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High-dose-rate brachytherapy alone post-hysterectomy for endometrial cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 42, No. 5, pp. 1033–1039, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/98/$–see front matter
PII S0360-3016(98)00292-2
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Clinical Investigation HIGH-DOSE-RATE BRACHYTHERAPY ALONE POST-HYSTERECTOMY FOR ENDOMETRIAL CANCER CRAIG MACLEOD, F.R.A.C.R.,* ALLAN FOWLER, F.R.A.C.R.,* PETER DUVAL, F.R.A.C.R., F.R.C.R.,† IETA D’COSTA, M.R.C.P., F.R.A.C.R.,‡ CHRIS DALRYMPLE, F.R.A.C.O.G., C.G.O.,§ IAN FIRTH, PH.D.,* PETER ELLIOTT, F.R.A.C.O.G., C.G.O.,§ KEN ATKINSON, F.R.A.C.O.G., C.G.O.,§ § AND JONATHAN CARTER, F.R.A.C.O.G., C.G.O.
*Department of Radiation Oncology and §Gynaecological Oncology, Royal Prince Alfred Hospital and King George V Hospital, Camperdown, New South Wales, Australia; †Department of Radiation Oncology, St Vincent’s Hospital, Darlinghurst, Australia; and ‡ Department of Radiation Oncology, Peter MacCallum Hospital, Melbourne, Australia Purpose: To evaluate the outcome of post-hysterectomy adjuvant vaginal high-dose-rate (HDR) brachytherapy. Methods and Materials: A retrospective analysis was performed on a series of 143 patients with endometrial cancer treated with HDR brachytherapy alone post-hysterectomy from 1985 to June 1993. Of these patients, 141 received 34 Gy in four fractions prescribed to the vaginal mucosa in a 2-week period. The median follow-up was 6.9 years. Patients were analyzed for treatment parameters, survival, local recurrence, distant relapse, and toxicity. Results: Five-year relapse free survival and overall survival was 100% and 88% for Stage 1A, 98% and 94% for Stage IB, 100% and 86% for Stage IC, and 92% and 92% for Stage IIA. The overall vaginal recurrence rate was 1.4%. The overall late-toxicity rate was low, and no RTOG grade 3, 4, or 5 complications were recorded. Conclusion: These results are similar to reported international series that have used either low-dose-rate or HDR brachytherapy. The biological effective dose was low for both acute and late responding tissues compared with some of the HDR brachytherapy series, and supports using this lower dose and possibly decreasing late side-effects with no apparent increased risk of vaginal recurrence. © 1998 Elsevier Science Inc. High-dose-rate, Brachytherapy, Endometrial cancer.
this probably facilitates patients completing therapy, as in a recent LDR series, only 56% of the patients received the planned brachytherapy (2). Since Joslin’s original description of post-hysterectomy HDR vaginal brachytherapy (3), there have been a number of series that show excellent local control with HDR brachytherapy; however, the optimal total dose and fraction size remains arguable (3–9). The basic treatment for endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO), but increasingly formal surgical staging is performed with partial or complete pelvic lymphadenectomy and pelvic washings being taken. Proponents of formal surgical staging have argued that there is a clinical benefit, namely selecting patients who have a low risk of extrauterine disease and deleting external beam irradiation and sometimes brachytherapy from their management, and avoiding the associated side-effects and financial cost (2,
INTRODUCTION Post-hysterectomy adjuvant therapy for Stage I and II endometrial cancer is controversial. The only prospective randomized trial that examined the role of radiotherapy evaluated the role of external beam therapy in clinical Stage I patients; all received low-dose-rate (LDR) brachytherapy after hysterectomy and were randomized to 40 Gy of pelvic irradiation or no therapy (1). This trial showed a statistically significant reduction in vaginal and pelvic recurrence with external beam therapy, but no improvement in overall survival. Vaginal brachytherapy, irrespective of technique, reduces vaginal recurrences. The gold standard has been LDR brachytherapy, and usually a dose of 60 Gy is prescribed to the vaginal mucosa. This requires admission to the hospital and confinement to bed for the duration of treatment. Highdose-rate (HDR) brachytherapy has logistic advantages such as allowing comparatively quick outpatient treatment;
ESTRO Brachytherapy Meeting, Naples 1998. Acknowledgments—The assistance and advice of Roger Houghton, Professor of Gynaecological Oncology, and John Solomon, Senior Visiting Specialist, of Royal Prince Alfred Hospital is appreciated. Accepted for publication 23 July 1998.
Reprint requests to: Dr. Craig MacLeod, Department of Radiation Oncology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales, 2050 Australia. E-mail: [email protected] This data was presented at the Australian Society of Gynaecological Oncologists, Tasmania 1998 and by Michael Jackson at the 1033
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10, 11). However, there is a contrary argument that extensive surgical staging in these often old, obese, and sometimes frail women itself causes significant morbidity, or is technically not possible to adequately perform, and that equivalent outcome can be achieved with TAHBSO alone and adjuvant radiotherapy can be based on the histopathological findings of the uterus (12, 13). Possibly the most morbid treatment protocol is to perform a TAHBSO and complete lymphadenectomy, disregard these findings in selecting a post-operative adjuvant therapy, and routinely give external beam irradiation for high risk Stage I and II endometrial cancer. The Royal Prince Alfred Hospital has previously published its experience of LDR brachytherapy post-hysterectomy in early stage endometrial cancer (14). This study, in over 900 patients with FIGO Stage I or II disease, showed improvement in local control and survival for brachytherapy versus no brachytherapy. This retrospective analysis documents the treatment and outcome of 143 patients treated with HDR brachytherapy. METHODS AND MATERIALS The study group comprised a total of 143 patients posthysterectomy. All patients have been treated at Royal Prince Alfred Hospital since the introduction of the Selectron HDR brachytherapy unit in August 1985 until June 1993. Patients were identified by reviewing the medical records of the departments of gynecologic oncology and radiation oncology. Ten patients treated in this time period were excluded from the analysis because they were from another country and follow-up details were not available. Uterine sarcomas were excluded from the analysis but all other histologies were included. All patients were referred from gynecologic oncologists after the diagnosis of carcinoma of the endometrium was confirmed histologically and staging investigations had been performed. One hundred and forty-three patients had a TAHBSO, and 52 patients also had a complete lymphadenectomy prior to vaginal brachytherapy. The high-dose-rate source was a single line radioactive source train with multiple cobalt60 pellets (4-Ci total source activity). The applicators used were standard Selectron intrauterine vaginal cylinders of 2.5, 3.0, 3.5, and 4 cm in diameter. The most commonly used applicator was 3.0 cm in diameter. A single line radioactive high-dose-rate source and remote afterloading equipment were used. HDR brachytherapy was performed twice a week with the patient in the lithotomy position. No anesthesia was required, and rarely was a patient given oral or intramuscular medication because of anxiety. The dose was prescribed to the vaginal mucosa and the dose was relatively symmetrical at depth, but this depended upon the applicator diameter, and ranged from approximately 60% and 41% for a 2.5 cm applicator to 72% and 54% for a 4.0 cm applicator at 0.5 cm and 1.0 cm depth from the vaginal mucosa, respectively. The whole residual length of the vagina proximal to the urethral orifice was usually treated, but 11 patients had vault
