59_05
Perianal Cancer
The most common histologic type of invasive cancer of the perianal skin is squamous cell carcinoma, usually keratinizing. Basal cell cancers and adenocarcinomas can also occur.
Wide local excision with a 1-cm margin is recommended for all histologic types, provided anal continence can be preserved (73). Radiation alone or in combination with chemotherapy is also effective (9,85), but may produce symptomatic long-term skin changes. Radiation-based protocols identical to those for anal canal cancer are preferred when anal continence would be impaired by surgery. In the UKCCCR trial, one in four patients had a cancer that arose in the perianal skin (anal margin). Results by site of cancer origin were not reported, but local control and cause-specific survival rates favored combined modality therapy (121).
The regional nodes for the perianal skin are the ipsilateral inguinal nodes. Perirectal and pelvic node metastases are uncommon unless the cancer involves the anal canal extensively. The risk of inguinal node metastases is about 10%, primarily with category T3 or T4 tumors or poorly differentiated cancers. Elective bilateral inguinal nodal irradiation may be considered for these tumors, with inclusion of the pelvic nodes if the anal canal is invaded. The management of abnormal inguinal nodes is similar to that for anal canal cancer.
The principles of management for the uncommon basal cell and adenocarcinomas of the perianal skin are similar to those for these histological types elsewhere on the skin.
Patients with HIV/AIDS
Patients with HIV infection, especially those with a history of anal-receptive intercourse, are at increased risk of anal squamous cell cancer. The median age at diagnosis is in the fourth decade, about 20 years earlier than in non-HIV infected patients. Anal cancers in several small series of HIV-infected patients have been treated by combined modality therapy or radiation alone (16,30,60,61,97,101). HIV-infected patients are at increased risk of toxicity, particularly in the perineal skin and anorectal mucosa, when treated with radiation with or without chemotherapy, although the mechanisms for this are not known (37). However, the more recent reports suggest that it is not necessary to electively modify standard protocols of radiation (with respect to dose, fractionation, or volume) and chemotherapy (either 5-FU and mitomycin, or 5-FU and cisplatin), but modifications should be based on the severity of side effects in each individual patient (16,60). Two factors may predict for heightened acute normal tissue toxicity and/or poor cancer control, namely, a CD4 count <200/µL at the start of treatment or the presence of AIDS (61,101), but these findings are not inevitably associated with poor tolerance. Concurrent antiretroviral therapy does not reliably reduce the severity or incidence of toxicity of radiation and chemotherapy (74). Complete primary cancer remission rates of about 70% or better are generally described, but it is difficult to obtain reliable data on long-term tumor control, particularly in patients with AIDS.
Adenocarcinomas
Most adenocarcinomas involving the anal canal arise from rectal-type mucosa that extends below the upper muscular boundary of the canal. They are generally treated similarly to those that arise in the rectum. The uncommon adenocarcinomas that develop from anal glands or in fistulae have also usually been managed by abdominoperineal resection. Five-year survival rates following surgery alone are commonly <50%, with local recurrence rates of about 25% (8,73,84,119). Any advantage from adjuvant radiation and chemotherapy is unknown, although, by analogy, protocols used for primary rectal cancers are sometimes applied. Other centers have treated these anal adenocarcinomas by the protocols developed for squamous cell cancers. Experience is limited, but anorectal function has been retained, and apparent cures have been reported following treatment with radiation alone or with radiation and chemotherapy (8,69).
Small Cell Carcinomas
Small cell carcinomas are rare cancers characterized by early metastases and have a poor prognosis (10). The primary tumor
P.1392
may be managed by surgery or radiation. Systemic chemotherapy similar to that used for small cell cancers that arise elsewhere may be combined with radiation for the primary tumor and used to treat metastases, but responses are generally limited.
