* 59 O'Connell ~3 IB/IIB 28 19 63 54 Rot te 17 I-m 1 ! 2 237 74 69 Kuipers 41 I-I_l/ 111 145 62 65 Taina 42 I/II 40 30 905 73:[: Shigematsu 2l I IB/m 143 106 55 55 Inoue 43 I-IV 75 64 77"~ 811" Smit 44 IB 51 34 81" 85*

Overall (5 y only) I-1V 3,891 4,630 61.2 55.5

NOTE. All results refer to 5-year survival rates, except where noted. *Originally reported as actuarial survival but reduced here to crude data by use of a conversion factor (see text). ~Two-year survival rate. SThree-year survival rate.

9.34 Colin G. Orton

analysis of the crude and actuarial 5-year survival data published in two recent International Federa- tion of Gynecology and Obstetrics (FIGO) reports 45,46 for 43,730 cervical cancer patients treated in the years 1976 to 1981. As shown in Table 2, the ratio of actuarial-to-crude 5-year survival rates is quite consistent across all stages of disease, with a mean value of 1.12.

Table 3 presents the 5-year survival results of the three surveys that have been published. Combining these with the 5-year survival results in Table 1 shows that, with about 12,000 patients treated by each modality, 5-year survival rates were 61.1% versus 56.4% for HDR versus LDR. However, such a combination of data from these studies is not really appropriate because some of the patients are counted twice and some even three times. For this reason, and also because hardly any of the data have been derived from a controlled, randomized clinical trial, a P value for the difference in the HDR and LDR survivals has not been computed.

However, even though a statistically significant improvement in survival cannot be proven, the improvement from 56.4% to 61.1% is nevertheless significant from a clinical perspective because it shows that good results can definitely be achieved with HDR. In this regard, it is interesting to compare these data with some of the very best LDR results published in the literature, viz, from the Groupe des 9, a consortium of nine French radiotherapy centers which, about 20 years ago, initiated a cooperative study of cervical cancer LDR therapy based on the Fletcher System, and now has mature data on 1,383 patients. 47 These results are also shown in Table 3, where the French actuarial data has been reduced to crude statistics using the 1.12 conversion factor. Note that the overall 61.1% 5-year survival rate results for HDR are almost identical to the 61.6% achieved by the Groupe des 9. But what about complications?

Table 4 shows the severe complications data published in 13 reports comparing HDR with LDR.

Table 2. Comparison of Crude and Actuarial 5-Year Survival Rates for Cervical Cancer

Crude 5-Year Actuarial 5-Year Stage Survival Rate Survival Rate Ratio

I 75.8% 84.5% 1.11 II 54.8% 60.8% 1.11 III 28.9% 32.8% 1.13 1V 7.2% 7.8% 1.08

Overall 54.0% 60.3% 1.12

NOTE. From 1976 to 1981,43,730 patients were treated. 45,~

As were the survival rate comparisons in Table 1, with only a few exceptions, 21,51 these were nonrandomized studies, although the HDR and LDR treatments were performed in the same institutions, usually by the same physicians. All the reported complication rates are crude values. Because individual definitions of what constitute serious complications are highly variable, an attempt has been made to carefully review the data in each of the published reports and only to count as serious complications fistulae (vesico- vaginal, enterovaginal, and enterocervical) and all those injuries that required surgical intervention or were the cause of death. These criteria are similar to those of Chassagne, 52 which define grade 3 and 4 injuries.

From Table 4, the overall mean rates of serious complications were 3.5% and 7.7% for HDR and LDR, respectively, ie, the morbidity of HDR procedures was about half that of LDR. This finding is in agreement with that reported in the three surveys, as shown in Table 5. Combining these results with all those reported in Table 4 yields overall mean complication rates of 2.7% and 6.2% for HDR and LDR, respectively, from an analysis of over 15,000 HDR and 11,000 LDR patients. However, as before, addition of all these results is not entirely legitimate because some data are counted more than once. Calculation of a P value for the difference in complications is not appropriate but clearly the decreased morbidity of HDR is impressive. This is especially so when compared with complications data published by one of the Groupe des 9 institutions. 53 As also shown in Table 5, serious complications were observed in 9.8% of 368 patients with this gold standard (Elf el, personal communication, 1991) ofLDR brachytherapy.

Endometrial Data

Compared with cervical cancer, there have been fewer published studies comparing HDR with LDR and apparently no surveys. Table 6 gives the results of seven such comparisons, none of which is from a randomized trial. All the survival data are crude. Overall, the mean 5-year survival rates are 81% and 73% for HDR versus LDR, respectively. As before, a P value is not appropriate for such nonrandomized data, but it is worth noting that in all seven reports HDR survival rates exceed those for LDR. Severe complication rates were given in only four of these studies, and these are shown in Table 7. The overall means of 1.0% and 1.4% for HDR and LDR, respectively, are essentially the same.


