Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

17. Anal Cancer

Daniela Addeo • David P. Horowitz

Anal Cancer – Highlights

Key Recent Clinical Studies

Kachnic et al. (IJROBP 2012) reported the early results of RTOG 0529, a phase II evaluation of dose-painted IMRT in combination with chemotherapy, and reported low rates of nonhematologic acute toxicity and good rates of local control and colostomy-free survival. (PMID 21095071)

Gunderson et al. (JCO 2012) reported the long-term results of RTOG 98-11 and found that concurrent chemoradiation with fluorouracil and mitomycin had a higher rate of disease-free survival and overall survival than induction plus concurrent fluorouracil and cisplatin. (PMID 23150707)

New Target Delineation Contours

FIGURE 17-6c. CTV1 and CTV2 delineation in a 55-year-old man with T2N0M0 squamous cell carcinoma of the anal canal who underwent definitive chemoradiotherapy with IMRT.

1. ANATOMY

• The anal canal extends from the rectum to the perianal skin, and is 3 to 4 cm in length. The proximal margin is at the dentate (pectinate) line, which is at the level of the puborectalis muscle of the anorectal sling. The distal margin is the anal verge. Epithelium of the anal canal is a modified, nonkeratinized squamous epithelium. Around the dentate line, there is a transitional zone with epithelium containing rectal, urothelial, and squamous features. Above the dentate line, glandular mucosa predominates within the rectum.

• Anal margin (or perianal skin) is defined as 5 cm radius around the anal verge. Histologically, the perianal skin is similar to hair and gland-bearing skin elsewhere.

• Blood supply within the anal region contains anastomoses between the portal and systemic venous systems. Venous plexuses in the proximal anal canal drain to the portal system through the superior rectal vein and inferior mesenteric vein, while the anal canal distal to the dentate line drains to the systemic system through the internal pudendal and internal iliac veins (see Fig. 17-1).

• Lymphatics from the perianal skin and anal canal distal to the dentate line drain to primarily the superficial inguinal lymph nodes, with less common drainage directly to femoral and external iliac nodes. Proximal to the dentate line, lymphatics drain to the perirectal, internal pudendal, hypogastric, and obturator lymph nodes of the internal iliac system (see Fig. 17-2).

• Anorectal continence is maintained through voluntary and autonomic control. The striated muscles of the external sphincter are under voluntary control, and are innervated by the inferior rectal nerve (a branch of the pudendal nerve that arises from S2, S3, and S4). Smooth muscle of the internal sphincter is under the control of parasympathetic nerves from S2-4 and sympathetic fibers from the hypogastric plexus.

FIGURE 17-1. Anatomy of anal canal and sphincter. (Reprinted from Agur AMR, Dalley AF. Grant’s Atlas of Anatomy, 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2009:211.)

FIGURE 17-2. Lymphatic drainage of the rectum and anal canal. (Reprinted from Agur AMR, Dalley AF. Grant’s Atlas of Anatomy, 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2009:213.)

2. NATURAL HISTORY

• It was estimated that 7,060 new cases of cancer of the anus, anal canal, and anorectum will be diagnosed in 2013, with 880 deaths from the disease. This accounts for approximately 2.2% of all gastrointestinal cancers.1 Anal canal cancers are three to four times more common than those arising in the perianal skin.

• The incidence rate of invasive anal carcinoma in the United States has increased 1.9-fold for men and 1.5-fold for women from 1973–1979 to 1994–2000.2

• Risk factors for anal carcinoma include

º Infection with high-risk subtypes of human papilloma virus (especially HPV 16 and 18). HPV 16/18 DNA has been found in 72% to 84% of anal cancer specimens in systematic reviews.35

FIGURE 17-3. Patterns of spread for anal cancer. (A) Male. (B) Female. T-stages are indicated by colored arrows: Tis, yellow; T1, green; T2, blue; T3, purple; T4; red. (Reprinted from Rubin P, Hansen JT. TNM Staging Atlas with Oncoanatomy, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2012:363.)

