Detailed overview of Chemoradiotherapy in anal canal cancer

1. Chemo-Radiotherapy In Anal
Canal Cancer
Dr Atul Gupta
DM Resident
Radiotherapy & Oncology
AIIMS Jodhpur

2. • Carcinoma of the anal canal is a rare malignancy, although its incidence continues to steadily increase.
• Multifocal process largely associated with the human papillomavirus (HPV).
• The treatment approach to this disease has evolved significantly over recent decades and serves as a model for
organ-preserving therapy, transitioning from radical surgery by abdominoperineal resection (APR) to a nonsurgical
approach of definitive chemoradiotherapy with 5-fluorouracil (5-FU) and mitomycin C (MMC), leading to successful
preservation of anorectal function in most patients.
• Unique among gastrointestinal (GI) malignancies in that it has a low propensity for metastatic spread.
Introduction-

3. Epidemiology-

4. • Human Papilloma Virus (HPV)- A recent meta-analysis suggests that HPV16 is found more frequently
(75%) and HPV18 less frequently (10%) in anal carcinomas than in cervical carcinomas.
• HIV- Patients with HIV have approximately 19-fold higher risk of anal cancer compared to that in the general
population
• Age >55yrs
• Smoking
• Immunosuppression- Solid organ transplant recipients with chronic immunosuppressive therapy have a six
times higher risk to develop anal cancer relative to the general population.
Risk Factors-

8. Role of Surgery in Anal Canal Cancer -
• Until the mid-1970s, surgery was the gold standard for the treatment of anal canal cancer.
• The standard surgical technique was APR, requiring a permanent colostomy and removal of the rectum, ischio-rectal
fat, levator sling, perirectal and superior hemorrhoidal nodes, and a wide area of perianal skin.
• Long-term sexual and urinary dysfunction are potential consequences of an APR. The 5-year OS rate for APR for all
patients with anal cancer was approximately 50%. ¹
• For superficial lesions without lymph node involvement, the Mayo Clinic reported a 5-year OS rate of 90% with
radical surgery however, with muscle invasive, node-positive disease, outcomes were poor with a 5-year OS of 32%. ²
• A subsequent review from the Mayo Clinic of 118 anal canal cancers treated with APR showed an OS rate of 70%
and an overall recurrence rate of 40%. Over 80% of patients with known recurrence sites had either exclusively local
recurrence or a local recurrence component. ³
1. Brown DK, Oglesby AB, Scott DH, Dayton MT. Squamous cell carcinoma of the anus: a twenty-five year retrospective. Am Surg. 1988;54(6):337–342.Pintor MP, Northover JM,
Nicholls RJ. Squamous cell carcinoma of the anus at one hospital from 1948 to 1984. Br J Surg. 1989;76(8):806–810.
2. Beahrs OH, Wilson SM. Carcinoma of the anus.Ann Surg. 1976;184(4):422–428.
3. Boman BM, Moertel CG, O’Connell MJ, et al. Carcinoma of the anal canal. A clinical and pathologic study of 188 cases. Cancer. 1984;54(1):114 125

9. • For early-stage, small (<2 cm), well-differentiated anal canal cancers without other adverse histologic
features that are not invading the underlying sphincter and have no clinical lymph node involvement,
local excision is considered an option.
• For these highly selected patients, OS at 5 years has been reported to be over 80%. However, local
excision should be considered only for lesions of the anal margin in which the sphincter can be spared.⁴
• Selective utilization of a wide local excision (WLE) in patients with superficially invasive SCCA (SISCCA).
SISCCA is defined as anal cancer that has been completely excised to negative margins with ≤3 mm of
basement membrane invasion and ≤7 mm of horizontal spread.⁵
4. Greenall MJ, Quan SH, Stearns MW, et al. Epidermoid cancer of the anal margin. Pathologic features, treatment, and clinical results. Am J Surg. 1985;149(1):95–101.
5. Darragh TM, Colgan TJ, Cox JT, et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus
recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med. 2012;136:1266-1297.

