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Brachytherapy

Several isotopes are available, although at present cesium-137 (137Cs) is the most popular LDR source and iridium-192 (192Ir) for HDR. Brachytherapy can be delivered with intracavitary techniques using a variety of applicators consisting of an intrauterine tandem and vaginal colpostats or, when necessary, vaginal cylinders, the majority of which are afterloading. Radiographs are always obtained using dummy sources, and the active sources can be inserted after the films have been reviewed and the position of the applicators judged to be satisfactory (Fig. 66.16). The vaginal packing is soaked in 40% iodinated contrast material to identify it on the radiographs.

Nag et al. (431) carried out a survey of brachytherapy practice for cervical cancer in the United States in 1995; of 521 responses, 206 (40%) did not perform any brachytherapy for

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carcinoma of the cervix. For LDR treatments, the median pelvic EBRT dose was 45 to 50 Gy and the LDR brachytherapy dose was 42 and 45 Gy for early and advanced cancers, respectively. For HDR treatments, the median EBRT dose was 48 to 50 Gy and the median HDR dose was 29 and 30 Gy for early and advanced cancers, respectively. The median HDR dose per fraction was 6 Gy with a median of five fractions. Interstitial brachytherapy was used as a component of treatment in 6% of the patients by 21% of responders.

With regard to prescribing the doses, it is noteworthy that in 91 LDR applications with Fletcher-Suit applicators, Potish et al. (495) used linear least-squares regression to show that although there was a moderately good correlation between the milligram hours and dose to point A, it was markedly affected by the position of the colpostats and the tandem, making it difficult to formulate a simple conversion factor between the two systems. Therefore, computer-generated dose distributions provide the best means of determining the doses to point A, point B, bladder, and rectum. ICRU Report 38 (271) defines the dose and volume specifications for reporting intracavitary therapy in gynecologic procedures.

Basic principles of the clinical application of brachytherapy and use of remote afterloading devices (LDR or HDR) are discussed in Chapters 19, 20, 21, and 22. In general, an intrauterine tandem with three or four sources [15 or 20-10-10-(10) mCi mgRaEq with LDR] is inserted in the uterus and two colpostats (2 cm in diameter, loaded with 20 mCi mgRaEq LDR sources) are placed in the vaginal vault and packed with iodoform gauze to deliver 0.6 to 0.8 Gy per hour to point A.

If the vaginal vault is narrow, it may be impossible to insert regular-sized colpostats, in which case miniovoids should be used (usually loaded with 10 mCi mgRaEq LDR sources).

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Special attention should be paid to obtain as symmetric and homogeneous dose distribution as is technically allowed by the geometry of the cervix/vagina and the configuration of the tumor. When even miniovoids cannot be inserted, it is better to use a protruding source in the vaginal vault, which is inserted in the afterloading tandem (usually 20 to 30 mCi mgRaEq) with an overlying plastic sleeve (3 cm in diameter).

With HDR intracavitary applicators the use of a rectal retractor has been shown to substantially reduce the rectal dose (455). Lee et al. (368), in a study of 15 patients, found that this reduction was significant only in the subgroup who received >70% of the prescription dose (p <0.05).

Interstitial implants with radium-226 (226Ra), 137Cs needles, or 192Ir afterloading plastic catheters to limited tumor volumes are helpful in specific clinical situations (e.g., localized residual tumor, parametrial extension; Fig. 66.17). The use of Syed-Neblett and the Martinez perineal applicators has been discussed in Chapter 66. A ring applicator modified to allow simultaneous insertion of interstitial needles was described (325).

The American Association of Physicists in Medicine (13) and the American Endocurietherapy Society (656) recommend the air-kerma strength (measured in free space) to express source strength; the units are cGy•cm2•h-1 for LDR and cGy•cm2•s-1 for HDR sources:

• 1 Uh = 1 unit of air-kerma strength for LDR sources

• 1 mgRaEq = 8.23 Uh

• 1 Us = 1 unit of air-kerma strength for HDR sources

Further, the American Endocurietherapy Society recommended that mgh and mgRaEq be replaced by the integrated reference air-kerma.

As Fletcher (160) emphasized, conditions for an adequate intracavitary insertion include the following:

• The geometry of the insertion must prevent underdosing around the cervix;

• Sufficient dose must be delivered to the paracervical areas; and

• Vaginal mucosal (and, we add, bladder and rectal) tolerance doses must be respected.

Katz and Eifel (304) quantified the M.D. Anderson criteria for acceptable implant geometry to relate intracavitary brachytherapy prescription to Manchester and ICRU reference doses in measurements from films of 808 intracavitary applications, and correlated these parameters with outcome in 396 patients who completed definitive treatment for cervical cancer. The median distance from the tandem to the sacrum was 4 cm, or one-third the distance from the pubis to the sacrum. The distance between the vaginal ovoids and cervical marker seeds was 7 mm,

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and the median distance between the tandem and the posterior edge of the ovoids was 50% of the ovoid length. In 92% of insertions, vaginal packing was posterior to or within 5 mm of a line that passed through the posterior edge of the ovoids, parallel to the tandem. The median doses to point A and rectal, bladder, and vaginal surface reference points were 87 Gy, 68 Gy, 70 Gy, and 125 Gy, respectively. The average ratios between the doses at bladder or rectal reference points and point A were somewhat greater when smaller vaginal applicators were used. There was no significant correlation between the doses to standard reference points and the rates of central recurrence or major complications.

Haie-Meder et al. (222) and Potter et al. (498) published explicit recommendations from the gynecological GEC ESTRO working group for dose prescription and specification of brachytherapy in cervix cancer based on volume parameters defined by 3D–image-based anatomy, physics, and radiobiology principles (Fig. 66.18). Specifications include dose to gross tumor volume (GTV), CTV, and pelvic organs at risk. The linear quadratic model is applied to both brachytherapy (BT) and external beam RT calculations. Lang et al. (353), in a multicenter study, confirmed the feasibility of these recommendations, with total doses to point A from both BT and EBRT, ranging from 85 to 91 Gy and to CTV within 69 to 73 cGy. Doses to organs at risk were comparable to those obtained with standard dosimetric methods, more accurately determined in dose–volume histograms.