º Immunosuppression, particularly with chronic use of immunosuppressive drugs6 or HIV,7 facilitates persistent infection with HPV.8

º Tobacco smoking is associated with a five-fold increase in anal cancer.9

º Benign anal conditions and inflammatory bowel disease do not appear to be associated with an increased risk of squamous cell anal cancer.1012

• Squamous cell carcinoma comprises approximately two-thirds of anal cancer, with transitional (cloacogenic) carcinomas accounting for one-fourth of anal cancer. Adenocarcinoma can arise from anal crypt cells and account for 5% to 7% of cancers of the anal canal. Melanoma, lymphoma, and neuroendocrine tumors rarely occur.

• Anal squamous cell carcinoma is usually preceded by high-grade anal intraepithelial neoplasia (AIN). The rate of progression from AIN to invasive cancer is approximately 1% per year.

• Local extension of tumor and lymphatic spread are more common than hematogenous dissemination.

º At the time of presentation, pelvic lymph node metastases are found in 30% of patients; inguinal lymph node involvement is seen in 15% to 35% of patients.13

º About 10% of patients present with extrapelvic visceral metastases. Anal cancer most commonly metastasizes to the liver and lungs.

• Figure 17-3 illustrates the patterns of spread by T-stage of anal cancer.

3. DIAGNOSIS AND STAGING WORKUP

3.1. Signs and Symptoms

• History: The most common presenting symptoms are bleeding and anal pain; other symptoms include pruritus ani and the presence of a palpable mass.

• Physical examination (including digital rectal exam and regional lymphatic nodal palpation), with evaluation of risk factors for HIV infection when applicable. Pelvic gynecologic examination in women to evaluate for involvement of the rectovaginal septum, as well as screening for cervical cancer.

3.2. Additional Workup

• Proctoscopy with biopsy of the primary tumor. Evaluation of HPV status of the tumor should be obtained.

• Biopsy of inguinal lymph nodes, if clinically suspicious.

• Blood work should include complete blood count with differential, basic metabolic panel and liver function tests. HIV testing should be considered if risk factors present. HIV-positive patients should have CD4 count quantified before start of treatment.

3.3. Imaging

• Chest x-ray

• Computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis

• Positron emission tomography (PET)/CT is useful in diagnosis of nodal disease and distant metastases. It upstages 17% of CT-staged N0 patients to N+.14 Comparing MRI staging in 88 patients, Bhuva et al.15 showed that PET/CT changed staging in 42% of patients, predominantly though changes in N staging. Sveistrup et al.16 reported a series of 95 patients in which PET/CT upstaged the disease in 14% of cases, and changed the treatment plan in 17% of cases. At present time, however, the 2012 NCCN guidelines does not consider PET/CT a replacement for diagnostic CT.

• Transanal ultrasound has not been validated as a staging tool, but can identify the depth of tumor invasion.17

3.4. Staging

• American Joint Commission on Cancer’s (AJCC) 7th edition of staging guidelines is unchanged from the 6th edition for anal canal cancer.18

• Staging of the primary site is predominately based on the size of the tumor. T1 tumors are 2 cm or smaller; T2 tumors measure 2 to 5 cm; T3 are over 5 cm in diameter. Tumors invading adjacent organs (excluding the perirectal skin, rectal wall, sphincter or subcutaneous tissues) are staged as T4.

• Regional lymph nodes include perirectal (anorectal, perirectal, and lateral sacral), internal iliac (hypogastric), and inguinal chains. Perirectal nodal involvement alone is N1; unilateral internal inguinal and/or iliac involvement is N2; bilateral nodal involvement or perirectal and inguinal nodal involvement is N3. All other nodal groups represent sites of distant metastasis.

• Perianal tumors are biologically similar to other skin cancers, and are staged in the same manner as cutaneous squamous cell carcinomas. Please refer to AJCC guidelines (7th edition) for an update on staging of skin cancer.18

4. PROGNOSTIC FACTORS

• The presence of extrapelvic metastatic disease is the strongest predictor of poor prognosis.2,19

• In patients with nonmetastatic disease, higher T- and N-stages were independently associated with higher probability of locoregional failure. Higher N-stage was also associated with distant metastases and lower overall survival.20

• Basaloid histology has been associated with higher incidence of distant metastases.20

• Increasing age and decreasing performance status are associated with poorer survival.

• Women have better prognosis than men.