10.  Incorporating concurrent pelvic radiation therapy and chemotherapy (5-FU and MMC) prior to surgical
resection, resulting in high rates of pathologic complete response and survival, later verified by other
investigators.
 Eighty-four percent of patients in that follow-up study had a clinical CR to CRT. In addition, the 5-year OS rate
was 67%, and the 5-year colostomy-free survival (CFS) rate was 59% for the cohort.
 This led to significant interest in a definitive chemoradiotherapy approach
 The initial Nigro regimen consisted of a 5-fluorouracil (5-FU) (1000 mg/m2 as a continuous infusion on
days 1-4 and 29-32) and mitomycin-C (MMC) (10-15 mg/m2 on day 1) with concurrent radiation to a
total dose of 30 gray (Gy).
1974

11.  585 patients were randomised to receive initially either 45 Gy radiotherapy in twenty or twenty-five fractions over 4–5
weeks (290 patients) or the same regimen of radiotherapy combined with 5-fluorouracil (1000 mg/m2 for 4 days or 750
mg/m2 for 5 days) by continuous infusion during the first and the final weeks of radiotherapy and mitomycin
(12 mg/m2) on day 1 of the first course (295 patients).
 Assessed clinical response 6 weeks after initial treatment: good responders were recommended for boost radiotherapy
and poor responders for salvage surgery.
1996

12. CONCLUSION-
 After a median follow-up of 42 months (interquartile range 28–62), 164 of 279 (59%) radiotherapy patients had
a local failure compared with 101 of 283 (36%) CMT patients.
 This gave a 46% reduction in the risk of local failure in the patients receiving CMT (relative risk 0·54, 95% CI
0·42–0·69, p<0.0001
 The risk of death from anal cancer was also reduced in the CMT arm (0·71, 0·53–0·95, p=0·02).
 There was no overall survival advantage (0·86, 0·67–1·11, p=0·25).
 Early morbidity was significantly more frequent in the CMT arm (p=0·03), but late morbidity occurred at similar
rates.
 The trial shows that the standard treatment for most patients with epidermoid anal cancer should be a
combination of radiotherapy and infused 5-fluorouracil and mitomycin, with surgery reserved for those who fail
on this regimen

13.  Twelve years after treatment, for every 100 patients treated with chemoradiation, there are an expected 25.3
fewer patients with locoregional relapse (95% confidence interval (CI): 17.5 – 32.0 fewer) and 12.5 fewer anal
cancer deaths (95% CI: 4.3 – 19.7 fewer), compared with 100 patients given RT alone.
 Only 11 patients suffered a locoregional relapse as a first event after 5 years
 5 year colostomy free survival better in CTRT arm (47% vs 37%)
 12 year OS benefit of 5.6% (statistically insignificant) in CTRT arm

14. Results-
 On subgroup analyses, 5-year OS was 86% with CRT (n=1,216) and 84.2% with RT (n=103) (P=0.74) in stage I
(T1N0) patients
 5-year OS was 72.8% with CRT (n=2,766) and 66.4% with RT (n=203) (P=0.13) in stage II (T2-3N0) patients.
 CRT was associated with improved median OS in stage II patients (119 months vs. not reached, P=0.04)
Conclusion-
 OS benefit in patients with stage II SCC of the anus treated with CRT compared to RT alone, with no such benefit in
patients with stage I disease.
 In patients with stage I anus cancer, clinicians should weigh the potential improvement in clinical outcomes with the
added toxicity of systemic therapy.
 Definitive RT as monotherapy may be appropriate in patients with tumors less than 2 cm.

15. Can MMC be omitted in Def CTRT ?

16.  310 patients were randomized to receive either radiotherapy (RT) and fluorouracil (5-FU) or radiotherapy,
5-FU, and MMC.
 Of 291 assessable patients, 145 received 45 to 50.4 Gy of pelvic RT plus 5-FU at 1,000 mg/m2/d for 4
days,
 and 146 received RT, 5-FU, and MMC (10 mg/m2 per dose for two doses).
 Patients with residual tumor on posttreatment biopsy were treated with a salvage regimen that consisted
of additional pelvic RT (9 Gy), 5-FU, and cisplatin (100 mg/m2).
S/E of Mitomycin :-Significant
myelosuppression and dermatitis,
less common side effects of pulmonary
fibrosis, hemolytic-uremic syndrome,
and therapy-related myelodysplastic
syndrome

