Brian G. Czito
Nasir H. Siddiqi
Harvey J. Mamon
Christopher G. Willett
Brachytherapy in the Treatment of Gastrointestinal Malignancies
Brachytherapy is the temporary or permanent insertion of radioactive sources into a tumor and/or peritumoral tissues. In many gastrointestinal malignancies, treatment with conventional radiation and chemotherapeutic approaches results in high rates of local–regional failure. Brachytherapy permits focal dose escalation of the tumor and peritumoral tissues, resulting in higher effective doses of radiation therapy with sparing of the surrounding normal tissues. This dose escalation should result in improved local control. Although a number of isotopes are available for brachytherapy (226Ra, 60Co, 137Cs, 192Ir, and 90Sr), 192Ir is the most widely used source in clinical practice given its high specific activity, short half-life, and ease in shielding. Brachytherapy implants are categorized as interstitial or intracavitary, depending on whether the source is placed directly into tumor-bearing tissues or into a body cavity. Both techniques have been used in the treatment of gastrointestinal malignancies, including at the time of surgery (i.e., intraoperative radiotherapy). The use of these techniques in gastrointestinal malignancies is discussed in the following text.
Esophageal Cancer
An estimated 14,500 new cases of esophageal cancer will be diagnosed in the United States in 2005.1 The standard treatment modalities include radiation therapy, chemotherapy, and/or surgery. For early stage disease, resection may be an appropriate treatment option. In most patients with locally advanced disease, radiation therapy with chemotherapy, with or without surgery, is frequently used. In medically inoperable/unresectable esophageal patients, a Radiation Therapy Oncology Group study demonstrated improved 3-year local control and survival with the addition of concurrent cisplatin and 5-flourouracil to radiation therapy compared with radiation therapy alone (32% vs. 54% and 0% vs. 30%, respectively).2 Despite this, contemporary chemoradiation approaches result in poor local control rates; approximately 50% of treated patients will develop local failure (see Table 7.1). Similarly, surgery results in poor survival outcomes and high local failure rates; contemporary studies have reported 3-year survival rates of 6% to 23%.3,4,5
Because local–regional failure is frequent after conventional chemoradiation approaches, investigators have evaluated dose escalation techniques. A randomized Intergroup trial comparing two combined modality regimens using moderate or high-dose external beam radiation therapy (EBRT) doses (50.4 Gy vs. 64.8 Gy) in patients with squamous cell and adenocarcinoma histology showed no benefit in survival or local control for patients receiving high-dose radiation therapy.6 Other investigators have studied brachytherapy techniques as a dose escalation technique.
|
Table 7.1 Nonoperable Esophageal Cancer—Randomized Phase III Trial Results Using Concurrent External Beam Radiation and Chemotherapy |
||||||||||||||||||||
|
Gaspar et al. reported the results of a prospective trial evaluating intraluminal brachytherapy in patients with nonoperable esophageal cancer. Patients initially received 50 Gy of EBRT with concurrent chemotherapy, followed by a 2-week break and brachytherapy administration. Patients received either 15 Gy using high dose rate (HDR) techniques over 3 consecutive weeks (5 Gy per fraction) or a single administration of 20 Gy using low dose rate (LDR) techniques. The treatments were accomplished by the placement of a 10–12 French applicator inserted transnasally or transorally. The target length was defined as the pretreatment tumor length with a 1-cm margin proximally and distally, as determined by computed tomography (CT) scan, barium swallow, and endoscopy. EBRT and brachytherapy were given concurrently with 5-fluorouracil (5-FU) chemotherapy. Dose was prescribed to 1 cm from the source axis. Following the development of fistulas in six patients, the HDR dose was reduced to 10 Gy in 2 fractions. The LDR arm was ultimately closed because of poor accrual. The results showed a median survival of 11 months in all patients. Local persistence/recurrence was observed in 63% of 49 eligible patients receiving HDR therapy. Six patients developed esophageal fistulas, resulting in three deaths. These fistulas were deemed treatment related. The 1-year actuarial fistula development rate was 18%. The investigators conclude that esophageal brachytherapy, particularly in conjunction with chemotherapy, should be approached with caution.8Review of other combined brachytherapy/EBRT series suggests that fistula formation rates range from 0% to 12%, with a possible trend toward a higher incidence in patients receiving concurrent chemotherapy with brachytherapy. The incidence of brachytherapy-related mortality varies from 0% to 8%, with most series reporting rates at 4% or less.9 Table 7.2 shows study results of these techniques.
