LDR VR HDR

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Current Controversies in High-Dose-Rate versus

Low-Dose-Rate Brachytherapy for Cervical Cancer

Alexandra J. Stewart, BM, MRCP

Akila N. Viswanathan, MD, MPH

Department of Radiation Oncology, Brigham and

Women’s Hospital, Dana-Farber Cancer Institute,

Boston, Massachusetts.

The use of brachytherapy in the treatment of cervical cancer has increased

worldwide since its initial introduction over 100 years ago. However, certain

aspects of the use of high-dose-rate (HDR) versus low-dose-rate (LDR) bra-

chytherapy continue to be controversial, particularly the role of HDR in FIGO

Stage III cervical cancer and the use of HDR with concurrent chemotherapy. This

study represents a systematic literature review of prospective and retrospective

series of patients with cervical carcinoma treated with external-beam radiation

(EBRT) followed by either HDR or LDR radiation. The local control rates, survivalrates, and treatment-related complications in patients with Stage III cervical can-

cer treated with HDR or LDR and those treated with concomitant chemotherapy

are examined. Patients with Stage III cervical cancer treated with EBRT and bra-

chytherapy have a local control rate of >50% in most series. Randomized pro-

spective and retrospective studies show overall statistically equivalent local

control, overall survival, and complication rates between HDR and LDR. How-

ever, LDR may be preferable for large, bulky tumors at the time of brachytherapy.

Retrospective studies of HDR and concurrent chemotherapy are limited but have

demonstrated toxicity rates similar to those with LDR. Selected patients with

Stage III cervical carcinoma who have an adequate response to EBRT and conco-

mitant chemotherapy may be treated with HDR brachytherapy. The existing lit-

erature shows no significant increase in complications in patients treated with

HDR and concurrent chemotherapy; however, sufficient tumor shrinkage prior to

HDR and careful monitoring of the dose to the normal tissues are imperative.

Cancer 2006;107:908–15.Ó 2006 American Cancer Society.

KEYWORDS: Stage III cervical cancer, high-dose-rate (HDR) brachytherapy, low-

dose-rate (LDR) brachytherapy, concomitant chemotherapy.

L ocally advanced carcinoma of the cervix must be treated with a

combination of external-beam radiotherapy (EBRT) and intraca-

vitary radiotherapy. Studies show that the use of brachytherapy

increases local control and survival in FIGO Stage III cervical can-

cer.1,2 Brachytherapy is a form of conformal dose escalation and

decreases the risk of residual cancer and pelvic relapse.3,4 Since1999, concurrent chemotherapy with radiation has been the stan-

dard of care in the treatment of cervical cancer.5

Intracavitary radiation in the form of low-dose-rate (LDR) bra-

chytherapy has been in use for the treatment of cervical cancer for

nearly a century, although the method has been greatly refined.

High-dose-rate (HDR) brachytherapy for carcinoma of the cervix

has been in use for over 30 years. LDR is defined as a dose of 0.4–2

Gray (Gy)/h, and HDR is defined as a dose of >12 Gy/h.6 HDR is

widely used throughout Asia and Europe, and its use is steadily

increasing in North America.7 The Patterns of Care Studies show

Dr. Stewart’s current address: Royal Marsden

Hospital, Surrey, England, UK.

Address for reprints: Akila N. Viswanathan, MD,

MPH, Department of Radiation Oncology, Brigham

and Women’s Hospital, Dana-Farber Cancer Institute,

75 Francis Street L2, Boston, MA 02115; E-mail:

[email protected]

Received December 19, 2005; revision received

March 31, 2006; accepted April 5, 2006.

ª 2006 American Cancer Society

DOI 10.1002/cncr.22054

Published online 27 July 2006 in Wiley InterScience (www.interscience.wiley.com).

