Stephen Ko
In the United States, anal cancer represents a rare malignancy and accounts for 2.2% of all gastrointestinal malignancies; 6,230 new cases are diagnosed annually. The incidence has been increasing over the last four decades. The most significant risk factors are sexually transmitted viruses, tobacco smoking, and immunosuppression. Progress has been made over the years in the management of anal cancer. In the 1970s, treatment focused on abdomino-perineal resection (APR). Initially Nigro at Wayne State employed preoperative chemotherapy with 5-FU and mitomycin (MMC) with radiation therapy (30 Gy) to improve on local control. Complete pathologic responses were discovered and ushered in the concept of definitive chemoradiation, which continues to be the mainstay of therapy for localized anal canal cancer.
EPIDEMIOLOGY
The annual age-adjusted rates in the U.S. Surveillance, Epidemiology, and End Results (SEER) registry for 1994 to 2000 had risen to 1.59 per 100,000 for males and 1.84 for females. Cancers of the anus, anal canal, and anorectum are some of the few cancers that are more common in females than in males at nearly all ages. A potential reason for the rise in females may relate to the evolving sexual practices and association with anal HPV infections. Median age at diagnosis is 60 to 65. Advancing age is a risk factor for anal canal cancer. In certain populations such as men who have sex with other men (MSM) and homosexuals, the rate of anal cancer can be as high as 37 per 100,000.
ETIOLOGY AND RISK FACTORS
Several risk factors have been associated with the development of anal cancer:
1.Sexual activity
a.10 or more lifetime sexual partners
b.receptive anal intercourse before the age of 30
c.history of gonorrhea or syphilis or herpes simplex 2 or chlamydia
d.history of cervical cancer
2.Human papillomavirus infection. Up to 93% of SCC of the anal canal has been associated with HPV infection. Women are more likely to have an HPV-associated anal cancer than men. Also HPV infection is more common in MSM. HPV 16 and 18 are the most frequently associated strains linked with anal cancer and account for 90% of anal cancers.
3.HIV infection. The effect of HIV infection on the incidence of anal cancer is not known with certainty. It is unknown whether HIV directly affects the pathogenesis or if the impact is through the interaction with HPV.
4.Cigarette Smoking. Case–control studies indicate increased risk in smokers and especially among current smokers.
PATHOLOGY
Anatomy
■The anal canal measures approximately 3 to 4 cm in length. It extends from the anal verge to the puborectalis muscle of the anorectal ring. The dentate line is situated within the anal canal and the histology separates depending on the location above or below the dentate line. Proximal to the dentate, the histology is columnar epithelium, and distal to the dentate, the histology becomes squamous cell epithelium.
■The anal margin has been arbitrarily defined as an area within 5 cm of the anal verge.
■Lymphatic nodal pathways. Drainage proximal to the dentate line follows the distal rectum to the internal iliac lymph nodes (pudendal, hypogastric, and obturator). Drainage from the perianal skin, anal verge, and the region distal to the dentate line follows the superficial inguinal lymph nodes with some flow to the femoral nodes and external iliac lymphatics.
HISTOLOGY
The anus comprises three different histologic types: (1) glandular, (2) transitional, and (3) squamous mucosa. Cancers arising from the transitional or squamous mucosa develop into squamous cell carcinomas.
The basaloid or transitional carcinomas (formerly known as cloacogenic or junctional tumors) develop from the transitional mucosa. Those cancers developing above the dentate line are nonkeratinizing squamous cell carcinomas versus those distal to the dentate line are keratinizing squamous cell carcinomas. Tumors arising from the glandular mucosa of the anal canal develop into adenocarcinomas.
Anal margin tumors develop within the hair-bearing skin distal to the transitional mucosa.
PRESENTATION
Rectal bleeding and anal discomfort are the two most common symptoms and occur in over half of the patients. Pruitus and discharge are other symptoms. Pain can be severe. Changes in bowel habits can be a presenting symptom, especially with proximal anal canal cancers. Patients may be asymptomatic as well.
WORKUP
Workup should include anoscope with biopsy (incisional), digital rectal examination (DRE), inguinal lymph node evaluation (biopsy or FNA of any suspicious lymph nodes), chest CT, abdominal/pelvic CT or MRI. Pelvic examination should be performed on women including screening for cervical cancer. Consider HIV testing and CD4 levels for patients at risk. Consider PET/CT, which may be helpful for diagnosis but may aid in radiation treatment planning. Full chemistries and CBC should be performed as well.