Dose Rate Impact on Outcome

Haie-Meder et al. (220), in 204 patients with cervical cancer randomized to receive one of two preoperative LDR brachytherapy (0.4 or 0.8 Gy per hour), noted similar local tumor control (93%) and overall survival (85%) rates at 2 years with either dose rate. Grade 3 late complications were observed in 7% of patients treated with 0.4 Gy per hour and in 13% of patients treated with 0.8 Gy per hour. There was one small bowel obstruction in the 0.4 Gy per hour group (1%) in contrast with five (5%) in the 0.8 Gy per hour group. Vesicovaginal fistulas were observed in 2% and 4%, respectively.

Fowler (162) analyzed results in 270 patients with carcinoma of the cervix treated with either 75 cGy per hour from manually loaded cesium or 150 cGy per hour by remote afterloading (440). There was an increase in grade 3 late complications from 4% to 22%, in spite of a reduction of 20% in dose, implying a rather large difference in biologic effect between the two systems. The effect of the increased dose rate was also described by Leborgne et al. (360). A Linear quadratic modeling was used to calculate biologically effective doses in the clinical protocols used. When the LDR was doubled, it was called medium dose rate (MDR). The maximum ratios calculated for the biologic effective doses of 16 Gy at MDR to 20 Gy at LDR were 1.06 to 1.15, assuming α/β = 4 to 2 Gy, the latter being an unlikely extreme for rectal or urinary complications. The theoretically ideal dose reduction factors, calculated using the t1/2 values derived from the clinical data, are in the range of 24% to 29% instead of 20%.

Rodrigus et al. (517) analyzed late complications in 143 patients with cervical cancer treated with two different brachytherapy schedules and external radiation. Seventy-seven patients had two intracavitary applications with a dose rate 0.54 Gy per hour and 66 patients with 1.07 Gy per hour. Because of the expected increase in complications with higher dose rate, the latter dose per application was reduced from 25 Gy to 20 Gy. Late intestinal and urinary complications were scored in 49/77 patients and in 46/68, respectively. Actuarial estimates at 5 years showed 42% and 54.1% late intestinal complications and 16.9% and 24.1% late urinary complications, respectively. Thus, despite the dose reduction, there was a clear dose rate effect on late morbidity. These studies emphasize the importance of dose rate of brachytherapy in carcinoma of the cervix.

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Low–Dose-Rate Brachytherapy

Intracavitary brachytherapy, with its rapid dose fall-off as a function of distance, yields a high dose to the uterus and paracervical tissues, but it is inadequate to treat the pelvic lymph nodes, and external irradiation is necessary to supplement the parametrial dose.

Rotmensch et al. (530) compared the outcome in 140 patients with early stage cervical cancer undergoing whole pelvis radiation therapy with one versus two LDR intracavitary brachytherapy applications. The two groups had similar 5-year local tumor control (p = 0.83), disease-free (p = 0.23), and cause-specific (p = 0.29) survival. Late complications were similar in the two groups. These results support the use of a single LDR application in patients with early stage disease undergoing definitive radiation therapy when 45-Gy external-beam pelvic irradiation is administered.

Perez et al. (474), in a retrospective analysis, noted that in patients with cervical cancer treated with radiation therapy alone for stage IB tumors <2 cm in diameter, the pelvic failure rate was under 10% with LDR doses of 70 to 80 Gy to point A, whereas for larger lesions, even doses of 85 to 90 Gy resulted in 25% to 37% pelvic failure rates. In stage IIB with LDR doses of 70 Gy to point A, the pelvic failure rate was approximately 50% compared with 20% in nonbulky and 30% in bulky tumors with doses >80 Gy. In stage III unilateral lesions, the pelvic failure rate was approximately 50% with 70 Gy or less to point A versus 35% with higher doses, and in bilateral or bulky tumors it was 60% with doses <70 Gy and 50% with higher doses.

Careful assessment of the quality of brachytherapy and dose distributions is critical. Suyama et al. (589) analyzed the minimal radiation dose to the peripheral area of the cervix in relation to local tumor failure using CT images taken at the time of intracavitary brachytherapy in 80 patients with carcinoma of the cervix. After CT scanning, isodose curves were superimposed on the CT images. Histograms of both the minimum percentage peripheral dose and the dose to the cervical area showed significant correlation in the local tumor control and local failure groups (p <0.001).

Biology of High–Dose-Rate Brachytherapy for Cervical Carcinoma

To achieve tumor control using HDR equivalent to that with LDR brachytherapy, attention to the dose/fractionation schedule and to normal tissue doses is mandatory (165,223,455). In general, the α/β values for tumor and early responding tissues is approximately 10 (Gy10), and for late-responding tissues 3 to 5 (Gy3-5) (480). The values derived are not actual doses but biologically effective ones that take into consideration dose rate and impact of fraction size.

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Orton et al. (455) suggested an LDR-to-HDR reduction factor of 0.54 to 0.6 (Table 66.13). Patel et al. (463) calculated a similar correction factor of 0.58. These conversion factors are valid when three to five HDR fractions are used, but with a higher number of fractions (six to eight), the conversion factor is closer to 0.75.

Figure 66.19 illustrates late normal tissue effect, which is proportional to log cell kill, and the relationship to the number of HDR treatment fractions (163). Each full curve is calculated assuming the same log cell kill. Late damage rises sharply as the number of HDR fractions is decreased. When these curves are above the dashed lines that represent the maximum late effect of 70 Gy of LDR brachytherapy given at 0.5 Gy per hour, the risk of late complications increases. Displacing the bladder and rectum away from the HDR sources for the short duration of therapy may offset the radiobiologic disadvantage of using a few brachytherapy fractions (455).