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Table 1. Distribution of cases according to FIGO staging criteria Stage
n 5 143
%
IA IB IC IIA IIB IIIA
8 110 7 13 3 2
5.6 76.9 4.9 9.1 2.1 1.4
radiotherapy alone. The length irradiated ranged from 2.5 to 10 cm. Treatment time depended upon applicator diameter, length of vagina irradiated, and the activity of the source, and ranged from approximately 5 to 20 minutes. Patients were reviewed in the radiation oncology department 4 – 6 weeks after radiation and subsequently by a gynecologic oncologist, and/or radiation oncologist or the primary referring general gynecologist. Local failure was defined as recurrence within the vagina and this was biopsy-proven in all cases. Metastatic failures included all other pelvic and extra-pelvic sites and was either biopsy-proven or clinically determined. Late side-effects were defined as sequelae reported 3 months from completion of the radiotherapy and were recorded for the bladder, bowel, vagina, skin, and other. RTOG toxicity criteria were used. Unfortunately, sexual dysfunction was not specifically recorded. Patterns of recurrence and morbidity were recorded and an audit of deaths was performed at the NSW Cancer Registry. Survival was calculated using the actuarial life table method. The log-rank test was used for the univariate analysis. The computer program used for these functions was SPSS for Windows Release 6.0. RESULTS The median follow-up time was 6.9 years . No patients were lost to follow-up at less than 3 years. The patients’ ages ranged from 38 to 90 years and the median age was 62 years. Corpus Cancer Surgical Staging, FIGO 1988 was used for the 52 patients who had pelvic lymphadenectomy. For the other patients it was based on myometrial penetration as described for Corpus Cancer Surgical Staging, FIGO 1988, that is, IA confined to endometrium, IB invasion to less than half the myometrium, and IC invasion to greater than half the myometrium. The FIGO Stage was: 1A in 8 (5.6%), IB in 110 (76.9%), IC in 7 (4.9%), IIA in 13 (9.1%), IIB in 3 (2.1%), and IIIA in 2 (1.4%) (Table 1). The histology was endometrioid in 124 (86.7%), adenosquamous in 10 (7.0%), and other in 9 (6.3%), of which 6 were serous, 2 were mixed endometrioid and serous, and 1 was clear cell histology (Table 2). Two patients had concurrent cancers diagnosed at other sites during their staging; one had a Stage IA grade 1 endometriod ovarian cancer with a Stage IB grade 2 endo-
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Table 2. Distribution of grade according to FIGO staging criteria Stage
Grade 1
Grade 2
Grade 3
Other
IA IB IC IIA IIB IIIA Total Percent
4 67 4 9 2 0 86 60.1
2 28 3 1 0 0 34 23.8
2 9 0 1 1 1 14 9.8
0 6 0 2 0 1 9 6.3
metrial cancer, the other a Stage IIA grade 2 ovarian cancer with a Stage IB grade 2 endometrial cancer. This second patient received 6 cycles of cisplatin and cyclophosphamide chemotherapy after vaginal brachytherapy. Another patient received 6 cycles of carboplatin and cyclophosphamide for a Stage IIB serous papillary endometrial cancer after brachytherapy. The dose of brachytherapy given to 141 patients was 34 Gy in four fractions. The dose was prescribed to the mucosal surface of the vagina. Two patients had only two or three fractions of the planned treatment (Table 3). Overall 5- and 10-year relapse-free survival was 96% (Fig. 1). It was 100% for Stage 1A, 98% for Stage IB, 100% for Stage IC, and 92% for Stage IIA (Table 4). Overall 5- and 10-year actuarial survival to death from all causes was 91% and 90%, respectively (Fig. 2). Three patients died of disease and 10 died from other causes. Five-year survival was 88% for Stage 1A, 94% for Stage IB, 86% for Stage IC, and 92% for Stage IIA (Table 4). Five patients (3.5%) relapsed (Table 5). Two relapsed in the vagina (1.4%); the first in-field at the vault at 20 months (Stage IIB grade 1 node-negative) and the second outside the radiotherapy cylinder volume at the urethral orifice at 13 months (Stage IB grade 1 node-negative). The first woman was salvaged with surgery but died 7 months later of heart disease without evidence of recurrent disease. The second woman was salvaged with surgery and is disease free at 76 months. Three patients relapsed systemically, one in the lung at 10 months (Stage IB grade 2 nodes not resected), one in the pelvis and inguinal nodes at 25 months (Stage IIA serous papillary node-negative), and one with ascites at 15 months (Stage IIIA grade 3 node-negative). These patients all died of endometrial cancer.
Table 3. Technical details of brachytherapy No. patients Whole vagina Vault of vagina 4 Fractions 2 or 3 Fractions
132 11 141 2
%
Prescribed location
Total dose (Gy)
91.7 — 7.6 — 98.6 Applicator surface 1.4 Applicator surface 17
— — 34 or 25.5
Fig. 1. Relapse-free survival.
Acute toxicity was not analyzed since there was insufficient information in the medical records. It was common, however, for women treated with whole vaginal brachytherapy to experience a moderate vaginal reaction with discomfort, and patchy mucositis was seen at the introitus; it peaked 1 or 2 weeks after the last brachytherapy fraction. Thirty-three patients (23.1%) had at least one site of late toxicity and the most commonly involved organ was the vagina (Table 6). The majority of vaginal toxicity was recorded as mild but there was no functional assessment. Two of the 22 affected patients used regular topical vaginal creams. All of the bladder, skin, and bowel toxicity was mild. Two patients had mild bilateral lymphoedema; however, both of these patients had a lymphadenectomy which would explain this complication. One patient developed a recto-vaginal fistula; however, this occurred directly after a hemorrhoidectomy, and was not included as a complication of the TAHBSO or vaginal brachytherapy. On univariate analysis neither stage, grade, nor histology were statistically significant for relapse-free survival (Table 7). This may reflect the relatively small numbers of patients in this analysis; larger studies have shown stage and grade to be statistically significant (4, 13, 14).
Table 4. Five-year relapse free and 5-year survival results Stage
5-year relapse free survival %
5-year survival %
Overall IA IB IC IIA IIB IIIA
96 100 98 100 92 67 50
91 88 94 86 92 33 50
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Table 6. Late toxicity
Fig. 2. Overall survival.
DISCUSSION The practice of post-operative adjuvant radiation therapy has been in transition at this hospital as the practice of complete lymphadenectomy has become more common. Is this procedure diagnostic, therapeutic, or both? Such debate is outside the scope of this discussion, but we have adopted the practice that after a negative complete lymphadenectomy external beam irradiation is unnecessary. The findings of only a negative lymph node sampling are disregarded, because only a small percentage of involved nodes are enlarged (15, 16) and the patient is treated on the pathological information supplied by the hysterectomy specimen. In general, for patients who have not had a complete lymphadenectomy, our policy has been to advocate no treatment for Stage IA grade 1 and 2, whole vaginal brachytherapy for Stage IA grade 3 and Stage IB grade 1 and 2, and external beam therapy with or without brachytherapy for more advanced stages of disease. The treatment protocols have not been rigidly adhered to and have been altered based on surgical and patient input. For example, if there is heavy vaginal contamination with tumor spill at the TAHBSO, vaginal brachytherapy is advocated based upon the possible etiology of vaginal recurrence being genital tract metastatic implantation. Nevertheless, the outcome in adopting these selection criteria seems Table 5. Any local or distant relapse by stage Stage
Local relapse (grade)
Distal relapse (grade)
IA IB IC IIA IIB IIIA
0 1 (G1) 0 0 1 (GI) 0
0 1 (G2) 0 1 (SP) 0 1 (G3)
SP 5 serous papillary.