STAGING
Staging is based on the seventh edition of the American Joint Committee on Cancer (AJCC), which employs a TNM system for the staging of anal canal cancers. T stage is based partly upon the size of the primary lesion or the invasion of nearby structures such as the bladder, prostate, vagina, or urethra. The N stage is determined by the presence of perirectal, internal iliac, or inguinal lymph nodes. The M stage is based upon the presence or absence of distant metastases.
PROGNOSTIC FACTORS
■Tumor size. The size of the primary lesion has been shown to be one of the most significant factors in predicting local control and survival for lesions confined to the pelvis.
■Lymph nodes. The presence or absence of lymph nodes also has been shown to impact survival.
■Metastasis. The most significant prognostic risk factor for overall survival is the presence or absence of extrapelvic metastases.
■HIV status. High viral load and low CD4+ count in some series have predicted for survival and local control.
■Other: Hemoglobin levels ≤10 g/L and male gender have impacted prognosis in some studies.
TREATMENT
Surgery
Anal Canal Lesions
In the 1970s, surgical resection with an APR was considered standard of care. APR produced local control rates of 70%, and overall survival rates from 20% to 70% (average 50%). With inguinal lymph node involvement, some series showed 5-year survivals of 10% to 20%. After the 1974 publication by Nigro showing complete pathologic response in three patients treated with chemoradiation, anal cancer patients are rarely treated with upfront surgery, and definitive chemoradiation remains the current standard of care. APR is reserved for salvage after failure with definitive chemoradiation or reserved for management of radiation complications.
Surgery alone with local excision may be considered with small, localized T1N0M0 squamous cell carcinomas of the anal canal. Several small retrospective series have demonstrated good local control and 5-year survival with such an approach. The key to offering local excision is patient selection. Patients with small tumors <2 cm, well differentiated, and no involvement of the sphincter may be considered candidates. Otherwise, chemoradiation should be offered.
Anal Margin Lesions
Early anal margin cancers have traditionally been treated with local excision. Such lesions behave more like a skin cancer, although this concept has never been validated prospectively. Wide local excision has been reserved mostly for well-differentiated T1N0M0 lesions with good local control. In a retrospective review of 48 patients with SCCA of the anal margin were reviewed. Thirty-one patients underwent local excision, and 11 were treated by APR. Local excision provided satisfactory results with a 5-year survival of 88%. However, larger lesions T2 or > or N+ should be treated with definitive chemoradiation.
Radiation Therapy
Since the 1974 Nigro publication, radiation therapy has involved into the primary curative modality for the treatment of anal cancer. Radiation techniques also have evolved over time and varying types of radiation therapy have been used including external beam radiation therapy (3D and intensity-modulated radiation therapy [IMRT]), electrons, and brachytherapy.
Radiation alone has been used to treat early anal cancer (T1–T2N0M0) with relative success; most retrospective studies have demonstrated modest local control and 5-year survivals; however, not all studies show good local control with radiation alone. Tumors < 2 cm particularly appear to have better local control. NCCN guidelines, however, recommend combined modality for even small T1N0M0 squamous cell carcinomas of anal canal. For the very elderly or those with significant comorbidities, radiation alone may be a reasonable approach.
Combined Radiation Therapy and Chemotherapy
In 1972, Nigro at Wayne State developed the concept of treating anal cancer patients preoperatively in order to decrease APR failures. He employed the Nigro regimen, 5-FU 1,000 m2 on days 1 to 4 and 29 to 32 and mitomycin-c 10 to 15 mg/m2 and mitomycin-c on day 1, combined with moderate pelvic RT dose of 30 Gy. With the discovery of three pathologic complete responses after preoperative chemoradiation, the focus changed to preserving the sphincter using chemoradiation and reserving APR for salvage.
Since Nigro’s original publication, definitive chemoradiation therapy has become the standard. Several retrospective series have demonstrated the success achieved with chemoradiation therapy in terms of local control and overall survival (Table 10.1).
Radiation Therapy Alone versus Combined-Modality Therapy
Two prospective randomized trials have been conducted that have compared radiation alone versus chemoradiation (Tables 10.2 and 10.3).