Other studies have suggested that HDR brachytherapy is effective for palliation of dysphagia in up to 90% of patients.9 Danish investigators described 209 patients with dysphagia due to inoperable esophageal or gastroesophageal junctional tumors. Patients were randomized to either endoscopic stent placement or single-dose HDR brachytherapy. Patient exclusion criteria included tumors >12 cm, tumors within 3 cm of the upper esophageal sphincter, deeply ulcerated tumors, tracheoesophageal fistula/tracheal involvement, presence of a pacemaker, and previous radiation treatment or stent placement. Brachytherapy was delivered through a flexible 1-cm applicator, delivering a dose of 12 Gy prescribed to 1 cm from the source axis. The treatment length was defined as gross disease plus 2 cm proximally and distally. Sucralfate and omeprazole were prescribed for 1 month following brachytherapy for odynophagia prophylaxis. Although trial results showed a more rapid improvement in dysphagia following stent placement, long-term dysphagia relief was significantly improved in the group receiving brachytherapy. Patients undergoing brachytherapy experienced more days with low-grade/no dysphagia compared with patients with stent placement. Complication rates were higher following stent placement (33% vs. 21%), primarily due to an increased incidence of late hemorrhage in the stent group. The authors concluded that single-dose brachytherapy is preferable to stent placement as the initial treatment for patients with progressive dysphagia due to inoperable esophageal or gastroesophageal junction carcinoma.16
|
Table 7.2 Comparative Toxicity Rates of Selected Brachytherapy Series in Esophageal Cancer |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sur et al. reported a randomized study evaluating 232 patients with advanced squamous cell carcinoma (>5 cm). Patients with cervical esophageal disease, disease extending <1 cm from the gastroesophageal junction, tracheoesophageal fistula, poor performance status, or vascular involvement were excluded. Patients were randomized to two brachytherapy regimens (18 Gy in 3 fractions on alternating days or 16 Gy in 2 fractions on alternating days). The treatment was delivered with an HDR 192Ir source, with dose prescribed to 1 cm from the source axis. A 2-cm margin around the gross disease was used proximally and distally. Dysphagia-free survival and overall survival were similar between the two groups (7.1 and 7.9 months overall, respectively). The rates of stricture and fistula formation were similar between the two groups (25 and 23 patients, respectively). The authors concluded that fractionated HDR brachytherapy alone is an effective method of palliating advanced esophageal cancer.13
|
Table 7.3 Selection Criteria for Brachytherapy in the Treatment of Esophageal Cancer |
|||||||||||||||
|
|||||||||||||||
|
Table 7.4 Suggested Schema for Definitive External Beam Radiation and Esophageal Brachytherapya |
||
|
For patients treated with curative intent (unifocal thoracic tumors <10 cm, no distant metastases and no airway involvement or cervical esophageal location), the American Brachytherapy Society recommends a brachytherapy dose of 10 Gy in 2-weekly fractions of 5 Gy each (HDR) or 20 Gy in a single course at 0.4 to 1 Gy per hour (LDR). The dose is prescribed to 1 cm from midsource and delivered through a 6- to 10-mm applicator. The recommended active length is the visible mucosal tumor with a 1 to 2 cm proximal and distal margin. Ideally, brachytherapy is started 2 to 3 weeks following completion of concurrent EBRT/chemotherapy to allow mucositis resolution. Concurrent chemotherapy with brachytherapy is not recommended. In palliative cases, a similar approach is recommended, with delivery of 10 to 14 Gy in 1 to 2 fractions (HDR) or 20 to 25 Gy in a single course (LDR). In poor performance patients, a dose of 15 to 20 Gy in 2 to 4 fractions (HDR) or 25 to 40 Gy (LDR) is recommended. Table 7.3 describes selection criteria for brachytherapy in the treatment of esophageal cancer. Tables 7.4 and 7.5 summarize the treatment recommendations. The techniques were described in Chapter 6.
|
Table 7.5 Suggested Schema for External Beam Radiation and Brachytherapya in the Palliative Treatment of Esophageal Cancer |
||
|
Pancreatic Cancer
Pancreatic cancer remains a formidable malignancy. In 2005, an estimated 32,180 cases were diagnosed in the United States with 31,800 deaths.1 Mortality rates exceeded 95%. Most patients with pancreatic cancer presented with either locally advanced (45%) or metastatic (40%) disease. In the former group, combined EBRT and 5-FU-based chemotherapy were commonly used, resulting in improved local control and survival.17 However, local–regional failure remains the predominant mode of failure (50% to 80%) in patients with locally advanced disease. These high rates are due to the persistence of residual disease following conventional EBRT approaches.
Because of poor local control rates achieved with EBRT and chemotherapy approaches, brachytherapy for dose escalation has been investigated. Most reports of brachytherapy in pancreatic cancer involve the placement of interstitial sources at laparotomy in patients with locally advanced tumors. Early reports from the Massachusetts General Hospital described the interstitial placement of 125I seeds followed by EBRT with chemotherapy, delivering a dose of 160 Gy. These authors reported an actuarial 2-year survival and local control rate of 20% and 75% respectively.18 Eighty-one patients with locally advanced disease from Thomas Jefferson University were treated with 125I implantation, EBRT, and perioperative chemotherapy. Seeds were implanted to ensure a minimum dose of 120 Gy, followed by EBRT (50 to 55 Gy) and systemic therapy. Perioperative mortality was seen in 5% of patients (three cases of fulminant pancreatitis/abscess formation). Early morbidity was noted in 34% of patients, whereas late complications were observed in 32% of patients. Median and 5-year survivals were 12 months and 7%, respectively. Local control was achieved in 71%. Late complications included gastrointestinal bleeding, cholangitis, enteritis, and gastric/bowel obstruction. The authors concluded that combined modality therapy with 125I achieved high local control rates and long-term survival in select patients.19 Investigators from the University of Pennsylvania described 43 patients with locally advanced disease undergoing 125I implantation. When compared with similarly matched patients treated with intraoperative electron radiotherapy, patients receiving brachytherapy experienced higher complication rates (40% vs. 18%). Median survival in the brachytherapy group was 15 months. The authors concluded that intraoperative irradiation could be administered with fewer complications than 125I seed implantation.20 Investigators from Memorial Sloan-Kettering Cancer Center described 11 patients with locally advanced pancreatic carcinoma treated with 103Pd brachytherapy followed by EBRT and/or adjuvant chemotherapy. Median peripheral dose was 124 Gy. Local control was achieved in 45% of patients. Four patients experienced acute postoperative complications, whereas one patient suffered from radiation enteritis. Patients receiving >115 Gy were more likely to develop complications, and median survival in these patients was 1.7 months. The authors concluded that 103Pd brachytherapy as a component of treatment of locally advanced disease did not improve survival and was associated with high complication rates.21 German investigators described 19 patients with locally advanced pancreatic carcinoma receiving 10 to 34 Gy using 1.9 to 5 Gy fractions with HDR 192Ir, followed by EBRT with varying chemotherapy regimens. Local control was achieved in 70% of patients and brachytherapy was well tolerated.22
In a review of approximately 300 cases, Dobelbower et al. concluded that interstitial brachytherapy, when combined with EBRT and systemic chemotherapy, provided the best possible local control for locally advanced patients, although seed placement was generally described as a “hazardous procedure in most hands.” They recommended that pancreatic interstitial implantation be undertaken by experienced physicians at facilities with capability to deal with possible severe complications.23 In summary, focal dose escalation using brachytherapy techniques may result in improved local control in patients with locally advanced pancreatic cancer. However, the development of acute and late brachytherapy-related complications is common. Because of the propensity for the development of distant metastases, ultimate success in the treatment of this disease will likely come from improvements in systemic therapy.
Biliary Cancers
Carcinomas of the gallbladder and biliary system are uncommon, with an estimated 7,500 new cases in the United States in 2005.1 Most patients with biliary cancers present with unresectable or metastatic disease, resulting in an overall 5-year survival rate of <5%.24,25 Surgery is the only potentially curative option for patients with biliary carcinoma; however, only 10% to 35% of patients are potential surgical candidates at presentation.26,27,28 In resected patients, outcome is closely associated with the pathologic findings of the depth of tumor penetration and nodal metastases.