Clinical Experience

There is increasing use of HDR sources in brachytherapy of carcinoma of the cervix; basic principles of brachytherapy are similar to those of LDR (642). At Washington University, patients are treated with HDR brachytherapy with a tandem or a vaginal cylinder, which is placed in the patient before each treatment with sedation and without anesthesia. An indwelling bladder catheter is used during the procedure, and gentle packing of the vagina with iodoform gauze helps to maintain the applicators in place. Their position is verified with anteroposterior and lateral pelvic radiographs taken before the actual HDR treatment in each application. The usual dose per fraction prescribed at 0.5-cm depth is 3 to 6 Gy, and three to six fractions are given once or twice weekly.

No randomized trials in the United States have compared HDR and LDR brachytherapy for cervical cancer, although some have been carried out in other countries (as described later). Each center has developed unique HDR treatment schedules, dose specification systems, and time–dose fractionation protocols that reflect their understanding of radiobiologic issues and their patient population base (5,247,520).

Roman et al. (520) do not use central blocking for any stage; at institutions that use a central block, a 5-HVL block is most commonly used. Wayne State University uses a step-wedge central shielding method (5). Most HDR insertions are performed weekly and are interdigitated by giving four fractions of EBRT per week with one HDR treatment per week (Fig. 66.20).

Treatment schedules integrating external-beam irradiation and brachytherapy were initially designed with regard to the disease stage and volume by Arai et al. (21). The number of HDR fractions used to treat cervical cancer varies among centers from as few as two to more than 10. The optimal time–dose–fractionation scheme and the technique for remote-control

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afterloading intracavitary brachytherapy for cervical cancer have yet to be established through systematic clinical trials (429).

El-Baradie et al. (149) published a prospective study in which 45 patients with carcinoma of the uterine cervix were randomly allocated to either HDR or MDR. The external-beam radiation dose was the same in the two groups. The point A dose rate correction factor from LDR to HDR was 0.53, and from LDR to MDR 0.6. The 3-year survival and locoregional tumor control rates for both modalities were equivalent (62% and 67% for HDR and 68% and 74% for MDR). The rectal and bladder complication rates were the same in both groups (29% at 3 years). Tanaka et al. (596) also compared HDR and MDR brachytherapy in 150 and 56 patients, respectively. The survival was equivalents in the two groups; grade 2 or greater late toxicity tended to be higher in the HDR group (14% vs. 6%, respectively)

Orton et al. (455) noted that dose per fraction of HDR brachytherapy significantly influenced toxicity: Morbidity rates were highly significantly lower for point A doses/fractions of 7 Gy or less for both severe (1.28% vs. 3.44%; p <0.0001) and moderate plus severe injuries (7.58% vs. 19.51%; p <0.001). The effect of dose/fractionation on cure rates was equivocal.

Wayne State University uses a highly fractionated brachy-therapy course with eight to 12 HDR fractions (5), which was chosen to keep the rectal dose for each HDR fraction to 2 to 2.5 Gy. The intracavitary technique uses an intrauterine stent so that applicators can be placed quickly without cervical dilatation and using little or no sedation. Treatment planning is performed on the initial insertion and is duplicated for all fractions by verifying the applicator position with fluoroscopy or radiographs.

Petereit et al. (482) uses 45 Gy in 25 fractions for external-beam irradiation to the pelvis combined with five HDR fractions (5.5 to 6 Gy per fraction) or four HDR fractions (6.5 to 7 Gy per fraction). The equivalent LDR brachytherapy at point A is 80 Gy with 67 Gy delivered to the bladder or the rectum, assuming these tissues receive 70% of the prescribed point A dose. For advanced stages, such as IIB or IIIB, the intracavitary dose may be increased to 7.5 Gy per fraction, to give an LDR equivalent dose of 85 to 90 Gy to point A. Petereit and Pearcey (480), based on their preliminary results and published reports in the literature, recommend the doses and fractionation schedules summarized in Tables 66.14 and 66.15.

Kuipers et al. (340) described a method to improve target coverage and locoregional tumor control with HDR tandem and ovoid applications, whereby HDR endocavitary and interstitial brachytherapy are applied in the same session for tumors with a lateral expansion of 25 mm or more from the axis of the cervical canal. Seventy-six combined applications were given to 41 patients. With a follow-up average of 23 months, in stage IIB tumors, 3-year DFS was 75%. No severe early or persistent late complications were observed.

Dose Specifications for High–Dose-Rate Brachytherapy

Dose specification reporting systems for HDR brachytherapy vary by institution. However, many combine the Tod and Meredith point A as a paracervical dose with ICRU Report 38 on bladder and rectal points (271). In vivo bladder and rectal dosimetry is performed during the HDR procedure by Roman et al. (520). Other centers obtain normal tissue doses from points located on dosimetry films and dose distribution curves.

Treatment planning for HDR brachytherapy can be accomplished by a variety of techniques, ranging from use of an atlas of applications and source loadings, to planning of only the initial insertion followed by replicating the insertion for subsequent treatments, to customized optimization of source loading for each HDR insertion (21). Himmelmann et al. (247) described individualized computer treatment planning and a reconstruction system used to achieve individual dosimetry. Computerized optimization of source position and the dwell time for each position is a potential advantage of HDR brachytherapy that can provide customized treatment planning on a case-by-case basis. However, customized optimization is not commonly performed because it increases the time needed for planning and requires experience on the part of the physics and dosimetry staff (605).

Three-Dimensional Brachytherapy Treatment Planning

Fellner et al. (153) compared treatment planning for cervical carcinoma based on CT sections and 3D dose computations, or, when these techniques were not available, dose evaluation based on orthogonal radiographs. The CT-based planning provides information on target and organ volumes and dose–volume histograms. The radiography-based planning provides dimensions and doses only at selected points. For the study, 28 patients with 35 applications receiving HDR treatment with 192Ir

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were investigated. For a dose prescription of 7 Gy at point A, 83% (44 cm3) of the CTV received at least 7 Gy.