The United Kingdom Coordinating Committee on Cancer Research (UKCCCR) trial enrolled patients with T1–T4, N0–N3, M0–M1 anal cancer and small number of anal margins patients and demonstrated improved local control and colostomy-free survival (CFS) with combined modality treatment (CMT) but no statistical difference in overall survival. Even for early anal cancer patients (T1–T2N0M0), there appeared to be a benefit favoring CMT on multivariate analysis.
The European Organization for Research and Treatment of Cancer (EORTC) conducted a similar trial comparing radiation alone to radiation with chemotherapy (5-FU and MMC), which also demonstrated an advantage toward CMT. This trial enrolled locally advanced anal canal cancer patients, T3–T4, N0–N3, M0. Again, CMT showed a statistically significant advantage for CMT in terms of local control, colostomy rate, and disease-free survival (DFS) but not for overall survival.
Thus, both the UKCCCR and EORTC trials established the principle that combined modality is superior to single modality radiation alone.
Value of MMC in the Combined-Modality Regimen
Due to the hematologic toxicity of MMC in CMT, two prospective phase III trials (RTOG/ECOG 8704 and RTOG 98-11) have evaluated the importance of MMC (Tables 10.2 and 10.3).
RTOG/ECOG 8704 was the first randomized trial to evaluate prospectively the importance of MMC in CMT and compared 5-FU and MMC with RT (standard arm) versus 5-FU and RT (experimental arm). The primary endpoint was DFS. At 4 years, DFS was 73% for 5-FU and MMC compared to 51% for 5-FU. Colostomy rate was 22% with 5-FU vs. 9% with 5-FU, MMC (P = 0.002). Despite the higher toxicity of MMC, the authors concluded that MMC was still the preferred regimen, given the higher DFS and lower colostomy rate.
RTOG 98-11 was the second randomized trial to evaluate prospectively the role of MMC in CMT and compared 5-FU and MMC with concurrent radiotherapy (standard arm) versus induction 5-FU and CDDP followed by concurrent 5-FU and CDDP with radiotherapy (experimental arm). The primary endpoint was again DFS. With a median of 2.51 years, the initial report revealed no statistically significant difference in 5-year DFS (60% MMC vs. 54% CDDP), 5-year OS (75% MMC vs. 70% CDDP), 5-year local-regional control rates (25% MMC vs. 33% CDDP) or 5-year distant metastasis (DM) rates (15% MMC vs. 19% CDDP). The cumulative colostomy rate proved to be statistically significantly higher with CDDP, 19% vs. MMC, 10%.
However, the updated RTOG 98-11 examined the long-term impact of treatment on survival (DFS, OS, CFS), as well as colostomy failure (CF), and locoregional failure (LRF), and DM. With longer follow-up, 5-FU/MMC regimen produced statistically significant improvement in DFS and OS for RT + 5-FU/MMC vs. RT + 5-FU/CDDP (5-year DFS; 67.8% vs. 57.8%; P = 0.006; 5-year OS, 78.3% vs. 70.7%; P= 0.026). There was a trend toward statistical significance for CFS, LRF, and CF. Thus, the authors conclude that RT + 5-FU/MMC remains the preferred standard of care.
ACT III (abstract form only) addressed two questions: (1) whether substituting CDDP for MMC improves the complete response rate and (2) whether two cycles of maintenance chemotherapy (5-FU/CDDP) reduce recurrences. The randomization employed a 2 × 2 factorial, and patients were randomized to 5-FU/MMC with concurrent radiotherapy (standard arm) or CDDP/5-FU with concurrent radiotherapy. Patients were then randomized to receive either two cycles of maintenance chemotherapy (CDDP/5-FU) or no maintenance therapy. At a median follow-up of 3 years, the complete response rate was 94% for MMC and 95% for CDDP (P = 0.53). No statistically significant differences in terms of recurrence-free survival and overall survival were noted between the maintenance and the no maintenance arms. The authors again concluded that 5-FU/MMC with RT should remain the standard of care.
The data from ACT III and the updated RTOG 98-11 may seem to contradict one another: the CDDP arm in RTOG 98-11 appears to have a detrimental effect on DFS and OS, whereas the ACT III shows that CDDP may be at least equivalent to that of MMC. However, the trial designs were quite different. RTOG employed the use of neoadjuvant chemotherapy prior to the start of concurrent chemoradiotherapy. The prolongation of the overall treatment time may account for the inferior results of the CDDP arm. However, given the current data available, 5-FU/MMC should remain the standard of care.