Site
Grade 1 (%)
Grade 2 (%)
Bladder Bowel Skin Vagina Lymphoedema Total patients affected
8 (5.6) 3 (2.1) 3 (2.1) 20 (13.9) 2 (1.4) 31 (21.7)
— — — 2 (1.4) — 2 (1.4)
Grade 3 or above (%) — — — — —
to have been supported for all stages up to and including Stage IIA, even in patients with high-risk histologies. There are too few patients to comment in Stages IIB and IIIA. The gold standard for comparing outcome remains LDR brachytherapy, and in this series the local recurrence rate, overall survival, and disease-free survival are similar to our previous LDR series (14), and other LDR series (2, 17–21). There is currently not a gold standard for HDR vaginal brachytherapy. Four of the HDR series have included patients treated with a combination of external beam and brachytherapy (3, 5–7) and four (4, 8, 9), including this series, have used brachytherapy alone as adjuvant posthysterectomy therapy (Table 8). The dose prescription used in this series was 34 Gy given in four fractions to the vaginal mucosa. It is difficult to compare series because of differences in technique, total dose, and fraction size. Compounding these differences is the inherent dose inhomogeneity of brachytherapy with rapid dose fall-off at increasing distance from the source. Nevertheless, an attempt has been made to compare the doses in terms of total dose and fraction size at the mucosal surface and biologically by using two modifications of the linear quadratic equation. The first equation, known variously as the extrapolated response dose (ERD) by Barendson (22), and the biological effective dose (BED) by Fowler (23) is: Table 7. Univariate analysis
Stage IA IB IC IIA Age (years) 30–60 61–70 711 Grade Low Intermediate High Other Histology Endometriod Adenosquamous Other
5-year relapse-free survival
P value
1.00 0.98 1.00 0.92
0.54
0.97 0.96 0.97
0.94
0.98 0.97 0.93 0.89
0.50
0.97 1.00 0.89
0.41
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Table 8. Series that have used HDR brachytherapy
Series
Number of patients
Total dose (Gy)
Fraction size (Gy)
Prescription point
Vaginal recurrence (%)
Joslin (3) #Sorbe (4) Mandell (5) Nori (6) Fanning (7) #Gumbs (8) #Noyes (9) #MacLeod (current)
256 404 330 300 60 286 63 143
35 27–36 21 21 21 21 32.4 34
7 4.5–9 7 7 7 7 16.2 8.5
0.5 cm depth 1 cm depth 0.5 cm depth 0.5 cm depth 0.5 cm depth 0.5 cm depth mucosal surface mucosal surface
1.2 0.7 2.7 includes pelvic 2.0 0 2.4 0 1.4
# 5 Brachytherapy alone as adjuvant therapy.
S
ERD or BED 5 nd 1 1
d a/b
D
The dose of 34 Gy in four fractions reflected a compromise between the twin concerns of tumor control and late side-effects as well as patient and department logistics. This dose appears similar to the popular North American dose of 21 Gy in three fractions prescribed to a 0.5-cm depth from the vaginal mucosal surface (Tables 8 and 9). In this series the local-failure rate in low-risk disease, defined as grade 1 and 2 and confined to the inner half of the myometrium, was 1.0%; that is 1 of 101 patients failed in the vagina, although the patient only had her vaginal vault treated and she relapsed outside this volume in the periurethral region of the vagina. It is difficult to estimate from the other HDR series which subgroup of patients had low-risk disease and what their outcome was. However, in the two series that used HDR brachytherapy alone, the local recurrence rate was 0.7% in Sorbe’s (4) series (of which 89.6% of patients had less than 1/3 myometrial invasion and only 6.7% were poorly differentiated cancers) and was 1.1% for Stage IA and 3.7% for Stage IB in Gumbs (8) series (of which only 2.0% were poorly differentiated cancers). The dose given by Gumbs (8), by most of the North American centers (4, 7), and in this
The second equation, known as the standard relative effectiveness (SRE) as described by Yaes (24), with conversion tables described by Barton (25) is: SRE 5 n1d1
S
D
a / b 1 d1 a/b 1 2
The advantage of the Yaes modification is that, for the clinicians, it gives an intuitive feel for tumor control and normal tissue tolerance because it is comparative to standard 2 Gy fractionation. For a given dose and fraction size, the value calculated for ERD or BED is greater than for SRE. Obviously, assumptions have been made in calculating these doses (an a/b ratio of 10 Gy and 3 Gy for earlyand late-responding tissues, respectively; the midplan dose of a 3.0 cm vaginal cylinder treating 7.5 cm vaginal length; no correction for repopulation) that warrant caution in terms of its specific applicability. However, in a broad comparative sense, Table 9 may be useful.
Table 9. Depth-dose data, SRE and ERD/BED, at the vaginal mucosa, for acute and late responding tissues Acute tissues Series Joslin (3) Sorbe (4)
Mandell (5) Nori (6) Fanning (7) Gumbs (8) Noyes (9) MacLeod (current)
Total dose
Late tissues
Fraction size
Surface dose
0.5 cm dose
1-cm dose
SRE
ERD
SRE
ERD
35 36 30 30 27
7 9 6 5 4.5
49.3 67.9 56.6 56.6 50.9
35 50.7 42.3 42.3 36.1
26.1 36 30 30 27
81.5 152.6 100.6 91.6 78.4
97.9 183.2 120.7 110.0 94.1
126.7 271.2 162.1 140.7 116.9
211.3 452.1 270.2 234.6 194.8
21
7
29.6
21
15.9
49.0
58.8
76.1
127.0
16.2 8.5
32.4 34
22.9 24.0
17.3 18.1
74.7 52.4
84.9 62.9
124.4 78.2
270.4 130.3
32.4 34
Calculations based upon assumption that a 3-cm diameter vaginal cylinder has been used, 7.5 cm length of vagina has been treated, and the depth-dose data has been calculated for the id-plan. All doses in Gy. a/b 5 10 Gy for early reacting tissues and a/b 5 3 Gy for late reacting tissues. Figures in bold 5 dose prescription point.