• Hemoglobin levels <130 g/L at diagnosis have been found to be associated with decreased progression-free survival, distant relapse-free survival, and overall survival.21

• The literature is discrepant regarding the association of low CD4 count and high HIV viral load with local control, survival, and impaired tolerance of chemoradiation.2232

5. MANAGEMENT

• Concurrent chemotherapy and radiation has replaced upfront abdominal–perineal resection. With high cure rates, the anal sphincter is preserved and colostomy is avoided.

• This standard of care has been pioneered initially by Nigro et al.33,34 at Wayne State University and later consolidated by institutional experience and randomized trials (Table 17-1).3539

• At present time, the standard approach for treating anal canal cancer is a combination of concurrent radiotherapy and systemic chemotherapy administered in week 1 and 5 of radiation consisting in 5-fluorouracil (5FU) and mitomycin-C (MMC).

• Alternative chemoradiation regimens have been tested in a continuing effort to avoid significant toxicity associated with MMC.

• Cisplatinum is a cytotoxic chemotherapeutic agent with radiosensitizing effects. It has been tested in combined modality regimens for anal canal cancers, in an attempt to replace MMC and improve toxicity profile. UK ACT II and RTOG 98-11 randomized trials showed better outcome with 5FU/MMC versus 5FU/cisplatin39,40 (Table 17-1).

• Therefore, MMC and 5FU administered concomitantly with radiotherapy remain the preferred modality of treatment of anal canal cancer.

6. INTENSITY-MODULATED RADIATION THERAPY

• Traditionally, radiotherapy (RT) was administered using two-dimensional planning (fields designed based on bony landmarks) and three-dimensional (3D) planning (guided by CT images obtained at the time of simulation). The treatment plan consisted parallel opposed pelvic fields, with anterior larger port to include pelvic and inguinal areas in addition to the tumor. Posterior field was narrower to avoid the femoral heads and the dose to inguinal areas was supplemented by en face electron fields.

• Toxicity from the treatment has been significant, leading to treatment interruptions, increase in overall treatment time, and lower total dose administered, with negative impact on disease control.

• For anal cancer, correlation has been found between overall treatment time, total dose administrated, and the risk of colostomy and local control.4143 Subsequently, minimizing toxicity from radiotherapy is important to allow dose escalation and shorter treatment time.

• As a more advanced form of 3D planning, intensity-modulated radiation therapy (IMRT) has been implemented for anal canal cancer to conformally treat the target volume using modulation of the intensity across the radiation beams. This allows delivery of higher dose to areas of concern and lower dose to neighboring normal structures.

• Modulation of the beam is achieved using either dynamic IMRT (Multileaf collimator [MLC] leaves are moving across the beam while beam is on and radiation is delivered) or static/“step-and-shoot” IMRT (MLC leaves change position across the treatment field while the beam is turned off), both approaches with the same result.

• Table 17-22 illustrates selective published clinical and dosimetric studies of IMRT application for anal canal cancer.

• The goal of IMRT plans is to provide adequate target coverage for disease control with decreased toxicity as a result of lower dose to surrounding normal structures. Subsequently, treatment breaks are minimized and dose escalation is possible.

• Regarding fractionation, one approach is using initial larger fields to include the anal tumor, involved nodes, and regional lymphatics and structures at risk for microscopic disease to a dose of 45 Gy, followed by additional dose of 9 to 14.4 Gy to a cone-down volume of gross disease. The entire treatment is administered at 1.8 Gy/fraction.

• A second approach that gained popularity is the use of different fraction sizes simultaneously to different volumes at risk by dose-painted IMRT (DP-IMRT). Different target volumes are treated at the same time with different-sized doses per fraction and to various total radiation doses, based on the stage of disease and risk for microscopic involvement.4446

• Patients are treated in supine or prone position and custom immobilization is created for each patient using devices such as Vac Fix or Alpha Cradle.

• Target volumes and critical normal structures are delineated using information provided by physical examination, endoscopic examination, and imaging studies (CT scan with contrast, PET/CT scan).

• An RTOG consensus panel contouring atlas was published in 2009 to provide guidelines for target volumes definition for definitive therapy of anal cancer and adjuvant treatment of rectal cancer.47 This can be found on the RTOG web site.48

• The Australasian Gastrointestinal Trial Group has published in 2012 their consensus planning guidelines for anal cancer treatment to complement the existing RTOG atlas.49

6.1. Target Volume Delineation

• Following is a brief description of the volumes to be contoured:

• The gross tumor volume (GTV) includes all known gross disease:

º GTV A is the gross anal tumor.

