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Pulsed low dose rate brachytherapy for pelvic malignancies
Int. J. Radiation Oncology
PI1 SO360-3016(96)00564-O
ELSEVIER
l
Biol. Phys., Vol. 37, No. 4, pp. 811-817, 1997 Copyright 0 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/97 $17.00 + .OO
Clinical Investigation PULSED LOW DOSE RATE BRACHYTHERAPY FOR PELVIC MALIGNANCIES PATRICK
S. SWIFT, M.D., C. BETHAN
PHILIP PURSER, PH.D., L. W. ROBERTS, BARBY PICKETT, POWELL, M.D. AND THEODORE L. PHILLIPS, M.D.
PH.D.,
Department of Radiation Oncology, University of California, San Francisco, CA Purpose: The pulsed low dose rate remote afterloading unit was designed to combine the radiation safety and isodoseopthnization advantages of high dose rate technology with the radiobiologic advantages of continuous low dose rate brachytherapy. This is the first report of a prospective clinical trial evaluating the relative incidence of acute toxicity and local control in patients with pelvic malignancies who underwent interstitial or intracavitary brachytherapy with the pulsed low dose rate remote afterloader. Methods and Materials: From 5/D/92-6/21/95,65 patients underwent 77 brachytherapy procedures as part of their treatment regimen for pelvic malignancies. Using the pulsed low dose rate Selectron, equipped with a single cable-driven 0.3-1.0 Ci Ir19’ source, target volume dosesof 0.40-0.85 Gy per pulse were prescribed to deliver the clinically determined dose. Forty-five intracavitary and 32 interstitial procedures were performed. Fifty-four patients had primary and 11 recurrent disease. Patients were followed closely to assessincidence of Grade 3-5 acute and delayed toxicity, local control, and survival. Results: With a median follow-up of 16.1 months (range l-29), 33 patients are NED, 10 alive with disease, 13 dead with disease,4 dead of intercurrent disease,and 5 lost to follow-up. Local control was maintained until last follow-up or death in 48 cases,local failure occurred in 11, unknown in 5. Grade 3-5 acute toxicities (requiring medical or surgical intervention) occurred in 5 out of 77 procedures (6.5%), delayed complications in 10 patients (15% actuarial incidence at 2 years). In the 52 procedures performed for 42 patients with cervix cancer, the acute toxicity incidence was 5.8%, with a 14% 2-year actuarial incidence of delayed complications. Of 32 interstitial templates performed on 30 patients for pelvic malignancies, there were three incidences of acute toxicity and five delayed toxicities. Conclusion: Using the parameters described for this initial clinical study in patients treated for pelvic malignancies, pulsed low dose rate brachytherapy shows no significant increase in acute toxicity above that seen with the standard continuous low dose rate approach. Using the isodose optimization possible with pulsed brachytherapy, local control is excellent in patients treated at initial presentation, although longer followup is required for full assessment of local control and late toxicity. Further trials will need to be carried out to determine if larger doses per pulse and shorter total treatment times have comparable therapeutic ratios. 0 1997 Elsevier Science Inc. Cervix neoplasms, Brachytherapy, Remote after loading, Pulsed low dose rate, Interstitial.
Compared to continuous low dose rate manually afterloaded approaches, pulsed brachytherapy has the advan-
INTRODUCTION
tages of elimination of radiation exposure to medical per-
Pulsed brachytherapy refers to the delivery of radiation treatment using a remote afterloading device with a single cable-driven radioactive source that is propelled through an array of positions within an implanted volume or a set of intracavitary instruments. The source stops for a specified duration at a preselected number of locations within the array during its transit, delivering a cumulative dose to the entire volume. This dose may be delivered as a rapidly delivered large fraction, as in the case of high dose-rate treatment (HDR), or as a series of small doses delivered at a given frequency over a period of days, called pulsed low dose rate (PLDR) treatment.
sonnel, reduction in the inventory of radioactive sources required for multiple patients, and the ability to optimize the isodose distributions
through manipulation
of the lo-
cation and number of source-stopping (“dwell”) positions, and the time the source spends at each dwell position within the implanted array. The theoretical advantage of PLDR over HDR is that the expected effect on late-reacting tissues would be less with multiple small doses compared with a smaller number of large fractions. Radiobiologic data by Hall (10, 12), Brenner (4-6), and Fowler (7, 8) suggest that pulsed low dose rate therapy
Reprint requests to: Patrick S. Swift, M.D., Department of Radiation Oncology, University of California, Room L-08, 505
PamassusAvenue, San Francisco, CA 94143. Accepted for publication 11 October 1996. 811
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could be delivered in such a way that responses of both acute-reacting (tumor and normal) tissues, as well as latereacting tissues would be comparable to those seen with traditional continuous low dose rate brachytherapy, as long as certain dosing and interval guidelines were followed. The present report is the first to provide clinical data on acute toxicity with the pulsed low dose rate approach to support this hypothesis. METHODS
AND MATERIALS
In early 1992, guidelines were established for the use of the Pulsed low dose rate Selectron from Nucletron Corporation in patients requiring brachytherapy for part of their management at the University of California, San Francisco. Any patient deemed appropriate for traditional continuous low dose rate brachytherapy was eligible for treatment with the pulsed low dose rate Selectron (Nucletron). This report deals only with those patients with malignancies in the pelvic region. Patients who had not received prior pelvic radiation were treated with external beam radiotherapy directed at the pelvis (nodes and primary) using standard two- or four-field techniques with 6 or 18 MV photons, to doses of 45-54 Gy. A midline block was routinely placed at 3640 Gy, and the technique switched to APIPA only to reduce dose to bladder and rectum. Patients with recurrent disease who had received prior external beam therapy to the pelvis did not receive external beam therapy at the time of recurrence. Patients then proceeded to the brachytherapy component of their treatment. After insertion or implantation of appropriate applicators (tandem and ovoids, ovoids only, vaginal cylinder, or perineal interstitial template), films were obtained for dosimetric planning. Prior to January 1995, the localizing films were either orthogonal (AP and lateral) or AP stereo. The film data was digitized and entered using an in-house brachytherapy planning program (28). Source dwell positions and times were optimized manually by the planning physicist and radiation oncologist. After a satisfactory plan was obtained, the treatment program was printed out, and subsequently programmed manually into the treatment unit. After January 1995, the Nucletron Plato brachytherapy planning system was used. The localizing films were either orthogonal or “variable angle” isocentric (AP + 20”). Film data was digitized and entered, and source positions chosen manually. The volume geometric method for optimizing the isodose distribution was used (15). After a satisfactory plan was obtained, the program was automatically transferred to the treatment unit by a reuseable program card. An effort was made to keep the dose per pulse to a range of 50-100 Gy, because the majority of our clinical experience with continuous low dose rate brachytherapy was gained using this dose range and we sought to change as few parameters as possible in moving to the pulsed system. The total dose from the brachytberapy procedure was
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determined by the radiation oncologist, based on the clinical setting, history of prior irradiation to the site, and the total dose of external beam therapy planned for the course of therapy. Pulses were delivered hourly, and continued around the clock with no planned interruptions. After completion of therapy, the patients were followed at 2 weeks, 1 month, 3 months, and then every 3 months up to 1 year. After 1 year, the patients were seen every 46 months for the next year, then every 6 months afterwards. Patients were assessed for evidence of local or systemic failure, with all complications listed according to the RTOG acute radiation morbidity scoring criteria and the RTOG/EORTC late radiation morbidity scoring scheme (29). The absolute incidence of acute Grade 3-5 toxicity (i.e., events recorded within 90 days of completion of the brachytherapy), and the actuarial incidence of delayed Grade 3-5 toxicity are reported here. The actuarial incidence of local failure, survival, and disease-free survival are also reported, with a further analysis of those patients with a diagnosis of cervical carcinoma. RESULTS