908

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that, in the United States, the use of HDR for treat-

ment of cervical cancer increased from 9% during

1992–1994 to 16% during 1996–1999, although this

increase did not reach significance (P ¼ .3).8

LDR uses fixed source positions and strengths to

calculate the dose at the prescription point. Dosescan be varied slightly by using sources of different

activities. Tapering of the dose at the tandem

tip results in a lower dose to the small bowel and sig-

moid and decreases grade 3–5 late complications

without affecting local control.9 Source dwell times

can be optimized with HDR to customize the dose to

the patient’s anatomy and tumor volume, thereby

decreasing doses to normal tissues of the rectum,

bladder, and vaginal mucosa.10 However, standard

treatment parameters as derived from LDR must be

considered. Specifically, the dose to the surface of

the ovoids should be approximately twice the dose to

point A, and the standard loading pattern (15-10-10)

of LDR should be converted to HDR, with only slight

modifications to consider normal tissue tolerance.

Most commonly, a high dose to the sigmoid requires

decreasing the top dwell times. LDR tolerance limits

for the rectum and sigmoid (70 Gy) and vagina (130

Gy) must be maintained. HDR optimization to main-

tain a rectal biologically equivalent dose (BED) below

tolerance is recommended to decrease late complica-

tions.19

HDR has several practical advantages over LDR

and is therefore increasing in popularity, particularly

in the developing world. These will be discussed ingreater detail below. However, these benefits must be

weighed against any potential risk of decreased tumor

control or increased late complications (Table 1).

Radiobiologic ConsiderationsIn carcinoma of the cervix, the response to radiother-

apy is clearly dose-dependent; as the dose increases,

so too does the probability of tumor control. How-

ever, the risk of damage and late complications in

normal tissues also increases with the dose. This

applies to both the overall dose from LDR and thedose per fraction for HDR treatment.

Repair

The lower the dose rate of radiation a cell is exposed

to, the greater the likelihood of repair. Late-reacting

normal tissues seem more capable of repair than

tumor; at a given therapeutic dose, the tumor is pre-

ferentially killed over normal tissue. The time course

of LDR treatment (several days) allows for sublethal

damage repair. The short treatment time of HDR

prohibits this repair during the actual irradiation.

However, if an interval of more than 24 hours is

maintained, normal tissues can undergo full repair.11

Therefore, LDR may allow recovery of more normal

tissues during treatment, but HDR may offer theadvantage of increased cytotoxicity to the tumor.

Repopulation

Various studies have shown improved tumor control

and increased patient survival in carcinoma of the

cervix when radiotherapy is given in the shortest

overall time.12,13 Shorter treatment times decrease

the tumor cell repopulation time and shorten the

time for accelerated repopulation. The continuous

administration of LDR prevents repopulation during

treatment. HDR at the end of a radiotherapy regimen

may increase overall treatment time, decrease tumor

control and disease-free survival, although not mor-bidity.14

The fractionated nature of HDR allows for the

integration of brachytherapy within the EBRT sche-

dule, permitting shorter overall treatment times. The

American Brachytherapy Society (ABS) recommends

starting HDR for small tumors after 2 weeks of pelvic

EBRT at one fraction per week, continuing EBRT on

the other 4 days of the week, or after the fourth week

for patients with bulkier tumors, with all treatment

completed within 56 days.15

TABLE 1The Advantages and Disadvantages of LDR and HDR Brachytherapy for Cervical Cancer

LDR HDR

ADVANTAGES@100 years of data Outpatient treatment

Standardized doses Shor t administ ration t ime

Standardized treatment plan Standard source strength

Standardized treatment time Source easily available

Maximum two insertions IV conscious sedation feasible

Reassess tumor size with multiple

fractions

Dose optimization of normal tissues

Minimal staff exposure

Applicator stabilized by board

during treatment

DISADVANTAGES

Inpatient treatment High risk of errors:

Radiation exposure to staff Intense quality assurance

Limited by source strength

Intense maintenanceLimited sources available Intense physician/physicist time

Spinal or general anesthesia >Two fractions required

Prolonged bedrest : Treatment required on day of insert ion Need for anticoagulation Expensive Constipating medication Caution with large tumors Need for inpatient pain control Caution with normal tissue dose