º GTV lymph nodes (LN) includes the lymph nodes involved by gross disease.

º Clinical target volume (CTV) includes the GTV.

º CTV A is defined as gross anal tumor (GTV A) plus margins of 2 to 2.5 cm in all directions.

º CTV LN is defined as macroscopic lymph node disease plus margins of 1.5 cm. Additional subclassification of the CTV based on the size of the LN— e.g., <3 cm versus >3 cm—is used if DP is applied for dose prescription.

º CTV for regions at risk for harboring microscopic disease like perirectal and presacral nodes, right and left inguinal, external and internal iliac nodes: microscopic disease is contoured by adding 8 mm around blood vessels (e.g., around bilateral femoral, internal and external iliac vessels) based on estimated risk for involvement. Perirectal nodes are included with contours extending to the levator muscles and superior to recto-sigmoid junction. For presacral area, 1.5 to 2 cm margin anterior to the sacrum is contoured. The transition between external iliac and inguinal regions is arbitrary, but commonly considered at the upper edge of the pubic symphysis. Care should be paid when inguinal–femoral nodal regions are contoured. A recent review of 22 patients treated for pelvic malignancies with positive inguinal nodes based on PET/biopsy/size more than 1.5 cm on CT scan found that in order to properly cover lymph nodes in this area, circumferential margins around femoral vessels should be more than 2 cm, especially medial and anteromedial to the femoral vessels.58

º CTV contours are trimmed-off uninvolved normal structures like bone and muscles. It is suggested that if uninvolved directly by tumor, about 1 cm of the posterior bladder should be included to account for daily variation in those organs’ position.

• Pattern of local regional tumor recurrence was evaluated from the records of 180 patients treated for anal canal cancer at MSKCC with conventional radiotherapy.59 The authors concluded that bilateral inguinal nodes and all pelvic nodes below the common iliac arteries bifurcation should be treated with IMRT. Their suggestion is that in cases with advanced tumor or nodal disease (clinical T3 or N2), common iliac nodes should be included in CTV as well.

• The planning target volumes (PTVs) are obtained by expanding the above-described CTVs by 7 to 10 mm in all directions. PTV is subtracted by 3 to 5 mm off the skin.

6.2. Boost Volumes

• Boost volumes include

º CTV A boost: GTV plus 2 cm margins in all directions

º CTV LN boost: GTV LN plus 1.5 cm margins in all directions. Additional subclassification of the CTV based on the size of the LN—e.g., <3 cm versus >3 cm—is used if DP is applied for dose prescription.

º The boost planning target volumes (PTVs boost) are obtained by expanding the boost CTVs by 7 to 10 mm in all directions. PTV is subtracted by 3 to 5 mm off the skin.

• Critical normal structures are outlined as follows:

º Right and left femoral heads (from the bony top to lesser trochanter).

º Urinary bladder.

º External genitalia (vulva in women, penis and scrotum in men).

º Small bowel and large bowel drawn to 1 cm above the most cephalad PTV contour. Some protocols recommend that bowel is contoured as individual loops while others as entire peritoneal cavity.

º Iliac crests (from the bony top to the superior portion of the acetabulum).

6.3. Patient IMRT Contours

• Figure 17-4 illustrates contours for a patient with T3N2M0 squamous cell carcinoma of the anal canal treated with definitive chemotherapy and radiation.

• Figure 17-5 shows target volume contours for a 72-year-old female with T2N1 squamous cell carcinoma of the anal canal who underwent definitive chemoradiotherapy with FU and MMC using IMRT.

• Corresponding contours for a 55-year-old male with T2N0 squamous cell carcinoma of the anal canal who received definitive chemoradiotherapy with FU and MMC using IMRT are shown in Figure 17-6.