Radiation Therapy Techniques
Anal Canal
The treatment volumes of interest are determined by the philosophy adopted with regard to which lymph node groups should be treated and whether the primary tumor and lymph nodes should be treated in continuity. Only well-differentiated squamous cell cancers ≤2 cm in size situated in the distal canal appear to have a risk of nodal metastases <5% (10,44). Treatment of larger cancers by interstitial brachytherapy alone resulted in failure in pelvic nodes above the treated volume in 16% (14/88) in one study (94). The finding in surgical series of histopathologically verified metastases in the pararectal and internal iliac nodes in up to 30% and in inguinal nodes in up to 20% has encouraged most centers to irradiate these node groups electively. As a result, planning target volumes may be extensive. There is some evidence that acute and late morbidity can be reduced by avoiding tangential irradiation to the sensitive skin of the perineum and external genitalia or, if techniques that require tangential irradiation are elected, by the use of daily fractions ≤2 Gy. The irregularities and curvatures of the perineum and lower pelvis make homogenous radiation distributions difficult to achieve. Measurements with in vivo thermoluminescent dosimeters found dose variations of as much as 10% from predicted levels in the region of the anocutaneous junction (129). Computerized dose planning systems may not provide accurate values at skin–air interfaces. Care must be taken as far as possible to avoid regions of excessive dose.
Whole-Pelvis Techniques
Many radiation oncologists prefer to treat the primary tumor and the posterior pelvic and inguinal nodes in continuity. An anterior-posterior–opposed pair of fields is the most common arrangement. If the patient is prone, the anus can be visualized readily and bolus placed selectively over any perianal tumor extension. Alternatively, the patient may be treated supine to reduce some of the inhomogeneities produced by the natural curvatures of the pelvic soft tissues. The upper border of the field is placed at the lumbosacral junction if the intent is to include the common iliac, upper presacral, and rectosigmoid nodes in the treated volume. This border is commonly moved down during treatment to the lower end of the sacroiliac joints, thus encompassing only the perirectal, lower presacral, and internal iliac nodes (and, if the volume is sufficiently wide, the lower external iliac nodes), in order to lessen the risk of radiation enteritis (36) (Fig. 59.2). Some authors consider elective treatment of radiologically normal lymph nodes above the level of the lower border of the sacroiliac joints unnecessary (22,23,80). The inferior field border is placed 3-cm distal to the lowermost extension of the primary tumor, which should be indicated with a radio-opaque marker during simulation.
The position of the lateral borders depends on the philosophy adopted with respect to the desirability of treating a continuous homogenous volume or the preference to minimize irradiation of the femoral head and neck. Options include anterior and posterior fields of equal size encompassing the inguinal nodes; anterior and posterior fields of equal size, but restricted to include the medial borders of the pelvis only, the inguinal nodes being treated by anterior electron beams matched to the photon fields; and asymmetric photon fields, with a larger anterior field to cover the primary tumor, pelvic and inguinal nodes in continuity, and a posterior beam restricted to the primary tumor and pelvic nodes. In this latter arrangement, anterior electron beams are used to supplement the dose to the inguinal nodes to the desired level. The location and depth of the inguinal nodes should be obtained by axial imaging (75). When asymmetric and/or matched fields are used, there is potential for both over and under dosage (15). Considerable care is required in planning and in patient positioning.
Posterior Pelvis Techniques
If it is elected to irradiate the posterior pelvic tissues and inguinal nodes discontinuously for all or part of the prescription, or to treat the posterior pelvis only, the volume irradiated is reduced compared with that of whole-pelvis techniques. The anal canal and posterior pelvic nodes may be treated by multiple beam techniques. These are commonly three- or four-field techniques, such as a direct posterior or anterior-posterior/posterior-anterior (AP/PA) fields, and opposed lateral beams, analogous to those used for rectal cancer. Recently, multiple-field conformal techniques, including intensity-modulated radiation therapy (IMRT), have been de-scribed (15,83,125) (Fig. 59.3). Conformal techniques can re-duce the mean dose to the perineum and external genitalia by about 30%. Although these techniques generally include beams tangential to the perineum, doses of at least 54 Gy in 1.8-Gy fractions can be delivered with only occasional need for treatment breaks due to skin or gastrointestinal toxicity (83,125). Early accounts of IMRT techniques have described the use of patient immobilization devices, but have not discussed the possible effects on dose distribution of internal organ motion.
Dose–Time Factors
All external-beam therapy is given by megavoltage equipment. The choice of beam energy should be based on the technique used and on the tissues to be included in the planning target volume and treated volume.
