Brachytherapy: Applications and Technique, 1st Edition

9. Gynecologic Brachytherapy

 

Akila N. Viswanathan

Daniel G. Petereit

Brachytherapy, the placement of radioactivity for therapeutic purposes at a close distance from a tumor, integrates and requires an understanding of radiobiology, physics, and surgical techniques. Radiation oncologists must familiarize and educate themselves in these areas in order to provide appropriate individualized treatments for patients. The use of brachytherapy in gynecologic malignancies increases the likelihood of local control of the tumor, and when properly applied, may impact survival.1,2

In order to eliminate all gross and microscopic disease, sufficient doses of radiation must be administered. The vagina and uterus are hollow organs with a relatively high tolerance for radiation, allowing for therapeutic doses to be placed in direct contact with the tumor. Although the vagina and uterus are highly mobile, gynecologic brachytherapy applicators move with the patient and stay in direct contact with the tumor. Therefore, dose escalation is feasible in a way not possible in many other sites in the body. However, maintaining sufficient distance between critical normal tissue and the radiation sources is essential to protect the function of the tissue and decrease the risk of side effects.

Anatomy

In order to ensure proper applicator placement and maximize the effect of brachytherapy, a thorough understanding of pelvic anatomy is required. The uterine corpus has a thick muscular wall with a hollow central canal, and may lie anteverted, straight, or retroverted in the pelvis. The uterine cervix, which is primarily composed of fibrous tissue, sits inferior to the uterine corpus and at the cephalad end of the vagina (see Fig. 9.1). The endocervical canal extends from the external os to the internal os, where it opens to the endometrial cavity. Laterally, the cervix is connected to the broad ligament and the parametrium, through which the pelvic vessels traverse to reach the cervix. The flexibility of the broad ligament results in significant mobility of the cervix.3 On computed tomography (CT) with intravenous (IV) contrast, the superior border of the cervix may be approximated to the level where the uterine vessels begin to run adjacent to the inferior portion of the uterus (see Fig. 9.2).

External beam (EB) radiation planning requires knowledge of the pelvic lymphatic drainage patterns. The cervix drains into the paracervical lymph nodes and subsequently to the internal and external iliac nodes, including the obturator nodes. The pelvic lymphatics drain into the common iliac and the para-aortic lymph nodes. Skip lesions may occur from the pelvic nodes to the para-aortic and supraclavicular nodes. Presacral lymph nodes represent secondary echelon lymph node chain for the cervix, as cervical cancer may spread along the uterosacral ligaments posteriorly. Brachytherapy provides additional dose to the paracervical, obturator, and presacral lymph nodes.

Figure 9.1 Coronal diagram of the anatomy of the uterus, cervix, and vagina demonstrating the spatial relationships and the terminology. (From Moore's Clinically Oriented Anatomy, Transpose Baltimore and MD: Lippincott Williams & Wilkins. Used with permission.).

Cancer in the female gynecologic tract can significantly distort normal anatomy, resulting in permanent changes in normal organ function. Posterior extension may cause pressure on the rectum. Anterior extension encroaches on the bladder. Superiorly, the rectosigmoid flexure and small bowel may be compressed. In the postoperative setting, loops of small bowel may fall into the pelvis, filling the space previously occupied by the uterus. The tumor may grow circumferentially or laterally in the pelvis, compressing the ureters and causing hydronephrosis.

Figure 9.2 Axial treatment planning computed tomography (CT) scan of the cervix with intravenous contrast highlighting the uterine vessels at the cervicouterine junction. Bladder and rectum are contoured anterior and posterior to the cervix with CT-compatible tandem within the cervical canal. The left-sided Point B is also marked.

Imaging

Radiologic studies may be used at the time of diagnosis, immediately preceding brachytherapy, and when feasible, at the time of each brachytherapy insertion, to guide clinical care. At the time of diagnosis, a chest x-ray (CXR) and intravenous pyelogram (IVP) are permitted for clinical staging of cervical cancer.4However, in the United States, many centers may choose to order CT or magnetic resonance imaging (MRI) diagnostic studies to delineate the tumor and suspicious lymph node involvement. An MRI immediately before brachytherapy can assess the amount of tumor regression, tumor dimension, and location of the normal uterus, cervix, vagina, and tumor.

MRI has been reported to be superior to any other available modality in imaging the normal anatomy of the female pelvis, including the bladder and rectum, and delineating tumors of the uterus and uterine cervix.5,6,7 MRI can assess tumor size, depth of invasion, and the local–regional extent of the disease including direct invasion of the parametrium, pelvic sidewall, bladder, or rectum. Prior studies have shown that the regression of cervical tumors can be clearly documented by MRI.8 MRI at the time of brachytherapy provides clear delineation of the tumor, parametrial invasion, and the organs at risk (OAR).9 CT has been used for brachytherapy guidance and treatment planning by several institutions.10,11,12 CT cannot, however, provide an adequate delineation of the tumor as is possible with MRI because of lack of multiplanar capability, tissue contrast, and anatomic detail.11 The use of IV contrast for CT or MRI greatly enhances visualization of tumor and vasculature but caution must be used as there is a risk of allergic reaction.

Positron-emission tomography (PET) using 2-[fluorine 18]-fluoro-2-deoxy-D-glucose (FDG) detects metabolically active cancer, including nodal metastases in cervical cancer.13 For pelvic malignancies, urinary FDG activity can be a confounding factor, and a Foley catheter and diuretics should be used, if possible, to minimize collection of the tracer in close proximity to the primary area to be evaluated. Positive persistent uptake on PET of the cervix at 3-month follow-up correlates significantly with an increased risk of local recurrence.14

Low Dose Rate, High Dose Rate, and Pulsed Dose Rate

Low dose rate (LDR) brachytherapy typically implies a dose rate of 0.4 to 2 Gy per hour, in contrast to high dose rate (HDR) brachytherapy, where the dose rate exceeds 12 Gy per hour.15 The use of LDR radiation to cure cervical cancer has been proved over the past century. LDR radiation results in continual administration of radiation over several days; therefore, cells may be more likely to move from the radioresistant S to G2 transition phase to the more radiosensitive late G2 and M phase of the cell cycle. Therefore, LDR increases the likelihood of sublethal damage repair of normal tissues. However, with LDR, acute hypoxia could be corrected during treatment.16

In HDR, the larger fraction sizes may increase the risk of long-term side effects; therefore, paying careful attention to the location of normal tissues at the time of treatment is imperative. At least 24 hours between HDR fractions is recommended, in order to allow for maximum normal tissue repair;17 however, most repair occurs by 6 hours, which may allow for twice-daily fractionation.18,19,20,21,22 HDR causes significant tumor shrinkage, thereby increasing the oxygenation of chronically hypoxic regions. As with all dose rate paradigms, the geographic displacement of OARs may provide the best therapeutic ratio.

Pulsed dose rate (PDR), primarily used in Europe, requires an afterloading device with a single stepping source of Iridium 192 (192Ir). Ten-minute pulses every hour give a dose equivalent of 60 cGy per hour.23,24 The biologic effect mimics LDR, and the dose optimization mimics HDR.

 

Table 9.1 The Advantages and Disadvantages of Low Dose Rate and High Dose Rate Brachytherapy for Cervical Cancer

Advantages

Disadvantages

LDR

HDR

LDR

HDR

>100 y of data

Outpatient treatment

Inpatient treatment

 

Standardized doses

Short administration time

Radiation exposure to staff

Intense quality assurance

Standardized treatment plan

Standard source strength

Limited by source strength

Intense maintenance

Standardized treatment time

Source easily available

Limited sources available

Intense physician/physicist time

Maximum two insertions

Intravenous (IV) conscious sedation feasible

Spinal or general anesthesia

>2 fractions required

 

Reassessment of tumor size with multiple fractions

Prolonged bed rest

Treatment required on day of insertion

 

Dose optimization of normal tissues

Need for anti-coagulation—risk of blood clots or emboli

Start up cost

 

No staff exposure

Constipating medication

Caution with large tumors

 

Applicator stabilized during treatment

Need for inpatient pain control

Caution with normal tissue dose (organs at risk)

HDR, high dose rate; LDR, low dose rate.

HDR and LDR are primarily used for brachytherapy in the United States. A decision about LDR versus HDR is determined by multiple factors, including the size of residual disease remaining after EB, the patient's preference, and the institutional equipment available. Some of the pros and cons of HDR and LDR brachytherapy are listed in Table 9.1. Interestingly, in Sao Paulo, Brazil, as many as 25 to 30 HDR insertions are performed in the center per week for cervical cancer; the institutional preference is HDR given the long wait period to start treatment with LDR. In addition, the staff and patients report that HDR was more convenient than LDR.25,26

The most commonly used method for equating doses is the biologically equivalent dose, commonly called the BED formula. The assumptions are that the α/β ratio (see Chapter 1) for tumor in cervical cancer is typically chosen to be 10, and that the α/β for normal tissue is typically chosen to be 3.18,19,20,21,22 The linear quadratic effective dose (LQED) is a very useful parameter that converts BEDs into dose equivalents for a 2-Gy fraction EQD2. The normalized total dose (NTD) is another term used, which is synonymous with the LQED. For most clinicians, EQD2 gives a better sense of the amount of potential tumor and late tissue effects (see Table 9.2).

