ACHO 2017 - Anal Cancer - Version 3

Avances en el tratamiento de cáncer anal
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia
Hotel Sonesta
Bogotá, 29.07.2017
1er Simposiso de Cáncer
Gastrointestinal - ACHO

Simplified TNM/Stage
- Anal cancer -
T N M Stage
1 (≤ 2 cm) 0 0 I (T1N0M0)
2 (>2-5 cm) 1 (Peri-rectal LN)
1 (Distant
metastasis)
II (T2-3N0M0)
3 (>5 cm)
2 (Unilateral inguinal
and/or Iliac LN)
IIIA (T1-3N1M0;
T4N0M0)
4 (Invades
organ)
3 (Peri-rectal AND
Inguinal/Iliac; or
bilateral LN)
IIIB (T4N1M0;
Any TN2-3M0)
IV (Any T, Any
M, M1)

Anal carcinoma: FDG PET/CT in staging, response evaluation, and
follow-up.
Cited by: Saboo, S. S., Zukotynski, K., Shinagare, A. B., Krajewski, K. M., & Ramaiya, N. (2013). Anal carcinoma: FDG PET/CT in staging, response
evaluation, and follow-up. Abdominal Imaging, 38(4), 728–735. https://doi.org/10.1007/s00261-012-9958-3
Author N Altered staging
Bhuva 43 42 %
Wells 37 37 %
Winton 61 23 %

Mid eighties first phase III
Trial Arm A Arm B
US (RTOG 8704) XRT + FU XRT + FU-MMC
EORTC 22861 XRT XRT + FU-MMC
UKCCCR ACT I XRT XRT + FU-MMC
XRT: Radiation therapy; FU: 5-Fluorouracil; Mitomicyn-C

RTOG-87-04: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the
definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study.
Colostomy-free
Survival (%)
5-yr OS (%)
Colostomy-free rate
(%)
n=310
* Statistically significant
Complete response (%)
100%
66%
33%
Flam, M., John, M., Pajak, T. F., Petrelli, N., Myerson, R., Doggett, S., … Murray, K.
(1996). Role of mitomycin in combination with fluorouracil and radiotherapy, and of
salvage chemoradiation in the definitive nonsurgical treatment of epidermoid
carcinoma of the anal canal: results of a phase III randomized intergroup study.
Journal of Clinical Oncology, 14(9), 2527–2539.
https://doi.org/10.1200/JCO.1996.14.9.2527
XRT + FU + MMC
XRT + FU
71*
92
91*
78
59*
86
78*
71

Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal
cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy
and Gastrointestinal Cooperative Groups.
Colostomy-free
Survival (%)
5-yr OS (%)
5-yr Local failure-free
(%)
n=110 T3-4NO-3 or T1-2N1-3
Complete response (%)
100%
66%
33%
Bartelink, H., Roelofsen, F., Eschwege, F., Rougier, P., Bosset, J. F., Gonzalez, D. G., …
Pierart, M. (1997). Concomitant radiotherapy and chemotherapy is superior to
radiotherapy alone in the treatment of locally advanced anal cancer: results of a
phase III randomized trial of the European Organization for Research and Treatment
of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. Journal of Clinical
Oncology, 15(5), 2040–2049. https://doi.org/10.1200/JCO.1997.15.5.2040
XRT + FU + MMC
XRT 80*
68*
58
54*
50*
54
FU + MMC: 750 mg/m2 daily
fluorouracil as a continuous
infusion on days 1 to 5 and 29
to 33, and a single dose of
mitomycin 15 mg/m2
administered on day 1
Improved by 32%
in RT+CT

Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-
up of the first randomised UKCCCR Anal Cancer Trial (ACT I).
13-yr OS (%)
New cancer (%)
Distant Relapse-free
survival (%)
n=557
13-yr Loco-regional relapse-free survival (%)
100%
66%
33%
Northover, J., Glynne-Jones, R., Sebag-Montefiore, D., James, R., Meadows, H., Wan,
S., … Ledermann, J. (2010). Chemoradiation for the treatment of epidermoid anal
cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I).
British Journal of Cancer, 102(7), 1123–1128. https://doi.org/10.1038/sj.bjc.6605605
XRT + FU + MMC
XRT
71
68*
91
11
80
45*
92
6
FU+MMC: 5-fluorouracil (1000 mg m2 for 4 days or
750 mg m2 for 5 days) by continuous intravenous
infusion during the first and final weeks of radiotherapy,
and mitomycin C (12 mg m−2) as a single intravenous
bolus injection on day 1 of the first cycle of
chemotherapy