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If external-beam irradiation is given without concurrent chemotherapy, it is usual, as in other cancers, to prescribe doses close to the tolerance of the normal tissues. There have been no studies to establish the optimum dose–time factors. A dose to the primary tumor of 60 to 65 Gy over 6 to 7 weeks, in 1.8- to 2-Gy fractions, is commonly prescribed. The primary tumor and regional nodes are encompassed to a dose of 40 to 45 Gy in 4 to 5 weeks, after which the volume is reduced. The smaller clinical target volume includes the primary tumor with a margin of 2 to 3 cm. This reduced volume may be treated as most appropriate by interstitial therapy, by external-beam therapy with a perineal field, or by multifield techniques (23,36,94). A dose of 15 to 20 Gy in 2 weeks is given to the reduced volume. If low–dose-rate interstitial radiation is used, a dose of 15 to 20 Gy at 0.5 cm from the plane of the implant over 24 hours (Paris system) is recommended (94). Proven or suspected metastases in the inguinal nodes and abnormal perirectal or pelvic nodes should be treated to the same total dose as the primary tumor.
Delivery of the final reduced volume treatment phase by brachytherapy is more common in Europe than in North America, where external beam treatment is favored. There are a number of reports of effective brachytherapy, including low–dose-rate (LDR) (96,99), pulsed–dose-rate (PDR) (47,105), and high–dose-rate (HDR) techniques (71,123). Brachytherapy has usually been given 2 to 8 weeks after external-beam therapy, although one schedule introduced HDR in the interval during split-course external beam therapy (71). There is no agreement on whether the treatment volume should include the full extent of the initial primary cancer (71,94,99,105) or only the tumor remaining at the time of implant (29). The brachytherapy dose depends on the composite dose of the total radiation prescription. Occasionally, significant toxicity has been encountered (98,105). Techniques to reduce the risk of serious toxicity by minimizing the volume irradiated (94,99), avoiding fully circumferential implants (94), and reducing the dose to the uninvolved anal circumference (29,47,94,105,123), have been described. The merits of adjuvants to brachytherapy such as intracavitary (76) or interstitial (72) hyperthermia or concurrent chemotherapy are unproven.
When radiation is given with concurrent 5-FU and mitomycin, or 5-FU and cisplatin, some modification of these dose–time guidelines is usual. The modifications are intended to reduce acute toxicity or are based on the successful outcomes of the lower dose radiation schedules initially introduced as surgical adjuvant therapy. Recent protocols, however, have sought to improve local control rates, particularly for larger tumors, by intensifying radiation or chemotherapy or both. Increases in total radiation doses and shortening of overall time of treatment by eliminating elective interruptions in radiation (split course therapy) have been advocated. When combined with 5-FU and mitomycin, radiation doses of as little as 30 Gy in 15 fractions over 3 weeks have been shown to eradicate up to about 90% of cancers ≤3 cm in size. Higher doses, from 45 Gy in 25 fractions in 5 weeks to 54 Gy in 30 fractions in 6 weeks, sometimes supplemented by additional radiation after an interval of 6 to 8 weeks to a total of 60 to 65 Gy over a total time of about 12 weeks, have controlled from 65% to 75% of primary tumors >4 cm (see Table 59.4). Recent trials in North America have used 59 Gy in 32 fractions over 6.5 weeks (3,66,67,79); the effectiveness and tolerability of this schedule has not yet been reported in detail.
Short interruptions in external-beam treatment, generally of no more than 2 weeks but of up to 4 weeks in some series, were introduced into many combined modality protocols, either as elective breaks after about 3 weeks' treatment or as required by individual patients, to reduce the severity of acute anoproctitis and perineal dermatitis. Where further radiation was to be prescribed, based on the extent of clinical or histopathologic response to the first phase of treatment, longer intervals of 6 to 8 weeks were recommended to allow tumor regression. The possible adverse effects of split-course irradiation on the control of anal cancer have not been studied formally, but the limited data available on the potential tumor doubling time of anal cancer suggest that it is rapid, and of the order of 4 days (range 1 to 30 days; n = 26) (133), so some adverse effect may be expected from unnecessarily prolonged treatment. Overall treatment time was found to be more significant than the presence or absence of treatment interruptions in one study (54). In most studies that have considered treatment duration, better results have been achieved in patients who have had shorter treatment times (17,128). However, there are many potentially confounding factors in these nonrandomized comparisons, and the optimum treatment duration is not known. Several current studies seek to eliminate all interruptions or to reduce them to 2 weeks or less.