Several radiobiologic models have evolved over time for estimation of the dose rate correction factor, that is, TDF (time dose factor), NSD (nominal standard dose), and the linear quadratic model (LQM), the model that best fits the shape of the survival curve. Orton's data suggested an LDR to HDR conversion factor of 0.54 ± 0.06 to Point A.17 Patel et al.27 and Okawa et al.28 have calculated similar dose rate correction factors of 0.58.

If feasible, having both HDR and LDR brachytherapy available allows the physician flexibility in treatment selection. In cervical cancer, HDR is ideal for patients with a small volume of disease with a vagina that can hold sufficient packing that moves the bladder and rectum away from the high-dose regions. Certain rare histologies, such as melanoma or sarcoma, may benefit from a large fraction size. Patients with lupus anticoagulant may be a very high risk for a thrombotic event during an inpatient stay, and may minimize risk with outpatients from HDR. LDR may be preferable for patients with a very large volume (i.e., >4 cm) of disease after EB, as intracavitary HDR brachytherapy may not adequately cover the tumor volume.29 However, most data does not indicate worse outcomes for patients with stage IIIB cervical cancers treated with HDR as opposed to LDR, as long as the disease has had a sufficient response to chemoradiation. Three-dimensional (3D) imaging with optimized HDR and the choice of an interstitial implant over an intracavitary implant may address this concern.

Table 9.2 Calculating the Biologically Equivalent Dose and the Linear Quadratic Equivalent Dose

   BED = total dose (1 + dose/fraction/[α/β])
      BED = biologically effective dose
      (1 + dose/fraction/[α/β]) = RE
      α/β term used to describe the response of the tumor/early responding tissues and the late-responding tissues to varying dose per fraction
      BED = nd (RE)
      Linear quadratic dose for a 2-Gy fraction (nd) 
   —RE = ([1 + d/(α/β])
   —RE = 1.2 for tumor (Gy 10)
      (1 + 2/10) = 1.2
   —RE = 1.67 for late-responding tissues (Gy 3)
      (1 + 2/3) = 1.67

RE, relative effectiveness.

On the basis of the data available, it appears that if HDR is carefully applied and treatment individualized, the outcomes can equal those obtained with LDR. There have been four prospective randomized studies30,31,32,33 (see Table 9.3) and a number of retrospective reviews34,3536,37,38,39,40,41,42,43 of HDR versus LDR for treatment of all stages of cervical cancer. Although the four randomized trials do have some significant flaws, the results are consistent with other phase II data from large, single institutional reviews that demonstrate the equivalency of both forms of treatment. On the basis of the current literature available, either form of brachytherapy will achieve similar results as long as the physician recognizes the importance of experience, fractionation, and technique and individualizes the therapy on the basis of the needs of the patient, the tumor, and the normal tissue anatomy. Controversies that remain include the accuracy of equating the doses between HDR and LDR, identification of the ideal strategy for treating large volume disease, particularly stage III cancers with large amounts of residual, clarifying whether any difference exists in long-term complications with adequate follow-up, particularly in the era of concurrent chemotherapy, and how best to respond to patient's preferences and/or needs for either inpatient or outpatient therapy.

Cervical Cancer Treatment

Management by Stage and Size

Staging for cervical cancer requires a thorough clinical assessment of the extent of disease. A meticulous, bimanual rectovaginal examination of the pelvis should be performed at the time of diagnosis and at the time of brachytherapy to evaluate sites of local–regional tumor spread including the parametrium, uterosacral ligaments, pelvic sidewalls, rectum, and bladder. Any suspected tumor invasion of the rectum or bladder should be confirmed by cystoscopy or proctoscopy with biopsy.

Patients with stage IA cervical cancer typically are managed by a radical hysterectomy alone. If these patients are considered inoperable, brachytherapy alone to a dose of approximately 80 Gy may be administered. Patients with stage IB cervical cancer may be managed by a radical hysterectomy alone if the tumor is <4 cm in size with no other adverse features. Those with tumors >4 cm, and all patients with stage IIA, IIB, IIIA, IIIB, and IVA cancer are managed with EB radiation with concurrent chemotherapy and brachytherapy.

Table 9.3 Randomized Trial Results of Toxicity, Overall Survival and Disease-Free Survival Comparing High Dose Rate and Low Dose Rate Cervix Brachytherapy

 

Stage

Overall Survival (%)a

Disease-Free Survival (%)a

Toxicity (%)b

 

HDR

LDR

HDR

LDR

HDR

LDR

Patel et al.30

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.31

Stage I

66

89c

85

93

7

3

 

Stage II

61

73

73

78

 

Stage III

47

45

53

47

Hareyama et al.33

Stage II

89

100

69

87

7.5

16.2

 

Stage III

69

70

51

60

Lertsanguansinchai et al.32d

Stage IIB

65

74

65

76

5

4

 

Stage IIIB

71

63

74

59

aFive-year results, unless otherwise stated.
bGrades 3 to 5 rectal and bladder toxicity combined.
cStatistically significant difference.
dThree-year results.
HDR, high dose rate; LDR, low dose rate.

Role of Brachytherapy

Brachytherapy plays a critical role in the successful treatment of cervical cancer. For cancers of the cervix, local–regional control correlates with cure and survival.44 Although occasionally these patients may present with metastatic disease, the vast majority have either early stage or locally confined disease. Adjacent critical structures often preclude oncologic, nonexenterative surgery in these sites, increasing the importance and potential benefit of curative local radiation therapy. Local failure results from inappropriate coverage and underdosing of the tumor, particularly with large volume disease, technical failure, and radioresistance. With ideal anatomy and adequate packing the normal tissue dose remains low enough to permit a curative dose of radiation to the tumor.

The use of brachytherapy in cervical cancer has significantly increased over time. Komaki et al. reviewed the Patterns of Care study results of 1973, 1978, and 1983. For patients with stage III cervical cancer, 61% received brachytherapy in 1973, compared with 77% in 1978, and 88% in 1983 (p <0.001).45 The 1996 to 1999 survey showed that over 92% of patients treated with curative intent received brachytherapy, of which 16% received HDR brachytherapy.46

Several series have suggested that control rates with EB and brachytherapy are significantly better than that with EB alone.2,47 Patients who received >80 Gy had a significantly decreased residual cancer rate at hysterectomy after completing the radiation.48 In another study, patients who received >6,000 mg per hour had a significantly decreased pelvic relapse rate.1 In general, doses of 80 to 90 Gy are required to sterilize gross disease for locally advanced or recurrent cervix, uterine, or vaginal cancer.

 

The clinical outcome of brachytherapy depends in part on the skill and expertise of the operator. Precise applicator placement is critical for improved local control and reduced morbidity. A small caseload may be insufficient to maintain the skills necessary to perform optimal brachytherapy insertions. Corn et al. showed that patients who received ≥85 Gy had a significant improvement in survival (p = 0.01), and the technical adequacy of the implant was an important determinant of local control. The 5-year local control rates for an unacceptable implant versus an acceptable implant were 35% versus 68% and the 5-year overall survival rates were 42% versus 61%.49 The Patterns of Care survey from 1996 to 1999 showed that patients treated at smaller facilities (<500 patients annually) were significantly more likely to have received a total dose of <80 Gy to Point A, to have had their treatment protracted to >70 days, and to have undergone an adjuvant hysterectomy.46

Duration of Treatment

Several studies estimate that survival decreases by <1% per day with prolongation of radiation treatments beyond 7 to 8 weeks;50,51,52,53,54,55 this may result from accelerated repopulation of surviving tumor clonogens. Therefore, treating cervical cancer immediately is critical. The total time of EB and brachytherapy with concurrent chemotherapy should not exceed 56 days.

Late complications, however, are not influenced by treatment time.55 In a study of LDR brachytherapy by Perez et al. no correlation of incidence of grade 2 or 3 toxicity was made with overall treatment time except with regard to rectal proctitis, which was 12% if treatment lasted longer than 9 weeks compared with 4% if treatment was for <7 weeks. Toxicity did increase with dose.56,57

EB shrinks a bulky cervical mass to an adequate size, allowing for tumor coverage with brachytherapy and good geometry with regard to the normal tissues. EB also sterilizes microscopic nodal, regional, and lateral paracervical disease that may not receive substantial dose from the brachytherapy. During the EB treatment, weekly or every 2-week examination of the cervical mass allows the physician to gauge the response of the tumor to treatment and plan for the proper equipment needed for brachytherapy.

For small cervical cancers, brachytherapy may be initiated near the beginning of external radiation, whereas for more advanced lesions brachytherapy is performed near the end of EB to allow for adequate tumor regression for either LDR or HDR brachytherapy.52,58 A rational approach is to begin intracavitary insertions after 4 to 5 weeks of EB radiation.

For HDR, to prevent excessive prolongation of treatment time, 2 fractions are given in a week. The safety of this number of HDR fractions in a single week has not been extensively studied. Le Pechoux et al. demonstrated higher complication rates when 2 fractions of 5 Gy were delivered in a single week compared with 6 Gy given in 1 week.59 However, at Wayne State University, only one significant complication was encountered in 15 patients with cervical cancer treated with 3 HDR fractions of 3.86 Gy per fraction in 1 week.60 Although it may appear safer to deliver only 1 HDR fraction per week, increasing the total treatment time by 4 to 5 weeks is of concern with regard to tumor kinetics and repopulation.