Eich et al. (137), in 11 applications of HDR brachytherapy for cervical carcinoma, calculated doses to ICRU bulletin points on orthogonal radiographs, and the doses at rectum reference points were compared with in vivo measurements. The in vivo measurements were 1.5 Gy below the doses determined for the ICRU rectum reference point (4.05 ± 0.68 Gy vs. 6.11 ± 1.63 Gy). The advantages of in vivo dosimetry are easy practicability and the possibility to determine rectal dose during radiation. The advantages of computer-aided planning at ICRU reference points are that calculations are available before radiation and they can be taken into account for treatment planning.

Gebara et al. (175) estimated the external, internal, and common iliac dose rates using 3D CT-based dose calculations in tandem and ovoid brachytherapy in 30 patients with carcinoma of the uterine cervix treated with LDR brachytherapy using a CT-compatible Fletcher-Suit-Delclos device. Thirty-six implants were performed, and the authors concluded that the point B dose is similar to the maximum common iliac nodal dose.

DeWitt et al. (119), in 15 patients with cervical cancer, defined target and organs at risk for planning of HDR brachytherapy and established guidelines for volume and dose constraint parameters using image-guided inverse treatment planning. Pelloski et al. (468) compared CT-based volumetric calculations and ICRU reference point radiation doses in 60 patients with cervix cancer treated with LDR brachytherapy. Of 118 insertions performed, 93 were evaluated and the minimal dose delivered to the 2 or 3 cm of bladder or rectum (DBV2 and DRV2, respectively) were determined on dose–volume histogram (DVH). They concluded that the ICRU dose was a reasonable surrogate for the DRV2 but not for the DBV2. Furthermore, these calculations may not be applicable to other treatment guidelines or intracavitary applicators.

Dose Fractionation in High–Dose-Rate Brachytherapy

The relationship between dose and fractionation for HDR and LDR intracavitary irradiation of stage I and II carcinoma of the cervix was examined by Arai et al. (22). The dose rate at point A was 2 to 3 Gy per minute (120 to 180 Gy per hour) for HDR and 0.6 to 0.9 Gy per hour for LDR irradiation. Concurrent EBRT was given to the whole pelvis (23 to 30 Gy) followed by 25 to 30 Gy with central shielding, along with brachytherapy. They concluded that the optimal dose fractionation schedules for HDR brachytherapy were 28 ± 3 Gy in four to five fractions, 34 ± 4 Gy in eight to 10 fractions, or 40 ± 5 Gy in 12 to 14 fractions at point A.

The importance of adopting biologically based equivalent doses when switching from LDR to HDR brachytherapy is exemplified in a report by Newman (440) on 115 patients treated with external irradiation (40 to 50 Gy) and manual afterloading cesium sources delivering 60 Gy to point A with a dose rate of 0.75 Gy per hour, or a Selectron device with 40-mCi sources, which delivered from 0.75 to 1 Gy per hour to point A. Because of the increased dose rate, the total intracavitary dose was reduced by 20%. Grade 3 genitourinary and gastrointestinal complications were observed in three of 87 patients (3.4%) treated with LDR, in contrast to 30/132 patients (22.7%) treated with the Selectron HDR sources. No significant differences in local tumor control and survival were found.

Chatani et al. (74) described a study in which 165 patients with carcinoma of the cervix were randomized to a HDR brachytherapy point A dose of 6 Gy (group A) or 7.5 Gy (group B) per fraction, both combined with external irradiation. The 5-year local failure rate was 16% in both groups, and distant failure rates were 23% and 29%, respectively (p = 0.2955). Moderate to severe complications requiring treatment were comparable (six patients, 7%) in the two groups.

Hama et al. (225) compared the effectiveness and safety of once versus twice-weekly HDR brachytherapy for cervical cancer in 124 patients treated with EBRT (50 Gy); 74 patients (group A) were treated with one HDR brachytherapy insertion weekly (three fractions of 7 Gy each to point A), and 50 patients (group B) were treated twice weekly (six fractions of 4.5 Gy each to point A). Overall survival rates were 65.2% and 65.3%, respectively (p = 0.96). Local recurrence-free survival rates were 69% for group A and 90% for group B (p <0.001). The rate of grade 2 (moderate) and grade 3 (severe) complications was significantly lower for group B (6%) versus 32% in group A (p <0.001).

Mayer et al. (405) compared HDR BT in two schedules to treat 210 patients with cervix cancer, one sequential (SRT) consisting of four fractions of 8 Gy followed by EBRT or continuous (CRT), consisting of five fractions of 6 Gy one session per week integrated with EBRT (four fraction per week). Total dose to point A was 68 to 70 Gy. Progression-free survival was 71% with CRT versus 56% with SRT (p = 1.0). Late bladder and rectal morbidity were 13% in the CRT and 25% in the SRT groups (p = 0.037), related to the higher dose per fraction (8 Gy).

Nam and Ahn (435) also compared, in a randomized study of 46 patients, two schedules of HDR BT (10 fractions of 3 Gy or five fractions of 5 Gy) followed by a small BT boost to residual tumor, in combination with EBRT (30.6 Gy to whole pelvis and 14.4 Gy to parametria with midline block). Three-year pelvic tumor control was 90% in both groups and disease-specific survival (DSS) 90.5% and 84.9% (p = 0.64), respectively. Late grade 2 or greater bladder or rectal morbidity was 23.8% and 9.1% (p = 0.24).

Liu et al. (381), based on the linear-quadratic model, developed isoeffect tables to convert traditional LDR doses and number of fractions to point A to HDR brachytherapy; depending on dose rate, different dose values can be calculated for various fractionation schedules. They predicted that, using therapeutic gain ratio, similar results would be obtained with either brachytherapy modality with two to four fractions of LDR and four to seven fractions of HDR.