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series, were biologically lower for cancer than either Sorbe’s series or other series. The vaginal recurrence rate of 3.7% for predominantly low risk Stage IB disease with only a median follow-up of 35 months reported by Gumbs et al. appears to be high, compared with the expected long-term vaginal recurrence rate of 4% for untreated patients with low-risk Stage I disease (10, 14). Moreover, in low-risk groups (variously defined as grade 1 and 2, and confined to the inner third or inner half of the myometrium) treated with total vaginal LDR brachytherapy the vaginal recurrence rate is only about 0.1% (14, 17–19). The series are possibly not comparable because of differences in staging, the surgical procedure itself, and different volumes of vagina being treated; however, clinicans must remain vigilant to the possibility of under-dosing the vagina, especially if a dose is used that is probably biologically inferior to the gold standard of 60 Gy using LDR brachytherapy. Therefore, is 21 Gy to 0.5-cm depth, or indeed our own 34 Gy in four fractions to the vaginal mucosal surface, which is very similar biologically in terms of tumor control, too low (Table 9)? Although there is not a standardized dose for HDR vaginal brachtherapy in this setting, the excellent results with long-term follow-up and low morbidity that have been reported by Sorbe (4) using their lowest dose of 27 Gy in six fractions at 1.0 cm depth probably indicate that this dose fractionation schedule should be the benchmark against which other series are compared. Increasingly, the use of any brachytherapy is questioned in low-risk disease post-hysterectomy. The benefit in this setting is small, with a crude 5-year local recurrence rate of about 3.2% (10) and an actuarial 20-year recurrence rate of 4.9% (14) without brachytherapy, but both of these results are from busy single institutions and may represent best possible untreated outcome. Also, the Carey results have been criticized since only 54% of the patients had a 5-year follow-up (26). Nevertheless, we are not dogmatic about its use, but find that many patients with low-risk disease opt for therapy despite the small apparent gain. A simplistic analogy of similar benefit is seen for adjuvant chemotherapy or hormonal therapy in node-negative breast cancer which showed a decrease in recurrence of about 5% at 10 years, and a survival benefit of about 4% at 10 years; however, this statistically significant benefit required a large meta-analysis to show (27, 28). In patients with high-risk Stage I, and any Stage II disease, (since the risk of vaginal recurrence is high) it is standard practice to give adjuvant radiotherapy. This hospital’s previous series demonstrated that in patients who did not receive adjuvant brachytherapy there was a 14.6% vaginal recurrence rate for Stage I grade 3 or those tumors which invaded the middle third of the endometrium or beyond, and a 16.7% vaginal recurrence rate for Stage II disease. In this group of patients we had our only in-field recurrence, in a patient who had Stage IIB node-negative grade 1 disease. The vaginal recurrence rate was thus 2.4% for high risk disease. Our policies appear to be supported in
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the presence of a negative staging lymphadenectomy for high-risk disease with the exception of Stage IIB or beyond. Currently, the decision to use HDR or LDR brachytherapy for postoperative adjunctive therapy for endometrial cancer is topical, and many radiation oncology departments with access to both techniques may question which to use. The relative advantages and disadvantages of LDR compared to HDR brachytherapy have been well described in the literature (29). In general, the radiobiological advantages of LDR brachytherapy have not translated into improved outcome in terms of local control or reduced sideeffects in cervix cancer if a dose per fraction to “point A” of 7.0 Gy or less is used (30); this will probably also be demonstrated for a range of doses and fraction sizes in endometrial cancer. A deficiency of the analysis is that sexual function was not assessed; however, many patients in this age group would have other factors that would confound the interpretation of the etiology of any sexual dysfunction, such as being elderly, lack of a partner, no documented sexual history prior to therapy, and anatomical distortion from the surgery. Other investigators have found brachytherapy alone to be an uncommon cause of sexual dysfunction (4, 31). LDR and HDR brachytherapy costs in this country include both a professional and capital component, and are set by the Australian government. They are approximately US $1200 for 60 Gy in one application, which includes the hospital bed, operating room, and anesthetic fee, and are US $2400 for 34 Gy in four fractions. The national adjusted standardized United States costs have been reported as $3467 and $5381 for LDR and HDR brachytherapy, respectively (11). Therefore, based on these figures, if the treatments are equally effective, HDR brachytherapy is substantially more expensive. However, in both of the above examples, the costs have been analyzed as payor costs, that is, the fee raised with the service. Costs can be analyzed in different fashions, for example, they can focus on patient costs, payor costs, or societal costs. Articles that have reviewed this issue concluded that cost-equivalence is based on patient load and is achieved at approximately 50 patients a year. Below this number, LDR is less expensive, and above this, HDR is less expensive. (32, 33). However, there is considerable international variability in costs which probably make these findings specific rather than generally valid. The results achieved at RPA are in keeping with both reported LDR (2, 18 –21) and HDR (3–9) series . The optimal dose per fraction and number of fractions of HDR brachytherapy is not established, and comparison between different series is confounded by many factors. Adopting the use of selective HDR vaginal brachytherapy to a dose of 34 Gy in four fractions, giving two fractions per week alone after TAHBSO for Stage I–IIA endometrial cancers, appears effective for low-risk disease, and for high-risk disease if the pelvic lymphadenectomy is negative. This treatment has a low rate of late toxicity.
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REFERENCES 1. Aalders J, Abeler V, Kolstad P, et al. Postoperative external irradiation and prognostic parameters in stage I endometrial cancer. Obstet Gynecol 56:419 – 426. 2. Orr JW, Holiman JL, Orr PF. Stage I corpus cancer: Is teletherapy necessary? Am J Obstet Gynecol 1997; 76:777– 787. 3. Joslin CA, Vaishampayan GV, Mallik A. The treatment of early cancer of the corpus uteri. Br J Radiol 1977; 50:38 – 45. 4. Sorbe BG, Smeds AC. Post-operative vaginal irradiation with high dose rate afterloading technique in endometrial carcinoma stage I. Int J Radiat Oncol Biol Phys 1990; 18:305–314. 5. Mandell LM, Nori D, Anderson LL, et al. Post-operative vaginal radiation in endometrial cancer using a remote afterloading technique. Int J Radiat Oncol Biol Phys 1985; 11: 473– 478. 6. Nori D, Merimsky O, Batata M, et al. Postoperative high dose rate brachytherapy combined with external irradiation for early stage endometrial cancer: A long term follow-up. Int J Radiat Oncol Biol Phys 1994; 30:831– 837. 7. Fanning J, Nanavati PJ, Hilgers RD. Surgical staging and high dose rate brachytherapy for endometrial cancer: Limiting external radiotherpay to node-positive patients. Obstet Gynecol 1996; 6:1041–1044. 8. Gumbs AA, Turner BC, Knisely JPS, et al. Post-operative high dose rate vaginal apex brachytherapy in stage I endometrial adenocarcinoma. (Abstr.) 38th ASTRO Proceedings 2101. Int J Radiat Oncol Biol Phys 1996; 36:327. 9. Noyes WR, Bastion K, Edwards SA, et al. Postoperative vaginal cuff irradiation using high dose rate remote afterloading: A phase II clinical protocol. Int J Radiat Oncol Biol Phys 1995; 32:1439 –1443. 10. Carey MS, O’Connell GJ, Johanson CR, et al. Good outcome associated with a standardized protocol using selective postoperative radiation in patients with clinical stage I adenocarcinoma of the endometrium. Gynecol Oncol 1995; 57:138 – 144. 11. Konski AA, Bracy PM, Jurs SC, et al. Cost minimization analysis of various treatment options for surgical stage I endometrial cancer. Int J Radiat Oncol Biol Phys 1997; 37: 367–372. 12. Berlinson JL Lee KR Badger GL, et al. Clinical stage I adenocarcinoma of the endometrium - analysis of recurrences and potential benefits of staging lymphadenectomy. Gynecol Oncol 1992; 44:17–23. 13. Rush S, Gal D, Potters L, et al. Pelvic control following external beam radiation for surgical stage I endometrial adenocarcinoma. Int J Radiat Oncol Biol Phys 1995; 33:851– 854. 14. Elliot P, Green D, Coates A, et al. The efficacy of postoperative vaginal irradiation in preventing vaginal recurrence in endometrial cancer. Int Gynecol Cancer 1994; 4:84 –93. 15. Creaseman WT, Morrow CP, Bundy BN, et al. Surgical pathological spread patterns of endometrial cancer. A GOG study. Cancer 1987; 60:2035–2041. 16. Zaino RJ, Kurman RJ, Diana KL, et al. Pathological models to predict outcome for women with endometrial cancer. The importance of the distinction between surgical stage and clinical stage - a GOG study. Cancer 1996; 77:1115–1121.