FIGURE 17-4. IMRT contours for a patient with T3N2M0 squamous cell carcinoma of the anal canal treated with definitive chemotherapy and radiation. The green contour is GTV A; the red contour is GTV LN, involved left inguinal nodes; the yellow contour is CTV anal tumor (A) + CTV involved LN + CTV microscopic disease (inguinal, perirectal, presacral, iliac nodal groups); the blue contour is PTV: 0.8 mm added to CTV. The PTV received 4,500 cGy/180-cGy fraction followed by a cone down to a PTV boost based on GTV A and GTV LN contours (not shown) and treated to a dose of 5,560 cGy/180-cGy fraction.

FIGURE 17-5. Target volume contours for a 72-year-old female with T2N1 squamous cell carcinoma of the anal canal who underwent definitive chemoradiotherapy with fluorouracil (FU) and mitomycin C (MMC) using IMRT. Contours are GTV, green; CTV1, red; CTV2, blue. The right and left femoral heads are contoured in magenta and aqua, respectively.

FIGURE 17-6. IMRT target contours for a 55-year-old male with T2N0 squamous cell carcinoma of the anal canal who received definitive chemoradiotherapy with FU and MMC. Contours are GTV, green; CTV1, red; CTV2, blue. The right and left femoral heads are contoured in magenta and aqua, respectively.

6.4. Dose Prescription

• Sequential boost plan:

º PTV that includes CTV A, CTV LN, and CTV for regional microscopic disease: 4,500 cGy/180-cGy fractions in 25 fractions.

º Followed by boost to gross disease—PTV boost: additional 900–1,440 cGy/180-cGy fractions, depending on the size of macroscopic disease.

• Concomitant boost plan: DP-IMRT:

º PTV A (for anal tumor):

• 5,040 to 5,400 cGy/180-cGy fraction for T1-T2 tumors

• 5,400 to 5,940 cGy/180-cGy fraction for tumors staged T3-T4

º PTV LN:

• PTV for involved LNs larger than 3 cm in maximum dimension: 5,400–5,940 cGy/180 cGy fraction

• PTV for involved LNs smaller than 3 cm in maximum dimension: 5,040–5,400 cGy/180 cGy fraction

• PTV for uninvolved LNs clinically but at risk for harboring microscopic disease are treated with fraction sizes smaller than 180 cGy. For example, RTOG 0529 used for these areas the following fractionation:

– 4,200 cGy/150 cGy fraction for T1-T2N0 tumors

– 4,500 cGy/150 cGy fraction for T3-T4N0 or N+ tumors.

• A review of outcome for 34 patients consecutively treated between 2005 and 2009 at Mayo Clinic with IMRT and elective doses per fraction less than 180 cGy revealed that at a median follow up of 22 months there was no failure in clinically uninvolved regions treated with doses between 150 and 180 cGy.60

• Suggested goals for target coverage:

º More than 95% of the PTV should receive 100% of the prescribed dose (PD).

º Less than 5% of the PTV should receive more than 115% of the PD.

º Less than 5% of the PTV should receive less than 90% of the PD.

6.5. Suggested Normal Structure Constraints for IMRT Planning

• Small bowel:

º No more than 100 cm3 above 45 Gy

º No more than 400 cm3 above 30 Gy

º None above than 50 Gy

• Femoral heads:

º No more than 50% above 30 Gy

º No more than 30% above 40 Gy

º None above than 50 Gy

• Iliac crests:

º No more than 50% above 40 Gy

º No more than 35% above 45 Gy

º No more than 5% above 50 Gy

• External genitalia:

º No more than 50% above 30 Gy

º No more than 35% above 40 Gy

º No more than 5% above 50 Gy

• Bladder:

º No more than 50% above 35 Gy

º No more than 35% above 40 Gy

º No more than 10% above 50 Gy

• Large bowel:

º No more than 200 cm3 above 30 Gy

º No more than 100 cm3 above 45 Gy

7. CONCLUSIONS

• IMRT for anal canal cancer using sequential boost to macroscopic disease or dose-painted plans is effective as part of chemoradiation therapy regimen. It was found feasible in multi-institutional setting and has been adopted in clinical practice. However, about 80% of the RTOG 0529 plans needed changes after central review indicating a learning curve for volume contouring and the importance of following the stringent guidelines.

• This approach decreases acute toxicity allowing dose escalation and minimizing treatment breaks. Longer-term follow-up is necessary to assess late toxicity and durability of tumor control.

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