Most patients receive approximately 40 to 45 Gy of EB over the first 5 weeks of treatment, with cis-platinum being given once a week. The first LDR procedure occurs at the beginning of the sixth week; the second tandem and ovoid implant is inserted before the eighth week. The final, sixth dose of chemotherapy may be given before the eighth week with the second tandem and ovoid in order to allow blood counts to normalize. If a patient requires a lateral parametrial sidewall nodal boost dose, a central midline block is placed in the pelvic EB field between the first and second tandem, and ovoid implants.

The number of HDR insertions varies between institutions, with 3, 4, or 5 insertions routinely administered. At the Brigham and Women's Dana-Farber Cancer Institute, the most common regimen employs 5 tandem and ovoid insertions with 6 weeks of weekly chemotherapy. Figure 9.3 represents tandem and ovoid treatment schemata for LDR and HDR used in many institutions. Brachytherapy is not typically given on the same day as EB, nor is chemotherapy given on the same day as a tandem and ovoid implant for either dose rate.

 

Figure 9.3 Combined chemo radiotherapy treatment schemata for both low dose rate (LDR) (A) and high dose rate (HDR) (B). Whereas traditional LDR is incorporated after most external beam radiotherapy is completed, HDR can be integrated into the treatment schedule earlier. CDDP (cis-platinum 40 mg per m2); tandem/ovoid (T/O) (low dose rate tandem and ovoid); boosts (lymph node/parametrial additional dose.).

Preprocedure Preparation

A complete history and physical examination is essential before radiation. Patient factors to be assessed include the patient's performance status, medical history, age, and normal tissue anatomy and history. In all patients, the clinical examination documents the tumor anatomy and spread. This examination is recorded (see Fig. 9.4) before the initiation of therapy, and at the time of each brachytherapy insertion, in order to determine regression and clinically determine sites at risk. Knowledge of a history of irritable bowel syndrome, preexisting cardiac condition, hemorrhoids, skin infections, active presence of sexually transmitted diseases such as herpes simplex lesions, multiple thromboembolic events resulting from a syndrome such as lupus, or a history of bladder or rectal surgery that may result in fixation of the uterine cervix to an adjacent organ is optimal.

Before any insertion, the patients' laboratory and radiologic studies should be reviewed. Laboratory studies include a complete blood count with differential, assuring that the patient is not neutropenic creatinine and potassium assessment is important for a patient with hydronephrosis, or for patients on antihypertensive diuretic medication. In patients receiving IV contrast for a CT at the time of brachytherapy, creatinine clearance must be calculated on the day of injection. Radiologic studies including the MRI can depict uterine position and assist with selection of the proper tandem curvature; Figure 9.5 depicts an MRI of a retroverted uterus immediately before brachytherapy.

Medications must also be scrutinized. Anticoagulative medications must be stopped, and the international normalized ratio (INR) normalized before insertion. Warfarin (Coumadin) and aspirin are usually held 1 week before the procedure. Patients on Coumadin may switch to enoxaparin (Lovenox); enoxaparin is held 24 hours before the procedure. Any history of allergies to narcotics must be carefully noted.

All patients must have a thorough understanding of the procedure and potential complications. Informed consent for anesthesia, the procedure, the administration of radiation, and the use of IV contrast if given during imaging must be obtained before initiating therapy.

The day before the procedure, patients staying overnight (all LDR cases) require a preoperative bowel regimen: 2 tablets of senna (Senokot), 2 tablets of docusate sodium (Colace), and sodium phosphate (Fleet Enema). The patient is instructed to have a clear liquid diet 24 hours before the procedure, and to take nothing by mouth after midnight the night before the procedure.

 

Figure 9.4 Clinical tumor diagram used in some centers to document the clinical examination at different points of the therapy.

Figure 9.5 Sagittal (T1 post Gad) magnetic resonance imaging depicting a retroverted uterus.

 

Location of the Brachytherapy Procedure

The key elements required for an HDR program include an HDR remote afterloader, planning software, procedural room where the applicators are placed, imaging capabilities for planning, typically anterior–posterior (AP) and lateral x-ray, CT or MRI, and a shielded room for treatment delivery, typically a linear accelerator (LINAC) vault, a dedicated suite, or a simulation room. The dedicated brachytherapy suite at the Dana Farber Brigham and Women's Cancer Center (DFCI-BWHCC) is shown in Figure 9.6. The primary advantages of a dedicated brachytherapy suite are minimizing patient's time and maximizing the comfort. Further, minimizing the movement increases the accuracy of treatment. For institutions that perform the insertion in the operating room (OR), the patient is typically moved three or more times, from the operating table to the stretcher, the stretcher to the simulator table, back to the stretcher, and perhaps to a an inpatient bed or a treatment room. Such transfers can add an additional 60 to 90 minutes in which the applicators are kept in the patient and during which there is a risk that the applicators may shift. Alternatively, one can perform the insertion in the LINAC vault, and image the insertion using a portable unit to generate an AP and lateral x-ray, or perform insertion, imaging, and treatment in a shielded simulator room. The disadvantage is inaccessibility of the LINAC vault or the simulator room for EB patients.

HDR patients may receive cervical dilation with or without Smitt sleeve (Nucletron Corp, Veenendal, NL) placement in an OR or in a dedicated suite on the first insertion, with subsequent insertions performed under conscious sedation in an examination room if a dedicated suite is not available. If patients receive spinal or general anesthesia, the anesthesiologist requires an OR or a dedicated brachytherapy suite with proper airflow construction and a sterile medication cart. Regardless of the type of room, proper equipment, lighting, patient positioning, and sedation are necessary to correctly place the applicator and packing. A portable ultrasound may also be useful to assist with tandem placement. The patient should be able to lie at the edge of the bottom of the table in lithotomy position. At the DFCI-BWHCC, the control room for the brachytherapy suite is equipped with flat panel TV monitors, allowing visualization of the patient at all angles during scanning and treatment, a vital signs control monitor for the anesthesiologist, a CT control device, computers, a contouring workstation, and light boxes (see Fig. 9.7). The audio, visual, and vital signs monitors run continuously during therapy.

Figure 9.6 A dedicated brachytherapy suite in which patients receive implant, await dosimetry, and receive high dose rate treatment without being moved. General, epidural, and spinal anesthesia can be employed as indicated.

Figure 9.7 A dedicated brachytherapy suite control room in which the control consoles for the computed tomography scanner, the high dose rate (HDR) afterloader, remote anesthesia monitoring, sounds and multiple camera monitors make for safe remote afterloading for patients with gynecologic problems receiving HDR brachytherapy.

Setup in Room

The basic tray used for the insertion and accompanying instruments is depicted in Figure 9.8. A standard dilatation and curettage (D&C) kit that includes uterine sound, a set of uterine dilators, two different-sized speculum, two right-angle retractors, two short retractors, long DeBakey forceps without teeth, short forceps, suture needle holder, tenaculum, clamps, and suture should be present. The radiation applicators necessary for the case are sterilized before the procedure. Equipment to deal with bleeding, including suction, sponge sticks, and topical thrombin (FloSeal), and absorbable suture should be available in the event of a severe laceration of the vaginal mucosa. A gynecologic oncologist should be available on call in the event of a complicated laceration or other injury requiring surgical intervention.

Anesthesia

Adequate sedation of brachytherapy patients is a critical component in successful treatment delivery. Potential options for anesthesia include general, spinal, or IV conscious sedation. If the patient is not adequately relaxed with IV conscious sedation, the levator muscles tighten, which makes the insertion very difficult to perform. A good test of whether a patient can tolerate manipulation of the uterine canal under conscious sedation is how she undergoes a pelvic examination during her initial assessment. If a patient is intolerant of a pelvic examination, she most likely will not tolerate the procedure unless regional or general anesthesia is given.

Conscious sedation with IV fentanyl and midazolam, administered by a registered nurse (RN) and supervised by the radiation oncologist, requires continual monitoring vital signs.


Approximately two thirds of the fentanyl and midazolam doses are administered while inserting the gynecologic applicators. Once the applicators are in place, smaller doses of each drug are given. During the planning time, the patient usually becomes increasingly conscious because of clearance of the drugs and decreased need for pain control. Most patients complain of dull, but tolerable, pelvic cramping. The best policy is to closely observe and monitor patients for at least 90 minutes after the last sedative dose. Patients must have a friend or a family member provide transportation.

Figure 9.8 A sterile table set up for high dose rate computed tomography-compatible tandem and ovoid brachytherapy. The basic dilatation and curettage operating room set is augmented by a set of dilators, a flexible intrauterine sound, a ruler, a tenaculum, sponge sticks, gauze moistened with surgical lubricant, and right-angled retractors.

General or spinal anesthesia result in complete immobility of the patient during the insertion; however, an anesthesiologist must give clearance for the use of anesthesia and must be present during the entire procedure. In a dedicated brachytherapy suite, if HDR is administered, the patient is kept under anesthesia for the duration of insertion and treatment delivery. Patients require approximately 2 to 4 hours of sedation.

Procedural Details

The patient is brought into room and an IV inserted after the identity is confirmed and an armband is placed. Before administration of any anesthesia, consents must be signed and placed in the patient's chart. After anesthesia induction, pneumoboots and compression stockings are placed on the patient's legs, which are then moved into lithotomy position in stirrups. Once the patient is relaxed in lithotomy position, the buttocks should be aligned horizontally and at the end of the table.

