ABSTRACT: The contemporary treatment of anal cancer is combined-modality therapy with radiation therapy, fluorouracil, and mitomycin. This therapy results in long-term disease-free survival and sphincter preservation in the majority of patients. Tempering these positive results is the high rate of treatment-related morbidity associated with chemoradiation therapy for anal cancer. The use of intensity-modulated radiation therapy (IMRT) has the potential to reduce acute and chronic treatment-related toxicity, minimize treatment breaks, and potentially improve disease-related outcomes by permitting radiation dose escalation in selected cases.
Historically, the treatment of squamous cell carcinoma of the anal canal has been an abdominoperineal resection (APR), resulting in loss of the anus and rectum with need for a permanent colostomy. In addition to loss of sphincter function, high rates of urinary/sexual dysfunction, wound morbidity, and perioperative mortality have been reported. Studies evaluating outcomes following APR reported 5-year survival rates of 30% to 71%, with locoregional recurrence occurring in 19% to 45% of patients.[1,2]
Given these poor results, Nigro and coinvestigators from Wayne State University treated three patients with low-dose (30 Gy) preoperative radiation therapy concurrently with continuous-infusional fluorouracil (5-FU) and mitomycin followed by APR. The surgical specimens of two patients showed no evidence of residual disease, whereas a third patient refused surgery and remained disease-free. Since this report, similar studies have confirmed high rates of clinical and pathologic response using preoperative chemoradiotherapy and surgery,[4-8] leading to trials evaluating radiation therapy alone or combined chemoradiation as primary radical therapy, with surgery reserved for salvage. These studies demonstrated that the majority of patients treated by these approaches achieved long-term disease-free survival without surgery.
The contemporary treatment of anal cancer is founded on the results of five randomized trials (Table 1). Collectively, these demonstrate that combined-modality therapy with radiation therapy, 5-FU, and mitomycin result in long-term disease-free survival and sphincter preservation in the majority of anal cancer patients. Furthermore, the combination of radiation therapy, 5-FU, and mitomycin was shown to be superior to radiation therapy alone, radiation therapy with 5-FU only, and induction cisplatin/5-FU followed by concurrent radiation, cisplatin, and 5-FU.[9-13]
Tempering these positive results is the high rate of treatment-related morbidity associated with chemoradiation for anal cancer (Table 1). The acute toxicity induced by these treatments can be severe. In the recent Radiation Therapy Oncology Group (RTOG) 98-11 trial, in which conventional radiation therapy techniques were employed (Figure 1), 87% of patients experienced grade 3/4 acute toxicity. Patients who received 5-FU/mitomycin with radiation therapy as part of this trial experienced Common Toxicity Criteria for Adverse Events (CTCAE) v2.0 grade 3/4 skin and gastrointestinal toxicity rates of 48% and 35%, respectively. Similarly, preliminary results of a United Kingdom Coordinating Committee on Cancer Research (UKCCCR) study comparing 5-FU/mitomycin–based chemoradiotherapy to a cisplatin/5-FU–based chemoradiotherapy regimen reported a 61% grade 3/4 nonhematologic toxicity rate in the mitomycin arm. Treatment breaks induced by or used to mitigate these high treatment-associated toxicity rates are common and likely compromise therapeutic efficacy (discussed below).
Although chemotherapy clearly enhances the acute toxicity of radiation therapy in the treatment of anal cancer, radiation therapy contributes to the majority of acute and chronic therapy-related toxicities. The use of intensity-modulated radiation therapy (IMRT) has the potential to reduce acute and chronic treatment-related toxicity, minimize treatment breaks due to excessive grade 3/4 skin toxicity (notably in skin outside of the immediate perianal region) and bowel toxicity, while potentially improving disease-related outcomes by permitting radiation dose escalation in selected cases (because radiation toxcity to the bowel is avoided).
Intensity-Modulated Radiation Therapy
The two goals of optimizing a radiation treatment plan are to provide adequate dose coverage to the tumor/target volume and to minimize dose to adjacent normal tissue structures. To date, most trials in anal cancer have used either two-dimensional (2D) planning, in which radiation treatment fields are defined using orthogonal radiographs with known anatomic markers (primarily bony landmarks), or three-dimensional (3D or computed tomography [CT]-guided conformal) techniques, which allow for identification of target and normal tissue structures using axial CT images, facilitating improved treatment accuracy, delivery, and dose quantification. Both techniques, however, use uniform, static fields for radiation therapy delivery.
Imaging and radiation planning software improvements allowed for an evolution from 2D and 3D approaches in the late 1980s to the introduction of IMRT in the 1990s.[14,15] In contrast to 3D-based planning, where the physician designs treatment fields based on a “beam’s-eye view” of the target volumes and normal structures, IMRT-based planning entails setting strict radiation dose constraints to normal organs, a prescription dose to varying target volumes, and the use of “inverse planning” computer algorithms to design unconventional treatment fields that would not otherwise be possible with standard planning methods.