The rationale for escalating the total radiation dose is based on the observation in randomized and nonrandomized studies that the control rate of larger tumors was inferior to that of smaller cancers and analyses of nonrandomized studies that suggest a dose–control relationship (17,103). Review of 50 patients showed improved 5-year survival and local control rates following total radiation doses of 54 Gy or more (17). In another series of 34 patients with tumors >2 cm, local control rates were 38% (5/13) for those who received a total dose of <45 Gy, 69% (9/13) for 50 to 55 Gy, and 88% (7/8) for >60 Gy (103). The need to continue to review dose–time factors and techniques carefully is reflected by the finding of excessive acute and late toxicity when 5-FU and mitomycin were given concurrently with high-dose radiation, 50 Gy in 20 fractions of 2.5 Gy over 4 weeks, using anterior and posterior beams to 25 Gy followed by a three-field posterior pelvic technique for the remaining 25 Gy (22). In an RTOG phase II trial, 9/18 patients planned to receive an uninterrupted course of 59.4 Gy in 33 fractions over 6.5 weeks, with concurrent 5-FU and mitomycin, required a break in treatment of 2 weeks or more (66,67).
When clinically normal lymph nodes are irradiated electively, doses of about 36 Gy in 18 fractions in 3.5 weeks in combination with chemotherapy appear adequate (36), and doses as low as 24 Gy in 12 fractions in 2.5 weeks have been used successfully (22). Nodal metastases should be treated to the same dose as the primary cancer.
Perianal
If small (<4 cm) perianal cancers with low risk of regional node metastases are treated by radiation, a dose of 60 to 66 Gy in 2-Gy fractions over 6 weeks may be used. A direct perineal field is preferred as this minimizes the area of skin irradiated. Orthovoltage equipment may suffice, although electrons or low
P.1394
energy megavoltage photons (with bolus) are used more commonly. Care should be taken to flatten the perineum as much as possible to avoid areas of over or under dosage. Larger perianal cancers, or cancers invading the anal canal, are usually treated by the techniques and schedules of radiation and chemotherapy used for anal canal cancers. The upper border of the fields is usually placed at the lower end of the sacroiliac joints. The final phase of radiation may be given by direct perineal photon or electron therapy. Although brachytherapy may be used for the final phase, full treatment of perianal cancers by brachytherapy has been associated with high rates of necrosis in some series.
Sequelae of Therapy
Some nonrandomized series have described higher acute and late toxicity rates from combined modality therapy than those reported in the multicenter randomized trials. This probably results from use of different criteria for recording and reporting toxicity.
In programs that combined radiation therapy, 96-hour infusions of 5-FU and bolus injections of mitomycin, moderate leukopenia, thrombocytopenia, anoproctitis, and perineal dermatitis were recorded in about 30% of patients after doses of 25 to 30 Gy in 2.5 to 3 weeks (22,111). More profound proctitis and dermatitis occurred in up to 55% of those who received from 50 Gy in 4 to 5 weeks (22,118) to 59.4 Gy in 6.5 weeks (66). When cisplatin is substituted for mitomycin, marrow toxicity may be less, but at radiation doses of 59.4 Gy in 6.5 weeks, acute soft tissue toxicity rates are similar (3,79). All large studies of radiation, 5-FU, and mitomycin or cisplatin have reported an incidence (<2% overall) of mortality associated with acute toxicity, usually as a result of neutropenia with sepsis.
Serious late toxicity has not been reported after doses of 30 Gy in 3 weeks with 5-FU and mitomycin, but significant complications, often requiring surgery, have been recorded in about 5% to 15% of those receiving higher radiation doses. It is probable that these reports, many of which were retrospective, overlooked some treatment-related toxicity. For example, a large cohort study of 556 women aged 65 or over who developed anal cancer showed a higher risk of pelvic fracture, principally of the hip, in those who received radiation (n = 399) compared to those not irradiated (n = 157). The cumulative 5-year fracture rate was 14% versus 7.5% (p <.01) (7).
Less serious side effects are very common and may cause patients considerable discomfort (5,19,65,124). These include changes in anorectal function such as urgency and frequency of defecation bleeding from anorectal telangiectasia, perineal dermatitis, dyspareunia, and impotence. These lower-grade side effects are usually managed medically with varying success. Systematic and prospective evaluation of the function of the anorectum and of other organs potentially affected by treatment has begun only recently, as have formal quality-of-life studies. There is often dissociation between a patient's account of anal and rectal function and continence and physiologic measurements of anorectal function, and the few studies in this area have been inconclusive (11,124). Prospective studies of pelvic organ function can be expected to assist the development of radiation treatment protocols by facilitating correlation of function with time–dose factors and radiation–chemotherapy interactions.