Table 3. Published Surveys of HDR Versus LDR Comparisons of 5-Year Crude Survival Data for Cervical Cancer Treatments

No. of Patients Survival Rate (%)


Orton 26 I-IV 7,468 4,738 60.8 59.0 Fu 25 I-IV 1,724 2,340 59.9 51.7 Okawa 27 I-III 300 251 72 69

Overall (Table 1 and survey data combined) I-IV 13,383 11,959 61.1 56.4

Groupe des 947 I-IV - - 1,383 - - 61.6"

*Originally reported as actuarial survival but reduced here to crude by use of a conversion factor (see text).

Physical Considerations From the physical point of view, there are considerable differences between HDR and LDR for the treatment of gynecologic cancers. The most important differences relate to radiation safety, fixation, and placement of sources and applicators, ie, mechanical aspects, and convenience.

Radiation Safety Of all the criteria responsible for the establishment of HDIL radiation safety must be placed at the top of the list. This is especially the case in Japan where, in the aftermath of Hiroshima and Nagasaki, unnecessary radiation exposure of personnel is simply not acceptablefl 3 With HDR under normal operating conditions there is no exposure of radiotherapy or gynecologic staff, nurses, other patients, or visitors. This is a distinct improvement over conventional LDR brachytherapy but is only slightly better than LDR delivered with remote afterloading equipment.

The HDR advantage of maintaining the source (or sources) in the controlled environment of the radiotherapy department is offset by the potential increased hazard to personnel if an HDR source becomes detached, especially if this occurs in a catheter inside the patient. With good radiation safety and quality assurance procedures, such emer- gency situations can be controlled without unaccept- able personnel or patient exposures, but HDR sources are extremely hazardous if handled improperly.

Mechanical Aspects HDR is a "high-tech" procedure that uses the latest developments in applicator design and computeriza- tion of source positioning and treatment planning. It is quite likely that this was a major contributor towards the increased survival and reduced morbidity rates shown in the preceding tables, especially when historical LDR data were used for comparison. Hence, it would be unfair here to compare the mechanical aspects of modern HDR treatments with

Table 4. Published Comparisons of Severe (grades III and IV) Complications of HDR Versus LDR for Cervical Cancer Treatments

No. of Patients Complications (%)


Arai 28 I-IV 1,022 257 6.4 3.6 Uze148 I-IV 590 326 4.5 14.1 Loh 31 MII 350 165 0 0 Akine 32 I-IV 84 3 72 2.4 5.0 Chen 33 IIB/IIIB 297 43 5.7 4.3 Glaser 34 I-IV 1,131 623 0.9 18.9 Cikaric 35 I-1II 140 187 3.6 9. I Kuipers 49 I-If[ 142 152 9.8 9.3 Himmelmann 36 IB-ILA 107 484 0 3.0 Vahrson 37 1/IV 147 835 8.2 4.4 Shigematzu 21 IIB-III 143 106 2.0 7.0 Rotte ~~ I-III 462 533 2.5 8.3 Sharma s~ I-IlI 203 220 0 1.8

Overall I-IV 4,818 4,303 3.5 7.7

236 Colin G. Orton

Table 5. Published Surveys ofHDRVersus LDR Comparisons of Severe Complications Data for Cervical Cancer Treatments


Study Stages" HDR LDR HDR LDR

Orton ~6 I-IV 10,331 5,274 2.23 5.34 Fu 25 I-IV 342 1,352 4.5 4.8 Okawa 27 I-III 300 251 6.7 4.8

Overall (Table 4 and survey data combined) I-IV l 5,791 1 l, 180 2.7 6.2

Groupe des 95~ MV - - 368 - - 9.8

those of conventional LDR when high-tech LDR is available, viz, LDR remote afterloading.

However, even when compared with LDR remote afterloading, HDR shows some advantages. The most important benefit relates to improved fixation of the sources and applicators. With the long application times required with LDR, there is evidence that the sources and applicators move considerably between the time when the localization films are taken (or rectal and bladder doses are measured) and the time of removal. 59,6~ This leads to significant differences between the doses calculated to vulnerable normal tissues and the doses actually delivered. Furthermore, it has been reported that the doses to rectal and bladder tissues compared with Point A are 10% to 15% lower with HDR than with LDR, ~6 which is apparently attributable to either better retraction and/or packing achievable during the relatively short duration of each HDR procedure, or to the better dose distributions achievable with HDR remote afterloading equipment, especially with stepping-source technology. Maybe both play a role. This extra protection afforded rectum and bladder has fre- quently been cited as the major reason why HDR works so well in the treatment of cervical cancers,

especially with regard to reduction in serious complications.26,6~-63

Convenience

With regard to convenience, many physicians prefer to treat on an out-patient basis because the entire procedure can be conducted in the radiotherapy facility. The radiation oncologists and physicists do not have to leave the department to visit the patients, and no scheduling of shielded in-patient rooms is necessary. On the other hand, with LDR, fewer visits to the clinic are required because typical LDR regimens require only two fractions as opposed to an average of four to six fractions with HDR. 26

Radiobiologieal Considerations There have been several publications relating to the radiobiology of HDR versus LDR for gynecologic cancer therapy, 6164 typically using the linear-quadratic (L-Q) bioeffect dose model to evaluate dose- rate and fractionation effects. The general consensus from these articles is that, from purely radiobiological considerations, the therapeutic ratio with LDR will always be higher than for HDR unless a large

Table 6. Published Comparisons of Crude Survival Data for HDRVersus LDR for Endometrial Cancer Treatments



Kauppila 29 I-IV 139 158 91" 78* O'Connel113 I-II 42 31 83 78 Rotte f7 I-III 227 106 74 66 Sorbe 54 I 401 271 85 82 Nori 5~ I/II 300 560 90 69 Bekerus 56 I-IV 65 74 48 46 Rauthe 57 I-IV 209 643 79 72

Overall (5 y only) I-IV 1,244 1,685 81 73

NOTE. All data are for 5-year survival rate except where noted. *Two-year survival rate.