In essence, IMRT delivers the radiation dose by partitioning a radiation field into multiple smaller fields of varying shapes and sizes, varying the dose intensity between each area. This is carried out with either dynamic IMRT (where collimating leaves move in and out of the radiation beam path during treatment) or “step-and-shoot” IMRT (where the leaves change the radiation field shape while the beam is turned off). The end result is that the intensity of the radiation beam for a given field varies. Ultimately, the cumulative effect of all treatment fields results in a radiation dose-distribution that closely conforms the prescription (high) radiation dose around the target volumes while significantly reducing the high doses to surrounding normal tissues, which could not be achieved through conventional planning methods. Compared to 2D or 3D techniques, IMRT is effective at conforming radiation dose to irregular target volumes (particularly concave structures as are often seen in pelvic nodal basins) while limiting high doses to delineated sensitive normal tissues.
To create an IMRT plan, the treating physician uses physical exam, endoscopic exam, CT, PET-CT, and/or MRI findings to define the primary/gross disease (gross tumor volume, or GTV), and tissues at risk for subclinical tumoral involvement, including draining nodal basins (adding to the GTV to make the clinical target volume, or CTV). A third volume encompasses the gross and clinical target volumes, allowing additional “margin” to account for organ motion and daily positional differences (planning target volume, or PTV). IMRT plans may have multiple PTV volumes receiving differing radiation doses during any given fraction. This is the concept of “dose painting.” Alternatively, “sequential” PTV boosts, as are commonly carried out in non-IMRT 3D-conformal therapy, may be employed.
The use of IMRT for anal cancers also requires delineation of critical normal (avoidance) structures such as bladder, small bowel, genitalia, and the femoral heads. Radiation oncologists must determine which structures are most critical and dose-weight those appropriately during the treatment planning process. Importantly, the greater the number of avoidance structures, the more challenging it is to meet all dose constraints and still ensure appropriate CTV/PTV coverage. Physicians and medical physicists critically evaluate numerous plans until dose constraints are satisfactorily met. The result should be a series of radiation doses that closely conform to the target volumes while minimizing dose to normal tissues.
Figures 2 through 5 compare a 3D conformal radiation therapy plan (Figures 2 and 4) with an IMRT-based treatment plan (Figures 3 and 5). Figures 6 and 7 illustrate a representative IMRT field with associated dose fluence map. The differences in sagittal radiation dose distribution are shown between a 3D conformal plan (Figure 8) vs IMRT plan (Figure 9). A clinically significant advantage of IMRT includes a reduction in normal (high-dose) tissue irradiation resulting in less acute and chronic radiation-related toxicities, including nontarget bowel, bladder, and genitalia. These can often be significant using conventional radiation techniques, leading to potential treatment breaks with poor outcomes. Additionally, IMRT may permit safe radiation dose escalation in selected clinical situations.
Because the use of IMRT requires careful and accurate delineation of areas at risk for harboring subclinical disease spread and knowledge of patterns of dissemination, careful definition of target regions is critical, especially in light of the high cure rates and limitations of salvage therapies. In the multi-institutional RTOG 05-29 trial, which evaluated IMRT feasibility for anal cancer, 79% of patients enrolled required a change in the radiation treatment plan volumes following pretreatment central review, illustrating the learning curve of practitioners in this process and that knowledge of field design and experience is critical when using this approach. Based in part on this trial, the RTOG has made significant efforts to help better define clinical target structures for IMRT-radiation planning purposes.
In general, our practice has been to identify the following areas for inclusion in the CTV: the primary GTV (including nodal GTVs), the mesorectal space and presacral nodal basins, as well as the bilateral inguinal, internal, and external iliac nodal regions. CTVs may be modified based on concerns over the higher probability of poor treatment tolerance, such as for HIV patients with low CD4+ T-cell counts.
Anal Cancer Imaging and Radiation Planning
An important advance in the treatment of anal cancer is the use of 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET) and combined PET/CT in staging and IMRT-based treatment planning. These images are being increasingly used in clinical practice to better define sites of gross disease, as well as draining lymph node basins, which may not be appreciated by conventional imaging techniques.
Recent literature supports the use of PET in anal cancer staging and in advanced radiation treatment planning to more accurately delineate target structures. In three recent series, 17% to 24% of patients with clinically or radiographically uninvolved lymph nodes by CT demonstrated PET-positive nodal metastases.[20-22] It appears that PET increases sensitivity over conventional imaging and may change treatment goals or radiation therapy planning in a significant portion of patients. Multiple series have also demonstrated that PET scan resulted in modification of radiation treatment plans in up to one-fourth of patients.[22-24] Other investigators showed no detriment in radiation dose reduction to CT-enlarged but PET-negative inguinal lymph nodes. In a prospective study, Washington University investigators demonstrated that the findings of incomplete metabolic response to chemoradiotherapy on post-therapy PET (performed at a median 2.0 months post-treatment) predict for an inferior 2-year cause-specific and progression-free survival.
Thus, PET can guide radiation planning by preventing administration of insufficient doses to potential sites of disease (based on conventional imaging) as well as potentially avoiding excessive dose to metabolically inactive nodal basins. Moreover, PET may allow early prediction of outcomes to combined-modality therapy.
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