The most common histologic type of invasive cancer of the perianal skin is squamous cell carcinoma, usually keratinizing. Basal cell cancers and adenocarcinomas can also occur.
Wide local excision with a 1-cm margin is recommended for all histologic types, provided anal continence can be preserved (73). Radiation alone or in combination with chemotherapy is also effective (9,85), but may produce symptomatic long-term skin changes. Radiation-based protocols identical to those for anal canal cancer are preferred when anal continence would be impaired by surgery. In the UKCCCR trial, one in four patients had a cancer that arose in the perianal skin (anal margin). Results by site of cancer origin were not reported, but local control and cause-specific survival rates favored combined modality therapy (121).
The regional nodes for the perianal skin are the ipsilateral inguinal nodes. Perirectal and pelvic node metastases are uncommon unless the cancer involves the anal canal extensively. The risk of inguinal node metastases is about 10%, primarily with category T3 or T4 tumors or poorly differentiated cancers. Elective bilateral inguinal nodal irradiation may be considered for these tumors, with inclusion of the pelvic nodes if the anal canal is invaded. The management of abnormal inguinal nodes is similar to that for anal canal cancer.
The principles of management for the uncommon basal cell and adenocarcinomas of the perianal skin are similar to those for these histological types elsewhere on the skin.
Patients with HIV/AIDS
Patients with HIV infection, especially those with a history of anal-receptive intercourse, are at increased risk of anal squamous cell cancer. The median age at diagnosis is in the fourth decade, about 20 years earlier than in non-HIV infected patients. Anal cancers in several small series of HIV-infected patients have been treated by combined modality therapy or radiation alone (16,30,60,61,97,101). HIV-infected patients are at increased risk of toxicity, particularly in the perineal skin and anorectal mucosa, when treated with radiation with or without chemotherapy, although the mechanisms for this are not known (37). However, the more recent reports suggest that it is not necessary to electively modify standard protocols of radiation (with respect to dose, fractionation, or volume) and chemotherapy (either 5-FU and mitomycin, or 5-FU and cisplatin), but modifications should be based on the severity of side effects in each individual patient (16,60). Two factors may predict for heightened acute normal tissue toxicity and/or poor cancer control, namely, a CD4 count <200/µL at the start of treatment or the presence of AIDS (61,101), but these findings are not inevitably associated with poor tolerance. Concurrent antiretroviral therapy does not reliably reduce the severity or incidence of toxicity of radiation and chemotherapy (74). Complete primary cancer remission rates of about 70% or better are generally described, but it is difficult to obtain reliable data on long-term tumor control, particularly in patients with AIDS.
Adenocarcinomas
Most adenocarcinomas involving the anal canal arise from rectal-type mucosa that extends below the upper muscular boundary of the canal. They are generally treated similarly to those that arise in the rectum. The uncommon adenocarcinomas that develop from anal glands or in fistulae have also usually been managed by abdominoperineal resection. Five-year survival rates following surgery alone are commonly <50%, with local recurrence rates of about 25% (8,73,84,119). Any advantage from adjuvant radiation and chemotherapy is unknown, although, by analogy, protocols used for primary rectal cancers are sometimes applied. Other centers have treated these anal adenocarcinomas by the protocols developed for squamous cell cancers. Experience is limited, but anorectal function has been retained, and apparent cures have been reported following treatment with radiation alone or with radiation and chemotherapy (8,69).
Small Cell Carcinomas
Small cell carcinomas are rare cancers characterized by early metastases and have a poor prognosis (10). The primary tumor
P.1392
may be managed by surgery or radiation. Systemic chemotherapy similar to that used for small cell cancers that arise elsewhere may be combined with radiation for the primary tumor and used to treat metastases, but responses are generally limited.
Radiation Therapy Techniques
Anal Canal
The treatment volumes of interest are determined by the philosophy adopted with regard to which lymph node groups should be treated and whether the primary tumor and lymph nodes should be treated in continuity. Only well-differentiated squamous cell cancers ≤2 cm in size situated in the distal canal appear to have a risk of nodal metastases <5% (10,44). Treatment of larger cancers by interstitial brachytherapy alone resulted in failure in pelvic nodes above the treated volume in 16% (14/88) in one study (94). The finding in surgical series of histopathologically verified metastases in the pararectal and internal iliac nodes in up to 30% and in inguinal nodes in up to 20% has encouraged most centers to irradiate these node groups electively. As a result, planning target volumes may be extensive. There is some evidence that acute and late morbidity can be reduced by avoiding tangential irradiation to the sensitive skin of the perineum and external genitalia or, if techniques that require tangential irradiation are elected, by the use of daily fractions ≤2 Gy. The irregularities and curvatures of the perineum and lower pelvis make homogenous radiation distributions difficult to achieve. Measurements with in vivo thermoluminescent dosimeters found dose variations of as much as 10% from predicted levels in the region of the anocutaneous junction (129). Computerized dose planning systems may not provide accurate values at skin–air interfaces. Care must be taken as far as possible to avoid regions of excessive dose.