Long-Term Update of US GI Intergroup RTOG 98-11 Phase III Trial for Anal Carcinoma: Survival, Relapse, and Colostomy Failure
With Concurrent Chemoradiation Involving Fluorouracil/Mitomycin Versus Fluorouracil/Cisplatin.
Gunderson, L. L., Winter, K. A., Ajani, J. A., Pedersen, J. E., Moughan, J., Benson, A. B., … Willett, C. G. (2012). Long-Term Update of US GI Intergroup RTOG 98-11 Phase III Trial for Anal Carcinoma: Survival,
Relapse, and Colostomy Failure With Concurrent Chemoradiation Involving Fluorouracil/Mitomycin Versus Fluorouracil/Cisplatin. Journal of Clinical Oncology, 30(35), 4344–4351.
https://doi.org/10.1200/JCO.2012.43.8085
T2-4 N0 N+
CRT + FU +MMC FU + Cisplatin x2
CRT (FU +
Cisplatin)
n=682

Gunderson, L. L., Winter, K. A., Ajani, J. A., Pedersen, J. E., Moughan, J., Benson, A. B., … Willett, C. G. (2012). Long-Term Update of US GI Intergroup RTOG 98-11 Phase III Trial for Anal Carcinoma: Survival,
Relapse, and Colostomy Failure With Concurrent Chemoradiation Involving Fluorouracil/Mitomycin Versus Fluorouracil/Cisplatin. Journal of Clinical Oncology, 30(35), 4344–4351.
https://doi.org/10.1200/JCO.2012.43.8085

5-yr Colostomy-free
Survival (%)
5-yr OS (%)
5-yr Loco-regional
failure-free (%)
n=682
DFS (%)
100%
66%
33%
Gunderson, L. L., Winter, K. A., Ajani, J. A., Pedersen, J. E., Moughan, J., Benson, A. B.,
… Willett, C. G. (2012). Long-Term Update of US GI Intergroup RTOG 98-11 Phase III
Trial for Anal Carcinoma: Survival, Relapse, and Colostomy Failure With Concurrent
Chemoradiation Involving Fluorouracil/Mitomycin Versus Fluorouracil/Cisplatin.
https://doi.org/10.1200/JCO.2012.43.8085
XRT + FU + MMC
FU+Cisplatin followed by XRT + FU + Cisplatin
71*
67*
80
78*
65*
57*
74
70*

“Concurrent chemo-RT with FU +
Mitomycin-C remains the standard-
of-care with anal canal carcinoma”

Yu I, Cheung WY, Proc ASCO, 2017

Yu I, Cheung WY, Proc ASCO, 2017
486 patients

Gunderson, L. L., Winter, K. A., Ajani, J. A., Pedersen, J. E., Moughan, J., Benson, A. B.,
… Willett, C. G. (2012). Long-Term Update of US GI Intergroup RTOG 98-11 Phase III
Trial for Anal Carcinoma: Survival, Relapse, and Colostomy Failure With Concurrent
Chemoradiation Involving Fluorouracil/Mitomycin Versus Fluorouracil/Cisplatin.
https://doi.org/10.1200/JCO.2012.43.8085
CRT (FU/MMC)

Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-
cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial.
James, R. D., Glynne-Jones, R., Meadows, H. M., Cunningham, D., Myint, A. S., Saunders, M. P., … Sebag-Montefiore, D. (2013). Mitomycin or cisplatin chemoradiation with or without maintenance
chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. The Lancet Oncology, 14(6), 516–524. https://doi.org/10.1016/S1470-
2045(13)70086-X
Patient with confirmed primary epidermoid anal cancer, staged and
biopsied by EUA & CT scan
GFR greater than
50 mL/min
R
CRT (FU/MMC) CRT (FU/MMC) CRT (FU/Cisplatin) CRT (FU/Cisplatin)
No maintenance
Maintenance
5U/Cisplatin
No maintenance
Maintenance
FU/Cisplatin

James, R. D., Glynne-Jones, R., Meadows, H. M., Cunningham, D., Myint, A. S., Saunders, M. P., … Sebag-Montefiore, D. (2013). Mitomycin or cisplatin chemoradiation with or without maintenance
chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. The Lancet Oncology, 14(6), 516–524. https://doi.org/10.1016/S1470-
2045(13)70086-X

James, R. D., Glynne-Jones, R., Meadows, H. M., Cunningham, D., Myint, A. S.,
Saunders, M. P., … Sebag-Montefiore, D. (2013). Mitomycin or cisplatin
chemoradiation with or without maintenance chemotherapy for treatment of
squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label,
2×2 factorial trial. The Lancet Oncology, 14(6), 516–524.
https://doi.org/10.1016/S1470-2045(13)70086-X
Maintenance
chemotherapy in
anal cancer