The optimal time–dose–fractionation scheme for HDR brachytherapy for cervical cancer has yet to be established. The American Brachytherapy Society published recommendations

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for HDR brachytherapy for carcinoma of the cervix (429). Each institution should follow a consistent treatment policy, including complete documentation of treatment parameters and correlation with clinical outcome (pelvic tumor control, survival, and complications). The goals are to treat point A to at least a total LDR equivalent of 80 to 85 Gy for early stage disease and 85 to 90 Gy for advanced-stage disease. The pelvic sidewall dose recommendations are 50 to 55 Gy for early lesions and 55 to 65 Gy for advanced ones. As with LDR BT, every attempt should be made to keep the bladder and rectal doses below 80 Gy and 75 Gy LDR-equivalent doses, respectively. Interstitial brachytherapy should be considered when the tumor cannot be optimally encompassed by intracavitary brachytherapy. Some suggested dose and fractionation schemes for combining the external-beam radiation therapy with HDR brachytherapy for each stage of disease were presented, although they have not been thoroughly tested. It was emphasized that the responsibility for the medical decisions ultimately rests with the treating radiation oncologist.

Petereit and Pearcy (480), in a review of 24 HDR dose fractionation schedules published in the past three decades, found no dose relationship for either tumor control or late morbidity. They recommend that in the future all HDR publications for treatment of cervical cancer provide accurate and detailed fractionation and total-dose information. For additional discussion, see Chapters 21 and 22.

Results with Pulse–Dose Rate Brachytherapy

Rogers et al. (519) treated 52 patients with cervical carcinoma, 31 of which had staging laparotomy before radiation therapy. Brachytherapy was interstitial in 18 patients and intracavitary in 28. The median EBRT pelvis dose was 45 Gy in 25 fractions. Median total doses were 75.8 Gy to the implant volume with interstitial and 84.1 Gy to the A points with intracavitary at a median dose rate of 0.55 Gy per pulse per hour. Six patients had laparotomy-documented para-aortic node involvement and received EBRT to this site (45 Gy in 25 fractions). Thirty patients received concomitant weekly cisplatin chemotherapy (40 mg/m2). With a median follow-up of 25 months, the actuarial 4-year disease-free survival rates were 66% for the entire group (100% for stage IB, 69% for stage II, 68% for stage III/IVA, and 43% in patients treated for recurrences after surgery). Grade 4 complications occurred in two patients (4.3%). One patient (2.2%) had a grade 3 complication (frequent hematuria), and five (10.9%) had grade 2 complications.

Doses of Radiation

Stage IA (microinvasive) tumors are treated with intracavitary therapy only (LDR 60 Gy in one insertion or 75 to 80 Gy in two insertions to point A, or HDR 35 to 42 Gy in five to six insertions of 7 Gy to point A, one or two fractions per week).

The optimal dose for invasive carcinoma of the cervix is delivered with a combination of EBRT whole pelvis, intracavitary, and, at times, interstitial therapy. Some institutions such as ours use lower doses of whole pelvis external irradiation (10 Gy for stage IB and 20 Gy for stages IIA, IIB, and III) in addition to parametrial doses to complete 50 Gy in stage IB and IIA or 60 Gy to the involved parametrial tissues for more advanced stages. At Washington University, step-wedges designed in accordance with the isodose curves of the intracavitary applications are used to block the midline (Fig. 66.21). The LDR intracavitary insertions, usually two, deliver 7,000 to 7,500 mgh (65 to 70 Gy to point A) in stage IB tumors and 7,500 to 8,000 mgh (68 to 70 Gy to point A) for stage IIA, IIB, and III tumors. This technique affords a high central dose to the cervix, paracervical tissues, and parametria as well as a moderate homogeneous dose to the external iliac lymph nodes without exceeding the bladder and rectal tolerance doses (Fig. 66.22A).

Other institutions prefer higher doses of whole pelvis external irradiation (usually 40 to 45 Gy) with additional parametrial dose (with a midline 5-HVL rectangular block) to complete 50 Gy in patients with stage IB and IIA tumors and 55 to 60 Gy in patients with stage IIB, III, or IVA tumors. This is usually combined with one or two LDR intracavitary insertions for approximately 4,000 to 5,000 mgh (36 to 50 Gy to point A) to deliver a total dose of 85 to 95 Gy to point A, depending on the tumor volume and stage and age of the patient (Fig. 66.22B). We tend to reduce the total doses by 10% in women older than 70 years.

When 20 Gy is administered to the whole pelvis, for HDR brachytherapy the usual schedule is six fractions of 7 Gy or seven fractions of 6 Gy to point A. If 40 to 45 Gy is given to the whole pelvis, usually four fractions of 6 to 7 Gy to point A are administered.

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Radiation Therapy Techniques

Currently, the two main modalities of irradiation are external photon beam and brachytherapy. External irradiation is

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used to treat the whole pelvis and the parametria including the common iliac and para-aortic lymph nodes, whereas central disease (cervix, vagina, and medial parametria) is primarily irradiated with intracavitary sources. The techniques described apply, with some individualization, to most patients with cervical carcinoma (Table 66.12).


External-Beam Irradiation

External-beam pelvic irradiation is delivered before intracavitary insertions in patients with

Bulky cervical lesions or tumors beyond stage IIA to improve the geometry of the intracavitary application;
Exophytic, easily bleeding tumors;
Tumors with necrosis or infection; or
Parametrial involvement.
Volume Treated

In treatment of invasive carcinoma of the uterine cervix, it is important to deliver adequate doses of irradiation not only to the primary tumor but to the pelvic lymph nodes to maximize tumor control (146,478). Greer et al. (193) reported on intraoperative retroperitoneal measurements carried out in 100 patients at the time of radical surgery. Both common iliac bifurcations were cephalad to the lumbosacral prominence in 87% of the patients. Therefore, the superior border of the pelvic portal should be at the L4-5 interspace to include all of the external iliac and hypogastric lymph nodes. This margin must be extended to the L3-4 interspace if common iliac nodal coverage is indicated. The width of the pelvis at the level of the obturator fossae averaged 12.3 cm, and the distance between the femoral arteries at the level of the inguinal rings averaged 14.6 cm. Posterior extension of the cardinal ligaments in their attachment to the pelvic side wall was consistently posterior to the rectum and extended to the sacral hollow. The uterosacral ligaments also extended posteriorly to the sacrum. These anatomic landmarks must be kept in mind in the correct design of lateral pelvic portals.