Controversies in Brachytherapy for Cervical CA/Stewart and Viswanathan 909

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Reoxygenation

The effect of hypoxia on tumor control in carcinoma

of the cervix has been documented, with decreased

survival in patients with a low initial hemoglobin

level.16–18 Because of the duration of administration

of LDR, acute hypoxia may correct within the tumor

during treatment. With HDR treatment, the tumor

shrinks between insertions, allowing reoxygenation of

areas of chronic hypoxia. The oxygen enhancementratio is lower for LDR than for HDR.19

Reassortment

During the overall treatment time of LDR, tumor

cells may pass from the relatively radioresistant

phases of late S and early G2 to the more radiosensi-

tive phases of G2 and M. This might provide a theo-

retical advantage over HDR.

Dose and FractionationThe dose and fractionation of HDR are closely corre-

lated with local control and late complications.20,21Lack of standardization of the conversion used com-

plicates dose comparison between studies. The 1999

ABS survey on brachytherapy practice in the United

States showed that physicians administering HDR

gave an average dose of 48–50 Gy to the pelvis in

EBRT with an additional 30 Gy in five fractions of

HDR brachytherapy.7 Sixty-seven percent of physician

respondents used a midline shield after an average of

40 Gy. The use of a midline shield is controversial,

with reports of both increased and decreased bladder

and rectal toxicity.22 With HDR the probability of late

damage increases as the dose increases and the num-

ber of fractions decreases.20,21 This probability is also

related to the percentage of dose received by normal

tissue. If the normal tissue received 100% of the dose,

30 fractions would be needed for equivalent late

complications with LDR.

Brachytherapy for Stage III Cervical CancerThe use of HDR as an alternative to LDR for all

stages of cervical carcinoma has been reported in a

number of retrospective series23–36 and four rando-

mized prospective trials.37–40 However, the data com-

paring HDR to LDR for cancer of the cervix are

fraught with bias and may be difficult to compare

because of a lack of detailed information on the

radiation administered and a wide range of external-

beam and intracavitary dose and fractionation sche-

dules. The prospective trials do not represent blinded

clinical trials, and the retrospective series suffer from

the potential bias of historic controls, stage migrationover time, and improvement in radiotherapy tech-

niques and dosimetry with modern imaging.

The randomized trials of LDR versus HDR have

generally comparable results for all stages of cervical

cancer. No significant difference in disease-free survi-

val is detected for any stage of cervical cancer; how-

ever, Teshima et al.37 demonstrated an increased

overall survival for patients with Stage I disease

treated with LDR (Table 2). However, the randomiza-

tion techniques may be questioned. Patel et al.38 did

TABLE 2Randomized Trial Results of Toxicity, Overall and Disease-Free Survival Comparing HDR and LDR

FIGO stage

Overall survival

(%)*

Disease-free

sur vival (%)* Toxicity (%)y

HDR LDR HDR LDR HDR LDR

Patel et al.38 Stage I <3 cm 100 100 85 81 0.4 2.4

Stage II <3 cm 82 82 71 66

Stage I >3 cm 87 88 75 70

Stage II >3 cm 74 78 63 60

Stage III 71 76 43 50

Teshima et al.37 Stage I 66 89{ 85 93 9 4

Stage II 61 73 73 78

Stage III 47 45 53 47

Hareyama et al.40 Stage II 89 100 69 87 10 13

Stage III 69 70 51 60

Lertsanguansinchai et al.39 § Stage IIB 65 74 65 76 9 4

Stage IIIB 71 63 74 59

* 5-year results unless otherwise stated.y Combined bowel and bladder grades 3–5 late complications, reported for all stages.{ Statistically significant difference.§ 3-year results.