Best time to assess complete clinical response after chemoradiotherapy in squamous cell carcinoma
of the anus (ACT II): a post-hoc analysis of randomised controlled phase 3 trial
Glynne-Jones, R., Sebag-Montefiore, D., Meadows, H. M., Cunningham, D., Begum,
R., Adab, F., … Kadalayil, L. (2017). Best time to assess complete clinical response
after chemoradiotherapy in squamous cell carcinoma of the anus (ACT II): a post-hoc
analysis of randomised controlled phase 3 trial. The Lancet Oncology, 18(3), 347–
356. https://doi.org/10.1016/S1470-2045(17)30071-2
Assessment at 11 weeks Assessment at 18 weeks
Assessment at 36 weeks

356. https://doi.org/10.1016/S1470-2045(17)30071-2

356. https://doi.org/10.1016/S1470-2045(17)30071-2
“151 (72%) of the 209 patients who had not had a
complete clinical response at week 11 had a complete
clinical response by week 26*”.
*Some text editing for clarity

E3205 - Phase II - Cetuximab plus Chemoradiotherapy in
Anal Cancer
mab Plus Chemoradiotherapy in Immunocompetent Patients With Anal Carcinoma: A Phase II Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Rese

Cetuximab Plus Chemoradiotherapy in Immunocompetent Patients With Anal Carcinoma: A
Phase II Eastern Cooperative Oncology Group–American College of Radiology Imaging
Network Cancer Research Group Trial (E3205)
3-yr OS (%)
Grade 4 toxicity (%)
3-yr PFS (%)
n=61
3-yr Locoregional failure (%)
100%
66%
33%
Garg, M. K., Zhao, F., Sparano, J. A., Palefsky, J., Whittington, R., Mitchell, E. P., …
Benson, A. B. (2017). Cetuximab Plus Chemoradiotherapy in Immunocompetent
Patients With Anal Carcinoma: A Phase II Eastern Cooperative Oncology Group–
American College of Radiology Imaging Network Cancer Research Group Trial
(E3205). Journal of Clinical Oncology, 35(7), 718–726.
https://doi.org/10.1200/JCO.2016.69.1667
XRT + FU + Cisplatin + Cetuximab
83
23*
68
32
5% Treatment-
related deaths

Cetuximab Plus Chemoradiotherapy in Immunocompetent Patients With Anal Carcinoma: A
Phase II Eastern Cooperative Oncology Group–American College of Radiology Imaging
Network Cancer Research Group Trial (E3205)
Garg, M. K., Zhao, F., Sparano, J. A., Palefsky, J., Whittington, R., Mitchell, E. P., …
Benson, A. B. (2017). Cetuximab Plus Chemoradiotherapy in Immunocompetent
Patients With Anal Carcinoma: A Phase II Eastern Cooperative Oncology Group–
American College of Radiology Imaging Network Cancer Research Group Trial
(E3205). Journal of Clinical Oncology, 35(7), 718–726.
https://doi.org/10.1200/JCO.2016.69.1667
XRT + FU + Cisplatin + Cetuximab

Ongoing: InterAACT ECOG #2133
Morris, V., & Eng, C. (2016). Summary of emerging targets in anal cancer: the case for an immunotherapy based-approach.
Journal of Gastrointestinal Oncology, 7(5), 721–726. https://doi.org/
Epidermoid anal cancer
Inoperable, locally recurrent or
metastatic disease
ECOG PS 0-2
HIV+/- (controlled)
GFR 50+ mL/min
Adequate organ function
Cisplatin + FU
Endpoint
ORR
Carboplatin + Paclitaxel

Antiangiogenic therapy
in Anal Cancer

Tewari, K. S., Sill, M. W., Long, H. J., Penson, R. T., Huang, H., Ramondetta, L. M., … Monk, B. J. (2014). Improved Survival with
Bevacizumab in Advanced Cervical Cancer. New England Journal of Medicine, 370(8), 734–743.
https://doi.org/10.1056/NEJMoa1309748
GOG-240: Improved survival with bevacizumab in advanced
cervical cancer.
ORR (%)
median PFS (mo)
Chemotherapy
48^
8.2*
5.9*
13.3*
median OS (mo)
Chemotherapy + Bevacizumab
36*17*
n=452
Bevacizumab increases toxicity:
Hypertension of grade 2 or higher (25% vs. 2%),
Thromboembolic events of grade 3 or higher (8% vs. 1%), and
Gastrointestinal fistulas of grade 3 or higher (3% vs. 0%).