In patients who are resected for cure as well as in unresectable patients, the prognosis remains poor with local–regional failure being a dominant mode of failure and source of mortality.29,30 Single institutional series have suggested that dose escalation in patients with biliary cancer may result in improved outcomes.27,31,32 However, these results are likely confounded by heterogeneous disease stages and patient performance status with respect to dose selection. Most patients with cholangiocarcinoma treated with EBRT alone will die of disease-related local progression and biliary obstruction. Standard doses of EBRT are insufficient to reliably eradicate all diseases. Given high local failure rates, dose escalation using brachytherapy techniques is rational.
Usually, brachytherapy treatments are delivered through a percutaneous transhepatic biliary drainage (PTBD) tube under fluoroscopic guidance or through catheters placed in the tumor bed during surgery. Typical doses delivered with intraluminal therapy range from 20 to 30 Gy prescribed to 0.5 to 1 cm from the 192Ir source within the duct (LDR). Treatments are generally delivered along with a course of EBRT (45 to 50.4 Gy in 25 to 28 fractions) to achieve dose escalation.
Although no randomized trials comparing combined EBRT with brachytherapy or different combinations have been undertaken, reports have suggested improved survival for patients receiving combined treatment. Combined treatment may also provide durable palliation.33,34,35 Occasional reports have even described long-term survival in unresectable patients with the use of EBRT with transcatheter brachytherapy boost. Foo et al. reported the Mayo Clinic experience in which 24 patients with unresectable extrahepatic biliary ductal cancers were treated to a median EBRT dose of 50.4 Gy in 28 fractions and a median brachytherapy boost of 20 Gy delivered at 1-cm radius. Median survival for all patients was 12.8 months and the 5-year survival was 14%. Three patients were still alive at the time of the report at 10, 8.2 and 6.9 years following diagnosis. These authors recommended that 192Ir catheter brachytherapy boost be limited to 20 to 30 Gy when combined with EBRT 45 to 50 Gy in 25 to 28 fractions.36 Japanese investigators described 93 patients with unresectable extrahepatic bile duct carcinoma (including patients with metastatic disease) who received EBRT and 192Ir boost. EBRT was delivered at 2 Gy per fraction to a total dose of 50 Gy followed by intraluminal boost to a mean dose of 39 Gy (range 20 to 50 Gy). Median survival for all patients was 12 months with 1- and 5-year survivals of 50% and 4%, respectively. Four patients survived longer than 5 years. The local–regional failure rate was 44%, usually associated with distant metastases. No dose–response relationship to survival was observed.37
In addition to enhanced survival, the combination of EBRT and intraluminal brachytherapy may extend stent patency for patients with locally advanced biliary carcinoma. Eschelman et al. described a mean stent patency of 19.5 months and mean survival of 23 months for 11 patients with cholangiocarcinoma treated with EBRT and brachytherapy. This compared favorably with the surgical literature using stenting alone for malignant biliary obstruction (mean stent patency ranging 5 to 10 months).34 In the previously described Japanese series, 88 patients underwent metallic stenting followed by EBRT/192Ir brachytherapy for unresectable disease. Forty-nine percent of patients developed reobstruction at a mean duration of 11.6 months following treatment. In half of these patients, the cause was deemed to be tumor recurrence. Cumulative biliary patency rates at 1 and 3 years were 52% and 29%, respectively. In 20 patients undergoing autopsy, 17 showed no evidence of tumor-related obstruction. Nonmalignant causes of obstruction included debris, stones, and bleeding.37 Figure 7.1 depicts the placement of intraluminal 192Ir seeds through a PTBD tube.
|
|
|
Figure 7.1 Placement of intraluminal 192Ir seeds through a percutaneous transhepatic biliary drainage catheter. Varying pencil marks are used to identify radioactive seeds within the catheter. In contrast to high-activity 192Ir sources, a low-activity source is usually left in place for 24 to 48 hours to deliver the prescribed dose of radiation. |
In contrast to LDR brachytherapy, HDR brachytherapy uses a high-activity source, allowing rapid dose delivery compared with LDR techniques. University of Miami investigators reported a phase I/II dose escalation trial utilizing HDR brachytherapy. Eighteen patients with unresectable or subtotally resected extrahepatic biliary duct carcinoma received 45 Gy EBRT with concurrent 5-FU chemotherapy and HDR brachytherapy, using either 1-, 2-, or 3-weekly fractions of 7 Gy delivered at 1-cm depth. Median and 2-year survival was 12.2 months and 28%, respectively. Three patients survived longer than 5 years. Improved response was seen with increasing doses in the three groups (median survival 9 months vs. 12 months vs. 20 months). The authors concluded that HDR brachytherapy of 21 Gy in three divided weekly treatments with 45 Gy and 5-FU-based chemotherapy is well tolerated.38 At the University of Heidelberg, 30 patients undergoing palliative resection or with locally advanced tumors received HDR therapy using 192Ir. Most patients received weekly fraction sizes of 5 to 10 Gy, to a total dose of 20 to 45 Gy, along with EBRT to doses of 30 to 45 Gy. Median survival for the entire group was 10 months, with a 3-year survival rate of 8%. Seven patients developed duodenal ulceration; however, there was only one case in patients receiving 20 Gy in 4 fractions. The authors concluded that a treatment schedule of 40 Gy EBRT along with 20 Gy (5 Gy × 4) by HDR brachytherapy was appropriate for the treatment of cholangiocarcinoma (see Figs. 7.2 and 7.3).35
Given the caveats of patient selection and other uncontrolled factors, retrospective data suggests improved survival for locally advanced patients receiving intraluminal brachytherapy. The addition of intraluminal radiotherapy to EBRT may be beneficial, likely due to the increased delivery of radiation dose to the primary tumor along the bile ducts, where the largest volume of gross disease exists. Table 7.6 summarizes the outcome of selected series utilizing intraluminal therapy.