From 5/l l/92 through 6/21/95, 77 brachytherapy procedures were performed in 65 patients with pelvic malignancies as part of their management at the University of California, San Francisco (Table 1). Sites of disease were as follows: cervix, 42; prophylactic postoperative vaginal cuff irradiation for endometrial cancer, 8; vaginal recurrence of endometrial cancer, 5; rectal, 4; vaginal, 2; pelvic sarcoma, 1; prostate rhabdomyosarcoma, 1; urethra, 1; vulva, 1. Fifty-four patients were treated for primary disease, 11 for recurrent disease, and 5 had received prior irradiation to the site. Seventy-seven procedures were performed, including 32 interstitial implants using the MUPIT (Martinez universal perineal interstitial template (16) (3 of which were open implants), 34 tandem and ovoid insertions, 4 intravaginal ovoid placements, and 7 vaginal applications with a vaginal candle or Houdek applicator. For patients receiving perineal implants, between 13 and 18 needles were used in each case. All patients were followed for at least 6 months or until time of death. At last follow-up (mean follow-up 16.1 months, median 15.1 months, range 1-41.2 months), 49 patients were alive and 17 dead. Thirty-four patients were alive and free of disease, and 10 were alive with disease (6 of whom were locally controlled). Fourteen died due to their cancer, with 7 locally controlled. Three died of other causes, and four were lost to follow-up after short follow-up. Excluding the 4 lost to follow-up, local control was maintained in 50 of 61 patients. Sixty-five procedures were performed with doses per pulse of 0.40-0.80 Gy. The time required to deliver the pulse varied from 10 to 25 min in each hour, depending on the source activity at the time of the procedure (maximum 1 Ci, minimum 0.33 Ci), and on the volume of the
Pulsed
low dose rate brachytherapy for pelvic malignancies 0 P. S. SWIFT
Table 1. Disease sites and characteristics Primary Recurrent Prior radiation Procedures
54 11 Yll Interstitial Tandem and ovoids
32 34 4 7 42 8 5 2 4 1 1 1 1
Ovoids only
Vaginal candles Cervix Vag. cuff, post-hyst. Vag. cuff recurrence Primary vaginal Rectal recurrence Pelvic sarcoma Prostate rhabdo. Urethra Vulva
Sites
implant or insertion. Twelve patients were treated with doses per pulse in excess of 0.80 Gy: 5 had posthysterectomy radiation to the vaginal cuff with vaginal surface doses of 1 .OO-1.33 Gy per pulse; 4 had cervical carcinoma but multiple medical problems such as severe obesity or history of thrombophlebitis, treated with point A doses of 0.81-0.88 Gy per hour, thereby slightly shortening the overall treatment time; 3 patients were implanted for recurrent disease and had minimum tumor doses of 0.810.88 Gy per pulse. No acute complications were seen in this group of 12 patients. Two of the 12 returned to their native countries shortly after treatment and were lost to follow-up. No delayed complications have been reported in the remaining 10, 7 of whom are alive and free of disease.
Acute complications Acute complications of Grade 3 or greater by the RTOG acute radiation morbidity scoring criteria were seen in 5 of the 77 procedures, an absolute incidence of 6.5%. These complications are listed in Table 2. Of those patients treated at primary presentation, there were four compli-
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cations in 66 procedures, or 6%. Of those patients with recurrent disease, 1 out of 11 had an acute complication (partial small bowel obstruction managed conservatively). A univariate analysis of conditions that might contribute to acute complications, including dose rate, site, total brachytherapy dose, total overall dose, and primary vs. recurrent disease failed to show any significance for these factors.
Delayed complications The delayed complications of Grade 3 or greater by the RTOG/EORTC late grading scheme are listed in Table 3. Two of the Grade 4 delayed complications occurred in patients who were treated prior to the use of an integrated computerized planning system, and were related to excessive dose from manual misprogramming of the treatment unit after dosimetric optimization had been performed. In the first case, a woman with Stage IIIB cervical carcinoma with extensive lower vaginal involvement, manual misprogramming of the dwell time at a single position out of 10 along one catheter track was erroneously repeated in each of 18 catheter tracks, resulting in a maximum rectal dose of 60.0 Gy to a small volume of rectal mucosa at the level of the midvagina (external beam dose of 40 Gy plus the implant dose 60 Gy, for a total of 100 Gy). This was not detected until a review of dosimetry was carried out at the time of rectovaginal fistula development several months later. The patient was also found to have massive central failure of disease throughout the implanted area. The second case was a patient with carcinoma in situ of the urethra who was treated with brachytherapy to prevent the need for total cystourethrectomy. During one of the insertions, after prior approval of an optimized plan, the bedside control unit was manually m&programmed with dwell positions spaced at 5 mm intervals rather than the intended 10 mm intervals, resulting in a dose of 40.0 Gy rather than the intended 30.0 Gy to the urethral meatus and adjacent labia. This was detected on review of the printout at completion of the 36-h insertion. The patient
Table 2. Acute complications-Grade
3-5 according to the RTOG acute radiation morbidity scoring criteria (lo), in all pelvic patients treated with the pulsed low dose rate selectron
Site
Stage
Rectal
ret*
Cervix
IIB
Cervix
IIB
Cervix
IIB
Urethra
in situ
* ret-recurrent
Procedure Interstitial implant Interstitial implant Interstitial implant Intracavitary insertion Intraluminal (two) disease.
Dose per pulse (cGY)
PLDR dose
Total (cGY)
(cGY)
52
4500
8100
50
1500
69
Total dose Complication
Grade
Comment
Partial SBO
3
6860
Hematemesis
4
3600
7500
Perineal pain
3
Resolved, conservative tx Resolved, conservative tx Required narcotics for 3 months
65
4200
8700
Cystitis
3
75
7100
7100
Moist desquamation
3
Tumor involved base of bladder
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Table 3. Delayed complications-Grade 3-5 according to the RTOG/EORTC late radiation morbidity pelvic patients treated with the pulsed low dose rate selectron Dose per pulse Site
Stage
Procedure
(cGY)
Total PLDR dose (cGY)
Total dose (cGY)
Complication
Cervix
IIIB
Interstitial implant
60
3500
7500
Vagina
Rec.
69
4000
8500
Vagina
Rec.
70
3500
7480
Cervix
IIB
65
2000
6000
Cervix
IIB
69
3600
7500
Cervix
IIB
70
4200
9300
Cystitis
Cervix
IIB
Interstitial implant Intracavitary insertion Interstitial implant Interstitial implant Intracavitary insertion Intracavitary insertion
Rectovaginal, vesicovaginal fistulae Rectovaginal fistulae Rectovaginal tistulae Rectovaginal fistulae Perineal pain
65
4200
8700
Cystitis
Cervix
IB
Intracavitary insertion
80
6800
8500
Proctitis
Vulva
III
Interstitial implant
60
1500
6000
Soft tissue necrosis
Urethra
in situ
Intraluminal
75
7100
7100
Soft tissue necrosis
went on to develop soft tissue necrosis of the labia immediately adjacent to the urethral meatus after a total skin dose in this region of 70 Gy delivered in two insertions (20 h and 35 h) spaced a month apart. This healed with conservative nonsurgical intervention. These complications led to the integration of a computerized card system in which the optimized plan, approved by the physician, is recorded electronically on a card in the planning station and transferred via the card to the treatment unit. The actuarial incidence of delayed complications for the entire group was 15% at 2 years, with 10 complications noted to date. If the two n-&programmed cases are removed from the analysis, the actuarial incidence of delayed complications is 13%. Of the four patients who developed rectovaginal fistulae, three were found to have extensive local recurrence of disease contributing to the fistula formation. Omitting the patients with massive central recurrence of disease, the incidence of delayed complications falls to 8%. Of the two patients with Grade 3 bladder complications, one had a diagnosis of AIDS at the time of treatment, and the other had tumor extension to the bladder base prior to radiation, and received a maximal bladder dose of 90 Gy.
scoring scheme (lo), for all
Grade
Comment Massive central recurrence Massive central recurrence Massive central recurrence NED at autopsy Required narcotics for 3 months AIDS
4
Base of bladder involved with tumor, required therapy for 2 years Required laser tx, resolved within 1 year Open ulcer prior to implant, required HBO tx, eventually found to have recurrent disease Resolved without surgical intervention
Local control and survival With a mean follow-up of 16.1 months, the actuarial incidences of local control at 2 years for the entire group and for those with primary disease are, respectively, 78 and 85%. Four patients were lost to follow-up, after returning to their native countries. At the time of last evaluation, three of these patients were free of disease, (one of whom had Stage IA cervix carcinoma, two Stage II). The fourth was a patient with recurrent rectal cancer who had persistent disease at last follow-up. The actuarial 2year survivals are 67% for the entire group and 70% for those with primary disease.