17. Bond WH. Early uterine body carcinoma: Has post operative vaginal radiation therapy any value? Clin Radiol 1985; 36: 619 – 623. 18. Graham J. The value of preoperative and post operative treatment by radium for carcinoma of the uterine body. Surg Gynecol Obstet 1971; 132:855– 860. 19. Marchetti DL, Piver MS, Tsukada Y, et al. Prevention of vaginal recurrence of stage I endometrial adenocarcinoma with postoperative vaginal radiation. Obstet Gynecol 1986; 67:399 – 402. 20. Piver MS, Hempling RE. A prospective trial of post operative vaginal radium/cesium for grade 1-2 less than 50% myometrial invasion and pelvic radiation for grade 3 or deep myometrial invasion of stage I endometrial adenocarcinoma. Cancer 1990; 66:1133–1138. 21. Eltabbakh GH, Piver MS, Hempling RE. Excellent long-term survival and absence of vaginal recurrences in 332 patients with low-risk stage I endometrial adenocarcinoma treated with hysterectomy and vaginal brachytherapy without formal lymph node sampling: Report of a prospective study. Int J Radiat Oncol Biol Phys 1997; 38:373–380. 22. Barendsen GW. Dose fractionation dose rate and isoeffect relationships for normal tissue responses. Int J Radiat Oncol Biol Phys 1982; 8:1981–1997. 23. Fowler JF. Brief summary of radiobiological princples in fractionated radiotherapy. Semin Radiat Oncol 1992; 2:16 –21. 24. Yaes RJ, Pushpa P, Maruyama Y. On using the linear-quadratic model in daily practice. Int J Radiat Oncol Biol Phys 1991; 20:1353–1362. 25. Barton M. Tables of equivalent dose in 2Gy fractions: A simple application of the linear quadratic formula. Int J Radiat Oncol Biol Phys 1995; 31:371–378. 26. Lanciano RM, Greven KM. Adjuvant treatment for endometrial cancer: Who needs it? Gynecol Oncol 1995; 57:135–137. 27. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 1992; 339:1–15. 28. Early Breast Cancer Trialists’ Collabrative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 1992; 339:71– 85. 29. Orton CG. High dose rate versus low dose rate brachytherapy for gynecological cancer. Semin Radiat Oncol 1993; 4:232– 239. 30. Orton CG. Comparison of high dose rate versus low dose rate remote afterloading for cervix cancer and the importance of fractionation. Int J Radiat Oncol Biol Phys 1991; 21:1425– 1434. 31. Bruner DW, Lanciano R, Keegan R, et al. Vaginal stenosis and sexual functioning following intracavity radiation for the treatment of cervical and endometrial carcinoma. Int J Radiat Oncol Biol Phys 1993; 27:825– 830. 32. Bastion K, Buchler D, Stitt J, et al. Comparative cost analysis of high dose rate versus low dose rate brachytherapy for gynecological cancer. Am J Clin Oncol 1993; 16:256 –263. 33. Chenery SCA, Pla M, Podgorsak EB. Physical characteristics of the Selectron high dose rate intracavity afterloader. Br J Radiol 1985; 58:735–740.
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Clinical Investigation HIGH-DOSE-RATE BRACHYTHERAPY ALONE POST-HYSTERECTOMY FOR ENDOMETRIAL CANCER CRAIG MACLEOD, F.R.A.C.R.,* ALLAN FOWLER, F.R.A.C.R.,* PETER DUVAL, F.R.A.C.R., F.R.C.R.,† IETA D’COSTA, M.R.C.P., F.R.A.C.R.,‡ CHRIS DALRYMPLE, F.R.A.C.O.G., C.G.O.,§ IAN FIRTH, PH.D.,* PETER ELLIOTT, F.R.A.C.O.G., C.G.O.,§ KEN ATKINSON, F.R.A.C.O.G., C.G.O.,§ § AND JONATHAN CARTER, F.R.A.C.O.G., C.G.O.
*Department of Radiation Oncology and §Gynaecological Oncology, Royal Prince Alfred Hospital and King George V Hospital, Camperdown, New South Wales, Australia; †Department of Radiation Oncology, St Vincent’s Hospital, Darlinghurst, Australia; and ‡ Department of Radiation Oncology, Peter MacCallum Hospital, Melbourne, Australia Purpose: To evaluate the outcome of post-hysterectomy adjuvant vaginal high-dose-rate (HDR) brachytherapy. Methods and Materials: A retrospective analysis was performed on a series of 143 patients with endometrial cancer treated with HDR brachytherapy alone post-hysterectomy from 1985 to June 1993. Of these patients, 141 received 34 Gy in four fractions prescribed to the vaginal mucosa in a 2-week period. The median follow-up was 6.9 years. Patients were analyzed for treatment parameters, survival, local recurrence, distant relapse, and toxicity. Results: Five-year relapse free survival and overall survival was 100% and 88% for Stage 1A, 98% and 94% for Stage IB, 100% and 86% for Stage IC, and 92% and 92% for Stage IIA. The overall vaginal recurrence rate was 1.4%. The overall late-toxicity rate was low, and no RTOG grade 3, 4, or 5 complications were recorded. Conclusion: These results are similar to reported international series that have used either low-dose-rate or HDR brachytherapy. The biological effective dose was low for both acute and late responding tissues compared with some of the HDR brachytherapy series, and supports using this lower dose and possibly decreasing late side-effects with no apparent increased risk of vaginal recurrence. © 1998 Elsevier Science Inc. High-dose-rate, Brachytherapy, Endometrial cancer.
this probably facilitates patients completing therapy, as in a recent LDR series, only 56% of the patients received the planned brachytherapy (2). Since Joslin’s original description of post-hysterectomy HDR vaginal brachytherapy (3), there have been a number of series that show excellent local control with HDR brachytherapy; however, the optimal total dose and fraction size remains arguable (3–9). The basic treatment for endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO), but increasingly formal surgical staging is performed with partial or complete pelvic lymphadenectomy and pelvic washings being taken. Proponents of formal surgical staging have argued that there is a clinical benefit, namely selecting patients who have a low risk of extrauterine disease and deleting external beam irradiation and sometimes brachytherapy from their management, and avoiding the associated side-effects and financial cost (2,
INTRODUCTION Post-hysterectomy adjuvant therapy for Stage I and II endometrial cancer is controversial. The only prospective randomized trial that examined the role of radiotherapy evaluated the role of external beam therapy in clinical Stage I patients; all received low-dose-rate (LDR) brachytherapy after hysterectomy and were randomized to 40 Gy of pelvic irradiation or no therapy (1). This trial showed a statistically significant reduction in vaginal and pelvic recurrence with external beam therapy, but no improvement in overall survival. Vaginal brachytherapy, irrespective of technique, reduces vaginal recurrences. The gold standard has been LDR brachytherapy, and usually a dose of 60 Gy is prescribed to the vaginal mucosa. This requires admission to the hospital and confinement to bed for the duration of treatment. Highdose-rate (HDR) brachytherapy has logistic advantages such as allowing comparatively quick outpatient treatment;
ESTRO Brachytherapy Meeting, Naples 1998. Acknowledgments—The assistance and advice of Roger Houghton, Professor of Gynaecological Oncology, and John Solomon, Senior Visiting Specialist, of Royal Prince Alfred Hospital is appreciated. Accepted for publication 23 July 1998.