Table 7. Published Comparisons of Severe Complications of HDR Versus LDR for Endometrial Cancer Treatments



Sorbe > I 206* 271 0.5* 1.1 Rotte 5a I-III 227 106 0 1.8 Bekerus 56 I-IV 65 74 1.5 5.4 Rauthe 57 1-11I 191 577 2.6 1.0

Overall I-IV 689 1,028 1.0 1.4

*This data for the 5 to 8 Gy/fraction in a dose-searching study. Higher morbidity was observed with increased dose/fraction.

number of fractions are used or, possibly, if there is a very, fortuitous difference in the repair kinetics of tumor and normal tissue cells: specifically, if tumor cells repair sublethal damage significantly faster than normal, late-reacting tissue cells. Because the latter condition is unlikely to be true for all tumors and all normal tissues, even if it does apply to some, and because large numbers of HDR fractions have been shown to be unnecessary to achieve good results, it has been generally concluded that it must be the physics of HDR that makes it work and not the biology.

Cost-Effect iveness

The cost-effectiveness of HDR versus LDR is highly controversial. If cost containment requires that hospi- talization of patients be minimized, then HDR may be better. But with remote afterloading, HDR equipment is slightly more expensive than LDR, and the cost of building a heavily shielded HDR room can be considerable. In a busy clinic, this is offset by the increased number of patients that can be treated by each HDR unit. Then again, this is offset by the far greater labor intensity of fractionated HDR treatments, both with respect to the physician doing the procedure and the increased support staffrequired.

Clearly, the economy of HDR versus LDR is very complex, but three articles addressing this issue, two from Canada 65,66 and one fi'om the United Sta tesy come to essentially the same conclusions: for a radiotherapy facility, the cost-effectiveness of HDR is dependent on patient load, and the break-even point lies somewhere between 35 and 50 patients per year. These numbers refer specifically to the profit (or loss) to a facility, but of equal importance is the cost to the public. This was assessed by means of a survey of 95 gynecologic brachytherapy services showing that overall charges for LDR gynecologic treatments were over 200% higher than for HDR, primarily because of reductions in hospital and operating room

expenses. 67 In addition to this reduction in overall costs, the study showed that, for a typical gynecologic brachytherapy service in the United States, HDR generated a cost-shift by which radiotherapy billings increased by over 400%.

Summary and Conclus ions

Compared with historical controls, HDR has been shown to yield slightly improved 5-year survival rates for both cervical and endometrial cancer patients. Morbidity is reduced for the cervix treatments and essentially unchanged for endometrium. Even compared with the gold standard of LDR brachytherapy, the average HDR cervical cancer results are equivalent as far as survival is concerned and much better in terms of complications. However, because none of these conclusions is based on the results of a randomized clinical trial, it is not appropriate to state unequivocally that HDR is better than LDR, or even that it is as good as LDR if the most modern remote afterloading equipment is used for both. Neverthe- less, there is no question that the introduction of HDR technology has forced gynecologic brachytherapy to go high tech, and that this has been to the significant benefit of patients because of reduced morbidity; of staff because of reduced radiation exposures; of the public because of reduced overall costs; and of radiation oncology facilities because of increased income caused by cost-shifting. On the negative side, HDR gynecologic treatments are more labor intensive, especially for physicians and physicists, and quality assurance and radiation safety programs need to be far more comprehensive.

In summary, can HDR produce results equivalent to, or even better than those achieved with conventional LDR treatments? Absolutely. Should a gynecologic brachytherapy service, which is known to obtain good tumor control with low morbidity, change from LDR to HDR? Absolutely no, unless this is made desirable by extenuating circumstances such as radi-

238 Colin G. Orton

a t ion safety or economica l cons t ra in ts . Finally, w h a t

abou t the typical convent iona l L D R b r a c h y t h e r a p y

service, where ou t comes are s imi lar to those for L D R

t r e a t m e n t s r epo r t ed in this article? Yes, a change to

H D R should cer ta in ly be cons idered and is p robab ly

w a r r a n t e d in a busy d e p a r t m e n t . Bu t i f a change is

made , pa t i en t s should not be t r e a t e d unt i l a thor-

ough review of the l i t e ra tu re has b e e n m a d e to

d e t e r m i n e the app rop r i a t e doses and f r ac t iona t ion to

be used for each type of t r e a t m e n t . H D R is defini tely

he re to stay, bu t we h a d b e t t e r use it wisely.

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High dose rate versus low dose rate brachytherapy for gynecological cancer