Toxicity of Combined-Modality Therapy
Toxicity from CMT can be divided into acute and late effects. A variety of toxicity criteria have been employed in the different randomized trials, which makes analysis difficult (Table 10.4).
Acute Toxicity
Patients typically experience moderate to severe acute toxicities from the combination of both chemotherapy (5-FU and MMC) and radiation therapy. Side effects include nonhematologic toxicities (nausea/vomiting, abdominal pain, increased frequency of stool, diarrhea, skin irritation, fatigue, weight loss) and hematologic toxicities (neutropenia, thrombocytopenia, anemia).
Toxic deaths from CMT have ranged from 0% to 5%). In the UKCCCR study, 6/116 (2%) experienced toxic death, mostly due to septicemia. The EORTC trial reported on 1 toxic death out 110 patients. In the RTOG 8704 study, four patients (3%) experienced death in the MMC arm. More recently, there were no reported toxic deaths in both RTOG 98-11 and ACT II trials. The ACCORD 03 trial, a four-arm randomized trial, showed similar toxic deaths across all four arms (A = 1 [1%], B = 2 [2.6%], C = 3[3%], D = 1[1%]). No patient required an APR for acute toxicity in any of the arms during the induction phase or the concurrent chemoradiation phase.
Late Toxicity
Late effects have not been well documented within the randomized trials. Part of the challenge in evaluating late effects is the differing toxicity scales used in the various trials. Early toxicity criteria used in the randomized trials did not allow for characterizing radiation-induced side effects.
Both the early EORTC and UKCCCR did not demonstrate a difference in long-term complications between those receiving CMT vs. RT alone. RTOG 8704 similarly revealed no significance difference in long-term toxicity between RT-5-FU and RT and 5-FU/MMC, although two patients from each arm required stoma secondary to RT-related complications. In the RTOG 9811 update, the most common types of late grade 3 or 4 toxicity included skin, small/large intestine, subcutaneous tissue, or other. There did not appear to be a difference between the MMC or CDDP arms for grade 3/4 toxicity (13.1% vs. 10.7%; P = 0.35). In the ACCORD 03 trial, late toxicities were primarily of grade 1 or 2. However, nine patients experienced grade 4 toxicities including necrosis, fistula, bleeding, or pain of whom five were treated with an APR and four underwent colostomy alone.
Chemoradiation in HIV-Positive Patients
HIV-positive patients pose a particular treatment challenge due to their inability to tolerate CMT. Early reports indicated that some patients were receiving less than optimal therapy due to concerns for treatment toxicity. However, patients with a CD4 count of ≥200 can have excellent control of their disease with acceptable morbidity. Those with CD4 counts of <200, however, may require a modification in their treatment regimen such as omission of MMC or a reduction in the RT field and/or dose. UCSF analyzed 17 HIV-positive patients and documented CD4 counts. All nine patients with a CD4 count ≥ 200 had control of their disease. Four patients did require a treatment break of 2 weeks, but no hospitalizations occurred. Among the eight patients with CD4 counts < 200, four experienced lowered blood counts, intractable diarrhea, or moist desquamation. Four of eight ultimately required colostomies for either treatment-related toxicity or for salvage of their disease. Disease, though, was controlled in seven of eight patients. Thus, based on the UCSF experience with HIV-positive patients, one should consider modifying the treatment regimen particularly if CD4 counts are less than 200.
Dose of Radiation
Local-regional failures occur in 20% to 30% after definitive chemoradiation. Because of such local-regional failures, RTOG 92-08, a phase II, dose escalation trial was designed to escalate dose to 59.4 Gy, with a mandatory treatment break of 2 weeks after the initial 36 Gy. The initial study included 47 patients with a mandatory break. The update of RTOG 92-08 analyzed not only the original 47 patients with the mandatory break but also analyzed 20 additional patients who did not have a planned break. Both groups of patients showed no difference in OS or LRF when compared historically to patients on RTOG 87-04 MMC arm. The higher dose likely did not result in improved outcomes because of the treatment break, which may have allowed for tumor repopulation and/or repair of sublethal damage.