910 CANCER September 1, 2006 / Volume 107 / Number 5

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not state their randomization method but stratified246 LDR patients and 236 HDR patients according to

stage. Teshima et al.37 stated that they fully rando-

mized before 1979, after which they ‘selectively ran-

domized,’ with older, more infirm patients being

placed in the HDR arm. This gave 171 LDR patients

and 258 HDR patients. Hareyama et al.40 randomized

71 patients to LDR and 61 patients to HDR by month

of birth. Lertsanguansinchai et al.39 stratified by age

and stage and then randomized 109 LDR patients and

112 HDR patients before starting EBRT.

The role of HDR in Stage III cancer of the cervix

is controversial, with two retrospective series23,32

showing a significant survival advantage for LDR,and one showing an advantage for HDR26 (Table 3).

Although other retrospective series do not demon-

strate a significant survival difference, none have a

sufficient number of patients and resulting power to

detect a difference between HDR and LDR if such a

difference exists. Ferrigno et al.32 reported all Stage

III results together and stated that the BED for the

HDR patients was below that for the LDR patients,

which may account for the survival advantage with

LDR. In contrast, Kucera et al.26 showed a survival

advantage with HDR. The authors stated that theimprovement in EBRT practice over the time of ana-

lysis must be considered in addition to a higher BED

for the HDR patients.

Petereit et al.23 showed equivalent 3-year survival

and pelvic control rates with HDR or LDR bra-

chytherapy for all stages of cervical cancer except

Stage IIIB. Survival and local control rates were 58%

and 75% for LDR versus 33% and 44% for HDR,

respectively. Possible explanations for the disparity in

survival include insufficient tumor shrinkage, higher

than expected local control rates in the LDR patients,

and significantly higher rates of hydronephrosis in

the HDR group. The timing of HDR may have con-tributed to these results.23 HDR commenced at week

one of pelvic EBRT, when tumor shrinkage would not

yet have been adequate. This would give a volume

advantage to LDR in these advanced cases with bulky

tumors. Rates of pelvic control improved with the

first brachytherapy insertion after most of the EBRT

had been delivered, allowing for better dose distribu-

tions around a smaller tumor volume. With HDR, the

outer margins may be missed if the implant is opti-

mized to point A without 3D imaging and the tumor

TABLE 3Stage III Overall Survival, Pelvic Control and Toxicity in Retrospective Series

Low-dose rate High-dose rate

No.

Overall

survival

{

(%)

Pelvic

control,(%) Toxicity*(%) No.

Overall

survival(%)

Pelvic

control,(%) Toxicity*(%)

Akine et al.30y{ 212 38 61 37 54 64

Arai et al.31y{ 143 46.5 508 52.2

Falkenberg et al.36§y|| 23 45 72 4.8 6 33 83 3.5

Ferrigno et al.32{ 69 46 } 58 3.7 56 36

} 50 2.5

Hsu et al.29{# 73 50.2 16.8 30 51.1 (6)

42.9 (4)

25.6 (6)

11.0 (4)

Kim et al.24** 8 35.7 0 16 43.8 1.4

Kucera et al.26§ 212 37.3} 78 53.8

} 9.0

Okkan et al.28y{ 21 47.3 53 10.4 98 31.6 45 2.4

Orton et al.27{ 1464 42.6 9.1 2721 47.2 22.7

Petereit et al.23y§ 50 58}

75 } 50 33

}44

}

Sarkaria et al.25§ 57 46 63 10.0 12 58 50 2.5

Lorvidhaya et al.

35y{

675 47.8 68.8 7.0Sakata et al.33{ 48 63

Souhami et al.41y 77 42

Wong et al.34y{ 51 25 63.2 2.8

* Combined grades 3–5 late complications, reported for all stages.y FIGO Stage IIIB results.{ 5-year results.§ 3-year results.|| Cause-specific survival reported.} Statistically significant differences.# 6 and 4 fraction results.

** Adenocarcinoma only.


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has not regressed sufficiently by the time of the

implant. Use of CT or MR imaging with the brachy-

therapy applicator in place and optimization to the

tumor volume as well as to the standard prescription

points may obviate this discrepancy between HDR

and LDR in large-volume cancers.42–44 A metaanaly-

sis of the primary data from 56 centers27

showed anoverall survival advantage at 5 years for HDR over

LDR for groups with advanced disease (47.2% vs.