Greer et al. (194), based on anatomic and radiographic studies, used expanded pelvic radiation fields in 38 women with stage IIB and III cancers of the cervix. The median length and width of the anteroposterior–posteroanterior fields were 20 and 17.5 cm, respectively. Lateral fields had a median width of 16.5 cm and the posterior border encompassed the entire sacral silhouette.

Bonin et al. (45), in a review of 22 patients on whom detailed anatomic mapping of the anatomy of the pelvic lymph nodes was carried out by lymphangiography, concluded that if the criteria for adequacy of standard pelvic fields as defined by the GOG were applied (anteroposterior: 1.5-cm margin on the pelvic rim; lateral field anterior edge is a vertical line anterior to the pubic symphysis and posterior border), 10 patients (45%) would have had inadequate nodal coverage in the irradiation fields. The incompletely irradiated lymph nodes were in the lowest lateral external iliac group. However, if the irradiation portals are designed as we outline in this chapter and in previous publications, almost all of the pelvic lymph nodes would be within the irradiated volumes. With the advent of IMRT to treat gynecological tumors several authors have published guidelines emphasizing imaging methods to more accurately define target volumes, including lymph nodes (50, 601) .

For stage IB disease, conventional anteroposterior and posteroanterior portals 15 by 15 cm at the surface (approximately 16.5 cm at isocenter) are sufficient. For patients with stage IIA, IIB, III, and IVA carcinoma, somewhat larger portals (18 by 15 cm at surface, 20.5 by 16.5 cm at isocenter) are required to cover all of the common iliac nodes in addition to the cephalad half of the vagina (Fig. 66.7A). A 2-cm margin lateral to the bony pelvis is adequate. If there is no vaginal extension, the lower margin of the portal is at the inferior border of the obturator foramen.

When there is vaginal involvement, the entire length of this organ should be treated down to the introitus (Fig. 66.7B). It is very important to identify the distal extension of the tumor at the time of simulation by placing a radiopaque clip or bead on the vaginal wall or inserting a small rod with a radiopaque marker in the vagina (Fig. 66.8). Use of implanted cervical markers

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to localize the vaginal apex or the cervix during simulation is more accurate than using a vaginal rod, according to Kim et al. (316); all patients showed a mean displacement of the cervical markers by the vaginal rod of 1.9 cm (range, 0.6 to 3.6 cm). The greatest displacement was cephalad (mean, 1.5 cm; range, 0.5 to 2.4 cm). Displacement was anterior in 5/8 patients, posterior in three patients, and lateral in four patients.


In patients with tumor involving the distal half of the vagina, the portals should be modified to cover the inguinal lymph nodes because of the increased probability of metastases (Fig. 66.9).

The lateral ports anterior margin is placed at the pubic symphysis; the posterior margin usually is designed to cover at least 50% of the rectum in stage IB tumors, and it should extend to the sacral hollow in patients with more advanced tumors (Fig. 66.10). The use of lateral fields allows a decrease in dose to the small bowel, but care must be taken to include all structures of interest (193, 478, 535).


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Zunino et al. (671) reviewed the appropriateness of radiation therapy box technique for cancer of the cervix in 35 sagittal MRIs and 10 lymphangiograms. An anatomic evaluation was conducted in cadavers to identify aortic bifurcation, lymph nodes, and uterus flexion. Dissection of female pelvises showed that the aortic bifurcation occurred at the inferior plate of L4 in 80% of the cadavers. The anatomic borders of the box technique used were the superior border of the anteroposterior–posteroanterior fields at the inferior edge of L4; inferior border at the inferior edge of the ischium; the lateral borders 2.5 cm outside of the bone pelvis rim; the anterior border of the lateral fields over the anterior edge of the pubic symphysis; and the posterior at the S2-3 interspace. In 50% of the patients with FIGO IB and in 67% with stage IIA disease, the posterior border of the lateral field was inadequate to encompass the PTV. In stage IIB, the posterior border was inadequate in eight patients (42%). In patients with stage IIB and IVA disease, the PTV was not encompassed. On the 35 sagittal MRIs, the placement of the posterior border of the lateral field was inadequate in 49% and the anterior border in 9% of the cases. The standard design of the lateral fields of the four-field technique based on anatomic bone references failed to encompass the PTV in a significant number of patients.

Further, Knocke et al. (329) used standard simulator planning, guided by bony landmarks for pelvic irradiation in 20 patients with primary cervical carcinoma, stages I to III, using four-field box technique. After defining the PTV with a three-dimensional (3D) planning system, the field configuration of the simulator planning was compared with a second one based on the defined PTV and evaluated regarding encompassment of the PTV by the treatment volume (International Commission on Radiation Units and Measurements [ICRU]). Planning by simulation resulted in one geographic miss, and in 10 more cases the coverage of the PTV by the treatment volume was inadequate. Three-dimensional treatment planning for pelvic irradiation of cervical carcinoma may reduce the treated volume, but further research must be done to determine whether the complication rate can be decreased as well.

Midline Shielding in Anteroposterior–Posteroanterior Portals

Depending on the institution and brachytherapy dose administered, midline shielding with rectangular or specially designed blocks are used for a portion of the external beam dose delivered with the anteroposterior–posteroanterior ports (478).

Wolfson et al. (658) compared the dose distribution in the pelvis with an individualized midline shield that conformed to the point A isodose line or a rectangular block in a retrospective review of 32 patients with invasive cervical carcinoma who underwent LDR brachytherapy. Patients were grouped as having a rectangular block (18 cases), customized block (five cases), or no block (nine cases). The point A isodose distribution from the implant was superimposed onto the whole pelvis simulation film. Approximately 72% of all cases (23/32) had tandem deviation up to 230 degrees, with a median of 50 degrees. This translated into a median percentage overdosage to point A right of 15% and left of 12.5%. Overall survival and incidence of chronic complications have not been affected by type of shielding (median follow-up of 17.7 months). Of 56 radiation facilities in the GOG surveyed concerning their use of a block, 34 (61%) responded; 88% (29/33) use a midline shield, most of them (76%) a rectangular central block that is not positioned with respect to possible tandem deviation.