Reprint requests to: Dr. Craig MacLeod, Department of Radiation Oncology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales, 2050 Australia. E-mail: [email protected] This data was presented at the Australian Society of Gynaecological Oncologists, Tasmania 1998 and by Michael Jackson at the 1033
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10, 11). However, there is a contrary argument that extensive surgical staging in these often old, obese, and sometimes frail women itself causes significant morbidity, or is technically not possible to adequately perform, and that equivalent outcome can be achieved with TAHBSO alone and adjuvant radiotherapy can be based on the histopathological findings of the uterus (12, 13). Possibly the most morbid treatment protocol is to perform a TAHBSO and complete lymphadenectomy, disregard these findings in selecting a post-operative adjuvant therapy, and routinely give external beam irradiation for high risk Stage I and II endometrial cancer. The Royal Prince Alfred Hospital has previously published its experience of LDR brachytherapy post-hysterectomy in early stage endometrial cancer (14). This study, in over 900 patients with FIGO Stage I or II disease, showed improvement in local control and survival for brachytherapy versus no brachytherapy. This retrospective analysis documents the treatment and outcome of 143 patients treated with HDR brachytherapy. METHODS AND MATERIALS The study group comprised a total of 143 patients posthysterectomy. All patients have been treated at Royal Prince Alfred Hospital since the introduction of the Selectron HDR brachytherapy unit in August 1985 until June 1993. Patients were identified by reviewing the medical records of the departments of gynecologic oncology and radiation oncology. Ten patients treated in this time period were excluded from the analysis because they were from another country and follow-up details were not available. Uterine sarcomas were excluded from the analysis but all other histologies were included. All patients were referred from gynecologic oncologists after the diagnosis of carcinoma of the endometrium was confirmed histologically and staging investigations had been performed. One hundred and forty-three patients had a TAHBSO, and 52 patients also had a complete lymphadenectomy prior to vaginal brachytherapy. The high-dose-rate source was a single line radioactive source train with multiple cobalt60 pellets (4-Ci total source activity). The applicators used were standard Selectron intrauterine vaginal cylinders of 2.5, 3.0, 3.5, and 4 cm in diameter. The most commonly used applicator was 3.0 cm in diameter. A single line radioactive high-dose-rate source and remote afterloading equipment were used. HDR brachytherapy was performed twice a week with the patient in the lithotomy position. No anesthesia was required, and rarely was a patient given oral or intramuscular medication because of anxiety. The dose was prescribed to the vaginal mucosa and the dose was relatively symmetrical at depth, but this depended upon the applicator diameter, and ranged from approximately 60% and 41% for a 2.5 cm applicator to 72% and 54% for a 4.0 cm applicator at 0.5 cm and 1.0 cm depth from the vaginal mucosa, respectively. The whole residual length of the vagina proximal to the urethral orifice was usually treated, but 11 patients had vault
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Table 1. Distribution of cases according to FIGO staging criteria Stage
n 5 143
%
IA IB IC IIA IIB IIIA
8 110 7 13 3 2
5.6 76.9 4.9 9.1 2.1 1.4
radiotherapy alone. The length irradiated ranged from 2.5 to 10 cm. Treatment time depended upon applicator diameter, length of vagina irradiated, and the activity of the source, and ranged from approximately 5 to 20 minutes. Patients were reviewed in the radiation oncology department 4 – 6 weeks after radiation and subsequently by a gynecologic oncologist, and/or radiation oncologist or the primary referring general gynecologist. Local failure was defined as recurrence within the vagina and this was biopsy-proven in all cases. Metastatic failures included all other pelvic and extra-pelvic sites and was either biopsy-proven or clinically determined. Late side-effects were defined as sequelae reported 3 months from completion of the radiotherapy and were recorded for the bladder, bowel, vagina, skin, and other. RTOG toxicity criteria were used. Unfortunately, sexual dysfunction was not specifically recorded. Patterns of recurrence and morbidity were recorded and an audit of deaths was performed at the NSW Cancer Registry. Survival was calculated using the actuarial life table method. The log-rank test was used for the univariate analysis. The computer program used for these functions was SPSS for Windows Release 6.0. RESULTS The median follow-up time was 6.9 years . No patients were lost to follow-up at less than 3 years. The patients’ ages ranged from 38 to 90 years and the median age was 62 years. Corpus Cancer Surgical Staging, FIGO 1988 was used for the 52 patients who had pelvic lymphadenectomy. For the other patients it was based on myometrial penetration as described for Corpus Cancer Surgical Staging, FIGO 1988, that is, IA confined to endometrium, IB invasion to less than half the myometrium, and IC invasion to greater than half the myometrium. The FIGO Stage was: 1A in 8 (5.6%), IB in 110 (76.9%), IC in 7 (4.9%), IIA in 13 (9.1%), IIB in 3 (2.1%), and IIIA in 2 (1.4%) (Table 1). The histology was endometrioid in 124 (86.7%), adenosquamous in 10 (7.0%), and other in 9 (6.3%), of which 6 were serous, 2 were mixed endometrioid and serous, and 1 was clear cell histology (Table 2). Two patients had concurrent cancers diagnosed at other sites during their staging; one had a Stage IA grade 1 endometriod ovarian cancer with a Stage IB grade 2 endo-
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Table 2. Distribution of grade according to FIGO staging criteria Stage
Grade 1
Grade 2
Grade 3
Other
IA IB IC IIA IIB IIIA Total Percent
4 67 4 9 2 0 86 60.1
2 28 3 1 0 0 34 23.8
2 9 0 1 1 1 14 9.8
0 6 0 2 0 1 9 6.3
metrial cancer, the other a Stage IIA grade 2 ovarian cancer with a Stage IB grade 2 endometrial cancer. This second patient received 6 cycles of cisplatin and cyclophosphamide chemotherapy after vaginal brachytherapy. Another patient received 6 cycles of carboplatin and cyclophosphamide for a Stage IIB serous papillary endometrial cancer after brachytherapy. The dose of brachytherapy given to 141 patients was 34 Gy in four fractions. The dose was prescribed to the mucosal surface of the vagina. Two patients had only two or three fractions of the planned treatment (Table 3). Overall 5- and 10-year relapse-free survival was 96% (Fig. 1). It was 100% for Stage 1A, 98% for Stage IB, 100% for Stage IC, and 92% for Stage IIA (Table 4). Overall 5- and 10-year actuarial survival to death from all causes was 91% and 90%, respectively (Fig. 2). Three patients died of disease and 10 died from other causes. Five-year survival was 88% for Stage 1A, 94% for Stage IB, 86% for Stage IC, and 92% for Stage IIA (Table 4). Five patients (3.5%) relapsed (Table 5). Two relapsed in the vagina (1.4%); the first in-field at the vault at 20 months (Stage IIB grade 1 node-negative) and the second outside the radiotherapy cylinder volume at the urethral orifice at 13 months (Stage IB grade 1 node-negative). The first woman was salvaged with surgery but died 7 months later of heart disease without evidence of recurrent disease. The second woman was salvaged with surgery and is disease free at 76 months. Three patients relapsed systemically, one in the lung at 10 months (Stage IB grade 2 nodes not resected), one in the pelvis and inguinal nodes at 25 months (Stage IIA serous papillary node-negative), and one with ascites at 15 months (Stage IIIA grade 3 node-negative). These patients all died of endometrial cancer.