42.6% for Stage III, P ¼ .05). However, patients with

larger tumors have a significantly shorter disease-free

survival than those with smaller tumors, independent

of FIGO stage, when HDR brachytherapy is used.45 In

Stage IIIB patients, the rate of local failure increases

four-fold if HDR brachytherapy is administered before

the 25th day of treatment.41 Therefore, individualized

treatment is crucial; the amount of disease present at

the time of brachytherapy is paramount in choosing

between HDR and LDR brachytherapy, with consid-

eration of the location and tolerance of normal tis-sues.

Interstitial ImplantationLow survival rates for patients with Stage III cervical

cancer may be due to inadequate radiation delivery.

Conventional intracavitary brachytherapy may not be

adequate to deliver a sufficient dose of radiation to

an extensive and bulky tumor, such as those with

lower vaginal involvement or pelvic sidewall involve-

ment. In these situations, the use of interstitial nee-

dles may assist with the delivery of radiation dose.

Interstitial implantation has conventionally been

used with a template and LDR radiation. Local con-

trol rates for Stage III range from 44% to 88%.46–48

With a median follow-up of 51 months, Syed et al.

reported a 10% rate of Grade 3 or 4 late gastrointestinaland genitourinary complications for all stages of cervi-

cal cancer. Stage III patients had a 5-year disease-

free survival of 49%; Stage IIIB patients had a locore-

gional control rate of 61%.49

For interstitial implantation with HDR, Demanes

et al. treated 62 patients with six fractions of HDR

over two insertions; with a mean follow-up of 40

months, the 5-year disease-free survival rate for

Stage III patients was 39%, but the regional pelvic

control rate was 79%.50 A report of a combined tan-

dem and ring with interstitial applicator using HDR

on a fractionated basis was published, though long-

term survival and toxicity data are not yet available.51

ChemotherapySeveral randomized trials set the current standard of

care for cervical cancer as radiotherapy with conco-

mitant chemotherapy 5; one of these studies allowed

the use of HDR, MDR (medium-dose-rate), or LDR.52

A total of eight studies have used chemotherapy with

HDR and reported toxicity. Three were single-arm

retrospective analyses in which all patients received

TABLE 4Fractionation and Toxicity of HDR and Concurrent Chemotherapy

HDR Toxicity (%)*

Follow-up

(months)Dose (Gy) No. fractions No chemo Chemo

Tseng et al.59y 4.3 6 6.5 (GI) 10 (GI) 47

3.2 (GU) 3.3(GU)

Pearcey et al.52y{ 8 3 9 (GI) 5 (GI) 82

7 (GU) 10 (GU)

Sood et al.57§ 9 2 5 (GI) 5 (GI) 36

Saibishkumar et al.58§ 9 2 1.1 (GI) 1.8 (GI) 39

1.0 (GI) 0 (GU)

Sood et al.56§ 9 2 10 6 28

Ozsaran et al.55|| 8.5–9 1–2 0 0 20

Souhami et al.53|| 10 3 28 (GI) 27

6 (GU)

Strauss et al.54|| 7 5 3.7 (GI) 19

3.7 (GU)

* Grades 3–5 late complications.y Prospective randomized trial.{ Retrospective comparison of patients treated with and without chemotherapy.§ Retrospective review, all patients received chemotherapy.|| Includes HDR, MDR, and LDR.


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chemo-radiation53–55; 3 retrospectively compared

patients treated with and without chemotherapy 56–58;

2 present prospectively collected data.52,59 None of

these studies shows a significant difference in Grades 3

and 4 gastrointestinal and genitourinary late complica-

tions (Table 4).The single-arm series all administered weekly

cisplatin. The comparative retrospective series admi-

nistered cisplatin on days to 5 in weeks 1 and 456,57

or weekly cisplatin.58 One prospective trial adminis-

tered weekly cisplatin,52 the other cisplatin, vincris-

tine and bleomycin every 3 weeks.59 All trials

administered daily external-beam radiation, with a

range of doses from 44–50.4 Gy. The HDR fractiona-

tion regimens are detailed in Table 4. Souhami

et al.53 reported a high rate of rectal toxicity; how-

ever, the fraction size was larger than that used in

the modern era. The randomized NCIC trial of

weekly cisplatin chemotherapy with radiation versusradiation alone allowed HDR (15%), MDR (8%), or