The ACCORD 03 trial evaluated both the value of treatment intensification by induction chemotherapy (two cycles of 5-FU and CDDP) and radiation dose escalation by incorporating a 20 to 25 Gy boost in patients with locally advanced anal cancer patients (T2 > 4 cm or T3–T4Nx or any T, N1–N3, M0). The trial was conducted as a factorial 2×2 study (A = ICT; B = ICT +HDRT; C = reference arm = pelvic RT 45 Gy per 25 fractions with two cycles of 5-FU-CDDP + boost of 15 Gy; D = HDRT). High-dose RT (HDRT) incorporated a boost of 20 to 25 Gy. Thus, arms A and C received 60 Gy total and arms B and D received 65 to 75 Gy total. There appeared to be no difference in their primary endpoint of CFS at 3 years, or in any secondary endpoints such as response rate, toxicity, local control, or overall survival.
Although controversy exists regarding the optimal dose, a reasonable approach is to treat between 55 to 59 Gy (RTOG 98-11) if 3D conformal radiation is being contemplated and 54 Gy if dose painting IMRT (DP IMRT) is being employed per RTOG 0529.
Intensity-Modulated Radiation Therapy
IMRT represents a specific radiation technique that requires specific hardware and software and most importantly technical expertise to deliver conformal radiation doses to target volumes and to limit dose to organs at risk (OAR) such as the intestine, rectum, bladder, skin, external genitalia, and bone. One of the greatest challenges in treating anal cancer is the morbidity from the CMT, and IMRT provides a means to reduce acute toxicity and potentially long-term toxicity. In the future, dose escalation may be possible through IMRT.
Early, single institution, retrospective trials demonstrated encouraging results in reductions in acute toxicity with the use of IMRT (Table 10.5). A multi-institutional phase II trial, RTOG 0529, has confirmed prospectively the reduction in acute toxicities with this technology. The goal of RTOG 0529 was to reduce grade 2+ combined acute GI and GU adverse events of 5-FU and MMC combined with DP IMRT by at least 15% compared with the conventional RT/5-FU/MMC arm from RTOG 98-11. Eligible patients included 52 evaluable, T2–T4N0–N3M0 anal cancers. As the primary endpoint, 77% experienced grade 2+ GI/GU AEs (9811 77%). However, there was a significant reduction in acute grade 2+ hematologic, 73% (98,11 85%; P = 0.032), grade 3+ GI, 21% (9811 36%; P = 0.0082) and grade 3+ dermatologic, AEs 23% (98,11 49%; P < 0.0001) with DP IMRT. Real-time quality assurance was conducted and on pretreatment review found 81% initial plans required replanning due to errors in creating volumes properly. Thus, this trial demonstrated that acute toxicity can be reduced but requires intimate knowledge of anatomy for proper planning and proper delivery. A separate publication regarding the efficacy (2-year local-regional control) and late effects of IMRT is forthcoming. Until further analysis can be performed, IMRT cannot be considered the standard of care. Although if reduced toxicity (acute and long term) is confirmed along with comparable efficacy of conventional radiotherapy, IMRT will become standard practice.
If 3D conformal radiation techniques are employed, patients should receive treatment as per the RTOG 98-11 study. If IMRT is contemplated, the guidelines published by RTOG for contouring the anatomy for GI pelvic tumors should be referenced as well as the RTOG 0529 atlas.
Tumor Regression after Chemoradiation
After patients have completed definitive chemoradiation therapy, patients should be followed up clinically in 8 to 12 weeks after therapy. Cummings demonstrated that mean time for tumor regression was 3 months but regression of a tumor could occur up to 12 months. Thus, if there is persistent disease at 8 to 12 weeks, patients should be followed up closely (every month) to document regression. As long as there is documented regression on serial examinations, patients may continue to be monitored. However, at any point if there is progression, then biopsy followed by salvage APR should be considered.
TREATMENT OPTIONS ACCORDING TO STAGE
Stage 0
■Surgical resection is the treatment of choice for the lesions of the perianal area that does not involve the anal sphincter.
Stage I
■Small, well-differentiated tumors of the anal margin not involving the anal sphincter can be treated with wide local excision.
■All other stage I tumors of the anal margin and anal canal are treated with chemoradiation with 5-FU/MMC.
■Patients who cannot tolerate chemotherapy, such as the very elderly or those with multiple comorbid conditions, may be treated with radiation alone.
■Surgical salvage with APR is reserved for residual cancer in the anal canal after chemoradiation.