Figure 9.9 Low dose rate (LDR) classical Fletcher Suit Delclos tandem and ovoid set. There are three angles of tandems and two sizes of ovoid caps. Spare locking screw, keels, tandem screw caps, and a wrench for the keel are shown. The specific left and right ovoid cesium carriers and the tandem cesium carrier that are inserted at the beginning of therapy are not shown.

Examination under Anesthesia

An examination under anesthesia requires a manual examination of the vaginal vault as well as an examination of the vagina and rectum simultaneously. First, a speculum is placed inside the vagina, in order to assess the visible vaginal and cervical extent of the disease, and determine if the cervical os is visible. A cervical mass can compress the anterior vagina, mimicking vaginal disease. During the examination, tumor factors that are to be assessed include the following: What is the size of the tumor? What is the size of the cervix? Is the tumor exophytic, is it endocervical, and is it symmetrically or eccentrically placed? What is the vaginal extent of disease? Are the fornices palpable? Has EB caused fibrosis or narrowing of the vagina that is likely to worsen with brachytherapy? What is the size of ovoids that can be placed? Is there a vesicovaginal or rectovaginal fistula clinically visible? Is the vagina large enough to accommodate adequate packing? Is the os visible or palpable? Will ultrasound guidance assist with tandem placement? Is the uterus mobile? Is the uterus anteverted or is it retroverted? What curvature of tandem will optimize the uterine position and minimize dose to the bladder and rectum? Will the simulation be performed with plain film, CT scan or MRI? On bimanual examination, fixation to one side or parametrial/uterosacral extension becomes evident. All of these factors should be considered by the radiation oncologist before the implant to determine which applicator is the most appropriate. When available, MRI images of the pelvis immediately before brachytherapy can be helpful in delineating nonvisible and nonpalpable extension of disease.

Applicator Selection

Low Dose Rate Applicators

The most common LDR applicator that is used is the Fletcher Suit Delclos (FSD) tandem and ovoid applicator system, which has a series of curved intrauterine tandems (see Fig. 9.9). This is an adaptation of the Manchester system and comes in both manual afterloading (LDR) and remote afterloading (HDR) configurations. There are multiple ovoids with different degrees of ovoid placement that also cover the upper vagina. The tandem and ovoid system results in a classically pear-shaped distribution of dose. LDR applicators come either with or without built-in tungsten shielding.

Distal vaginal involvement requires either a LDR tandem and cylinder or an interstitial implant. A tandem and cylinder can be used to treat distal vaginal involvement, but only if the depth of invasion is <5 mm. The tandem and cylinder may yield higher bladder and rectal doses as no packing may be placed, and the narrow dose distribution results in lower parametrial doses. It is feasible to treat a patient with a tandem/ovoid for 1 LDR fraction, and a tandem/cylinder for the second fraction if the disease has regressed completely with EB radiation.

Figure 9.10 Disposable interstitial template with sharp-tipped flexible catheters and vaginal obturator in place. This template is ideal for computed tomography or magnetic resonance imaging–based planning, as it has no metallic parts. The external ends of the catheters are carefully numbered. There are catheters in the grooves of the vaginal obturator as well as in selected outer circle positions. Observe that there are permanent ink marks so that the catheter movement can be noted.

An interstitial implant (see Fig. 9.10) is recommended if there is >5 mm of vaginal disease, particularly in the distal vagina. If an interstitial implant is placed in a patient with an intact uterus, a tandem should be inserted and loaded with cesium 137 or iridium 192. Patients who have had complete erosion of the cervix with very advanced disease may have no cervical os present whatsoever. In these cases, ultrasound should guide placement of a tandem into the center of the uterus (see Fig. 9.11). Patients who have had a hysterectomy and then have a local postoperative recurrence at the vaginal cuff may benefit from interstitial therapy after EB.

Figure 9.11 Ultrasound can be used intraoperatively to find the uterine cavity and the cervical canal. This sagittal ultrasound shows the bright signal of the tandem in a good position in the uterus.

High Dose Rate Applicators

For HDR, tandem and ovoid, tandem and cylinder, and tandem and ring applicators are available. A Smitt sleeve can be placed at the time of the first implant in order to avoid repeat cervical dilation with subsequent fractions.

The tandem and ring has a narrow distribution and covers the cervix. Erickson et al. at the Medical College of Wisconsin have been using the tandem and ring system for several years, and have reported their dosimetric experience.61 The tandem and ring applicator comes in both CT/MR scan–compatible (see Fig. 9.12) and non–CT/MR scan–compatible types (see Fig. 9.13). The ring applicator results in a slightly narrower distribution than that of a tandem and ovoid (see Figs 9.14, 9.15, 9.16 and 9.17). Packing to avoid dose to the bladder and rectum is very important. The applicator typically comes with a rectal shield, but packing is recommended, in addition to the shield. High dose rate tandem and ovoid applicators include the Fletcher Williamson applicator (see Fig. 9.18), which mimics the FSD LDR applicator. The Henschke applicator has a hemispherical ovoid shape (see Fig. 9.19) and may deliver increased dose to the lateral vaginal surface compared with the FSD ovoids. Both systems provide pear-shaped distributions. A tandem and cylinder (see Fig. 9.20), which has a narrow distribution, can cover the entire length of the vagina if there is <5-mm thick disease at the time of the implant. Interstitial HDR has been reported;62 more outcome data must be published before adopting this approach as an alternative standard treatment regimen.

Figure 9.12 CT/MR–compatible tandem and ring applicator set (Nucletron Corp, Veenendal, NL). The sets have various angles of anteversion. Each system's special geometry is set by interlocking grooves. Rings are either large or small. The posterior vaginal paddle is used to geometrically push the anterior rectal wall posteriorly. Nonetheless, posterior packing is necessary for the best effect.

 

Figure 9.13 Titanium (CT/MR scan–compatible) tandem and ring applicator set. As with the previous figure, these are in various angles of anteversion and cap size. The system's intrinsic geometry is set by interlocking the grooves. (Nucletron Corp, Veenendal, NL.).

Figure 9.14 Typical anterior–posterior isodose distributions of a high dose rate tandem and ovoid applicator. Note the classical pear-shaped distribution with Point A and B doses. By convention, the right ovoid is channel 1, the left channel is 2 and the tandem is channel 3.

 

Figure 9.15 Typical lateral isodose distributions of a high dose rate tandem and ovoid applicator. Note the bladder and rectal dose points.

 

Figure 9.16 Typical anterior–posterior isodose distributions of a high dose rate tandem and ring applicator. The classical pear-shaped distribution is maintained. By convention, the ring applicator is assigned to channel 1, and the tandem remains at channel 3.

Figure 9.17 Typical lateral isodose distributions of a high dose rate tandem and ring applicator. The selective use of the lateral dwell positions on the ring can improve the anterior and posterior doses to the bladder and rectum. This may be at the cost of delivering a higher vaginal mucosal dose laterally.

 

Figure 9.18 A Fletcher Williamson high dose rate tandem and ovoid applicator. The system has an adjustable keel.

 

Figure 9.19 A Henschke high dose rate tandem and ovoid applicator kit. Note the three tandems, large and small ovoid caps, keels, and a keel wrench. The ovoids are fixed on a hinge. An external caliper shows the distance between ovoids when inserted.

Figure 9.20 A typical high dose rate tandem and cylinder applicator kit. Cylinders are of sizes 2.0, 2.5, 3.0, and 3.5 cm with four stackable cylinder blocks per size. The cylinders can be made on a T-ended stem (inferiormost) for postoperative vaginal cuff therapy, or on any one of three different tandem lengths and angulations for therapy when the uterus is intact.

 

Pre-Procedural Preparation

After examination under anesthesia, the patient's skin is prepped with betadine (Betadine) and draped. A Foley catheter is inserted with radiopaque contrast inside the Foley balloon. The amount of contrast is determined by the imaging modality available for treatment planning. For fluoroscopic simulation, 7 mL of contrast is placed in the Foley balloon per International Commission on Radiation Units and Measurements (ICRU) recommendations.63 In a CT simulation, the 7 mL may be diluted to 2 mL of contrast and 5 mL of sterile saline. A rectal tube is inserted into the rectosigmoid with 20 to 30 mL of barium contrast. The cervix is visualized using right-angle retractors or a speculum placed in the vagina. A weighted speculum should be avoided particularly in patients recently treated with EB and concurrent chemotherapy, as the friable vaginal mucosa may tear under pressure.

Marker seeds may be placed if using plane films for treatment planning. Three marker seeds may be inserted on anterior and posterior lips of cervix. The seeds are loaded into the inserter, and the tip enters the cervix approximately 5 mm before depressing the plunger. A small amount of lubricant on the inserter tip holds the seeds in place in the applicator until they are placed in the cervix. On an x-ray, the seeds will lie approximately 1 cm superior to the inferior aspect of the cervix.

Sounding/Dilation

General suggestions for sounding the uterus are listed in Table 9.4. To sound the uterus, the anterior lip of the cervix is grasped with a single-toothed tenaculum. If the anterior lip is extremely friable because of tumor involvement or is effaced, a suture through a healthy portion of the cervix instead of a tenaculum can provide enough traction. To straighten and facilitate sounding of the uterine canal, the cervix is gently pulled 2 to 3 cm down the vagina. In order to avoid a perforation, a careful bimanual examination that locates the cervical os and assesses the position and size of the uterus is done. Reviewing the MRI before starting the implant can serve as a useful guide. The irregular shape of the cervix can make visualization of the os difficult. First all debris is swabbed, and then a careful attempt is made to probe the area with the sound in the area where the os should be located. The most common location for a perforation is in the posterior endocervix or the lower uterine segment, behind the cervical tumor. If the cervix is pulled to one side, the cervical os is usually located to the side where the cervix is being pulled.