17. RESULTS-
 Posttreatment biopsies were positive in 15% of patients in the 5-FU arm versus 7.7% in the MMC arm (P =
.135).
 At 4 years, colostomy rates were lower (9% v 22%; P = .002), colostomy-free survival higher (71% v 59%; P =
.014), and disease-free survival higher (73% v 51%; P = .0003) in the MMC arm.
 A significant difference in overall survival has not been observed at 4 years.
 Toxicity was greater in the MMC arm (23% v 7% grade 4 and 5 toxicity; P < or = .001).
 Of 24 assessable patients who underwent salvage CR, 12 (50%) were rendered disease-free.
CONCLUSION-
 Despite greater toxicity, the use of MMC in a definitive CR regimen for anal cancer is justified, particularly in
patients with large primary tumors.

18. Can MMC be replaced with Cisplatin?

19.  In this 2×2 factorial trial, patients were enrolled with
histologically confirmed squamous-cell carcinoma of the anus
without metastatic disease from 59 centres in the UK.
 Patients were randomly assigned to one of four groups, to receive
either mitomycin (12 mg/m² on day 1) or cisplatin (60 mg/m² on
days 1 and 29), with fluorouracil (1000 mg/m² per day on days 1–
4 and 29–32) and radiotherapy (50·4 Gy in 28 daily fractions);
with or without two courses of maintenance chemotherapy
(fluorouracil and cisplatin at weeks 11 and 14)
 Largest trial ever done in Ca Anal Canal (900 + patients)

20. Findings-
 Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin).
 The most common grade 3–4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs
135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468
[18%]).
 3-year progression-free survival was 74% (95% CI 69–77; maintenance) versus 73% (95% CI 68–77; no
maintenance; hazard ratio 0·95, 95% CI 0·75–1·21; p=0·70).
It concluded that 5-FU and mitomycin with 50·4 Gy radiotherapy in 28 daily
fractions should remain standard practice given the following-
(1) the high-grade hematologic toxicity seen with MMC did not significantly
increase sepsis rates;
(2) the MMC course was delivered over approximately 10 minutes compared
to two courses of either all day or overnight intravenous hydration with
cisplatin, with similar efficacy and overall toxicities between the
regimens;
(3) fewer chemotherapy cycles were required;
(4) there was requirement for fewer nonchemotherapy drugs;
(5) there was lesser expense; and
(6) there was no risk of neuropathy.

21. Can 5-FU be replaced with Capecitabine ?

22.  Clinical complete response was achieved in 41/46
patients (89.1%) with 5-FU and in 52/58 patients
(89.7%) with capecitabine.
 Three-year LRC was 76% and 79% (P=0.690, log-rank
test), 3-year OS was 78% and 86% (P=0.364, log-rank
test) and CFS was 65% and 79% (P=0.115, log-rank
test) for 5-FU and capecitabine, respectively.
 Capecitabine/MMC resulted in similar levels of
grade 3/4 toxicity overall compared with 5-
FU/MMC as CRT for ASCC, although
differences were found in the patterns of
observed toxicities, with less hematologic
toxicity with capecitabine

23. What is optimal Radiation Dose ?

24. Purpose- Definitive chemoradiotherapy represents a standard of care treatment for localized anal cancer. NCCN
guidelines recommend radiotherapy (RT) doses of ≥ 45 Gy and escalation to 50.4–59 Gy for advanced disease. Per RTOG
0529, 50.4 Gy was prescribed for early-stage disease (cT1-2N0), and 54 Gy for locally advanced cancers (cT3-T4 and/ or
node positive). They assessed patterns of care and overall survival (OS) with respect to the RT dose.
Method- The National Cancer Database identified patients with non-metastatic anal squamous cell carcinoma from
2004 to 2015 treated with chemoradiotherapy. Patients were stratified by RT dose: 40–< 45, 45–< 50, 50–54, and > 54–60
Gy. Crude and adjusted hazard ratios (HR) were computed using Cox regression modeling