|
|
|
Figure 7.2 Three-dimensional dose-optimized plan for high dose rate boost for Klatskin tumor. |
Colorectal Cancer
In 2005, an estimated 145,290 cases of colorectal cancer were diagnosed in the United States, with an estimated 54,200 deaths.1 Surgery remains the primary treatment, with curative resection possible in 75% of patients. Disease relapse is common. Tumors arising above the peritoneal reflection generally recur in the liver and/or peritoneal cavity. However, when disease is at or below the peritoneal reflection, pelvic failure is common, often within the mesorectum. On the basis of these patterns of failure, adjuvant chemotherapy is often delivered in patients with stage II/III disease arising above the peritoneal reflection, with resultant improvement in disease-free and overall survival rates.41,42,43 For patients with disease at or below the peritoneal reflection, the delivery of neoadjuvant or adjuvant radiation therapy with chemotherapy improves local control as well as survival.44,45,46 However, in this latter group, recurrence in the pelvis with involvement of adjacent organs/structures remains a significant cause of morbidity and mortality. Therefore, investigators have evaluated brachytherapy as a tool for dose escalation in select patients with anorectal cancers. Brachytherapy techniques used in the treatment of colorectal and anal tumors include interstitial implant, intraluminal (endocavitary) therapy and intraoperative irradiation therapy (IORT).
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Figure 7.3 Combined external beam radiation therapy and brachytherapy planning allows for composite isodose distribution and dose–volume histogram analysis. |
||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Table 7.6 Outcome of External Beam Radiotherapy Plus Brachytherapy for Biliary Cancers |
||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Interstitial brachytherapy is usually used with EBRT to allow focal dose escalation to the tumor. The templates used in the interstitial implantation of anal and rectal tumors vary. One method utilizes a plastic template sutured to the perianal skin. Steel guide needles are introduced through the template holes (usually spaced by 1 cm), through the skin and into the wall of the anus or rectum, depending on the tumor location (see Fig. 7.4). The needle path is guided manually to assure appropriate placement. Needles are placed in parallel, which can be confirmed by fluoroscopy before source loading (see Fig. 7.5). Afterloading with low-dose 192Ir wires is then performed, with a dose of 15 to 30 Gy delivered over 18 to 36 hours. Another approach, described as the “steel fork” technique, is generally reserved for rectal cancers >6 cm above the anal verge. This technique uses two 192Ir preloaded, hollow, 4-cm prongs attached to a base plate, separated by 16 mm. The patient is placed in the knee chest position and the implant is accomplished through a proctoscopic applicator. The “fork” is placed approximately 1 cm below the tumor and kept in place with packing sutured to the anal margin. Generally, a dose of 15 to 30 Gy is delivered to a reference isodose line over 12 to 30 hours. Another method, referred to as the “plastic loop” technique, can be performed after local excision. This consists of placement of two metallic needles on either side of a closed surgical scar, within the rectal wall. A plastic loop is then positioned in place of the two needles and afterloading with 192Ir is performed. Intraluminal brachytherapy techniques vary, with more common approaches utilizing a 1- to 2-cm diameter cylinder with peripherally situated catheters. The applicator is introduced into the rectum, followed by afterloading with 192Ir sources. Generally, doses of 4 to 8 Gy prescribed 0.5 cm from the cylinder surface are delivered. More recently, techniques using HDR sources have been adopted.
Gerard et al. described 62 patients with T2-3 rectal adenocarcinoma arising in the mid-rectum. Patients were treated with contact x-ray therapy (80 Gy in 3 fractions over 3 weeks) followed by EBRT (39 Gy in 13 fractions with a concomitant boost of 16 Gy in 4 fractions).
Following a 4- to 6-week interval, an 192Ir implant was performed, generally using a perineal template for lower tumors or a “rectal fork” for higher situated tumors. Median dose for all implants was 20 Gy over 22 hours, calculated to the 85% isodose or Paris system “basal dose.” Brachytherapy was not performed in seven patients. Local control of the primary tumor was achieved in 63% of patients. Overall pelvic disease control including surgical salvage was 73%. T stage was a strong prognostic factor, with 5-year overall survival rates (in patients <80 year old) of 84% and 53% for T2 and T3 lesions, respectively.47Papillon et al. described 90 patients with “limited” T1-2 rectal cancers treated with combined contact x-ray therapy and 192Ir implant using an iridium fork. The 5-year disease-free survival and anal preservation rates were 78% and 75%, respectively. Three patients underwent salvage abdominoperineal resection for local failure. Among cured patients, the anal preservation rate was 96%. These investigators also described 82 patients with low-lying T2-3 tumors judged to require abdominoperineal resection. Most patients were elderly and poor surgical risk patients (median age 75). Patients were treated with split course EBRT followed by 192Ir implant. Four-year disease-free survival was 60%, and eight patients developed local failure. Among disease-free patients at 4 years, almost all patients retained normal anal function. The investigators concluded that interstitial therapy should be considered in the conservative treatment of most cancers of the anal canal and select low rectal cancers.48
|
|
|
Figure 7.4 192Ir template with four needles for a single plane implant, with the template sutured to perineal skin. |
|
|
|
Figure 7.5 Anteroposterior x-ray film verifying needle placement, with Foley balloon of urethral catheter. |
Investigators from McGill University reported a phase I/II study enrolling 49 patients with potentially resectable T3-4, bulky rectal adenocarcinoma treated with preoperative HDR therapy. Patients underwent endorectal ultrasound and magnetic resonance imaging (MRI) for tumor staging. Radiopaque clips were placed during proctoscopy to mark the proximal and distal tumor margins and for positional quality control. All patients underwent three-dimensional treatment planning. Patients received treatment through an endorectal applicator consisting of a central flexible tube with 192Ir catheters positioned at its circumference. Dose was prescribed to the tumor radial margin/mesorectal deposits seen on MRI. Differential catheter loading was performed to obtain optimal dose conformity. Patients received 26 Gy delivered over four daily fractions of 6.5 Gy a week, prescribed to the clinical target volume (CTV) (defined as the gross tumor volume (GTV) and intramesorectal deposits). Primary tumor coverage was achievable in all cases, up to a maximum depth of 4 cm from the mucosa. In patients with pelvic nodal involvement, adjuvant external beam radiation was recommended. In 47 patients undergoing resection, 64% had a complete clinical response and 15 (32%) exhibited no pathologic evidence of disease at the primary site at the time of resection (see Fig. 7.6A and B).49
|
|
|
Figure 7.6 A: Multicatheter intrarectal applicator molds flexibly to anatomy. B: Intrarectal computed tomography scan treatment planning with isodose lines to cover clinical target volume shaded in red. |
|
|
|
Figure 7.7 HAM (Harrison-Anderson-Mick) applicator used to guide 192Ir source during high dose rate intraoperative irradiation. |
Patients developing pelvic recurrence of colorectal cancer are often treated with palliative intent. Local recurrence may result in pelvic pain owing to nerve invasion in the presacral space or pelvic sidewall. Resection is unlikely to be curative. For patients undergoing surgery alone for pelvic recurrence from rectal cancer, the reported 5-year survival is 0%.50 Techniques implementing EBRT are often employed; however, EBRT delivery is limited by surrounding normal tissue tolerance. In efforts to increase delivered dose, IORT techniques have been used. This allows delivery of additional radiation at the time of surgery to the tumor bed with sparing of surround normal tissues. IORT can be delivered by electrons and HDR brachytherapy. Advantages of HDR brachytherapy versus electron therapy include applicator flexibility (allowing improved conformity to most tumor beds) as well as the ability to treat tumors situated in complex anatomic positions. Treatments are delivered in a shielded operating suite using a HDR 192Ir source. After resection, the boundaries of the tumor bed are determined. A Harrison-Anderson-Mick applicator or a similar applicator is then applied onto the target area (see Fig. 7.7). Normal tissues (large and small bowel) are physically displaced. Lead shielding is often used to protect adjacent normal tissues outside the target area. The applicator is connected to an HDR afterloader and treatment is delivered remotely. As OR time was so limited, the dose was determined from dosimetric atlases which had precalculated plans for various dimensions with modifying factors for the degree of curvature of the applicator in place and for the decay of the high-activity iridium source.