Parametrial Boost

When parametrial tumor persists after 50 to 60 Gy is delivered to the parametria, an additional 10 Gy in five or six fractions may be delivered with reduced anteroposterior–posteroanterior portals (8 by 12 cm for unilateral and 12 by 12 cm portals for bilateral parametrial coverage). The central shield should be in place to protect the bladder and rectum.

Chao et al. (72) evaluated 343 patients with clinical stage IIIB cervical cancer treated with radiation therapy alone and identified 83 with clinical evidence of tumor in the uterosacral region. The average total dose, including external-beam and brachytherapy, to point A and the lateral pelvis was 80.3 to 86.5 Gy and 60.5 to 73.4 Gy, respectively. The external-beam dose to the lateral parametria was, on average, 10 Gy higher in patients with uterosacral involvement. The cumulative incidence of central/marginal failure at 5 years was significantly higher in the group of patients with uterosacral involvement (36%) compared with 21% for patients without involvement or unspecified involvement (p = 0.002). Lateral parametrial failure was similar for patients with and without uterosacral involvement (39% and 38% at 5 years, respectively; p = 0.42).

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Para-Aortic Lymph Node Irradiation

If para-aortic node metastases are present or suspected, patients are treated with 45 to 50 Gy to the para-aortic area plus a 5 to 10 Gy boost to enlarged lymph nodes through reduced lateral or rotational portals. With conventional techniques, the para-aortic lymph nodes are irradiated either with an extended field that includes both the para-aortic nodes and the pelvis or through a separate portal (Fig. 66.11) (478,492). In this case, a “gap calculation” between the pelvic and para-aortic portals must be performed to avoid overlap and excessive dose to the small intestines. The upper margin of the field is at the T12-L1 interspace and the lower margin at L5-S1. The width of the para-aortic portals (in general, 8 to 10 cm) can be determined by CT scans, MRI, lymphangiography, FDG-PET scans, or IV pyelography outlining the ureters. The spinal cord dose (T12 to L2-3) should be kept below 45 Gy by interposing a 2-cm wide 5–half-value layer (HVL) shield on the posterior portal (usually after 40-Gy tumor dose) or using lateral ports and the kidneys below 1,800 cGy. A technique using four isocentric fields weighted 2:1 anteroposterior–posteroanterior over lateral portals and 1.8-Gy fractions was described by Russell et al. (532) to deliver high-dose therapy (56 to 61 Gy), with 7/14 patients alive and free of disease from 11 to 78 months. Kodaira et al. (332) evaluated a four-field para-aortic irradiation technique with 10-MV photons (mean, 50.4 Gy) in 97 patients with cervical cancer. The 5-year cause-specific survival rate was 32.2%. Grade 1 or 2 stomach and duodenum sequelae developed in 26.8%, grade 2 sequelae of small bowel in 3.1%, and grade 2 sequelae of bone in 3.1%.

Esthappan et al. (150) described a technique using CT and FDG-PET retroperitoneal to treat the para-aortic lymph nodes (50.4 and 59.4 Gy) with IMRT (Fig. 66.12). Acceptable dose distribution of the target volumes and sparing of the stomach, liver, and colon was achieved. Sparing of the spinal cord was dependent on the number and arrangements of the beams, as was the small bowel, sparing of which was limited because of overlap with the target volume. Adjusting number of beams and prescription parameters minimally improved kidney sparing.


Beam Energies

Because of the thickness of the pelvis, with conventional irradiation high-energy photon beams (10 MV or higher) are especially suited for this treatment. They decrease the dose of radiation delivered to the peripheral normal tissues (particularly bladder and rectum) and provide a more homogeneous dose distribution in the central pelvis. With lower-energy photons (Cobalt-60 or 4- to 6-MV x-rays), higher maximum doses must be given, and more complicated field arrangements should be used to achieve the same midplane tumor dose (three-field or four-field pelvic box or rotational techniques) while minimizing the dose to the bladder and rectum and to avoid subcutaneous fibrosis (Fig. 66.13) (253). Biggs and Russell (38) noted that the presence of a metallic prosthesis when using lateral fields or a box pelvic irradiation technique may result in a dose decrease of approximately 2% for 25-MV x-rays and average increases of 2% for 10-MV x-rays and 5% for 60Co.

Allt (11) and Johns (285), in an update of a randomized study, reported better pelvic tumor control and survival and fewer complications in 65 patients with stage IIB and III cervical carcinoma treated with 23-MV photons compared with 61 treated with external irradiation with 60Co, in addition to brachytherapy in both groups. In contrast, Holcomb et al. (253) compared outcome of 195 patients with stage IIB-IVA cervical carcinoma treated with 60Co radiation therapy (group 1) and 53 treated with linear accelerators (group 2). There was no significant difference in overall survival, although there was a trend toward increasing pelvic recurrence in the 60Co group (50.8%) compared with group 2 (35.8%; p = 0.08).

Hyperfractionated or Accelerated Hyperfractionated Radiation Therapy for Locally Advanced Cervix Cancer

MacLeod et al. (391) reported on a phase II trial of 61 patients with locally advanced cervical cancer treated with accelerated hyperfractionated radiation therapy (1.25 Gy administered twice daily at least 6 hours apart to a total pelvic dose of 57.5 Gy). A boost dose was administered with either LDR brachytherapy or EBRT to a smaller volume. Thirty patients had acute toxicity that required regular medication. One patient died of acute treatment-related toxicity. The overall 5-year survival was 27%, RFS was 36%, and actuarial local tumor control was 66%. There were eight severe late complications observed in seven patients, who required surgical intervention (actuarial rate of 27%). Five patients also required total hip replacement.

Viswanathan et al. (638) reported on 30 patients with stage II or III cervical cancer randomized to receive either hyperfractionation (15 patients) or conventional fractionation (15 patients). At 5 years, two patients in the hyperfractionation group and eight patients in the conventional treatment group had recurrent tumor (p = 0.04). Delayed bowel complications (grade 2 and 3) occurred in nine women in the hyperfractionation group and two patients in the conventional group (p = 0.0006).