25. Results-
 A total of 10,524 patients were identified with a median follow-up of 40.7 months.
 The most commonly prescribed RT dose was 54 Gy.
 On multivariate analysis, RT doses of 40–< 45 Gy were associated with worse OS vs. 50–54 Gy (HR 1.68 [1.40– 2.03], p <
0.0001).
 There was no significant difference in OS for patients who received 45–< 50 or > 54–60 Gy compared with 50–54 Gy. For
early-stage disease, there was no significant association between RT dose and OS.
 For locally advanced disease, 45–< 54 Gy was associated with worse survival vs. 54 Gy (HR 1.18 [1.04–1.34], P = 0.009),
but no significant difference was detected comparing > 54–60 Gy vs. 54 Gy (HR 1.08 [0.97–1.22], P = 0.166).
Conclusions- For patients with localized anal cancer, RT doses of ≥ 45 Gy were associated with improved OS. For locally
advanced disease, 54 Gy but not > 54 Gy was associated with improved OS.

26. Future Directions in Radiotherapy-
1. The ACT4 (ISRCTN88455282) trial is a randomized phase II trial enrolling patients with T1-2 N0 anal
canal SCC or T2 N0 anal margin SCC, comparing LRF rates in those who receive standard-dose chemoradiation
(50.4 Gy in 28 fractions) compared to de-intensified chemoradiation (41.4 Gy in 23 fractions) ----- Result
expected in 2024
2. DECREASE study (NCT04166318) trial is comparing standard-dose chemoradiation (28 fractions) with
de-intensified chemoradiation (20 or 23 fractions, with exact dosages based on the T stage) to determine if there is
2-year disease control ≥85% while also improving health-related quality of life in patients receiving the de-
intensified regimen----- Result expected in 2025
3. The PLATO trial (Personalizing Anal Cancer Radiotherapy Dose) (International Standard
Randomized Controlled Trial [ISRCT] number ISRCTN88455282) is an integrated protocol comprising 3 separate trials
(ACT3, ACT4, and ACT5) that aim to optimize the radiation dose for low-risk, intermediate-risk, and high-risk SCCA
(Cancer Research UK trial number CRUK/15/007)
4. Proton therapy is also being investigated (ClinicalTrials.gov identifier NCT03018418).

27. When to assess response post Definitive CTRT ?

28. Conclusion-
 Many patients who do not have a
complete clinical response when
assessed at 11 weeks after
commencing chemoradiotherapy do
in fact respond by 26 weeks, and the
earlier assessment could lead to
some patients having unnecessary
surgery.
 Data suggests that the optimum
time for assessment of complete
clinical response after
chemoradiotherapy for patients with
squamous cell carcinoma of the anus
is 26 weeks from starting
chemoradiotherapy.

30. Is there any role of Induction chemotherapy or Radiation
Boost post Definitive CTRT ?

31. Patients with tumors 40 mm, or 40 mm and N1-3M0 were randomly assigned to
one of four treatment arms:
(A) two ICT cycles (fluorouracil 800 mg/m2 /d intravenous [IV] infusion, days 1
through 4 and 29 to 32; and cisplatin 80 mg/m2 IV, on days 1 and 29), RCT (45
Gy in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and
5), and standard-dose boost (SD; 15 Gy);
(B) two ICT cycles, RCT, and high-dose boost (HD; 20-25 Gy);
(C) RCT and SD boost (reference arm);
(D) RCT and HD boost.
 Of note is that a 3-week break was mandated following the completion of the
initial 45 Gy, prior to boost treatments

32. Group CFS OS
A (ICT-- CTRT--- SD BOOST) 69.6% Group A +B = 75%
B(ICT--- CTRT--- HD BOOST) 82.4% Group C+ D= 71%
C (CTRT--- SD BOOST) 77.1% Group A + C = 71%
D (CTRT--- HD BOOST) 72.7% Group B + D =74%
Conclusion-
 The trial authors concluded that induction chemotherapy does not improve outcomes, with the role of radiation
dose escalation in this disease remaining uncertain.
 Using CFS as main end point, they did not find an advantage for either ICT or HD radiation boost in LAACC.