Candidates for IORT usually include patients with a high probability of subtotal resection without evidence of distant metastases. Select patients with resectable single-organ metastasis, slow progression of systemic disease, and excellent chemotherapy options and patients with oligometastatic disease with slow systemic progression and high probability of symptomatic local failure may be considered for this technique. In radiation naïve patients, the preferred approach for patients with recurrent pelvic disease is preoperative EBRT (45 to 50 Gy using 1.8 to 2 Gy fractions) combined with 5-FU–based chemotherapy followed by resection and possible IORT. Theoretical advantages to this approach include avoidance of unnecessary surgery in patients with rapidly progressive disease, potential tumor down staging/facilitation of curative resection, and a theoretical reduction in risk of tumor seeding/cut-through at resection. Other potential advantages include delivery of EBRT/chemotherapy to disease with an intact vasculature (potentially improving radiosensitizing drug and oxygen delivery) as well as avoidance of prolonged recovery time associated with extensive surgical procedures with adjuvant treatment delay. A randomized study comparing neoadjuvant with adjuvant chemoradiation demonstrated significant improvements in local control and toxicity in rectal cancer patients treated neoadjuvantly.45
In select patients receiving prior irradiation, low-dose preoperative EBRT doses of 20 to 30 Gy at 1.5 to 1.8 Gy per fraction (often in conjunction with appropriate systemic agents) may be employed. The IORT dose should be based on the extent of residual disease at resection, the amount of EBRT delivered previously, and the type and volume of normal tissue irradiated. For patients who have received preoperative doses of 45 to 50 Gy (1.8 to 2 Gy per fraction, 5 days per week), HDR-IORT doses usually range from 10 to 20 Gy. For patients with microscopic residual or close margins, doses of 10 to 12.5 Gy are administered. Patients with gross residual disease require higher doses, ranging from 15 to 20 Gy. In previously irradiated patients, in whom additional EBRT is feasible (20 to 30 Gy), IORT doses generally range from 15 to 20 Gy. In patients in whom very limited or no EBRT is planned, IORT doses from 25 to 30 Gy have been administered; however, doses in this range should be judiciously employed given the risk of normal tissue damage, specifically peripheral nerve injury.
Investigators from Memorial Sloan-Kettering Cancer Center reported the results of 74 patients with pelvic recurrence of colorectal carcinoma treated with surgery and HDR-IORT. Approximately half of the patients were previously irradiated. In radiation naïve patients, most of them received preoperative EBRT to a median dose of 50.4 Gy with concurrent 5-FU-based chemotherapy. At operation, resection was performed and IORT doses of 10 to 18 Gy were delivered. Two- and 5-year actuarial local control rates were 55% and 39%, respectively. Five-year local control and overall survival following margin-negative resection (vs. involved margins) were 45% versus 26% (p = 0.02) and 36% versus 11% (p = 0.04), respectively. Two and 5-year disease-free and overall survival rates were 43% and 23% and 75% and 23%, respectively. Additionally, patients receiving EBRT in addition to IORT had an improved 5-year survival (39% vs. 22%, p = 0.04).51 Investigators from the Netherlands described 37 patients with locally advanced primary or recurrent rectal tumors treated with EBRT followed by close/margin-positive resection and HDR-IORT. Patients received 10 Gy prescribed to 1 cm depth from the applicator surface. Twelve (33%) patients developed local recurrence (five within the IORT field). Patients with recurrent tumors were more likely to experience local recurrence again. Margin status did not appear to influence the local recurrence rate. Five-year survival rate was 38%.52
Investigators from the University of Southern California reported the results of 30 patients with locally recurrent rectal cancer undergoing radical or debulking surgery followed by permanent implantation of 192Ir or 125I sources. Gross residual disease was present in 67% and microscopic disease, in 25%. Overall, the local control rate was 64%. The authors concluded that this approach was a therapeutic alternative to patients who are not candidates for IORT.53
Liver Metastases from Colorectal Carcinoma
The mainstay of management for liver metastases is chemotherapy. There have been various reports of intraoperative placement of radioactive seeds in metastasis resection sites. Symptomatic management has proved complex. There is an array of interventions, including EBRT with photons or protons and permanent radioactive seed placement at the time of resection. Interventional radiology approaches have included bland embolization, chemoembolization, acetate or ethanol injection, thermal techniques with cryoablation, RFA, microwave, and LASER.