Table 3. Technical details of brachytherapy No. patients Whole vagina Vault of vagina 4 Fractions 2 or 3 Fractions
132 11 141 2
%
Prescribed location
Total dose (Gy)
91.7 — 7.6 — 98.6 Applicator surface 1.4 Applicator surface 17
— — 34 or 25.5
Fig. 1. Relapse-free survival.
Acute toxicity was not analyzed since there was insufficient information in the medical records. It was common, however, for women treated with whole vaginal brachytherapy to experience a moderate vaginal reaction with discomfort, and patchy mucositis was seen at the introitus; it peaked 1 or 2 weeks after the last brachytherapy fraction. Thirty-three patients (23.1%) had at least one site of late toxicity and the most commonly involved organ was the vagina (Table 6). The majority of vaginal toxicity was recorded as mild but there was no functional assessment. Two of the 22 affected patients used regular topical vaginal creams. All of the bladder, skin, and bowel toxicity was mild. Two patients had mild bilateral lymphoedema; however, both of these patients had a lymphadenectomy which would explain this complication. One patient developed a recto-vaginal fistula; however, this occurred directly after a hemorrhoidectomy, and was not included as a complication of the TAHBSO or vaginal brachytherapy. On univariate analysis neither stage, grade, nor histology were statistically significant for relapse-free survival (Table 7). This may reflect the relatively small numbers of patients in this analysis; larger studies have shown stage and grade to be statistically significant (4, 13, 14).
Table 4. Five-year relapse free and 5-year survival results Stage
5-year relapse free survival %
5-year survival %
Overall IA IB IC IIA IIB IIIA
96 100 98 100 92 67 50
91 88 94 86 92 33 50
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Table 6. Late toxicity
Fig. 2. Overall survival.
DISCUSSION The practice of post-operative adjuvant radiation therapy has been in transition at this hospital as the practice of complete lymphadenectomy has become more common. Is this procedure diagnostic, therapeutic, or both? Such debate is outside the scope of this discussion, but we have adopted the practice that after a negative complete lymphadenectomy external beam irradiation is unnecessary. The findings of only a negative lymph node sampling are disregarded, because only a small percentage of involved nodes are enlarged (15, 16) and the patient is treated on the pathological information supplied by the hysterectomy specimen. In general, for patients who have not had a complete lymphadenectomy, our policy has been to advocate no treatment for Stage IA grade 1 and 2, whole vaginal brachytherapy for Stage IA grade 3 and Stage IB grade 1 and 2, and external beam therapy with or without brachytherapy for more advanced stages of disease. The treatment protocols have not been rigidly adhered to and have been altered based on surgical and patient input. For example, if there is heavy vaginal contamination with tumor spill at the TAHBSO, vaginal brachytherapy is advocated based upon the possible etiology of vaginal recurrence being genital tract metastatic implantation. Nevertheless, the outcome in adopting these selection criteria seems Table 5. Any local or distant relapse by stage Stage
Local relapse (grade)
Distal relapse (grade)
IA IB IC IIA IIB IIIA
0 1 (G1) 0 0 1 (GI) 0
0 1 (G2) 0 1 (SP) 0 1 (G3)
SP 5 serous papillary.
Site
Grade 1 (%)
Grade 2 (%)
Bladder Bowel Skin Vagina Lymphoedema Total patients affected
8 (5.6) 3 (2.1) 3 (2.1) 20 (13.9) 2 (1.4) 31 (21.7)
— — — 2 (1.4) — 2 (1.4)
Grade 3 or above (%) — — — — —
to have been supported for all stages up to and including Stage IIA, even in patients with high-risk histologies. There are too few patients to comment in Stages IIB and IIIA. The gold standard for comparing outcome remains LDR brachytherapy, and in this series the local recurrence rate, overall survival, and disease-free survival are similar to our previous LDR series (14), and other LDR series (2, 17–21). There is currently not a gold standard for HDR vaginal brachytherapy. Four of the HDR series have included patients treated with a combination of external beam and brachytherapy (3, 5–7) and four (4, 8, 9), including this series, have used brachytherapy alone as adjuvant posthysterectomy therapy (Table 8). The dose prescription used in this series was 34 Gy given in four fractions to the vaginal mucosa. It is difficult to compare series because of differences in technique, total dose, and fraction size. Compounding these differences is the inherent dose inhomogeneity of brachytherapy with rapid dose fall-off at increasing distance from the source. Nevertheless, an attempt has been made to compare the doses in terms of total dose and fraction size at the mucosal surface and biologically by using two modifications of the linear quadratic equation. The first equation, known variously as the extrapolated response dose (ERD) by Barendson (22), and the biological effective dose (BED) by Fowler (23) is: Table 7. Univariate analysis
Stage IA IB IC IIA Age (years) 30–60 61–70 711 Grade Low Intermediate High Other Histology Endometriod Adenosquamous Other
5-year relapse-free survival
P value
1.00 0.98 1.00 0.92
0.54
0.97 0.96 0.97
0.94
0.98 0.97 0.93 0.89
0.50
0.97 1.00 0.89
0.41
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Table 8. Series that have used HDR brachytherapy
Series
Number of patients
Total dose (Gy)
Fraction size (Gy)
Prescription point
Vaginal recurrence (%)
Joslin (3) #Sorbe (4) Mandell (5) Nori (6) Fanning (7) #Gumbs (8) #Noyes (9) #MacLeod (current)
256 404 330 300 60 286 63 143
35 27–36 21 21 21 21 32.4 34
7 4.5–9 7 7 7 7 16.2 8.5
0.5 cm depth 1 cm depth 0.5 cm depth 0.5 cm depth 0.5 cm depth 0.5 cm depth mucosal surface mucosal surface
1.2 0.7 2.7 includes pelvic 2.0 0 2.4 0 1.4
# 5 Brachytherapy alone as adjuvant therapy.
S
ERD or BED 5 nd 1 1
d a/b
D
The dose of 34 Gy in four fractions reflected a compromise between the twin concerns of tumor control and late side-effects as well as patient and department logistics. This dose appears similar to the popular North American dose of 21 Gy in three fractions prescribed to a 0.5-cm depth from the vaginal mucosal surface (Tables 8 and 9). In this series the local-failure rate in low-risk disease, defined as grade 1 and 2 and confined to the inner half of the myometrium, was 1.0%; that is 1 of 101 patients failed in the vagina, although the patient only had her vaginal vault treated and she relapsed outside this volume in the periurethral region of the vagina. It is difficult to estimate from the other HDR series which subgroup of patients had low-risk disease and what their outcome was. However, in the two series that used HDR brachytherapy alone, the local recurrence rate was 0.7% in Sorbe’s (4) series (of which 89.6% of patients had less than 1/3 myometrial invasion and only 6.7% were poorly differentiated cancers) and was 1.1% for Stage IA and 3.7% for Stage IB in Gumbs (8) series (of which only 2.0% were poorly differentiated cancers). The dose given by Gumbs (8), by most of the North American centers (4, 7), and in this
The second equation, known as the standard relative effectiveness (SRE) as described by Yaes (24), with conversion tables described by Barton (25) is: SRE 5 n1d1
S
D
a / b 1 d1 a/b 1 2
The advantage of the Yaes modification is that, for the clinicians, it gives an intuitive feel for tumor control and normal tissue tolerance because it is comparative to standard 2 Gy fractionation. For a given dose and fraction size, the value calculated for ERD or BED is greater than for SRE. Obviously, assumptions have been made in calculating these doses (an a/b ratio of 10 Gy and 3 Gy for earlyand late-responding tissues, respectively; the midplan dose of a 3.0 cm vaginal cylinder treating 7.5 cm vaginal length; no correction for repopulation) that warrant caution in terms of its specific applicability. However, in a broad comparative sense, Table 9 may be useful.