Cervix carcinoma patients Fifty-two of all procedures were performed in 42 patients with primary cervical carcinoma: 29 intracavitary insertions of tandem and ovoids, 21 interstitial implants, and 2 ovoid placements for vaginal cuff irradiation posthysterectomy. The stages of the patients were as follows: IA, 3; IB/IIA 12; IIB, 15; III, 11; IVA, 3. Intracavitary insertions were the preferred method of brachytherapy for cervical carcinoma patients. Interstitial implantation was used in those Stage IB-IIB cases with very poor anatomic
Pulsed
low
dose rate brachytherapy
for pelvic
geometry after external beam therapy (narrowed vagina, absent fomices), and patients with stage IIIA, IIIB, or IVA disease. Three acute complications were seen, for an incidence of 5.8%. Six delayed complications were reported, including one associated with dose misadministration mentioned earlier, for an actuarial incidence at 2 years of 14%. Total tumor doses (brachytherapy plus external beam) were calculated as the dose to point A for patients treated with intracavitary insertions, or as minimum tumor dose (the isodose volume that encompassed the entire clinical tumor volume as defined by the clinician) for those patients who underwent interstitial implantation, and ranged from 56.0-96.0 Gy. Rectal doses ranged from 52.9-100.0 Gy (with only one patient receiving in excess of 78 Gy), and bladder doses ranged from 47.52-96.00 Gy. Neither delayed nor acute complications correlated in a statistically significant fashion with doses to tumor, rectum, or bladder. At last follow-up (mean 17.3 months, median 16.0 months, range 141.2 months), 23 patients were alive and free of disease, 4 were alive with distant disease only, 9 had died due to the disease (3 of whom had failed locally), 3 have died of other causes, and 3 were lost to follow-up. Thirty-five were locally controlled at last follow-up, 4 failed locally, and 3 were lost to follow-up, for a 2-year actuarial local control rate of 86%, and an actuarial survival of 65%. The four failures included 1 of 8 Stage IB patients, 1 of 13 Stage IIB patients, and 2 of 11 Stage IIIB patients. Pelvic interstitial implants Thirty-two interstitial implants were performed in 30 patients: cervix, 20; recurrent rectal, 3; pelvic sarcoma, 2; vaginal recurrence of endometrial cancer, 4; vulva, 1. None of this group were lost to follow-up (mean 18.1 months). Acute complications were seen in 3 of 32 procedures (9.4%) and delayed in 5 of 30 patients (15%), 2 of whom were found to have recurrent disease contributing to the complication. Omitting those with massive central recurrence, the delayed complication rate falls to 7%. Twenty-two patients maintained local control, with 4 of the 8 failures occurring in patients who had received prior irradiation (68% local control). The actuarial 2-year survival for this group is 62%. DISCUSSION The advantages of pulsed low dose rate brachytherapy over manual-afterloading continuous low dose rate approaches include increased radiation protection with elimination of exposure to the staff attending to the medical needs of the patient as well as visitors, the elimination of the need to order costly new sources for each patient to be treated or to maintain a large inventory of sources for different clinical settings, and the ability to perform dose optimization within the implanted volume to both improve
malignancies
0 P. S. SWIFT et al.
815
dose homogeneity and reduce dose to normal structures in or near the volume. Alterations of the dwell positions and dwell times at each position allow for fine tuning of the isodose distributions that would be extremely difficult with static sources. The theoretical main advantage of PLDR over HDR is based on the fact that damage to latereacting tissues is closely related to the dose per fraction (12, 18, 26, 27). Whereas HDR involves the delivery of a small number of large fractions, PLDR involves the administration of a series of small doses over a prolonged period in an attempt to minimize the risk to late-reacting tissues. In situations where critical normal structures can be physically displaced from the radiation, as in tandem and ovoid placements where the rectal tissue can be maximally retracted and the bladder packed away from the source locations, this advantage of PLDR over HDR would be small. In the interstitial implant, on the other hand, the differential is significant. The main question remaining is whether a series of small pulses of radiation delivered by a single powerful iridium source is biologically equivalent to the same overall dose delivered in the same overall period by an array of low activity static sources, both in terms of the effect on early-reacting and late-reacting tissues. For any cell located within the irradiated volume, the instantaneous dose rate experienced by the cell as the source passes by is in the high dose rate range. However, because the dose per pulse is kept intentionally low, the absolute dose experienced by the cell is low. Brenner and Hall (4, 5) addressed these issues, utilizing the linear-quadratic formalism of Lea and Catcheside (14) in the analysis of in vitro dose-response data available for cell lines of human origin. Looking at experimental data from 36 human cell lines, using their observed values for (Y, p and to (characteristic repair time of the tissue), the authors defined the conditions under which pulsed therapy should be equivalent to continuous low dose rate therapy. The standard chosen for comparisons was a continuous low dose rate implant delivering a total.dose of 30 Gy over 60 h. Their conclusion was that lo-min pulses, separated by l-h intervals, with the overall implant duration kept constant at 60 h, would result in a similar cell survival for early reacting tissues and only a 2% increase in late effects when compared to the continuous regimen. In a separate effort to establish the conditions least likely to result in a decrease in the therapeutic ratio for PDR compared to continuous low dose rate, Fowler (7) calculated the expected effects of various pulsed regimens (with dose rates in the pulse varying from 0.5 to 120 Gy per hour, pulses delivered every l-4 h) on early and lateresponding tissues, using a wide range of possible halftimes of repair from 0.1 h to 3 h. Duration and total dose of the implant were kept at 70 Gy in 140 h, and all effects were considered relative to a continuous regimen at 0.5 Gy per hour. Looking first at early-reacting (normal and tumor) tissues, biologic effectiveness would not be expected to in-
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I. J. Radiation Oncology 0 Biology 0 Physics
crease by more than 3% if dose rates remained in the OS3 Gy per hour range and pulses were given hourly, regardless of the assumed tl12. As the dose per pulse and interval duration increase, the biologic effectiveness also increases for all tl,*. This is true for late-reacting tissues as well. If intervals increase to one pulse per 4 h, biologic effect in late tissue may increase as much as 15%. Tissues with the shortest tm of repair would be at greatest risk. This would necessitate a decrease in the overall dose to sustain levels of late effects similar to that seen with continuous low dose rate regimens, a decrease that would result in a less-than-desired effectiveness for tumor control. Fowler (7), therefore, arrived at a conclusion similar to that of Hall and Brenner (4)-keeping the repetition frequency at one pulse every 1 or 2 h would be comparable to a continuous regimen with a negligible increase in late effects. Although increasing dose rates result in increasing biologic effectiveness, they also are accompanied by a decline in the therapeutic ratio due to an expectation of increased late effects (11, 12, 23). This could occur in two ways: increasing the dose delivered per pulse and increasing the time between each given pulse. Keeping the total duration of an implant static but increasing the interval between pulses, thereby increasing the dose per pulse, increases the biologic effectiveness of a dose, particularly in cell lines with a shorter half-time of repair (t&. Because the amount of repair capacity is believed to be greater in late-reacting normal tissues than in early-reacting tissues (including most tumors), an increase in relative effectiveness would be expected to be more significant for late-reacting tissues than for early-reacting tissues, resulting in a decrease in the therapeutic ratio. If, however, the tl,* for late-reacting tissues is significantly longer than that of a particular tumor tissue, the effect of pulsed therapy on the therapeutic ratio would be minimized. Data from recent experiments on rodent kidney, spinal cord, and lung tissue suggest that a component of repair of late-responding tissue damage of approximately 4 h exists (I, 3, 17, 20, 27). If this is the case, and early-responding tissues including tumor tissue have half-times of repair considerably shorter than those of late-responding tissues, then the pulsed approach would be expected to result in levels of late tissue damage lower than that seen with the continuous low dose rate approach (6). Cell line studies by Armour et al.