|
|
|
Figure 7.8 Schematic of flow of radioactive spheres from shielded vials to patient. |
A more novel approach recently brought to the approval of the U.S. Food and Drug Association (FDA) is the transhepatic arterial embolization of metastases with radioactive microspheres. Currently, there are two commercially available products which carry β emitters on either glass or resin spheres ranging from approximately 25 to 30 µm in diameter. The isotope 90Y is a pure β emitter with an energy of 0.94 MeV. A dose range of 2 to 5 GBq is given with an estimated delivered dose to tissue of 50 Gy/kg/GBq. The half-life is 2.67 days.
|
|
|
Figure 7.9 Shielded V-vial inside Lucite Box protects staff during delivery of radioactive SIR-spheres (Sirtex Corp.). |
The indications are for colorectal metastases refractory to chemotherapy and suitable for this therapy as proved by a prescreening Tc 99m MAA lung shunting study (Fig. 7.12A). As there are potential risks to run off to the gastroduodenal arterial system, if this is seen, coiling of the feeding vessels is also necessary.
Dose is calculated by body surface area technique pretreatment. The therapy is delivered in the interventional radiology suite with sequential aliquots of microsphere slurry and contrast injections (see Figs. 7.8, 7.9, 7.10 and 7.11). As long as contrast can pass, the dose is given to completion of dose calculation. If the tumor is filled, then the procedure is complete even if the dose is not fully delivered. The final characterization of the administered dose is made by subtracting the activity dose dispensed from the radiopharmacy from the activity returned. A final bremstralung scan confirms the location of the activity in the liver (see Fig. 7.12B). Early clinical results have been encouraging (see Fig. 7.13, Tables 7.7, 7.8 and 7.9).
Anal Cancer
It is estimated that 3,990 cases of anal squamous cell carcinoma with 620 deaths occurred in 2005 in the United States.1 Treatment of patients with anal cancer consists of combined EBRT and chemotherapy (generally 5-fluorouracil and mitomycin/cisplatin).54,55 As in rectal cancer, local relapse is a common mode of failure, resulting in significant morbidity and mortality. Salvage therapy entails abdominoperineal resection with placement of permanent colostomy. Given the propensity for local failure following EBRT-only approaches, investigators have employed brachytherapy for dose escalation. Early studies investigating the use of radium 226Ra interstitial implants resulted in significant complications, often requiring colostomy.56 With the availability of 192Ir isotopes and plastic templates (described in the preceding text), improved source and dose distribution was achieved with acceptable complication rates. Papillon et al. pioneered the technique of combining EBRT with interstitial implantation, producing results similar to those seen with radical surgery.57 As in rectal cancer, the patient has guide needles placed through a plastic template consisting of a series of holes at evenly spaced intervals. A dose of 15 Gy has been recommended if complete response is achieved following EBRT. If gross disease persists, a dose of 20 to 25 Gy to the initial volume or 15 Gy plus an additional 10 to 15 Gy boost entailing two or three lines centering on residual disease is recommended. Restricting the dose rate to <80 cGy per hour has been described to be potentially beneficial.58
|
|
|
Figure 7.10 Brachytherapist and interventional radiologist infusing SIR-spheres during international radiology procedure. |
|
|
|
Figure 7.11 Interventional radiology approach for selective embolization and therapy for liver metastases. |
French investigators described 17 patients receiving pelvic EBRT to a median dose of 45 Gy followed by LDR interstitial boost. Two additional patients were treated with interstitial brachytherapy alone. Following EBRT, patients received a single plane implant by plastic template. The median implant dose was 20 Gy (range 20 to 30 Gy, calculated at the 85% reference isodose, Paris system). The median total dose to the tumor volume was 65 Gy.
Compared with patients receiving EBRT alone, those receiving brachytherapy boost showed a trend in improved 5-year disease-free survival (87% vs. 72%, p= 0.07). The authors concluded that in responding patients, interstitial brachytherapy allowed the treatment of reduced volumes with improved therapeutic index.59 Other French investigators described 218 patients receiving 192Ir brachytherapy boost 4 to 8 weeks following EBRT completion. A perineal template with single plane curved implant was used, with an average of five to six lines measuring 5 to 6 cm in length. A dose of 20 ± 5 Gy was delivered. Compared with similar patients receiving EBRT alone, patients undergoing implant were more likely to have improved 5-year disease-free and overall survival on univariate analysis. The use of brachytherapy positively impacted disease-free survival on multivariate analysis. No obvious dose response was seen in the brachytherapy group.60 In a report from Papillon et al., the 5-year survival of 221 patients with anal carcinoma treated with split course EBRT and 192Ir implant was 66%.57 Among the 5-year survivors, anal preservation and normal sphincter function were achieved in >90% of patients.
|
|
|
Figure 7.12 A: Pretreatment Tc-99m MAA scan shows no lung shunting. B: A final bremstralung scan confirms the location of the activity in the liver. |
|
|
|
Figure 7.13 Colorectal metastases—right lobe only treatment. Computed tomography scan before and after microsphere therapy. |
|
Table 7.7 Phase I/II SIRT + CPT-11 |
||||||||||||||||||||
|
||||||||||||||||||||
|
Table 7.8 Phase II Randomized SIRT + SYS 5-FU + LV |
||||||||||||||||||||
|
||||||||||||||||||||
|
Table 7.9 Phase III Randomized SIRT + HAC FUDR |
||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||
Scottish investigators described the outcome of 79 patients with cancer of the anal canal (predominantly squamous cell carcinoma) undergoing interstitial implantation with 192Ir. Seventy-six patients received EBRT following implant. In most patients, six to eight needles were placed with an average length of 8 cm. The mean implant dose was 24 Gy over 56 hours and the mean EBRT dose was 43 Gy. Complete clinical response and local control was achieved in 91% and 78% of patients, respectively. Anal function preservation with local control was seen in 71% of patients. Local control in patients with adenocarcinoma was worse than that in patients with squamous cell carcinoma (86% vs. 43%). Patients with T3 disease experienced significantly more local failures compared with patients having T1-2 disease. Six patients developed major complications requiring surgical intervention, and in most of these, the total dose exceeded 65 Gy. The authors recommended that the total dose not exceed 65 Gy and the implant boost dose does not exceed 25 Gy.61 In an Austrian study, 39 patients with anal canal cancer received split course EBRT with interstitial or intraluminal HDR 192Ir boost of 6 Gy performed during the break. In patients with incomplete response, a second HDR boost of 6 Gy was delivered 6 to 8 weeks following completion of the second EBRT course. For interstitial implants, dose was prescribed to the 85% isodose line (Paris system). For intraluminal implants, dose was specified at 0.5 cm from the cylinder surface. Five-year local control and disease-specific survival were both 76%. The crude rate of sphincter preservation was 77%, with a 5-year colostomy-free survival of 73%. The authors concluded that this technique resulted in excellent sphincter function without a significant increase in severe complications.62
Because few studies have reported on the efficacy of brachytherapy alone in the treatment of anal cancer and no direct comparison of brachytherapy to chemoradiation was made, an American College of Radiology consensus panel concluded that the results of brachytherapy alone were inferior to those of combined modality treatment with concurrent chemoradiation, and that concurrent chemoradiation is the standard of care.63 Therefore, brachytherapy should be considered selectively and not as a replacement to EBRT and chemotherapy in the treatment of squamous cell carcinoma of the anal canal.