Ultrasound guidance may prevent creation of a false tract. When using transabdominal ultrasound, the bladder is filled with 200 mL of normal saline (NS). This straightens the uterus and permits easier placement of the tandem. The flexible uterine sound is manually bent into a curve that will follow the curve suggested by the bimanual examination. The sound is advanced with slow and gentle pressure, and the tip of the sound will be visible on the ultrasound images as it ascends to the top of the uterine fundus (Fig. 9.11). If a perforation is detected after placement of the tandem (see Fig. 9.21), the outcome is not affected if the applicator is repositioned before treatment. Once the sound sits in the fundus, the depth of the uterus is recorded by grasping the exposed portion of the sound with a clamp at the cervix, and withdrawing the sound. The sound is measured from its tip to the clamp with a ruler.

Table 9.4 Uterine Sounding Suggestions

· Patient well sedated

· Buttocks on end of bed

· Adequately visualize cervix

· Tilt speculum more anteriorly

· Tenaculum on anterior cervical lip

· Reposition with second tenaculum if indicated

· Cervical dilators

· Fill bladder with 200- to 300-mL NS

· Repeat the above

· Ultrasound

· Call the gynecologic oncologist

· Cervical puncture—extreme cases

NS, normal saline.

Figure 9.21 Sagittal magnetic resonance imaging taken for treatment planning demonstrating inadvertent uterine perforation. This teaches the need for optimal image guidance during applicator placement.

Dilation for an HDR tandem is often easier because the HDR tandem has a smaller diameter than the LDR tandem. Leaving the dilator in place until the tandem is ready prevents spasm of the os. After dilation for HDR, a Smitt sleeve may be kept in place throughout the treatment and for all insertions, but must be removed after completion of the last fraction of brachytherapy.

The selection of the appropriate curvature of tandem is based on the position of the uterus on initial examination. A tandem may be selected in an attempt to straighten the uterus, allowing reduction of dose to the bladder during treatment by drawing the uterus into a midline position. Care must be taken, however, because a straight tandem may perforate an anteflexed uterus and may cause a high rectal dose. In order to construct the tandem, a keel is attached to the tandem. The keel is set on the tandem to the correct depth, as determined by the sound. The keel is tightened with the applicator specific wrench. No keel is present on the HDR tandem/ring or tandem/cylinder applicator, and marker seeds inserted into the cervix may assist with visualization of the cervix.

Once the cervical canal is dilated, the tandem is inserted at the predetermined distance; the most common length is 6 cm, and each LDR cesium source requires 2 cm, allowing for three sources. Firm traction on the suture will assure that the keel remains in contact with the cervix (see Fig. 9.22). Observation of the tandem position during the procedure is important to ensure that it has not rotated. In the event of a retroverted uterus, the tandem is placed to follow the cavity of the uterus and is then gently rotated into the anterior position so as to antevert the uterus.

 

Figure 9.22 A clinical photograph through the speculum demonstrating ideal placement of the high dose rate tandem and keel in the 12 o'clock position. The Foley catheter is draped superiorly out of the operating field.

The largest ovoid is placed into the vaginal fornices to increase tumor coverage. Smaller ovoids or miniovoids have no shielding and were designed to accommodate narrow vaginal vaults with minimal forniceal space. Caps of 2.5 and 3.0 cm diameter are available that fit over the 2.0 cm ovoid. Lubricating gel may be placed on the ovoids for ease of placement in the vagina, and on the inside of the caps to ensure easy removal at the end of the procedure. Built-in tungsten shields may provide an approximately 15% dose reduction to the anterior rectal wall.64

The ovoids are placed into the fornices one at a time, taking care to avoid vaginal lacerations. If the caps are too large, the ovoids may be forced down and away from the cervix and tumor. Smaller caps may be required to assure that the ovoids remain adjacent to the tumor. In situations in which one fornix has been effaced, caps of two different sizes may be needed. Depending on the instrumentation, the ovoids may be either locked together or left unattached. In either situation, it is important to maintain the positioning of the ovoids and tandem so that the keel bisects the ovoids (evaluated on the lateral film), the keel remains straight, and the ovoids rest on either side of the cervix (evaluated on AP film).

Insertion of an Interstitial Implant

A suture is placed at the top of the vagina to retract the vaginal apex during needle insertion. The vaginal obturator is inserted with the suture threaded through the center. A customized disposable gynecology template is positioned over the vaginal obturator. Once the obturator lies at the correct angle, the template is secured by suturing the four corners to the patient's perineal skin. Interstitial flexible sharp catheters and rigid obturators are inserted 1-cm apart through the modified-disposable gynecologic template into the perineum (see Fig. 9.23). A freehand interstitial requires either suturing the needles to skin or using a custom template (see Fig. 9.24). The catheters are numbered for identification and glued to the template to minimize movement during treatment. A record of the catheter number and location is placed in the patient's record for verification at time of loading or with each HDR treatment.

Figure 9.23 A clinical photograph of the external portion of a temporary interstitial template implant. The cervical suture it taken out through the central channel of the vaginal obturator. The catheters are numbered and marked for position. Rigid obturators prevent catheters from kinking between fractions. A Foley catheter is draped to the left for treatment planning. Xeroform gauze is interposed between the thighs and the template so as to prevent skin erosion. Compression stockings, pneumatic calf compression devices, and subcutaneous heparin are used as antithrombotic precautions.

Packing

Packing is a critical portion of the insertion, as it pushes the bladder and rectum away from the highest-dose regions. The potential radiobiologic disadvantages of HDR brachytherapy can be overcome through geometric advantages, packing, and fractionation. In LDR, packing also secures the applicator in place. The amount of packing used will vary between patients.

Packing is carried out using 1-in. wide gauze and the long DeBakey forceps or manual finger insertion. Packing may be coated with regular gynecologic gel or, for patients that are staying overnight, antibiotic impregnated gel. Radiopaque packing can be viewed on a lateral x-ray; CT scan or MRI requires nonradiopaque packing. The goal is to aim for the floor and the ceiling, but not cephalad to the ovoids, in order not to displace the cervix away from the ovoids. As the packing is placed, the retractors are gradually withdrawn. The amount of anterior and posterior packing must be balanced in order to ensure midline placement. The posterior packing is placed first because the tolerance of the rectum is slightly lower than the tolerance of the bladder. Causes of excessive rectal exposure include inadequate packing or caudad displacement of the ovoids. It is important to make sure that the packing is placed between the ovoids, to decrease the dose to the anterior rectal wall, particularly when using unshielded ovoids.

In LDR cases, the stitch may be kept in the cervix and used to provide retraction during packing to prevent pushing the cervix too far superiorly. However, the suture must be removed at the time of applicator removal. A labial suture after completion may secure the system in patients requiring overnight treatment.

Figure 9.24 A clinical photograph of a freehand interstitial implant. Individual catheters can be sutured to the perineal skin with buttons. A perforated Aquaplast grid can further stabilize the implant.

Imaging

Movement of the patient should be minimized, allowing the treatment scan and planning parameters to mimic the position at the time of treatment administration as closely as possible. If the insertion is performed in a dedicated brachytherapy suite or a simulator room, fluoroscopy may be part of the setup; if not, a portable unit can be used. Radiopaque dummy strand markers compatible with the remote afterloading system are placed in the tandem and colpostats, and a magnification ring is placed on the patient's skin. The Foley balloon is tugged securely into the bladder base and the Foley bag is always draped over the patient's left side before filming for consistent location, which may help prevent error for cases in which the loading or dwell times for the ovoids may be unequal.

Once satisfactory geometry has been established, a set of AP, lateral, and oblique orthogonal x-rays are obtained to plan the insertion. The lateral films may require double or even triple exposure at full intensity to get good penetration. A center close to the superior portion of the pubic symphysis is used for AP and lateral views of the pelvis. The field of view should include the entire system and bony anatomy landmarks. The HDR tandem is rigidly immobilized by attaching the stem to an immobilization board. The images and the geometry of the implant must be critically assessed. If either is inadequate, then the process must be repeated. This may include repositioning, repacking, and reimaging as may be needed. X-ray images should show that the tandem bisects the ovoids on a lateral film view. At least 4 cm of space between the two ovoids is necessary (AP film). The tandem should be placed between one third to one half the distance from the pubic symphysis to the sacrum. On plane film, there should be adequate packing blocking the bladder and the rectum away from the ovoids and the high-dose region (see Figs 9.25 and 9.26). Problems include slippage of the ovoids. In an analysis of 808 insertions in 396 patients, the median distance from the tandem to the sacrum was 4.0 cm, or one third the distance from the pubis to the sacrum. The mean distance between the vaginal ovoids and cervical marker seeds was 7 mm, and the median distance between the tandem and the posterior edge of the ovoids was 50% of the ovoid length. Average doses were as follows: to point A, 87 Gy; to the rectum, 68 Gy; to the bladder, 70 Gy; and to the vaginal surface, 125 Gy.65

Figure 9.25 Anterior–posterior treatment planning x-ray of classical low dose rate Fletcher Suit Delclos tandem and ovoid implant. The adequacy of the implant is shown by the relationship of the tandem and ovoid to the cervical markers, the Foley balloon, and the bony anatomy.