(3) and mouse jejunum trials by Mason et aZ.( 18), examining the relative biologic effectiveness of pulsed and continuous schemes failed to show a significant difference between the two regimens. The current analysis was performed to evaluate the incidence and pattern of acute toxicity seen with the pulsedapproach, and represents the first clinical data available for PLDR brachytherapy, employing the fractionation scheme proposed to have the lowest risk of worsening the therapeutic ratio (4, 7, 10): a single 10-20 min pulse of 0.40-0.80 Gy delivered hourly around the clock until the desired dose has been delivered. An incidence of 6% of
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Grade 3 or greater acute complications was seen in this cohort of 65 patients with pelvic malignancies, a level that is not a significant increase in the incidence over that seen in the authors’ experience with continuous low dose rate brachytherapy approaches, supporting the radiobiologic predictions. However, because most studies of complications after brachytherapy for pelvic diseases do not distinguish between acute and delayed complications (2, 9, 13, 19, 21, 22, 24, 25), a standard for comparison is difficult to find in the literature. In the subset of 42 patients with cervical carcinoma, there was also no marked rise in the incidence of acute reactions following the pulsed low-dose approach. Notably, there was not a measurable increase in degree or duration of vaginal mucositis, diarrhea, or cystitis requiring medical intervention. It must be pointed out, however, that in order to demonstrate a predicted difference of 2-3% in acute morbidity between PLDR and CLDR, large numbers of patients treated with both approaches would be required. No specific factors in this group could be identified that predicted for acute complications. The 5-year actuarial major complication rate in patients with cervix cancer treated with definitive radiation including intracavitary brachytherapy in Lanciano’s Patterns of Care Study report was 14% (13). The median time to occurrence of late complications was 13.5 months for bowel, 23.2 months for bladder, and 17.4 months for vagina. In that report, 80% of all complications were seen within 24.2 months (bowel), 39.4 months (bladder), or 45.1 months (vagina). In Sinistrero’s report of complications in cervix cancer patients treated with definitive radiation, using the France-Italian glossary for description of complications, 24 severe or fatal events were seen in 215 patients, but actuarial figures were not given (25). The mean time from treatment to onset of these complications was 26.7 months, with 80% occurring within 36 months. Perez reported an incidence of 15% major or severe complications in 8 11 patients treated with definitive radiation for cervix cancer (21). At a mean follow-up of 16-18 months for the current study, it remains too early to make a strong statement regarding the impact on late complications or local control, although the initial results appear promising. Delayed complication rates of 13-15% for this group fell to 7-8% if those patients with massive central recurrence of disease associated with their fistulae were removed from the analysis. Two of the long-term complications were also due in part to misprogramming using a manual system that has been replaced by an integrated planning system that precludes such events. At a mean follow-up of 18 months, the incidence of delayed complications in patients treated with perineal interstitial implants-is 7%, excluding massive recurrences. This rate compares favorably with those reported by other reports of delayed severe complication rates ranging from 6-42% after interstitial approaches (2, 9, 22, 24). This low rate is attributed in part to the optimization ability of the remote afterloading program.
Pulsed low dose rate brachytherapy for pelvic malignancies 0 P. S.
The use of a pulsed low dose rate (average per hour) brachytherapy approach shows no evidence of a major increase in acute complications, or a change in the pattern of complications over the standard continuous low dose rate approach, as long as pulses of IO-20 min duration are delivered each hour for a dose of 0.40-0.80 Gy per hour, hourly without planned interruptions, closely mimicking the time course of a standard continuous regimen. The benefits of the PLDR, namely elimination of radiation exposure to staff and visitors, with improved patient man-
SWIFT
et
al.
817
agement time between pulses, reduced need for radioactive source inventory, and improved dose distribution through optimization, are important steps forward in the use of brachytherapy. The temptation to further increase efficiency of management of multiple patients by increasing the dose per pulse considerably, increasing the interval between pulses beyond 4 h, or decreasing the pulse time well below 10 min with a greater activity source may, however, lead to a further decrease in the therapeutic ratio and should be approached cautiously.
REFERENCES 1. Ang, K. K.; Jiang, G. L.; Guttenberger, R.; Thames, H. D.; Stephens, L. C.; Smith, C. D.; Feng, Y. Impact of spinal cord repair kinetics on the practice of altered fractionation schedules. Radiother. Oncol. 25:287-294; 1992. 2. Aristizabal, S. A.; Woolfitt, B.; Valencia, A.; Ocampo, G.; Surwit, E. A.; Sim, D. Interstitial parametrial implants in carcinoma of the cervix Stage II-B. Int. J. Radiat. Oncol. Biol. Phys. 13:445-450; 1987. 3. Armour, E.; Wang, Z. H.; Corry, P.; Martinez, A. Equivalence of continuous and pulse simulated low dose rate irradiation in 9L gliosarcoma cells at 37 degrees and 41 degrees C. Int. J. Radiat. Oncol. Biol. Phys. 22:109-l 14; 1992. 4. Brenner, D. J.; Hall, E. J. Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy. Int. J. Radiat. Oncol. Biol. Phys. 20:181-190; 1991. 5. Brenner, D. J.; Hall, E. J.; Huang, Y .; Sachs, R. K. Optimizing the time course of brachytherapy and other accelerated radiotherapeutic protocols. Int. J. Radiat. Oncol. Biol. Phys. 29:893-901; 1994. 6. Brenner, D. J.; Hall, E. J.; Huang, Y.; Sachs, R. K. Potential reduced late effects for pulsed brachytherapy compared with conventional LDR [letter; comment]. Int. J. Radiat. Oncol. Biol. Phys. 31:201-202; 1995. 7. Fowler, J.; Mount, M. Pulsed brachytherapy: The conditions for no significant loss of therapeutic ratio compared with traditional low dose rate brachytherapy. Int. J. Radiat. Oncol. Biol. Phys. 23:661-669; 1992. 8. Fowler, J. F. Why shorter half-times of repair lead to greater damage in pulsed brachytherapy. Int. J. Radiat. Oncol. Biol. Phys. 26:353-356; 1993. 9. Gaddis, 0.; Morrow, C. P.; Klement, V.; er al. Treatment of cervical carcinoma employing a template for transperineal interstitial Ir 192 brachytherapy. Int. J. Radiat. Oncol. Biol. Phys. 9:819-827; 1983. 10. Hall, E. J. Failla Memorial lecture. From beans to genesBack to the future. Radiat. Res. 129:235-249; 1992. 11. Hall, E. J.; Brenner, D. J. The dose-rate effect revisited: Radiobiological considerations of importance in radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 21:1403-1414; 1991. 12. Hall, E. J.; Brenner, D. J. The dose-rate effect in interstitial brachytherapy: A controversy resolved. Br. J. Radio]. 65:242-247; 1992. 13. Lanciano, R. M.; Martz, K.; Montana, G. S.; Hanks, G. E. Influence of age, prior abdominal surgery, fraction size, and dose on complications after radiation therapy for squamous cell cancer of the uterine cervix. A Patterns of Care study. Cancer 69:2124-2130; 1992. 14. Lea, D. E.; Catcheside, D. G. The mechanisms of the induction by radiation of chromosome aberrations in tradescantia. J. Genet. 44:216-245; 1942. 15. Low, D. A.; Williamson, J. F. The evaluation of optimized implants for idealized implant geometries. Med. Phys. 22: 1477; 1995.