Conclusion
Local–regional relapse remains a common failure pattern in many gastrointestinal malignancies. The use of brachytherapy techniques permits focal dose escalation beyond that achievable with contemporary EBRT methods, usually without significant increases in toxicity. Although no randomized trials exist, proving the efficacy of brachytherapy over contemporary treatment methods, institutional and cooperative group experiences suggest that improvements in local–regional control and survival may be achieved when combined with standard therapeutic approaches. Additionally, the use of brachytherapy may provide an important palliative benefit in many gastrointestinal malignancies. The various uses of brachytherapy in gastrointestinal malignancies will continue to evolve with time.
References
1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 2005;55:10–30.
2. Al-Sarraf M, Martz K, Herskovic A, et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: An Intergroup study. J Clin Oncol. 1997;15:277–284.
3. Walsh T, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996;335:462–467.
4. Urba SG, Orringer MB, Turrisi A, et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001;19: 305–313.
5. Kelsen D, Ginsberg R, Pagak T, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998;339:1979–1985.
6. Minsky B, Pajak T, Ginsberg R, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: High-dose versus standard-dose radiation therapy. J Clin Oncol. 2002;20:1167–1174.
7. Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005;23:2310–2317.
8. Gaspar L, Quian C, Kocha W, et al. A phase I/II study of external beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 92-07): Preliminary toxicity report. Int J Radiat Oncol Biol Phys. 1997;37:593–599.
9. Vuong T, Szego P, David M, et al. The safety and usefulness of high-dose-rate endoluminal brachytherapy as a boost in the treatment of patients with esophageal cancer with external beam radiation with or without chemotherapy. Int J Radiat Oncol Biol Phys. 2005;63:758–764.
10. Kumar M, Swami K, Supe S, et al. Influence of intraluminal brachytherapy dose on the complications in the treatment of esophageal cancer. Int J Radiat Oncol Biol Phys. 1993;27: 1069–1072.
11. Hishikawa Y, Kurisu K, Taniguchi M, et al. High dose rate intraluminal brachytherapy for esophageal cancer: 10 years experience in Hyogo College of Medicine. Radiother Oncol. 1991;21:107–114.
12. Flores A, Nelems B, Evans K, et al. Impact of new modalities on the surgical management of cancer of the esophagus and cardia. Int J Radiat Oncol Biol Phys. 1989;17:937–944.
13. Sur RK, Levin CV, Donde B, et al. Prospective randomized trial of HDR brachytherapy as a sole modality in palliation of advanced esophageal carcinoma–an International Atomic Energy Agency study. Int J Radiat Oncol Biol Phys. 2002;53:127–133.
14. Gaspar L, Winter K, Kocha W, et al. A phase I/II study of external beam radiation, brachytherapy and concurrent chemotherapy for patients with localized carcinoma of the esophagus (Radiation Therapy Oncology Group study 9207: Final report). Cancer. 2000;88: 988–995.
15. Sharma V, Agarwal J, Dinshaw K, et al. Late esophageal toxicity using a combination of external beam radiation, intraluminal brachytherapy and 5-fluorouracil infusion in carcinoma of the esophagus. Dis Esophagus. 2000;13:219–225.
16. Homs MY, Steyerberg EW, Eijkenboom WM, et al. Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: Multicentre randomised trial. Lancet. 2004;364:1497–1504.
17. Moertel C, Frytak S, Hahn R, et al. Therapy of locally unresectable pancreatic carcinoma: A randomized comparison of high-dose (6000 Rads) radiation alone, moderate dose radiation (4000 Rads + 5-Fluorouracil) and high-dose radiation plus 5-Fluorouracil. Cancer. 1981;48: 1705–1710.
18. Shipley WU, Nardi GL, Cohen AM, et al. Iodine-125 implant and external beam irradiation in patients with localized pancreatic carcinoma: A comparative study to surgical resection. Cancer. 1980;45:709–714.
19. Mohiuddin M, Rosato F, Barbot D, et al. Long-term results of combined modality treatment with I-125 implantation for carcinoma of the pancreas. Int J Radiat Oncol Biol Phys. 1992;23: 305–311.
20. Shuricht A, Spitz F, Barbot D, et al. Intraoperative radiotherapy in the combined-modality management of pancreatic cancer. Am Surg. 1998;64:1043–1049.
21. Raben A, Mychalczak B, Brennan M, et al. Feasibility study of the treatment of primary unresectable carcinoma of the pancreas with Pd-103 brachytherapy. Int J Radiat Oncol Biol Phys. 1996;35:351–356.
22. Pfreundner L, Baier K, Schwab F, et al. 3D-CT-planned interstitial HDR brachytherapy + percutaneous irradiation and chemotherapy in inoperable pancreatic carcinoma. Methods and clinical outcome. Strahlenther Onkol. 1998;174:133–141.
23. Dobelbower RR, Montemaggi P. Brachytherapy for pancreatic cancer: A review. Hepatogastroenterology. 1996;43:333–337.
24. Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Surg Gynecol Obstet. 1978; 147:929–942.