If a CT scan is obtained, lateral and AP digitally reconstructed radiographs (DRR) are generated. Fifty milliliters of contrast is instilled in the empty bladder and the Foley is clamped before scanning. If IV contrast is available, this can help visualize the uterine vessels and determine the superior border of the cervix. Scrolling through the CT images allows the physician to note a perforation. If a perforation is detected, the applicator is removed and reinserted under ultrasound guidance, ensuring placement in the center of the uterus. CT images also allow one to contour the bladder, rectum, sigmoid, and tumor volume, permitting dose–volume histogram analysis of the dose to these structures.

Postoperative Orders

Postoperative orders must give attention to diet (clear liquids, advance to low residue as tolerated), fluid management, bed positioning (head of bed at or below 30 degrees during insertion), incentive spirometry, pain and symptom management, maintenance of the patient's routine medications, and antithromboembolic precautions. The development of deep venous thrombosis or pulmonary embolus is a serious concern in patients undergoing surgical procedures for gynecologic malignancies. A standard dose of 5,000 U of heparin is given subcutaneously every 8 hours thereafter until removal of the instruments. In addition, the use of external pneumatic calf compression devices is encouraged for the duration of the time the patient is immobilized.

 

Figure 9.26 Lateral treatment planning x-ray of classical low dose rate Fletcher Suit Delclos tandem and ovoid implant. The lateral film confirms the relationship of the tandem to the ovoids. The radiolucent packing displaces the rectum posteriorly and the bladder anteriorly.

Treatment Planning

Low Dose Rate Treatment Planning

The use of brachytherapy grew in many regions around the world, with each institution developing institution-specific practice guidelines and practices. In Paris, a fixed number of mg-hours was prescribed, whereas in England, Tod and Meredith developed a system relying on point dosimetry.66 They defined a central point, corresponding to an area encompassing the cervix, called point A, which was located 2-cm lateral and 2-cm superior to the cervical os. Instead of the selection of the os as at a midpoint of superior surface of the ovoids, an alternative is to use the flange. The flange must sit superior to the ovoids; if the flange is misplaced, a serious underdosing of the tumor could occur. Point B represents a point 2-cm superior and 5-cm lateral to the cervical os and corresponds to approximate the location of the obturator nodes. Although the intent of defining Point A was not for dose prescription, many institutions use it as a prescription point. The average of the right and left Point A doses can be taken if a single Point A dose is needed. Point A is important for reporting and for communication between institutions and physicians. Table 9.5 lists dose points with definitions.

Selecting the loadings for LDR intracavitary placement and specifying dose is an important aspect of treatment planning. The most traditional approach, the indirect or empirical approach, utilizes standardized placements, loadings, and treatment times. In order to achieve the appropriate dose rate, 35- to 40-mg Ra eq, or approximately 5- to 6-mg Ra eq per cm are placed in a 6- to 8-cm tandem. The most typical superior to inferior tandem loading is generally 15/10/10 mg Ra eq. For bulky disease or an expanded endocervix, increasing the activity in the center of the tandem will widen the isodose distribution. Because a bulky endocervix displaces the normal tissues, this will still yield an optimal therapeutic ratio. A shorter tandem requires higher activity per centimeter.

Table 9.5 Tandem and Ovoid Dose Points

Point A (right and left)

2 cm cephalad from keel or Smitt sleeve, 2 cm laterally from tandem

Point B (right and left)

2 cm cephalad from sail or Smitt sleeve, 5 cm laterally from midline

ICRU rectum

5 mm posterior to posterior vaginal wall as defined by speculum, radiopaque contrast-soaked packing, rectal retractor or the most posterior ovoid position

ICRU bladder

Anterior–posterior film—center of Foley bulb
Lateral film—midposterior position on Foley bulb

Ovoid surface

Dose points placed on lateral ovoid surface for HDR across from dwell positions 2–5 at a distance equal to the radius of ovoid

ICRU, International Commission on Radiation Units and Measurements.

Ovoid loading is generally based on diameter and the presence of shielding, and, on average, a loading of 10 to 20 mg Ra Eq results in a vaginal surface dose rate of between 70 to 100 cGy per hour. The cumulative vaginal surface dose should be limited to 120 to 140 Gy. The dose rate is typically between 40 to 45 cGy per hour to Point A with the FSD system, and the total dose to Point A is usually 40 to 45 Gy in two 48-hour implants. The classical goal was to achieve 6,500 mg Ra hours. This equated to a point A cumulative dose of >80 Gy. The treatment of poorly responsive tumor was more intensive; more activity was placed in the tandem with a higher vaginal surface dose. For asymmetric tumors, the tandem may be tilted, and the ovoid weighting of the sources may be asymmetric to increase the dose to the side of greatest disease. For patients who have vaginal extension, customized cylinders or interstitial catheters with 192Ir needles may be necessary to adequately cover the disease.

High Dose Rate Fractionation and Treatment

Regardless of whether one uses LDR or HDR, the fundamental principles of brachytherapy apply. Computerized dose optimization cannot make up for a very poor applicator position. However, slight errors in applicator placement may be improved with optimization (adjustment of the dwell times). Brachytherapy placed in the vagina and the uterus moves with the organ and the patient. For intact cervix cancer, in addition to substantial internal organ motion, regression of disease during the course of treatment can change the target volume. Multiple fraction brachytherapy plans can be adjusted between placements as the tumor responds.

The HDR optimization of sources results in an approximation of LDR dosimetry. HDR fractionation schedules reported in the literature vary markedly. General guidelines for dose and fractionation are listed in Table 9.6. Point A fractions range from 2 to 7 in number and 3 to 14 Gy, in dose. A typical fractionation scheme is 5 fractions of 5.5 Gy to 6 Gy per fraction to Point A. In an attempt to determine if an optimal HDR schedule exists, Petereit and Pearcey analyzed the fractionation schedules of 24 articles using the LQM to determine if doses can be correlated with local control and complication rates for each stage of cervical cancer.67 The Wayne State Group delivers as many as 12 HDR fractions to counter the potential radiobiologic disadvantages of HDR brachytherapy.60Ogino et al. initially used 8 HDR fractions, but switched to 5 HDR treatments because of patient discomfort and high patient volume.68 The decision to use 3 to 5 fractions, or as many as 10 fractions, must balance patient convenience with radiobiologically preferable fractionation schemes. The current “US standard” of 6 Gy × 5 in combination with 45 Gy to the whole pelvis and cis-platinum has come under questioning by radiation oncologists from other countries. Four studies demonstrating the efficacy of alternative dose fractionation schedules have been recently published. These include the Austrian experience of 7 Gy × 4,69 the Brazilian experience of 6 Gy × 4,25 the McGill experience of 8 Gy × 3,70 and Tata Memorial experience of 9 Gy × 2.71 All schedules include 45 Gy to the whole pelvis—most in combination with cis-platinum. These “cooler” schedules are frequently completed in <50 days. Jones and Dale predicted a 2- to 4- Gy10 equivalent for each pulse of chemotherapy with weekly cis-platinum × 4 during radiotherapy, which may also explain why these schedules are just as effective.72 The International Atomic Energy Agency (IAEA) is currently comparing a four-arm study of 9 Gy × 2 versus 7.0 Gy × 4 plus 45 Gy external beam radiotherapy (EBRT) with or without cis-platinum in developing countries.73 A single international standard has not yet been achieved.

Table 9.6 Guidelines for Radiation Dose and Fractionation

 

LDR

HDR

 

Dose

Number of Fractions

 

Endometrial Cancer

VB onlya

6,000 cGy

1,000

3

 

 

875

4

 

 

750

5

 

 

600

5

 

 

400

6

EB 45Gy + VBa

2,000—3,000 cGy

500

3

 

 

600

3

 

 

675

3

 

 

400

4

EB (45 Gy) + Double tandem (inoperable)

2,500—3,000 cGy or

575

3

 

7,500 cGy (no EB)

650

3

 

 

875

5

Cervical cancer

Tandem/Ovoid onlyb

7,500 cGy

875

5

 

3,750 cGy × 2

775

6

EB + Tandem/Ovoidb

1,750—2,250 cGy × 2

380

8

 

 

525

6

 

 

500

5

 

 

550

5

 

 

600

5

 

 

700

4

 

 

800

3

 

 

900

2

VB onlya

6,000 cGy

1,000

3

 

 

875

4

 

 

750

5

 

 

600

5

 

 

400

6

Vaginal cancer

VBa

7,000 cGy

1,000

3

 

 

900

4

 

 

800

5

 

 

700

5

 

 

500

6

EB (45 Gy) + interstitial

3,000—3,500 cGy

 

 

Recurrence: EB (45 Gy) + interstitial

2,500—4,000 cGy at 50–70 cGy/h

 

 

LDR, low dose rate; HDR, high dose rate; VB, vaginal brachytherapy; EB, external beam.
aDose prescribed at the vaginal surface.
bTandem/Ovoid dose prescribed at point A.