The Radiation Therapy Oncology Group (RTOG 88-05) conducted a phase II trial of hyperfractionation (1.2 Gy to the whole pelvis twice daily at 4- to 6-hour intervals, 5 days per week) with brachytherapy in 81 patients with locally advanced carcinoma of the cervix. Total dose to the whole pelvis was 24 to 48 Gy, followed by one or two LDR intracavitary applications to deliver 85 Gy at point A and 65 Gy to the lateral pelvic nodes. Grigsby et al. (209) updated the results and noted that external

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irradiation was completed in 71 (88%). The 5-year cumulative rates of grade 3 and 4 late effects for patients with stages IB2 or IIB tumors was 7% and at 8 years 10%, and with stage III or IVA disease, 12% at 5 years. The absolute survival was 48% at 8 years, and disease-free survival 33%, respectively. Comparison with historical control patients treated on other RTOG showed equivalent rates of pelvic tumor control, survival, and grade 3 and 4 toxicities at 3, 5, and 8 years, respectively.


Concomitant Boost

Kavanagh et al. (306) reported on 20 patients with FIGO stage III squamous-cell carcinoma of the cervix who were irradiated in a clinical trial involving a concomitant boost regimen. Patients received 45 Gy to the pelvis in 25 fractions in 5 weeks. On Monday, Wednesday, and Friday of the last 3 weeks, an additional 1.6-Gy boost was given 6 hours after the whole pelvis treatment (14.4 Gy) through lateral fields encompassing the parametria and primary tumor, for a total tumor dose of 59.4 Gy. A single LDR brachytherapy procedure was performed within 1 week after the external-beam radiation therapy to raise the point A dose to 85 to 90 Gy in 42 days. Mean total treatment time was 46 days. Results were compared with patients treated with conventional radiation therapy during the same years. The 4-year actuarial tumor control rates were 78% in the concomitant boost and 70% in the conventional irradiation group (p = not significant). Only two patients receiving concomitant boost required a treatment break because of acute toxicity, but severe late

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complications occurred in 8/20 patients. Further investigations into external-beam dose intensification should be conducted only with a more sophisticated technique than what was available during the time of the study to reduce toxicity.


Three-Dimensional or Intensity-Modulated Radiation Therapy

There is increasing experience with 3D or IMRT in cervical cancer, although results are preliminary. Portelance et al. (493) carried out IMRT as well as conventional planning with two- and four-field techniques in 10 patients. Prescription was 45 Gy in 25 fractions to the uterus and the pelvic and para-aortic lymph nodes. All IMRT plans were normalized to obtain a full coverage of the cervix with the 95% isodose curve (Fig. 66.14A). The volumes of small bowel receiving the prescribed dose (45 Gy) with IMRT technique were, with four fields, 11%; seven fields, 15%; and nine fields, 13.5% (Fig. 66.14B). These dose distributions were all significantly better than with two-field or four-field conventional techniques (p <0.05.) Ahmed et al. (7) arrived at similar conclusions in five patients with para-aortic node metastasis, and they demonstrated the feasibility of escalating the dose to 60 Gy while sparing the kidneys, spinal cord, small bowel, and bone marrow. Heron et al. (245), in a study of 10 patients, showed that with IMRT there was a reduction of 52% in the small bowel volume receiving >30 Gy and a decrease of 66% for the rectum and 36% for the bladder, compared with 3D continuous radiation therapy (CRT). D'Souza et al. (105), in 10 patients, also noted a reduction of small bowel volume (33%) with IMRT compared with four-field pelvic RT; however, small volumes of bowel received 55 to 60 Gy with the IMRT plans. A patient prone position on a “belly board” was shown to reduce volume of small bowel irradiated (4).

Brixley et al. (55) and Lujan et al. (389) also used IMRT planning to spare the bone marrow of patients with gynecological tumors. Brixey et al. (55), in 36 patients, noted no significant difference in hematologic toxicity with IMRT or conventional RT alone; however, in patients receiving chemotherapy less grade 2 white blood cell toxicity was observed with IMRT (31.2% vs. 60%, respectively).

Uncertainties in the definition of target volumes when using 3D techniques have been identified (646). Bladder-filling control and accurate definition of margins for the PTV with image-guided position verification have been advocated to achieve a better application of IMRT (227). An example of dose distribution achieved with IMRT pelvic irradiation is illustrated in Fig. 66.15.

Early results with IMRT have been published. Kavanagh et al. (307) described the outcome of a small cohort of patients with stage IIB or IVA cervical cancer with medical illness or severe tumor-related anatomic distortion that limited delivery of brachytherapy. IMRT was used to provide a simultaneous boost dose to the primary tumor at the time of external-beam treatment to a larger pelvic field given in conventional fractions. The toxicity of IMRT was acceptable, and early tumor responses were encouraging.

Guerrero et al. (214) proposed using an IMRT simultaneous integrated boost (SIB) as an alternative to conventional whole pelvis irradiation and used the linear quadratic equation to calculate equivalent uniform dose in multiple plans. For example, an SIB plan with 25 fractions of 3.1 Gy (77.5 Gy) is equivalent to 45 Gy whole pelvis with external beam and 30 Gy HDR in five fractions brachytherapy boost.

Molla et al. (415) proposed fractionated stereotactic RT as an alternative to brachytherapy to boost the dose to the vaginal and medial parametria in patients with carcinoma of the cervix or endometrium (2 × 7 Gy to PTV with 4-to 7-day intervals postoperatively or in nonoperated patients 5 × 4 Gy with 2-to 3-day intervals). None of 16 patients treated developed urinary or intestinal morbidity.

Although not as critical in older patients, it is important to keep in mind that while IMRT has dosimetric advantages over conventional RT, IMRT exposes a greater amount of normal tissues to lower irradiation levels, which has the potential to increase the incidence of radiation-induced second cancers (224), a phenomenon already described with conventional RT techniques (43).