25. Yee K, Shepperd B, Domreis J, et al. Cancers of the gallbladder and biliary ducts. Oncology. 2002;16:939–949.
26. Daines WP, Rajagopalan V, Grossbard ML, et al. Gallbladder and biliary tract carcinoma: A comprehensive update, Part 2. Oncology. 2004;18:1049–1059; discussion 1060, 1065–1046, 1068.
27. Mahe M, Romestaing P, Talon B. Radiation therapy in extrahepatic bile duct carcinoma. Radiother Oncol. 1991;21:121–127.
28. Donohue JH, Stewart K, Menck H. The National cancer data base report on carcinoma of the gallbladder, 1989–1995. Cancer. 1998;83:2618–2628.
29. Todoroki T, Gunderson LL, Nagorney DM. Biliary tract IORT. Totowa, NJ: Humana Press; 1999.
30. Maibenco D, Smith J, Nava H, et al. Carcinoma of the gallbladder. Cancer Invest. 1998;16: 33–39.
31. Mittal M, Romestaing P, Iwatsuki S. Primary cancers of extrahepatic biliary passages. Int J Radiat Oncol Biol Phys. 1985;11:849–854.
32. Alden M, Mohiuddin M. The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer. Int J Radiat Oncol Biol Phys. 1994;28: 945–951.
33. Buskirk SJ, Gunderson LL, Schild S. Analysis of failure after curative irradiation of extrahepatic bile duct carcinoma. Ann Surg. 1991;215:125–131.
34. Eschelman D, Shapiro M, Bonn J. Malignant biliary duct obstruction: Long-term experience with Gianturco stents and combined-modality radiation therapy. Radiology. 1996;200: 717–724.
35. Fritz P, Branbs H, Schraube P, et al. Combined external beam radiotherapy in intraluminal high-dose-rate brachytherapy on bile duct carcinoma. Int J Radiat Oncol Biol Phys. 1994;29: 855–861.
36. Foo ML, Gunderson LL, Bender CE, et al. External radiation therapy and transcatheter iridium in the treatment of extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys. 1997; 39:929–935.
37. Takamura A, Saito H, Camada T, et al. Intraluminal low-dose-rate Ir192 brachytherapy combined with external beam radiotherapy and biliary stenting for unresectable extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys. 2003;57(1):1357–1365.
38. Lu J, Baines Y, Abdel-Wahab M, et al. High-dose-rate remote after loading intracavitary brachytherapy for the treatment of extra hepatic biliary duct carcinoma. Cancer. 2002;8: 74–78.
39. Fields J, Emami B. Carcinoma of the extrahepatic biliary system-results of primary and adjuvant radiotherapy. Int J Radiat Oncol Biol Phys. 1987;13:331–338.
40. Montemaggi O, Costamagna G, Dobelbower R. Intraluminal brachytherapy in the treatment of pancreas and bile duct carcinoma. Int J Radiat Oncol Biol Phys. 1995;32:437–443.
41. Moertel C, Fleming T, MacDonald J, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322:352–358.
42. O'Connell M, Mailliard J, Kahn M, et al. Controlled trial of 5-FU and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997;15: 246–250.
43. Andre' T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–2351.
44. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med. 1985;312:1465–1472.
45. Krook J, Moertel C, Gunderson L, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med. 1991;324:709–715.
46. Sauer R, Heinz B, Werner H, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–1740.
47. Gerard JP, Chapet O, Ramaioli A, et al. Long-term control of T2-T3 rectal adenocarcinoma with radiotherapy alone. Int J Radiat Oncol Biol Phys. 2002;54:142–149.
48. Papillon J, Montbarbon J, Gerard J, et al. Interstitial curietherapy in the conservative treatment of anal and rectal cancers. Int J Radiat Oncol Biol Phys. 1989;17:1161–1169.
49. Vuong T, Devic S, Moftah B, et al. High-dose-rate endorectal brachytherapy in the treatment of locally advanced rectal carcinoma: Technical aspects. Brachytherapy. 2005;4:230–235.
50. Suzuki K, Gunderson LL, Devine RM, et al. Intraoperative irradiation after palliative surgery for locally recurrent rectal cancer. Cancer. 1995;75:939–952.
51. Alektiar KM, Zelefsky MJ, Paty PB, et al. High-dose-rate intraoperative brachytherapy for recurrent colorectal cancer. Int J Radiat Oncol Biol Phys. 2000;48:219–226.
52. Nuyttens J, Kolkman-Deurloo I, Vermaas M, et al. High-dose-rate intraoperative radiotherapy for close or positive margins in patients with locally advanced or recurrent rectal cancer. Int J Radiat Oncol Biol Phys. 2004;58:106–112.
53. Goes RN, Beart RW Jr, Simons AJ, et al. Use of brachytherapy in management of locally recurrent rectal cancer. Dis Colon Rectum 1997;40:1177–1179.
54. UKCCCR. Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet 1996;348: 1049–1054.
55. Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol. 1997;15: 2040–2049.
56. Dalby J, Pointen R. The treatment of anal carcinoma by interstitial radiation. Am J Roentgenol. 1961;55:515–520.
57. Papillon J, Montbarbon J. Epidermoid carcinoma of the anal canal: A series of 276 cases. Dis Colon Rectum. 1987;30:324–333.
58. Wagner J, Mahe M, Romestaing P, et al. Radiation therapy in the conservative treatment of carcinoma of the anal canal. Int J Radiat Oncol Biol Phys. 1994;29:17–23.
59. Deniaud-Alexandre E, Touboul E, Tiret E, et al. Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal. Int J Radiat Oncol Biol Phys. 2003;56: 1259–1273.
60. Chapet O, Gerard J, Riche B, et al. Prognostic value of tumor regression evaluated after a first course of radiotherapy for anal canal cancer. Int J Radiat Oncol Biol Phys. 2005;63:1316–1324.
61. Sandhu A, Symonds R, Robertson A, et al. Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: 10 year experience.Int J Radiat Oncol Biol Phys. 1998;40:575–581.
62. Kapp KS, Geyer E, Gebhart FH, et al. Experience with split-course external beam irradiation + /- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal. Int J Radiat Oncol Biol Phys. 2001;49:997–1005.
63. John MJ, Merrick GS, Coia LR, et al. Anal cancer. American College of Radiology. ACR Appropriateness Criteria. Radiology. 2000;215(Suppl):1501–1511.