Stages II to IIIB
■Chemoradiation with 5-FU/MMC is the recommended initial approach.
■Patients who cannot tolerate chemotherapy may be treated with radiation alone.
■Surgical salvage with APR is reserved for residual disease in the anal canal after chemoradiation.
Stage IV
There are limited data regarding the treatment of metastatic disease given the overall rarity of the disease. There are no available phase III data and only very limited phase II prospective data are available. The most widely used regimen is cisplatin plus 5-FU, which is the recommended as first-line therapy by NCCN. Response rates have been as high as 50% to 66% and median survivals of 12 to 34.5 months. Clinical trials should be encouraged. Palliative efforts remain an important component of care.
PERSISTENT OR RECURRENT ANAL CANCER
Surgery with APR is considered the treatment of choice for either persistent or recurrent disease and 20% to 40% of patients may achieve long-term control. For persistent disease, RTOG 8704 treated 22 patients with a 9 Gy boost with 5-FU and CDDP as salvage. Ultimately, 12 of 22 remained disease-free after surgical intervention. Given the limited data, surgery should remain the standard for chemoradiation failures.
Follow-Up
There are no prospective data regarding the optimal follow-up regimen. NCCN suggests the following: DRE, anoscopy, inguinal node palpation every 3 to 6 months for 5 years. For T3–T4 or positive inguinal lymph nodes at diagnosis, one should consider chest/abd/pelvic imaging annually for 3 years.
Prognosis
The National Cancer Database has provided 5-year survival of anal canal carcinoma patients by stage for both squamous and nonsquamous histologies. The database is based on cases diagnosed from 1998 to 1999 and includes 3,598 cases.
For squamous cell histology, the 5-year survival is as follows: stage I = 71.4%, stage II = 63.5%, stage IIIA = 48.1%, stage IIIB = 43.2%, and stage IV = 20.9%. For nonsquamous histology, the 5-year survival is as follows: stage I = 59.1%, stage II = 52.9%, stage IIIA = 37.7%, stage IIIB = 24.4%, and stage IV = 7.4%. The prognosis shows a statistically worst survival stage for stage between squamous and nonsquamous cell histologies, except for stage IIIA.
REVIEW QUESTIONS
1.A 63-year-old female has been diagnosed with a clinical stage IIIA, T2N1M0 squamous cell carcinoma of the anal canal. The patient presented with mild rectal bleeding but otherwise is healthy and has a good performance status, ECOG 1. What is her best treatment option?
A.Neoadjuvant CDDP + 5-FU followed by concurrent CDDP + 5-FU with RT
B.Concurrent 5-FU + MMC with RT
C.Concurrent 5-FU + MMC with RT + adj chemo (5-FU + CDDP)
D.Concurrent 5-FU +RT
2.A 63-year-old female has been diagnosed with a clinical stage IIIA, T2N1M0 squamous cell carcinoma of the anal canal. The patient asked about her prognosis. What is her estimated 5-year overall survival?
A.75%
B.30%
C.50%
D.15%
3.A 44-year-old HIV+ male with a CD4 count of 630 was recently diagnosed with a clinical stage II, T3N0M0 squamous cell carcinoma of the anal canal. The patient is otherwise healthy with an ECOG of 0. What is his best treatment option?
A.Radiation alone
B.Radiation with 5-FU
C.Chemotherapy alone with 5-FU and MMC
D.5-FU/MMC with radiation alone
4.A 55-year-old female who was diagnosed with a stage IIIB, T4N1M0 squamous cell carcinoma of the anal canal just completed definitive chemoradiation with 5-FU and MMC with 59 Gy of radiation (45 Gy to the pelvis + 14 Gy boost to the primary tumor). Ten weeks after completing therapy, a DRE is performed. A small nodule remains within the anal canal. What is the patient’s best treatment option?
A.immediate APR
B.chemotherapy alone with 5-FU and CDDP
C.4-week reevaluation with repeat DRE, inguinal node palpation, and anoscope
D.reirradiation
5.A 67-year-old female with a newly diagnosed, locally advanced squamous cell carcinoma of the anal canal is having a consultation with the radiation oncologist. He is a very fit individual and has a good performance status, ECOG 1. Among his many questions, he inquires what is his chance of dying from the therapy?
A.5% to 15%
B.0% to 5%
C.10% to 20%
D.20% to 30%
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