Normal Tissue Dosimetry

The ICRU standardized the reporting of bladder and rectal doses from orthogonal films. The bladder dose points, with 7 mL in Foley balloon, are the maximum dose on the surface of this balloon. The rectal point is 5 mm from the vaginal mucosa, at the level of the bisection of the tandem and ovoids. The vaginal mucosa point is also reported at the level of the ovoids. A note must be made on the written directive regarding the prescribed dose, point A dose, dose rate, implant duration, radionuclide used, source strengths, loading pattern, the type of applicator used, and whether the applicator was shielded or unshielded.

The ICRU estimates of bladder and rectal points may be inaccurate. 3D dose distributions show that the average maximum dose could be as much as 2 times higher than the dose calculated from ICRU reference points.74,75,76,77 A very good approximation exists between the maximum 2 cc dose and the ICRU reference dose for the rectum; however, the ICRU bladder point is a poor surrogate.

The total ICRU bladder and rectal doses should be calculated for both HDR and LDR, in addition to the total BED to the bladder and rectum—Gy3s. A dose threshold for rectal complications begins at 110 Gy3s, increases significantly above 120 Gy3s, and is at least 10% with BED values above 138 Gy3s.78,79 These values correspond to an LQED of 66, 72, and 83 Gy, respectively. If it appears that these values will be exceeded, one should consider repacking the insertion, or increasing the fraction number with a lower dose per fraction.

A 3D assessment results in a better understanding of normal tissue doses and allows the generation of a database of dose–volume histograms. Dose specification guidelines for 3D imaging have recently been proposed by the Groupe Europeen de Curietherapie (GEC), European Society for Therapeutic Radiology and Oncology (GEC-ESTRO).80 The D0.1 cc, D1 cc, and D2 cc for the rectum, sigmoid, and bladder are routinely recorded. The high-risk clinical target volume (HRCTV) includes the area of the gross tumor volume (GTV) plus the entire cervix and the disease present at the time of brachytherapy. The intermediate risk clinical target volume (IRCTV) includes the planning target volume, expands the HRCTV by 1 cm, and takes into account tumor extent at the time of diagnosis.

Quality Control

Because HDR brachytherapy delivers larger doses of radiation over a short period of time, an extensive quality control system must be in place order to identify errors before treatment. Therefore, it is critical that HDR programs consist of a dedicated team composed of a physicist, a dosimetrist, nursing staff, a radiation therapist, and a physician. Once dwell times have been determined by a physicist and dosimetrist, a second team verifies the treatment plan and written directive (see Fig. 9.27). Before therapy commences, the position of the applicators is verified by the physician to check for patient movement. If the patient has moved, the implant must be re-imaged and replanned.

The physician and physicist must assess the written directive and the treatment plan for accuracy. The loading of radiation in LDR and the connections in HDR should be inspected and checked. Possible areas of misadministration in HDR include reversal of channels, incorrect dosage prescription and improper source location. LDR sources are loaded while the patient is in a shielded room with a physician and radiation safety personal present. Radiation safety precautions must be maintained throughout the duration of the treatment according to hospital practices and as per national safety standards. The use of a quality assurance (QA) check sheet has been suggested as a formalized method to minimize error (see Fig. 9.28). As the complexity of brachytherapy increases, the need for routine focused peer review of cases, routine examination of outcomes for new modalities, and analysis of morbidity and mortality also grows. National and international guidelines may continue to guide practice, but are no substitute for an intensely focused institutional QA program.

Figure 9.27 The written directive specifies the site, modality, dose rate, type of applicator or implant, isotope, prescription point, dose per fraction and total dose, as well as other measures of dose specification. Space exists for recording customized drawings for loadings and prescription points. The column on the right provides space for noting the physician approval for each fraction delivered and carries the cumulative dose. Directive modifications are noted in the lines below the directive. The bottom of the form has provision for the physician to sign and for recording the patient's identifications. The prescribed dose is also noted on a regular radiation prescription. If a patient has had EB in addition to brachytherapy, then the cumulative dose must be recorded on the prescription.

Figure 9.28 This clinical worksheet documents that all elements of the written directive have been carried out. The additional second calculation of dwell times, the pre and posttreatment survey, the identification of the patient, the daily quality assurance (QA) of the afterloader, and the signatures of the therapists, physicists, and physicians are recorded on this QA sheet.

Applicator Removal

Care must be taken when removing the applicator in order to avoid a laceration from trauma to the vaginal mucosa. Sutures placed at application must be removed. The packing must be taken out before removing the applicator. Typically, the ovoids are removed one at a time before the tandem. If a Smitt sleeve was placed, it must be removed with the last fraction of HDR. The tip of the tandem should always be covered with a finger at the time of applicator removal in order to prevent a mucosal tear.

Follow-up Care

Patients are instructed to be aware that vaginal discharge is quite common and may last months after applicator removal. Douching can be safely performed, and sexual intercourse resumed, approximately 2 weeks after insertion. Patients are seen in follow-up every 3 months, alternatively by the gynecologist and the radiation oncologist, for a pap smear for the first 2 years, then every 6 months for 3 years, and then annually.

Complications

When performing brachytherapy, determining a dose threshold for normal tissues is critical in order to guide the adequacy of the insertion, and to guide the dosimetry and doses of subsequent insertions—whether LDR or HDR. In LDR brachytherapy, it is common practice to limit the total bladder and rectal ICRU doses to 75 and 70 Gy, respectively, unless this would compromise tumor control. In HDR brachytherapy, these total doses will be lower, but it is not clear how much lower they are. Therefore, in an effort to determine this threshold, a number of series have correlated the total biologically effective rectal dose to complications. Other terms used for rectal BEDs include LQEDs and cumulative rectal biologic dose (CRBED).

Possible short- and long-term complications of LDR and HDR brachytherapy are listed in Table 9.7. Toxicity as per the randomized trials of HDR versus LDR appear to be equal as listed in Table 9.3. Patients who have a high central dose of EB, generally between 4 and 45 Gy, have a significantly higher rate of major small bowel complications, as do patients who have a pelvic lymph node dissection before external beam radiation.

Concurrent chemotherapy with HDR does not appear to increase this risk (see Table 9.8). In one study involving a large fraction size, rectal complications with concurrent cisplatin and HDR was 46% versus 14%.81 Severe rectal perforation with HDR has been reported.82


Uno et al. identified that the depth of the 6-Gy isodose volume determined on 3D has the best predictive value of late rectal complications, suggesting that the shape of the high-dose area influences the incidence of late rectal complications regardless of its volume.83

Table 9.7 Acute and Long-Term Complications from Low Dose Rate and High Dose Rate Brachytherapy

Acute

Late

Uterine perforation

Proctitis

Vaginal laceration

Ulceration of bladder or rectum

Fever

Fistula

Thrombotic events

Stricture

Anesthesia-related nausea

Vaginal stenosis

Table 9.8 Fractionation and Toxicity of High Dose Rate and Concurrent Chemotherapy

 

HDR

Toxicity (%)a

 

 

Dose (Gy)

No. of Fractions

Number of Chemo

Chemo

Follow-up (months)

 

Tseng et al.59b

4.3

6

6.5 (GI)

10 (GI)

47

 

 

 

 

3.2 (GU)

3.3 (GU)

 

 

Pearcey et al.52bc

8

3

9 (GI)

5 (GI)

82

 

 

 

 

7 (GU)

10 (GU)

 

 

Sood et al.84d

9

2

5 (GI)

5 (GI)

36

 

Saibishkumar et al.85d

9

2

1.1 (GI)

1.8 (GI)

39

 

 

 

 

1.0 (GU)

0 (GU)

 

 

Sood et al.86d

9

2

10

6

28

 

Ozsaran et al.87e

8.5–9

1–2

0

0

20

 

Petera et al.88

4

6

0

36

 

Pötter et al.89

7

4f

0 (GI)

33

 

 

 

 

 

2 (GU)

 

 

Souhami et al.90e

10

3

28 (GI)

27

 

 

 

 

 

6 (GU)

 

 

Strauss et al.91e

7

5

3.7 (GI)

19

 

 

 

 

 

3.7 (GU)

 

 

aGrades 3–5 late complications
bProspective randomized trial
cIncludes HDR, MDR, and LDR
dRetrospective comparison of patients treated with and without chemotherapy
eRetrospective review, all patients received chemotherapy
f 5–6 fractions for patients with small tumors.
LDR, low dose rate; MDR, medium dose rate; HDR, high dose rate.

 

The University of McGill Group was the first to publish on a correlation between rectal complication and fraction size. Their initial fractionation schedule was 30 Gy in 3 HDR fractions to point A, in conjunction with 46 Gy to the whole pelvis at 2 Gy per fraction.78,79,81,92 A dose response relationship was observed with a threshold appearing above 125 Gy 3s.78,79 Ogino et al. also reported a positive correlation between increasing rectal Gy 3s and rectal complications with a similar threshold.68,93 Chen reported a threshold at 110 Gy 3s (CRBED): 19.6% complication rate with a CRBED <110 and 36.4% with a CRBED >110.93 For patients with stage IIB–IVA disease, other risk factors for developing a rectal complication included cumulative rectal dose (EB and total ICRU rectal dose) >65 Gy and age >70. Chen's data suggested that the total rectal dose should be <65 Gy.93

Endometrial Cancer

Vaginal Cylinder

Postoperative therapy with a vaginal cylinder (see Figs 9.29A, B, and C) requires a careful examination of the vaginal apex and mucosa before insertion, in order to determine the diameter and length of the cylinder to be used. The goal is to insert the cylinder with the largest diameter feasible without significant discomfort. A smaller cylinder may not apposition to the mucosa of the upper vagina and may decrease the mucosal surface dose. The radiation may be either LDR or HDR. Patients are placed in the frog-leg position on a flat table in the treatment room and the cylinder is inserted. No sedation is usually required for most cylinder insertions. To ensure satisfactory placement, gentle apical pressure is applied before stabilizing the applicator in place. With HDR, the applicator is attached to an immobilizing board that rests on the treatment table. Ovoids may be used as an alternative. With LDR, patients must stay in a hospital bed for several days; LDR cylinders may not provide a uniform dose rate to the vaginal surface because of anisotropy and lack of optimization. This effect may be seen especially over the dome of the surface of the applicator.