16. Martinez, A.; Edmundson, G. K.; Cox, R. S.; Gunderson, L. L.; Howes, A. E. Combination of external beam irradiation and multiple-site perineal applicator (MUPIT) for treatment of locally advanced or recurrent prostatic, anorectal, and gynecologic malignancies. Int. J. Radiat. Oncol. Biol. Phys. 11:391-398; 1985. 17. Martinez, A. A.; White, J.; Armour, E.; Armin, A. R.; Edmundsen, G. K.; Corry, P. Continuous versus pulsed LDR: Preliminary analysis of rat rectal toxicity. In: Mould, R. F.; Battermann, J. J.; Martinez, A. A.; Speiser, B. L., eds. Brachytherapy from radium to optimization. The Netherlands: Nucletron International B. V.; 1994:260-269. 18. Mason, K. A.; Thames, H. D.; O&ran, T. G.; Ruifrok, A. C.; Janjan, N. Comparison of continuous and pulsed low dose rate brachytherapy: Biological equivalence in vim. Int. J. Radiat. Oncol. Biol. Phys. 28:667-671; 1994. 19. Montana, G. S.; Fowler, W. C. Carcinoma of the cervix: Analysis of bladder and rectal radiation dose and complications. Int. J. Radiat. Oncol. Biol. Phys. 16:95-100; 1989. 20. Moulder, J. E.; Fish, B. L. Repair of sublethal damage in the rat kidney. In: Chapman, J. D.; Dewey, W. C.; Whitmore, G. F., eds. Radiation research: A twentieth century perspective. San Diego: Academic Press; 1992:238. 21. Perez, C. A.; Breaux, S.; Bedwinek, J. M.; Madoc, J. H.; Camel, H. M.; Purdy, J. A.; Walz, B. J. Radiation therapy alone in the treatment of carcinoma of the uterine cervix. II. Analysis of complications. Cancer 54:235-246; 1984. 22. Prempree, T. Parametrial implant in Stage III B cancer of the cervix. III. A five-year study. Cancer 52:748-750; 1983. 23. Ruiz de Almodovar, J. M.; Bush, C.; Peacock, J. H.; Steel, G. G.; Whitaker, S. J.; McMillan, T. J. Dose-rate effect for DNA damage induced by ionizing radiation in human tumor cells. Radiat. Res. 134:S93-96; 1994. 24. Sewchand, W.; Prempree, T.; Patanaphan, V.; Carbone, D.; Salazar, 0. M. Radium needles implant in the treatment of extensive vaginal involvement from cervical carcinoma. A dosimetry appraisal. Acta Radiol. Oncol. 23:449-453; 1984. 25. Sinistrero, G.; Sismondi, P.; Rumore, A.; Zola, P. Analysis of complications of cervix carcinoma treated by radiotherapy using the France-Italian glossary. Radiother. Oncol. 26:203211; 1993. 26. Turesson, I.; Thames, H. D. Repair capacity and kinetics of human skin during fractionated radiotherapy: Erythema, desquamation, and telangiectasia after 3 and 5 year’s followup. Radiother. Oncol. 15:169-188; 1989. 27. van Rongen, E.; Thames, H. J.; Travis, E. L. Recovery from radiation damage in mouse lung: Interpretation in terms of two rates of repair. Radiat. Res. 133:225-283; 1993. 28. Weaver, K. A.; Pickett, B.; Roberts, L. W.; Stuart, A. Source localization for template implants with particular reference to stepping-source afterloaders. Med. Phys. 22:83; 1995. 29. Winchester, D. P.; Cox, J. D. Standards for breast-conservation treatment. Ca. Cancer J. Clin. 42:134-162; 1992.
PI1 SO360-3016(96)00564-O
ELSEVIER
l
Biol. Phys., Vol. 37, No. 4, pp. 811-817, 1997 Copyright 0 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/97 $17.00 + .OO
Clinical Investigation PULSED LOW DOSE RATE BRACHYTHERAPY FOR PELVIC MALIGNANCIES PATRICK
S. SWIFT, M.D., C. BETHAN
PHILIP PURSER, PH.D., L. W. ROBERTS, BARBY PICKETT, POWELL, M.D. AND THEODORE L. PHILLIPS, M.D.
PH.D.,
Department of Radiation Oncology, University of California, San Francisco, CA Purpose: The pulsed low dose rate remote afterloading unit was designed to combine the radiation safety and isodoseopthnization advantages of high dose rate technology with the radiobiologic advantages of continuous low dose rate brachytherapy. This is the first report of a prospective clinical trial evaluating the relative incidence of acute toxicity and local control in patients with pelvic malignancies who underwent interstitial or intracavitary brachytherapy with the pulsed low dose rate remote afterloader. Methods and Materials: From 5/D/92-6/21/95,65 patients underwent 77 brachytherapy procedures as part of their treatment regimen for pelvic malignancies. Using the pulsed low dose rate Selectron, equipped with a single cable-driven 0.3-1.0 Ci Ir19’ source, target volume dosesof 0.40-0.85 Gy per pulse were prescribed to deliver the clinically determined dose. Forty-five intracavitary and 32 interstitial procedures were performed. Fifty-four patients had primary and 11 recurrent disease. Patients were followed closely to assessincidence of Grade 3-5 acute and delayed toxicity, local control, and survival. Results: With a median follow-up of 16.1 months (range l-29), 33 patients are NED, 10 alive with disease, 13 dead with disease,4 dead of intercurrent disease,and 5 lost to follow-up. Local control was maintained until last follow-up or death in 48 cases,local failure occurred in 11, unknown in 5. Grade 3-5 acute toxicities (requiring medical or surgical intervention) occurred in 5 out of 77 procedures (6.5%), delayed complications in 10 patients (15% actuarial incidence at 2 years). In the 52 procedures performed for 42 patients with cervix cancer, the acute toxicity incidence was 5.8%, with a 14% 2-year actuarial incidence of delayed complications. Of 32 interstitial templates performed on 30 patients for pelvic malignancies, there were three incidences of acute toxicity and five delayed toxicities. Conclusion: Using the parameters described for this initial clinical study in patients treated for pelvic malignancies, pulsed low dose rate brachytherapy shows no significant increase in acute toxicity above that seen with the standard continuous low dose rate approach. Using the isodose optimization possible with pulsed brachytherapy, local control is excellent in patients treated at initial presentation, although longer followup is required for full assessment of local control and late toxicity. Further trials will need to be carried out to determine if larger doses per pulse and shorter total treatment times have comparable therapeutic ratios. 0 1997 Elsevier Science Inc. Cervix neoplasms, Brachytherapy, Remote after loading, Pulsed low dose rate, Interstitial.
Compared to continuous low dose rate manually afterloaded approaches, pulsed brachytherapy has the advan-
INTRODUCTION
tages of elimination of radiation exposure to medical per-
Pulsed brachytherapy refers to the delivery of radiation treatment using a remote afterloading device with a single cable-driven radioactive source that is propelled through an array of positions within an implanted volume or a set of intracavitary instruments. The source stops for a specified duration at a preselected number of locations within the array during its transit, delivering a cumulative dose to the entire volume. This dose may be delivered as a rapidly delivered large fraction, as in the case of high dose-rate treatment (HDR), or as a series of small doses delivered at a given frequency over a period of days, called pulsed low dose rate (PLDR) treatment.