LDR (77%). Long-term toxicities were not signifi-

cantly different between the 2 arms, although the

type of brachytherapy in relation to the use of che-

motherapy was not presented.52

A metaanalysis of concurrent cisplatin-based che-

motherapy and radiotherapy with both HDR and LDR

showed rates of grade 3–4 toxicity of 0%–15% for gas-

trointestinal toxicity and 1%–8% for genitourinary

toxicity.60 The Radiation Therapy Oncology Group

(RTOG) trial 90-01 required insertion of LDR bra-

chytherapy; with a median follow-up of 6.6 years, the

incidence of Grade 3 or higher late complications was

14% in both arms. No review with HDR and che-

motherapy has such long follow-up. However, the

RTOG 90-01 initially published, and their results with

a median follow-up of 43 months, which had a 12%

versus 11% rate of grade 3–4 late toxicity for those

treated with and without chemotherapy. These are

very similar to the follow-up time and toxicity rates

presented in the HDR retrospective reviews (Table 4).

Current clinical trials allow the use of HDR bra-

chytherapy and require that chemotherapy not be

administered on the same day as brachytherapy treat-

ment.

MorbidityThe risk of late normal-tissue complications depends

on a number of factors: whole-pelvic EBRT dose,

total dose of brachytherapy, number of fractions of

brachytherapy, normal-tissue proximity and dose,

intercurrent illnesses, and the use of chemotherapy

or other radiation sensitization. The rate of late nor-

mal-tissue toxicity of brachytherapy ranges between

5% and 35% for all grades of complications.11,27,28

The anterior rectal wall adjacent to the posterior

often receives the highest dose of radiation. With 3D

imaging, the recommended dose limit for HDR to a

2-cc volume of rectum is 70 Gy 3 and 90 Gy 3 for a 2-

cc volume of bladder.43

Most series show comparable rates of Grades 3–5late complications with LDR and HDR therapy. Toxi-

city rates in the randomized trials with LDR and

HDR are listed in Table 2 and for the Stage III retro-

spective series in Table 3. Table 4 lists the toxicity

with HDR and chemotherapy already described. An

analysis of the primary data from 56 centers27

showed a significant decrease in all major complica-

tions (grades 1–5) when HDR brachytherapy was

used (9% vs. 21% with LDR, P < .001). This corre-

sponded to a significant decrease in the bladder and

rectal maximum dose point of 13%.

CONCLUSIONSHDR may be an acceptable alternative to LDR bra-

chytherapy in carefully selected patients with carci-

noma of the cervix. To individualize treatment, it is

useful to have both HDR and LDR available. Ideal

candidates for HDR will have a small volume of dis-

ease, a vagina large enough to hold packing, and an

inability to complete treatment in less than 56 days,

or the ability to tolerate an inpatient stay. Ideal can-

didates for LDR are patients who cannot tolerate out-

patient treatment or who have bulky residual disease

at the time of implantation.

In the setting of Stage III carcinoma of the cer-vix, patients must have sufficient tumor shrinkage to

ensure adequate coverage of the target with radiation

when an optimized HDR treatment plan is used.

Patients with persistent large bulky tumors and/or

vaginal disease who do not respond to EBRT may

require interstitial therapy. HDR may be used with

chemotherapy, although doses to the bladder and

rectum must be monitored to prevent increased nor-

mal-tissue toxicity. As data mature, additional infor-

mation regarding late toxicities resulting from HDR

and concomitant chemotherapy will become avail-

able. Imaging with 3D techniques such as CT and

MRI during brachytherapy will allow for optimization

of dose away from normal tissues. Future studies

comparing LDR and HDR with CT or MR imaging

will be necessary to determine if visualization of cri-

tical structures will reduce long term morbidity and

increase local control for cervical cancer patients.

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