Figure 9.29 A: Clinical photograph of the placement of a high dose rate vaginal cylinder for postoperative brachytherapy for endometrial cancer. The cylinder should fit snugly into the mucosa at the cuff. Pretreating the vaginal mucosa with lidocaine jelly and some gentle manual dilatation help to minimize discomfort. The very anxious patient may benefit from some gentle sedation/anxiolysis. B: The stem of the applicator is fixed in position with an immobilizing board placed on the table between the legs. The thighs are rested on cushions. C: Treatment planning computed tomography scan confirms good position and allows for calculation of bladder, and rectal doses.

The target length of treatment is controversial, as most failures treated with surgery alone occur at the vaginal apex. Some patients may be spared the morbidity of undergoing treatment for the entire length. Most patients are treated at the upper one half to two thirds of the vagina. Figure 9.30 shows HDR CT-optimized treatment plan isodoses for a postoperative patient with endometrial cancer. Patients who have papillary serous or clear cell histology or lymphovascular space invasion usually receive treatment to the entire vaginal length because of the larger area that is at risk for recurrence.

Increased complications are noted with higher total dose and dose per fraction. Sorbe et al. compared 4 fractionation schedules among 404 patients receiving postoperative vaginal brachytherapy (VB) alone.94 An 87% incidence of late complications using 9 Gy per fraction was observed. After cylinder treatment, all patients must be educated in the use of a vaginal dilator if not sexually active to prevent dense adhesions in the superior vagina. These adhesions can cause pain on intercourse and greatly inhibit the clinical examinations during the follow-up. However, use of the dilator may result in some vaginal spotting from weakened mucosa and telangiectasia formation. Patients should not have intercourse or dilatation for approximately 2 weeks, to avoid irritation or bleeding.

Figure 9.30 Coronal isodose distribution of computed tomography–planned computer-optimized high dose rate cylinder brachytherapy. Optimization allows the gentle bowing out of the isodose lines at the location of the vaginal cuff.

Double Tandem

Medically inoperable endometrial cancer may have a double tandem placed for the boost component of therapy or for palliative endpoints (see Figs 9.31 and 9.32). These HDR applicators are available with or without the attached cylinder component. Simon capsules are available in both HDR and LDR versions, though the additional coverage from the capsules may be minimal in addition to that provided by the double tandem applicator. The treatment isodose distribution should cover the outer surface of the uterus and give an adequate dose to the gross disease(see Figs 9.33, 9.34 and 9.35)

Cancer in the Vagina

Tumors of the vagina, including vaginal cancer, recurrent endometrial or cervical cancer, or selected vulvar cancer cases with significant vaginal extension may involve the vaginal apex, lateral vaginal walls, or the upper/mid/distal anterior or posterior vagina.

 

Figure 9.31 Clinical photograph of the Martinez applicator. This double tandem intrauterine/vaginal two-channel high dose rate applicator is for the clinical setting of inoperable endometrial cancer and can carry radiation dose to the proximal vagina. The tandems are inserted separately but are attached to grooves in the cylinder to obtain a fixed geometry.

Figure 9.32 Clinical photograph of the Horiot high dose rate applicator. This double tandem intrauterine applicator is inserted in parts and then fixed together with a retaining screw and grooves.

 

Figure 9.33 Anterior–posterior treatment planning x-ray of Martinez applicator in place with three additional Simon capsules. Each channel has a unique dummy marker. The channel identities are carefully recorded on the films and in the written directive. Note the pale silhouette of the vaginal cylinder.

Figure 9.34 Right lateral treatment planning film of the same case as in Figure 9.33 with the rectal and bladder reference points.

 

Figure 9.35 Coronal isodose distribution superimposed on anterior–posterior treatment planning film to demonstrate conformality of dose distribution.

Vaginal Cylinder

For very superficial lesions involving the vaginal apex, an intracavitary LDR or an HDR cylinder monotherapy may suffice. Stage I vaginal cancer is treated with a cylinder if the cancer has <5-mm depth, or with an interstitial implant if the cancer has >5-mm depth. Approximately 6,000 cGy LDR is given for in situdisease, while 6,500 to 8,000 cGy is administered for invasive cancer. Shielded cylinders are also available for additional HDR boost doses (see Figs 9.36 and 9.37).

Interstitial: Template or Freehand

Interstitial implants may be performed under laparoscopic, MRI or CT guidance. If an open laparotomy or laparoscopy is performed, the omentum may be brought down over the needles to displace rectum and bladder and move the small bowel away from the tips of the needles. MRI or CT-guided brachytherapy, available at some institutions, enables the contouring of the target, rectum, bladder, and sigmoid (see Figs 9.38, 9.39, 9.40 and 9.41) and performing the dose–volume histogram analysis. Figure 9.41 demonstrates the added soft tissue definition available with CT-MR fusions.

A stitch is placed through the apex of the vagina, close to the tumor. The suture is then threaded through the center of the obturator and attached to a corner of the template. The obturator should always be pressed flush against the vaginal apex. For lateral vaginal wall lesions, a freehand technique may be done successfully while palpating the tumor in the vagina. For suburethral lesions, use of perforated Aquaplast material may decrease the divergence of freehand placement in order to ensure parallel positioning. In patients with lesions close to the bladder, placement of methylene blue in the bladder and the use of open-ended needles will show the blue dye through the needle tip if the bladder is punctured. A dose distribution from a template interstitial implant for a large lower vaginal lesion is shown in Figures 9.42, 9.43 and 9.44. If the target volume is indistinct, or there are critical structures close to regions of high dose, intensity modulated radiotherapy (IMRT) may also be considered if the tumor is fixed and internal organ motion is not an issue.

Figure 9.36 A high dose rate shielded cylinder applicator kit. Outer hollow plastic cylinders of 2.0, 2.5, 3.0, and 3.5 cm admit the same central stem, varying quartiles of steel shielding and the retaining screw cap. Shielding of 25%, 50%, or 75% can be achieved. Isodose distributions directly mimic the geometry of this shielding.

Figure 9.37 A high dose rate shielded cylinder is assembled. The location of the steel shielding segments is seen through the retaining plate of the central stem and continues to be visible at the external end of the cylinder after insertion into the patient. The dose will be delivered in the quartile segment(s) where the shielding pins are not seen. Plastic shielding surrogates are available for computed tomography–based planning.

 

Figure 9.38 Computed tomography scan–based computer-optimized interstitial brachytherapy showing highly conformal isodose lines and excellent bladder and rectal sparing.

Figure 9.39 This is the same case as that in Figure 9.38, demonstrating the vaginal obturator, interstitial catheters, intrarectal contrast, and Foley catheter without contrast. The small bowel in the region of the implant is carefully evaluated for the risk of inadvertent puncture as well as for dose to this organ at risk.

 

Figure 9.40 Computed tomography scan–based computer-optimized interstitial brachytherapy for more dominantly left-sided tumors. Note the excellent conformance of dose to contoured tumor with sparing of bladder and rectum.

Complications are, in general, more common in patients with advanced disease. Normal tissue destruction from proximity of the tumor to critical structures may have occurred, and high dose may be necessary to eradicate large volumes of tumor. In general, carefully tailored radiation therapy can achieve high control rates, but treatment should be individualized to the patient, tumor, and tumor location.

Figure 9.41 The same case as in Figure 9.40 but with magnetic resonance.

 

Figure 9.42 Coronal reconstruction of computed tomography–based computer-optimized interstitial implant of a lower vaginal tumor.

Figure 9.43 Sagittal reconstruction of the same case as in Figure 9.42 demonstrating rectal, small bowel, and bladder sparing.

 

Figure 9.44 An identical projection on the same implant as Figures 9.41 and 9.42 for magnetic resonance imaging.

Palliative Care

Palliative clinical scenarios that warrant consideration of palliative brachytherapy are highly varied. Patients with symptomatic vaginal bleeding should be treated early in the course of bleeding to prevent a significant blood loss. Other symptoms that may mandate palliative consideration include pain in the vagina from recurrent cancer. In the setting of patients who have already received EB or brachytherapy, the dose of brachytherapy must be closely monitored and tolerances of the vaginal respected, including limiting the introitus to no more than 80 to 90 Gy.95

Summary

Brachytherapy is an integral and necessary portion of the modern multimodality treatment for patients with most gynecologic malignancies for achieving optimal cure rates. However, treatment must be individualized, including the selection of dose rate, applicator type, and total dose, in order to maximize potential cure and minimize overall complication rates. Gynecologic brachytherapy requires a significant level of expertise as well as a team of professional caregivers around the patient.

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