sonnel, reduction in the inventory of radioactive sources required for multiple patients, and the ability to optimize the isodose distributions
through manipulation
of the lo-
cation and number of source-stopping (“dwell”) positions, and the time the source spends at each dwell position within the implanted array. The theoretical advantage of PLDR over HDR is that the expected effect on late-reacting tissues would be less with multiple small doses compared with a smaller number of large fractions. Radiobiologic data by Hall (10, 12), Brenner (4-6), and Fowler (7, 8) suggest that pulsed low dose rate therapy
Reprint requests to: Patrick S. Swift, M.D., Department of Radiation Oncology, University of California, Room L-08, 505
PamassusAvenue, San Francisco, CA 94143. Accepted for publication 11 October 1996. 811
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I. J. Radiation Oncology 0 Biology 0 Physics
could be delivered in such a way that responses of both acute-reacting (tumor and normal) tissues, as well as latereacting tissues would be comparable to those seen with traditional continuous low dose rate brachytherapy, as long as certain dosing and interval guidelines were followed. The present report is the first to provide clinical data on acute toxicity with the pulsed low dose rate approach to support this hypothesis. METHODS
AND MATERIALS
In early 1992, guidelines were established for the use of the Pulsed low dose rate Selectron from Nucletron Corporation in patients requiring brachytherapy for part of their management at the University of California, San Francisco. Any patient deemed appropriate for traditional continuous low dose rate brachytherapy was eligible for treatment with the pulsed low dose rate Selectron (Nucletron). This report deals only with those patients with malignancies in the pelvic region. Patients who had not received prior pelvic radiation were treated with external beam radiotherapy directed at the pelvis (nodes and primary) using standard two- or four-field techniques with 6 or 18 MV photons, to doses of 45-54 Gy. A midline block was routinely placed at 3640 Gy, and the technique switched to APIPA only to reduce dose to bladder and rectum. Patients with recurrent disease who had received prior external beam therapy to the pelvis did not receive external beam therapy at the time of recurrence. Patients then proceeded to the brachytherapy component of their treatment. After insertion or implantation of appropriate applicators (tandem and ovoids, ovoids only, vaginal cylinder, or perineal interstitial template), films were obtained for dosimetric planning. Prior to January 1995, the localizing films were either orthogonal (AP and lateral) or AP stereo. The film data was digitized and entered using an in-house brachytherapy planning program (28). Source dwell positions and times were optimized manually by the planning physicist and radiation oncologist. After a satisfactory plan was obtained, the treatment program was printed out, and subsequently programmed manually into the treatment unit. After January 1995, the Nucletron Plato brachytherapy planning system was used. The localizing films were either orthogonal or “variable angle” isocentric (AP + 20”). Film data was digitized and entered, and source positions chosen manually. The volume geometric method for optimizing the isodose distribution was used (15). After a satisfactory plan was obtained, the program was automatically transferred to the treatment unit by a reuseable program card. An effort was made to keep the dose per pulse to a range of 50-100 Gy, because the majority of our clinical experience with continuous low dose rate brachytherapy was gained using this dose range and we sought to change as few parameters as possible in moving to the pulsed system. The total dose from the brachytberapy procedure was
Volume 37, Number 4, 1997
determined by the radiation oncologist, based on the clinical setting, history of prior irradiation to the site, and the total dose of external beam therapy planned for the course of therapy. Pulses were delivered hourly, and continued around the clock with no planned interruptions. After completion of therapy, the patients were followed at 2 weeks, 1 month, 3 months, and then every 3 months up to 1 year. After 1 year, the patients were seen every 46 months for the next year, then every 6 months afterwards. Patients were assessed for evidence of local or systemic failure, with all complications listed according to the RTOG acute radiation morbidity scoring criteria and the RTOG/EORTC late radiation morbidity scoring scheme (29). The absolute incidence of acute Grade 3-5 toxicity (i.e., events recorded within 90 days of completion of the brachytherapy), and the actuarial incidence of delayed Grade 3-5 toxicity are reported here. The actuarial incidence of local failure, survival, and disease-free survival are also reported, with a further analysis of those patients with a diagnosis of cervical carcinoma. RESULTS
From 5/l l/92 through 6/21/95, 77 brachytherapy procedures were performed in 65 patients with pelvic malignancies as part of their management at the University of California, San Francisco (Table 1). Sites of disease were as follows: cervix, 42; prophylactic postoperative vaginal cuff irradiation for endometrial cancer, 8; vaginal recurrence of endometrial cancer, 5; rectal, 4; vaginal, 2; pelvic sarcoma, 1; prostate rhabdomyosarcoma, 1; urethra, 1; vulva, 1. Fifty-four patients were treated for primary disease, 11 for recurrent disease, and 5 had received prior irradiation to the site. Seventy-seven procedures were performed, including 32 interstitial implants using the MUPIT (Martinez universal perineal interstitial template (16) (3 of which were open implants), 34 tandem and ovoid insertions, 4 intravaginal ovoid placements, and 7 vaginal applications with a vaginal candle or Houdek applicator. For patients receiving perineal implants, between 13 and 18 needles were used in each case. All patients were followed for at least 6 months or until time of death. At last follow-up (mean follow-up 16.1 months, median 15.1 months, range 1-41.2 months), 49 patients were alive and 17 dead. Thirty-four patients were alive and free of disease, and 10 were alive with disease (6 of whom were locally controlled). Fourteen died due to their cancer, with 7 locally controlled. Three died of other causes, and four were lost to follow-up after short follow-up. Excluding the 4 lost to follow-up, local control was maintained in 50 of 61 patients. Sixty-five procedures were performed with doses per pulse of 0.40-0.80 Gy. The time required to deliver the pulse varied from 10 to 25 min in each hour, depending on the source activity at the time of the procedure (maximum 1 Ci, minimum 0.33 Ci), and on the volume of the
Pulsed
low dose rate brachytherapy for pelvic malignancies 0 P. S. SWIFT
Table 1. Disease sites and characteristics Primary Recurrent Prior radiation Procedures
54 11 Yll Interstitial Tandem and ovoids
32 34 4 7 42 8 5 2 4 1 1 1 1
Ovoids only
Vaginal candles Cervix Vag. cuff, post-hyst. Vag. cuff recurrence Primary vaginal Rectal recurrence Pelvic sarcoma Prostate rhabdo. Urethra Vulva
Sites
implant or insertion. Twelve patients were treated with doses per pulse in excess of 0.80 Gy: 5 had posthysterectomy radiation to the vaginal cuff with vaginal surface doses of 1 .OO-1.33 Gy per pulse; 4 had cervical carcinoma but multiple medical problems such as severe obesity or history of thrombophlebitis, treated with point A doses of 0.81-0.88 Gy per hour, thereby slightly shortening the overall treatment time; 3 patients were implanted for recurrent disease and had minimum tumor doses of 0.810.88 Gy per pulse. No acute complications were seen in this group of 12 patients. Two of the 12 returned to their native countries shortly after treatment and were lost to follow-up. No delayed complications have been reported in the remaining 10, 7 of whom are alive and free of disease.
Acute complications Acute complications of Grade 3 or greater by the RTOG acute radiation morbidity scoring criteria were seen in 5 of the 77 procedures, an absolute incidence of 6.5%. These complications are listed in Table 2. Of those patients treated at primary presentation, there were four compli-
813
et al.
cations in 66 procedures, or 6%. Of those patients with recurrent disease, 1 out of 11 had an acute complication (partial small bowel obstruction managed conservatively). A univariate analysis of conditions that might contribute to acute complications, including dose rate, site, total brachytherapy dose, total overall dose, and primary vs. recurrent disease failed to show any significance for these factors.
Delayed complications The delayed complications of Grade 3 or greater by the RTOG/EORTC late grading scheme are listed in Table 3. Two of the Grade 4 delayed complications occurred in patients who were treated prior to the use of an integrated computerized planning system, and were related to excessive dose from manual misprogramming of the treatment unit after dosimetric optimization had been performed. In the first case, a woman with Stage IIIB cervical carcinoma with extensive lower vaginal involvement, manual misprogramming of the dwell time at a single position out of 10 along one catheter track was erroneously repeated in each of 18 catheter tracks, resulting in a maximum rectal dose of 60.0 Gy to a small volume of rectal mucosa at the level of the midvagina (external beam dose of 40 Gy plus the implant dose 60 Gy, for a total of 100 Gy). This was not detected until a review of dosimetry was carried out at the time of rectovaginal fistula development several months later. The patient was also found to have massive central failure of disease throughout the implanted area. The second case was a patient with carcinoma in situ of the urethra who was treated with brachytherapy to prevent the need for total cystourethrectomy. During one of the insertions, after prior approval of an optimized plan, the bedside control unit was manually m&programmed with dwell positions spaced at 5 mm intervals rather than the intended 10 mm intervals, resulting in a dose of 40.0 Gy rather than the intended 30.0 Gy to the urethral meatus and adjacent labia. This was detected on review of the printout at completion of the 36-h insertion. The patient
Table 2. Acute complications-Grade
3-5 according to the RTOG acute radiation morbidity scoring criteria (lo), in all pelvic patients treated with the pulsed low dose rate selectron
Site
Stage
Rectal
ret*
Cervix
IIB
Cervix
IIB
Cervix
IIB
Urethra
in situ
* ret-recurrent
Procedure Interstitial implant Interstitial implant Interstitial implant Intracavitary insertion Intraluminal (two) disease.