Whole-Pelvis Techniques
Many radiation oncologists prefer to treat the primary tumor and the posterior pelvic and inguinal nodes in continuity. An anterior-posterior–opposed pair of fields is the most common arrangement. If the patient is prone, the anus can be visualized readily and bolus placed selectively over any perianal tumor extension. Alternatively, the patient may be treated supine to reduce some of the inhomogeneities produced by the natural curvatures of the pelvic soft tissues. The upper border of the field is placed at the lumbosacral junction if the intent is to include the common iliac, upper presacral, and rectosigmoid nodes in the treated volume. This border is commonly moved down during treatment to the lower end of the sacroiliac joints, thus encompassing only the perirectal, lower presacral, and internal iliac nodes (and, if the volume is sufficiently wide, the lower external iliac nodes), in order to lessen the risk of radiation enteritis (36) (Fig. 59.2). Some authors consider elective treatment of radiologically normal lymph nodes above the level of the lower border of the sacroiliac joints unnecessary (22,23,80). The inferior field border is placed 3-cm distal to the lowermost extension of the primary tumor, which should be indicated with a radio-opaque marker during simulation.
The position of the lateral borders depends on the philosophy adopted with respect to the desirability of treating a continuous homogenous volume or the preference to minimize irradiation of the femoral head and neck. Options include anterior and posterior fields of equal size encompassing the inguinal nodes; anterior and posterior fields of equal size, but restricted to include the medial borders of the pelvis only, the inguinal nodes being treated by anterior electron beams matched to the photon fields; and asymmetric photon fields, with a larger anterior field to cover the primary tumor, pelvic and inguinal nodes in continuity, and a posterior beam restricted to the primary tumor and pelvic nodes. In this latter arrangement, anterior electron beams are used to supplement the dose to the inguinal nodes to the desired level. The location and depth of the inguinal nodes should be obtained by axial imaging (75). When asymmetric and/or matched fields are used, there is potential for both over and under dosage (15). Considerable care is required in planning and in patient positioning.
Posterior Pelvis Techniques
If it is elected to irradiate the posterior pelvic tissues and inguinal nodes discontinuously for all or part of the prescription, or to treat the posterior pelvis only, the volume irradiated is reduced compared with that of whole-pelvis techniques. The anal canal and posterior pelvic nodes may be treated by multiple beam techniques. These are commonly three- or four-field techniques, such as a direct posterior or anterior-posterior/posterior-anterior (AP/PA) fields, and opposed lateral beams, analogous to those used for rectal cancer. Recently, multiple-field conformal techniques, including intensity-modulated radiation therapy (IMRT), have been de-scribed (15,83,125) (Fig. 59.3). Conformal techniques can re-duce the mean dose to the perineum and external genitalia by about 30%. Although these techniques generally include beams tangential to the perineum, doses of at least 54 Gy in 1.8-Gy fractions can be delivered with only occasional need for treatment breaks due to skin or gastrointestinal toxicity (83,125). Early accounts of IMRT techniques have described the use of patient immobilization devices, but have not discussed the possible effects on dose distribution of internal organ motion.
Dose–Time Factors
All external-beam therapy is given by megavoltage equipment. The choice of beam energy should be based on the technique used and on the tissues to be included in the planning target volume and treated volume.