33. Purpose- A multi-institutional phase 2 trial assessed the utility of dose-painted intensity modulated radiation therapy (DP-IMRT) in
reducing grade 2 combined acute gastrointestinal and genitourinary adverse events (AEs) of 5-fluorouracil (5FU) and mitomycin-C (MMC)
chemoradiation for anal cancer by at least 15% compared with the conventional radiation/5FU/MMC arm from RTOG 9811.
Conclusion- This trial concluded 12% improvement in grade ≥2 hematologic toxicity (P = .03), a 15% improvement in
grade ≥3 gastrointestinal toxicity, and a 26% improvement in grade ≥3 dermatologic toxicity (P < .01) with IMRT.
 At a median follow-up of 7.9 years, the rates of LRF, distant metastases, CFS, DFS, and OS were comparable to those
reported for cohorts of patients treated with more conventional radiation techniques, indicating that the reduced
toxicity of IMRT does not come at the expense of efficacy.
Conventional RT vs IMRT-

34. Novel Biological Radiosensitizer Agent-
 To date, no biologic agent has been granted FDA approval as an effective radiosensitizer in anal cancer.
 KRAS mutations were detected in 1.6% and BRAF mutations in 4.7% of the biopsies. No
impact of KRAS or BRAF status on survival was found. ¹
1. Serup-Hansen E, Linnemann D, Høgdall E, et al. KRAS and BRAF mutations in anal carcinoma. APMIS
2015;123(1):53–59

36. Key Points to be remembered-
Chemotherapy:
• Chemotherapy plus radiation is superior to radiation alone. (ACT I, EORTC 22861)
• MMC plus 5-FU is superior to 5-FU alone. (RTOG 87-04)
• MMC plus 5-FU is superior to cisplatin plus 5-FU. (RTOG 98-11, ACT II)
• Induction chemotherapy is not indicated. (RTOG 98-11)
• Maintenance chemotherapy is not indicated .(ACT II, ACCORD 3)
• Capecitabine can be used in place of 5-FU. (EXTRA, UK trial)
• No role for cetuximab. (ECOG 3205, ACCORD 16)
• Chemotherapy is indicated even for patients with T1N0 disease.
• Immunotherapy concurrent with radiation is being studied in ongoing trials.

37. Radiation therapy:-
• Dose escalation beyond 59 Gy for patients with stage T3-T4 disease is not beneficial .
• Patients with T1-T2 tumors can be safely treated with a maximal dose of 50.4 Gy to gross disease .
• IMRT is the preferred technique vs 3DCRT.
• There is currently no role for brachytherapy in the initial treatment for SCCA.
• Attempts at fine-tuning radiotherapy doses for various stages of the disease (i.e, escalating for
advanced disease and de-escalating for early disease) are ongoing.

38. Surgery:-
• Wide local excision is acceptable for T1 lesions defined as superficially invasive SCCA .
• Surgery also has a role in salvage after CRT .
Follow-up: -
• Wait until 26 weeks to assess for complete response to treatment .
• In-person clinical evaluation with digital rectal examination is essential.

57. THANKS

59.  Baseline glomerular filtration rate <60 ml/min and cisplatin were significantly associated with poor week 5 compliance to chemotherapy (P = 0.003 and
0.02, respectively).
 Omission of week 5 chemotherapy was associated with significantly worse locoregional failure-free survival [hazard ratio (HR) 2.53 (1.33-4.82) P =
0.005].
 Those in the mitomycin arm had a higher rate of completion (82%) of week 5 chemotherapy per protocol compared to those in the cisplatin arm (75%)
 Dose reductions/delays or omission of week 5 chemotherapy were associated with significantly worse PFS {HR: 1.56 [95% confidence interval (CI):
1.18-2.06], P = 0.002 and HR: 2.39 (95% CI: 1.44-3.98), P = 0.001, respectively} and OS [HR: 1.92 (95% CI: 1.41-2.63), P < 0.001 and HR: 2.88 (95%
CI: 1.63-5.08), P < 0.001, respectively].
 Receiving the target radiotherapy dose in >42 days is associated with worse PFS and OS [HR: 1.72 (95% CI: 1.17-2.54), P =0.006].