Dose per pulse (cGY)
PLDR dose
Total (cGY)
(cGY)
52
4500
8100
50
1500
69
Total dose Complication
Grade
Comment
Partial SBO
3
6860
Hematemesis
4
3600
7500
Perineal pain
3
Resolved, conservative tx Resolved, conservative tx Required narcotics for 3 months
65
4200
8700
Cystitis
3
75
7100
7100
Moist desquamation
3
Tumor involved base of bladder
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Volume 37, Number 4, 1997
Table 3. Delayed complications-Grade 3-5 according to the RTOG/EORTC late radiation morbidity pelvic patients treated with the pulsed low dose rate selectron Dose per pulse Site
Stage
Procedure
(cGY)
Total PLDR dose (cGY)
Total dose (cGY)
Complication
Cervix
IIIB
Interstitial implant
60
3500
7500
Vagina
Rec.
69
4000
8500
Vagina
Rec.
70
3500
7480
Cervix
IIB
65
2000
6000
Cervix
IIB
69
3600
7500
Cervix
IIB
70
4200
9300
Cystitis
Cervix
IIB
Interstitial implant Intracavitary insertion Interstitial implant Interstitial implant Intracavitary insertion Intracavitary insertion
Rectovaginal, vesicovaginal fistulae Rectovaginal fistulae Rectovaginal tistulae Rectovaginal fistulae Perineal pain
65
4200
8700
Cystitis
Cervix
IB
Intracavitary insertion
80
6800
8500
Proctitis
Vulva
III
Interstitial implant
60
1500
6000
Soft tissue necrosis
Urethra
in situ
Intraluminal
75
7100
7100
Soft tissue necrosis
went on to develop soft tissue necrosis of the labia immediately adjacent to the urethral meatus after a total skin dose in this region of 70 Gy delivered in two insertions (20 h and 35 h) spaced a month apart. This healed with conservative nonsurgical intervention. These complications led to the integration of a computerized card system in which the optimized plan, approved by the physician, is recorded electronically on a card in the planning station and transferred via the card to the treatment unit. The actuarial incidence of delayed complications for the entire group was 15% at 2 years, with 10 complications noted to date. If the two n-&programmed cases are removed from the analysis, the actuarial incidence of delayed complications is 13%. Of the four patients who developed rectovaginal fistulae, three were found to have extensive local recurrence of disease contributing to the fistula formation. Omitting the patients with massive central recurrence of disease, the incidence of delayed complications falls to 8%. Of the two patients with Grade 3 bladder complications, one had a diagnosis of AIDS at the time of treatment, and the other had tumor extension to the bladder base prior to radiation, and received a maximal bladder dose of 90 Gy.
scoring scheme (lo), for all
Grade
Comment Massive central recurrence Massive central recurrence Massive central recurrence NED at autopsy Required narcotics for 3 months AIDS
4
Base of bladder involved with tumor, required therapy for 2 years Required laser tx, resolved within 1 year Open ulcer prior to implant, required HBO tx, eventually found to have recurrent disease Resolved without surgical intervention
Local control and survival With a mean follow-up of 16.1 months, the actuarial incidences of local control at 2 years for the entire group and for those with primary disease are, respectively, 78 and 85%. Four patients were lost to follow-up, after returning to their native countries. At the time of last evaluation, three of these patients were free of disease, (one of whom had Stage IA cervix carcinoma, two Stage II). The fourth was a patient with recurrent rectal cancer who had persistent disease at last follow-up. The actuarial 2year survivals are 67% for the entire group and 70% for those with primary disease.
Cervix carcinoma patients Fifty-two of all procedures were performed in 42 patients with primary cervical carcinoma: 29 intracavitary insertions of tandem and ovoids, 21 interstitial implants, and 2 ovoid placements for vaginal cuff irradiation posthysterectomy. The stages of the patients were as follows: IA, 3; IB/IIA 12; IIB, 15; III, 11; IVA, 3. Intracavitary insertions were the preferred method of brachytherapy for cervical carcinoma patients. Interstitial implantation was used in those Stage IB-IIB cases with very poor anatomic
Pulsed
low
dose rate brachytherapy
for pelvic
geometry after external beam therapy (narrowed vagina, absent fomices), and patients with stage IIIA, IIIB, or IVA disease. Three acute complications were seen, for an incidence of 5.8%. Six delayed complications were reported, including one associated with dose misadministration mentioned earlier, for an actuarial incidence at 2 years of 14%. Total tumor doses (brachytherapy plus external beam) were calculated as the dose to point A for patients treated with intracavitary insertions, or as minimum tumor dose (the isodose volume that encompassed the entire clinical tumor volume as defined by the clinician) for those patients who underwent interstitial implantation, and ranged from 56.0-96.0 Gy. Rectal doses ranged from 52.9-100.0 Gy (with only one patient receiving in excess of 78 Gy), and bladder doses ranged from 47.52-96.00 Gy. Neither delayed nor acute complications correlated in a statistically significant fashion with doses to tumor, rectum, or bladder. At last follow-up (mean 17.3 months, median 16.0 months, range 141.2 months), 23 patients were alive and free of disease, 4 were alive with distant disease only, 9 had died due to the disease (3 of whom had failed locally), 3 have died of other causes, and 3 were lost to follow-up. Thirty-five were locally controlled at last follow-up, 4 failed locally, and 3 were lost to follow-up, for a 2-year actuarial local control rate of 86%, and an actuarial survival of 65%. The four failures included 1 of 8 Stage IB patients, 1 of 13 Stage IIB patients, and 2 of 11 Stage IIIB patients. Pelvic interstitial implants Thirty-two interstitial implants were performed in 30 patients: cervix, 20; recurrent rectal, 3; pelvic sarcoma, 2; vaginal recurrence of endometrial cancer, 4; vulva, 1. None of this group were lost to follow-up (mean 18.1 months). Acute complications were seen in 3 of 32 procedures (9.4%) and delayed in 5 of 30 patients (15%), 2 of whom were found to have recurrent disease contributing to the complication. Omitting those with massive central recurrence, the delayed complication rate falls to 7%. Twenty-two patients maintained local control, with 4 of the 8 failures occurring in patients who had received prior irradiation (68% local control). The actuarial 2-year survival for this group is 62%. DISCUSSION The advantages of pulsed low dose rate brachytherapy over manual-afterloading continuous low dose rate approaches include increased radiation protection with elimination of exposure to the staff attending to the medical needs of the patient as well as visitors, the elimination of the need to order costly new sources for each patient to be treated or to maintain a large inventory of sources for different clinical settings, and the ability to perform dose optimization within the implanted volume to both improve