P.1393
If external-beam irradiation is given without concurrent chemotherapy, it is usual, as in other cancers, to prescribe doses close to the tolerance of the normal tissues. There have been no studies to establish the optimum dose–time factors. A dose to the primary tumor of 60 to 65 Gy over 6 to 7 weeks, in 1.8- to 2-Gy fractions, is commonly prescribed. The primary tumor and regional nodes are encompassed to a dose of 40 to 45 Gy in 4 to 5 weeks, after which the volume is reduced. The smaller clinical target volume includes the primary tumor with a margin of 2 to 3 cm. This reduced volume may be treated as most appropriate by interstitial therapy, by external-beam therapy with a perineal field, or by multifield techniques (23,36,94). A dose of 15 to 20 Gy in 2 weeks is given to the reduced volume. If low–dose-rate interstitial radiation is used, a dose of 15 to 20 Gy at 0.5 cm from the plane of the implant over 24 hours (Paris system) is recommended (94). Proven or suspected metastases in the inguinal nodes and abnormal perirectal or pelvic nodes should be treated to the same total dose as the primary tumor.
Delivery of the final reduced volume treatment phase by brachytherapy is more common in Europe than in North America, where external beam treatment is favored. There are a number of reports of effective brachytherapy, including low–dose-rate (LDR) (96,99), pulsed–dose-rate (PDR) (47,105), and high–dose-rate (HDR) techniques (71,123). Brachytherapy has usually been given 2 to 8 weeks after external-beam therapy, although one schedule introduced HDR in the interval during split-course external beam therapy (71). There is no agreement on whether the treatment volume should include the full extent of the initial primary cancer (71,94,99,105) or only the tumor remaining at the time of implant (29). The brachytherapy dose depends on the composite dose of the total radiation prescription. Occasionally, significant toxicity has been encountered (98,105). Techniques to reduce the risk of serious toxicity by minimizing the volume irradiated (94,99), avoiding fully circumferential implants (94), and reducing the dose to the uninvolved anal circumference (29,47,94,105,123), have been described. The merits of adjuvants to brachytherapy such as intracavitary (76) or interstitial (72) hyperthermia or concurrent chemotherapy are unproven.
When radiation is given with concurrent 5-FU and mitomycin, or 5-FU and cisplatin, some modification of these dose–time guidelines is usual. The modifications are intended to reduce acute toxicity or are based on the successful outcomes of the lower dose radiation schedules initially introduced as surgical adjuvant therapy. Recent protocols, however, have sought to improve local control rates, particularly for larger tumors, by intensifying radiation or chemotherapy or both. Increases in total radiation doses and shortening of overall time of treatment by eliminating elective interruptions in radiation (split course therapy) have been advocated. When combined with 5-FU and mitomycin, radiation doses of as little as 30 Gy in 15 fractions over 3 weeks have been shown to eradicate up to about 90% of cancers ≤3 cm in size. Higher doses, from 45 Gy in 25 fractions in 5 weeks to 54 Gy in 30 fractions in 6 weeks, sometimes supplemented by additional radiation after an interval of 6 to 8 weeks to a total of 60 to 65 Gy over a total time of about 12 weeks, have controlled from 65% to 75% of primary tumors >4 cm (see Table 59.4). Recent trials in North America have used 59 Gy in 32 fractions over 6.5 weeks (3,66,67,79); the effectiveness and tolerability of this schedule has not yet been reported in detail.
Short interruptions in external-beam treatment, generally of no more than 2 weeks but of up to 4 weeks in some series, were introduced into many combined modality protocols, either as elective breaks after about 3 weeks' treatment or as required by individual patients, to reduce the severity of acute anoproctitis and perineal dermatitis. Where further radiation was to be prescribed, based on the extent of clinical or histopathologic response to the first phase of treatment, longer intervals of 6 to 8 weeks were recommended to allow tumor regression. The possible adverse effects of split-course irradiation on the control of anal cancer have not been studied formally, but the limited data available on the potential tumor doubling time of anal cancer suggest that it is rapid, and of the order of 4 days (range 1 to 30 days; n = 26) (133), so some adverse effect may be expected from unnecessarily prolonged treatment. Overall treatment time was found to be more significant than the presence or absence of treatment interruptions in one study (54). In most studies that have considered treatment duration, better results have been achieved in patients who have had shorter treatment times (17,128). However, there are many potentially confounding factors in these nonrandomized comparisons, and the optimum treatment duration is not known. Several current studies seek to eliminate all interruptions or to reduce them to 2 weeks or less.