Table 9. Depth-dose data, SRE and ERD/BED, at the vaginal mucosa, for acute and late responding tissues Acute tissues Series Joslin (3) Sorbe (4)
Mandell (5) Nori (6) Fanning (7) Gumbs (8) Noyes (9) MacLeod (current)
Total dose
Late tissues
Fraction size
Surface dose
0.5 cm dose
1-cm dose
SRE
ERD
SRE
ERD
35 36 30 30 27
7 9 6 5 4.5
49.3 67.9 56.6 56.6 50.9
35 50.7 42.3 42.3 36.1
26.1 36 30 30 27
81.5 152.6 100.6 91.6 78.4
97.9 183.2 120.7 110.0 94.1
126.7 271.2 162.1 140.7 116.9
211.3 452.1 270.2 234.6 194.8
21
7
29.6
21
15.9
49.0
58.8
76.1
127.0
16.2 8.5
32.4 34
22.9 24.0
17.3 18.1
74.7 52.4
84.9 62.9
124.4 78.2
270.4 130.3
32.4 34
Calculations based upon assumption that a 3-cm diameter vaginal cylinder has been used, 7.5 cm length of vagina has been treated, and the depth-dose data has been calculated for the id-plan. All doses in Gy. a/b 5 10 Gy for early reacting tissues and a/b 5 3 Gy for late reacting tissues. Figures in bold 5 dose prescription point.
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series, were biologically lower for cancer than either Sorbe’s series or other series. The vaginal recurrence rate of 3.7% for predominantly low risk Stage IB disease with only a median follow-up of 35 months reported by Gumbs et al. appears to be high, compared with the expected long-term vaginal recurrence rate of 4% for untreated patients with low-risk Stage I disease (10, 14). Moreover, in low-risk groups (variously defined as grade 1 and 2, and confined to the inner third or inner half of the myometrium) treated with total vaginal LDR brachytherapy the vaginal recurrence rate is only about 0.1% (14, 17–19). The series are possibly not comparable because of differences in staging, the surgical procedure itself, and different volumes of vagina being treated; however, clinicans must remain vigilant to the possibility of under-dosing the vagina, especially if a dose is used that is probably biologically inferior to the gold standard of 60 Gy using LDR brachytherapy. Therefore, is 21 Gy to 0.5-cm depth, or indeed our own 34 Gy in four fractions to the vaginal mucosal surface, which is very similar biologically in terms of tumor control, too low (Table 9)? Although there is not a standardized dose for HDR vaginal brachtherapy in this setting, the excellent results with long-term follow-up and low morbidity that have been reported by Sorbe (4) using their lowest dose of 27 Gy in six fractions at 1.0 cm depth probably indicate that this dose fractionation schedule should be the benchmark against which other series are compared. Increasingly, the use of any brachytherapy is questioned in low-risk disease post-hysterectomy. The benefit in this setting is small, with a crude 5-year local recurrence rate of about 3.2% (10) and an actuarial 20-year recurrence rate of 4.9% (14) without brachytherapy, but both of these results are from busy single institutions and may represent best possible untreated outcome. Also, the Carey results have been criticized since only 54% of the patients had a 5-year follow-up (26). Nevertheless, we are not dogmatic about its use, but find that many patients with low-risk disease opt for therapy despite the small apparent gain. A simplistic analogy of similar benefit is seen for adjuvant chemotherapy or hormonal therapy in node-negative breast cancer which showed a decrease in recurrence of about 5% at 10 years, and a survival benefit of about 4% at 10 years; however, this statistically significant benefit required a large meta-analysis to show (27, 28). In patients with high-risk Stage I, and any Stage II disease, (since the risk of vaginal recurrence is high) it is standard practice to give adjuvant radiotherapy. This hospital’s previous series demonstrated that in patients who did not receive adjuvant brachytherapy there was a 14.6% vaginal recurrence rate for Stage I grade 3 or those tumors which invaded the middle third of the endometrium or beyond, and a 16.7% vaginal recurrence rate for Stage II disease. In this group of patients we had our only in-field recurrence, in a patient who had Stage IIB node-negative grade 1 disease. The vaginal recurrence rate was thus 2.4% for high risk disease. Our policies appear to be supported in
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the presence of a negative staging lymphadenectomy for high-risk disease with the exception of Stage IIB or beyond. Currently, the decision to use HDR or LDR brachytherapy for postoperative adjunctive therapy for endometrial cancer is topical, and many radiation oncology departments with access to both techniques may question which to use. The relative advantages and disadvantages of LDR compared to HDR brachytherapy have been well described in the literature (29). In general, the radiobiological advantages of LDR brachytherapy have not translated into improved outcome in terms of local control or reduced sideeffects in cervix cancer if a dose per fraction to “point A” of 7.0 Gy or less is used (30); this will probably also be demonstrated for a range of doses and fraction sizes in endometrial cancer. A deficiency of the analysis is that sexual function was not assessed; however, many patients in this age group would have other factors that would confound the interpretation of the etiology of any sexual dysfunction, such as being elderly, lack of a partner, no documented sexual history prior to therapy, and anatomical distortion from the surgery. Other investigators have found brachytherapy alone to be an uncommon cause of sexual dysfunction (4, 31). LDR and HDR brachytherapy costs in this country include both a professional and capital component, and are set by the Australian government. They are approximately US $1200 for 60 Gy in one application, which includes the hospital bed, operating room, and anesthetic fee, and are US $2400 for 34 Gy in four fractions. The national adjusted standardized United States costs have been reported as $3467 and $5381 for LDR and HDR brachytherapy, respectively (11). Therefore, based on these figures, if the treatments are equally effective, HDR brachytherapy is substantially more expensive. However, in both of the above examples, the costs have been analyzed as payor costs, that is, the fee raised with the service. Costs can be analyzed in different fashions, for example, they can focus on patient costs, payor costs, or societal costs. Articles that have reviewed this issue concluded that cost-equivalence is based on patient load and is achieved at approximately 50 patients a year. Below this number, LDR is less expensive, and above this, HDR is less expensive. (32, 33). However, there is considerable international variability in costs which probably make these findings specific rather than generally valid. The results achieved at RPA are in keeping with both reported LDR (2, 18 –21) and HDR (3–9) series . The optimal dose per fraction and number of fractions of HDR brachytherapy is not established, and comparison between different series is confounded by many factors. Adopting the use of selective HDR vaginal brachytherapy to a dose of 34 Gy in four fractions, giving two fractions per week alone after TAHBSO for Stage I–IIA endometrial cancers, appears effective for low-risk disease, and for high-risk disease if the pelvic lymphadenectomy is negative. This treatment has a low rate of late toxicity.
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