malignancies
0 P. S. SWIFT et al.
815
dose homogeneity and reduce dose to normal structures in or near the volume. Alterations of the dwell positions and dwell times at each position allow for fine tuning of the isodose distributions that would be extremely difficult with static sources. The theoretical main advantage of PLDR over HDR is based on the fact that damage to latereacting tissues is closely related to the dose per fraction (12, 18, 26, 27). Whereas HDR involves the delivery of a small number of large fractions, PLDR involves the administration of a series of small doses over a prolonged period in an attempt to minimize the risk to late-reacting tissues. In situations where critical normal structures can be physically displaced from the radiation, as in tandem and ovoid placements where the rectal tissue can be maximally retracted and the bladder packed away from the source locations, this advantage of PLDR over HDR would be small. In the interstitial implant, on the other hand, the differential is significant. The main question remaining is whether a series of small pulses of radiation delivered by a single powerful iridium source is biologically equivalent to the same overall dose delivered in the same overall period by an array of low activity static sources, both in terms of the effect on early-reacting and late-reacting tissues. For any cell located within the irradiated volume, the instantaneous dose rate experienced by the cell as the source passes by is in the high dose rate range. However, because the dose per pulse is kept intentionally low, the absolute dose experienced by the cell is low. Brenner and Hall (4, 5) addressed these issues, utilizing the linear-quadratic formalism of Lea and Catcheside (14) in the analysis of in vitro dose-response data available for cell lines of human origin. Looking at experimental data from 36 human cell lines, using their observed values for (Y, p and to (characteristic repair time of the tissue), the authors defined the conditions under which pulsed therapy should be equivalent to continuous low dose rate therapy. The standard chosen for comparisons was a continuous low dose rate implant delivering a total.dose of 30 Gy over 60 h. Their conclusion was that lo-min pulses, separated by l-h intervals, with the overall implant duration kept constant at 60 h, would result in a similar cell survival for early reacting tissues and only a 2% increase in late effects when compared to the continuous regimen. In a separate effort to establish the conditions least likely to result in a decrease in the therapeutic ratio for PDR compared to continuous low dose rate, Fowler (7) calculated the expected effects of various pulsed regimens (with dose rates in the pulse varying from 0.5 to 120 Gy per hour, pulses delivered every l-4 h) on early and lateresponding tissues, using a wide range of possible halftimes of repair from 0.1 h to 3 h. Duration and total dose of the implant were kept at 70 Gy in 140 h, and all effects were considered relative to a continuous regimen at 0.5 Gy per hour. Looking first at early-reacting (normal and tumor) tissues, biologic effectiveness would not be expected to in-
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I. J. Radiation Oncology 0 Biology 0 Physics
crease by more than 3% if dose rates remained in the OS3 Gy per hour range and pulses were given hourly, regardless of the assumed tl12. As the dose per pulse and interval duration increase, the biologic effectiveness also increases for all tl,*. This is true for late-reacting tissues as well. If intervals increase to one pulse per 4 h, biologic effect in late tissue may increase as much as 15%. Tissues with the shortest tm of repair would be at greatest risk. This would necessitate a decrease in the overall dose to sustain levels of late effects similar to that seen with continuous low dose rate regimens, a decrease that would result in a less-than-desired effectiveness for tumor control. Fowler (7), therefore, arrived at a conclusion similar to that of Hall and Brenner (4)-keeping the repetition frequency at one pulse every 1 or 2 h would be comparable to a continuous regimen with a negligible increase in late effects. Although increasing dose rates result in increasing biologic effectiveness, they also are accompanied by a decline in the therapeutic ratio due to an expectation of increased late effects (11, 12, 23). This could occur in two ways: increasing the dose delivered per pulse and increasing the time between each given pulse. Keeping the total duration of an implant static but increasing the interval between pulses, thereby increasing the dose per pulse, increases the biologic effectiveness of a dose, particularly in cell lines with a shorter half-time of repair (t&. Because the amount of repair capacity is believed to be greater in late-reacting normal tissues than in early-reacting tissues (including most tumors), an increase in relative effectiveness would be expected to be more significant for late-reacting tissues than for early-reacting tissues, resulting in a decrease in the therapeutic ratio. If, however, the tl,* for late-reacting tissues is significantly longer than that of a particular tumor tissue, the effect of pulsed therapy on the therapeutic ratio would be minimized. Data from recent experiments on rodent kidney, spinal cord, and lung tissue suggest that a component of repair of late-responding tissue damage of approximately 4 h exists (I, 3, 17, 20, 27). If this is the case, and early-responding tissues including tumor tissue have half-times of repair considerably shorter than those of late-responding tissues, then the pulsed approach would be expected to result in levels of late tissue damage lower than that seen with the continuous low dose rate approach (6). Cell line studies by Armour et al.(3) and mouse jejunum trials by Mason et aZ.( 18), examining the relative biologic effectiveness of pulsed and continuous schemes failed to show a significant difference between the two regimens. The current analysis was performed to evaluate the incidence and pattern of acute toxicity seen with the pulsedapproach, and represents the first clinical data available for PLDR brachytherapy, employing the fractionation scheme proposed to have the lowest risk of worsening the therapeutic ratio (4, 7, 10): a single 10-20 min pulse of 0.40-0.80 Gy delivered hourly around the clock until the desired dose has been delivered. An incidence of 6% of
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Grade 3 or greater acute complications was seen in this cohort of 65 patients with pelvic malignancies, a level that is not a significant increase in the incidence over that seen in the authors’ experience with continuous low dose rate brachytherapy approaches, supporting the radiobiologic predictions. However, because most studies of complications after brachytherapy for pelvic diseases do not distinguish between acute and delayed complications (2, 9, 13, 19, 21, 22, 24, 25), a standard for comparison is difficult to find in the literature. In the subset of 42 patients with cervical carcinoma, there was also no marked rise in the incidence of acute reactions following the pulsed low-dose approach. Notably, there was not a measurable increase in degree or duration of vaginal mucositis, diarrhea, or cystitis requiring medical intervention. It must be pointed out, however, that in order to demonstrate a predicted difference of 2-3% in acute morbidity between PLDR and CLDR, large numbers of patients treated with both approaches would be required. No specific factors in this group could be identified that predicted for acute complications. The 5-year actuarial major complication rate in patients with cervix cancer treated with definitive radiation including intracavitary brachytherapy in Lanciano’s Patterns of Care Study report was 14% (13). The median time to occurrence of late complications was 13.5 months for bowel, 23.2 months for bladder, and 17.4 months for vagina. In that report, 80% of all complications were seen within 24.2 months (bowel), 39.4 months (bladder), or 45.1 months (vagina). In Sinistrero’s report of complications in cervix cancer patients treated with definitive radiation, using the France-Italian glossary for description of complications, 24 severe or fatal events were seen in 215 patients, but actuarial figures were not given (25). The mean time from treatment to onset of these complications was 26.7 months, with 80% occurring within 36 months. Perez reported an incidence of 15% major or severe complications in 8 11 patients treated with definitive radiation for cervix cancer (21). At a mean follow-up of 16-18 months for the current study, it remains too early to make a strong statement regarding the impact on late complications or local control, although the initial results appear promising. Delayed complication rates of 13-15% for this group fell to 7-8% if those patients with massive central recurrence of disease associated with their fistulae were removed from the analysis. Two of the long-term complications were also due in part to misprogramming using a manual system that has been replaced by an integrated planning system that precludes such events. At a mean follow-up of 18 months, the incidence of delayed complications in patients treated with perineal interstitial implants-is 7%, excluding massive recurrences. This rate compares favorably with those reported by other reports of delayed severe complication rates ranging from 6-42% after interstitial approaches (2, 9, 22, 24). This low rate is attributed in part to the optimization ability of the remote afterloading program.
Pulsed low dose rate brachytherapy for pelvic malignancies 0 P. S.
The use of a pulsed low dose rate (average per hour) brachytherapy approach shows no evidence of a major increase in acute complications, or a change in the pattern of complications over the standard continuous low dose rate approach, as long as pulses of IO-20 min duration are delivered each hour for a dose of 0.40-0.80 Gy per hour, hourly without planned interruptions, closely mimicking the time course of a standard continuous regimen. The benefits of the PLDR, namely elimination of radiation exposure to staff and visitors, with improved patient man-
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agement time between pulses, reduced need for radioactive source inventory, and improved dose distribution through optimization, are important steps forward in the use of brachytherapy. The temptation to further increase efficiency of management of multiple patients by increasing the dose per pulse considerably, increasing the interval between pulses beyond 4 h, or decreasing the pulse time well below 10 min with a greater activity source may, however, lead to a further decrease in the therapeutic ratio and should be approached cautiously.
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