The rationale for escalating the total radiation dose is based on the observation in randomized and nonrandomized studies that the control rate of larger tumors was inferior to that of smaller cancers and analyses of nonrandomized studies that suggest a dose–control relationship (17,103). Review of 50 patients showed improved 5-year survival and local control rates following total radiation doses of 54 Gy or more (17). In another series of 34 patients with tumors >2 cm, local control rates were 38% (5/13) for those who received a total dose of <45 Gy, 69% (9/13) for 50 to 55 Gy, and 88% (7/8) for >60 Gy (103). The need to continue to review dose–time factors and techniques carefully is reflected by the finding of excessive acute and late toxicity when 5-FU and mitomycin were given concurrently with high-dose radiation, 50 Gy in 20 fractions of 2.5 Gy over 4 weeks, using anterior and posterior beams to 25 Gy followed by a three-field posterior pelvic technique for the remaining 25 Gy (22). In an RTOG phase II trial, 9/18 patients planned to receive an uninterrupted course of 59.4 Gy in 33 fractions over 6.5 weeks, with concurrent 5-FU and mitomycin, required a break in treatment of 2 weeks or more (66,67).
When clinically normal lymph nodes are irradiated electively, doses of about 36 Gy in 18 fractions in 3.5 weeks in combination with chemotherapy appear adequate (36), and doses as low as 24 Gy in 12 fractions in 2.5 weeks have been used successfully (22). Nodal metastases should be treated to the same dose as the primary cancer.
Perianal
If small (<4 cm) perianal cancers with low risk of regional node metastases are treated by radiation, a dose of 60 to 66 Gy in 2-Gy fractions over 6 weeks may be used. A direct perineal field is preferred as this minimizes the area of skin irradiated. Orthovoltage equipment may suffice, although electrons or low
P.1394
energy megavoltage photons (with bolus) are used more commonly. Care should be taken to flatten the perineum as much as possible to avoid areas of over or under dosage. Larger perianal cancers, or cancers invading the anal canal, are usually treated by the techniques and schedules of radiation and chemotherapy used for anal canal cancers. The upper border of the fields is usually placed at the lower end of the sacroiliac joints. The final phase of radiation may be given by direct perineal photon or electron therapy. Although brachytherapy may be used for the final phase, full treatment of perianal cancers by brachytherapy has been associated with high rates of necrosis in some series.
Sequelae of Therapy
Some nonrandomized series have described higher acute and late toxicity rates from combined modality therapy than those reported in the multicenter randomized trials. This probably results from use of different criteria for recording and reporting toxicity.
In programs that combined radiation therapy, 96-hour infusions of 5-FU and bolus injections of mitomycin, moderate leukopenia, thrombocytopenia, anoproctitis, and perineal dermatitis were recorded in about 30% of patients after doses of 25 to 30 Gy in 2.5 to 3 weeks (22,111). More profound proctitis and dermatitis occurred in up to 55% of those who received from 50 Gy in 4 to 5 weeks (22,118) to 59.4 Gy in 6.5 weeks (66). When cisplatin is substituted for mitomycin, marrow toxicity may be less, but at radiation doses of 59.4 Gy in 6.5 weeks, acute soft tissue toxicity rates are similar (3,79). All large studies of radiation, 5-FU, and mitomycin or cisplatin have reported an incidence (<2% overall) of mortality associated with acute toxicity, usually as a result of neutropenia with sepsis.
Serious late toxicity has not been reported after doses of 30 Gy in 3 weeks with 5-FU and mitomycin, but significant complications, often requiring surgery, have been recorded in about 5% to 15% of those receiving higher radiation doses. It is probable that these reports, many of which were retrospective, overlooked some treatment-related toxicity. For example, a large cohort study of 556 women aged 65 or over who developed anal cancer showed a higher risk of pelvic fracture, principally of the hip, in those who received radiation (n = 399) compared to those not irradiated (n = 157). The cumulative 5-year fracture rate was 14% versus 7.5% (p <.01) (7).
Less serious side effects are very common and may cause patients considerable discomfort (5,19,65,124). These include changes in anorectal function such as urgency and frequency of defecation bleeding from anorectal telangiectasia, perineal dermatitis, dyspareunia, and impotence. These lower-grade side effects are usually managed medically with varying success. Systematic and prospective evaluation of the function of the anorectum and of other organs potentially affected by treatment has begun only recently, as have formal quality-of-life studies. There is often dissociation between a patient's account of anal and rectal function and continence and physiologic measurements of anorectal function, and the few studies in this area have been inconclusive (11,124). Prospective studies of pelvic organ function can be expected to assist the development of radiation treatment protocols by facilitating correlation of function with time–dose factors and radiation–chemotherapy interactions.
posted by stefanoxx at 6:00 AM
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