Immuno-Oncology
and Anal Cancer

Human Papillomavirus Genotyping and p16 Expression As
Prognostic Factors for Patients With American Joint Committee
on Cancer Stages I to III Carcinoma of the Anal Canal
vsteen, H. (2014). Human Papillomavirus Genotyping and p16 Expression As Prognostic Factors for Patients With American Joint Committee on Cancer Stages I to III Carcinoma of the Anal Can

Human papilloma virus load and PD-1/PD-L1, CD8+ and FOXP3 in
anal cancer patients treated with chemoradiotherapy: Rationale
for immunotherapy.
Rödel, C., … Rödel, F. (2017). Human papilloma virus load and PD-1/PD-L1, CD8 + and FOXP3 in anal cancer patients treated with chemoradiotherapy: Rationale for immunotherapy. OncoImmun
Marker
No. of
patients
CD8+ Low CD8+ High p-value
HPV-16 Low 67 51(56) 16(36)
4,3E+01
HPV-16 High 68 40(44) 28(64)
p16(INK4a)Low 73 54(55) 19(37)
5,8E+01
p16(INK4a) High 77 45(45) 32(63)

for immunotherapy.
Higher “immunogenicity” predicts higher response to CRT

for immunotherapy.
0.007, respectively) and DFS (p = 0.020 and p = 0.014, respective

Characterization of tumor mutation burden (TMB) in
gastrointestinal (GI) cancers.
M., Gatalica, Z., … Marshall, J. (2017). Characterization of tumor mutation burden (TMB) in gastrointestinal (GI) cancers. Journal of Clinical Oncology, 35(4_

PD-L1 expression in patients with SCCA
• Retrospective
• 41 patients with SCCA
• PD-L1 expression in 56%
• No difference in survival between PD-L1 +/-
• None received immune-directed therapy
, Batra A, et al. Programmed cell death-Ligand 1 (PD-L1) expression and outcome in patients with squamous cell cancer of anal canal (SCCAC). J Clin Onc
C. (2016). Summary of emerging targets in anal cancer: the case for an immunotherapy based-approach. Journal of Gastrointestinal Oncology, 7(5), 721–7

KEYNOTE-028: Pembrolizumab (MK-3475) for PD-L1-positive
squamous cell carcinoma (SCC) of the anal canal
• Of the 43 patients screened, PD-L1 expression was detected in 34 (74%),
• 25 patients were enrolled for treatment.
• 80% had at least one prior line of systemic therapy for distant metastases.
• Response
• PR in 5/26 patients [response rate 20%; 95% confidence interval (CI), 7–
41%],
• SD in 11 patients (response rate 44%; 95% CI, 24–65%).
• 20% of patients still on study after 12 months.
olizumab (MK-3475) for PD-L1-positive squamous cell carcinoma (SCC) of the anal canal: Preliminary safety and efficacy results from KEYNOTE-028. Euro

NCI9673: A multi-institutional eETCTN phase II study of
nivolumab in refractory metastatic squamous cell carcinoma
of the anal canal (SCCA).
• 37 patients
• Response
• CR: 5%
• PR: 19%
• SD: 46%
• DCR: 70%
• The median progression-free survival was 3.9 months.
Morris, V., & Eng, C. (2016). Proc ASCO 2016, Abstract 3503

NCI9673: A multi-institutional eETCTN phase II study of
nivolumab in refractory metastatic squamous cell carcinoma
of the anal canal (SCCA).
• 37 patients
• Response
• CR: 5%
• PR: 19%
• SD: 46%
• DCR: 70%
• The median progression-free survival was 3.9 months.
., Krajewski, K. M., & Ramaiya, N. (2013). Anal carcinoma: FDG PET/CT in staging, response evaluation, and follow-up. Abdominal Imaging, 38(4), 728–73

Comprehensive genomic profiling of anal squamous cell
carcinoma reveals distinct genomically defined classes
A. B., Palma, N. A., … Ali, S. M. (2016). Comprehensive genomic profiling of anal squamous cell carcinoma reveals distinct genomically defined classes. Annals of Onc
63% of cases. Clinically relevant GAs in genes involved in DNA repair, chromatin remodeling, or receptor tyrosine kinase signa

Comprehensive genomic profiling of anal squamous cell
carcinoma reveals distinct genomically defined classes
A. B., Palma, N. A., … Ali, S. M. (2016). Comprehensive genomic profiling of anal squamous cell carcinoma reveals distinct genomically defined classes. Annals of Onc

Venchiarutti, et al. Proc ASCO 2017

ADXS 11-001
ADXS 11-001 expresses a fusion Lm-LLO-E7 protein

Conclusions
• PET-CT may change clinical stage in 23-43% in anal cancer
• Concurrent chemo-RT with FU + Mitomycin continues to be the standard-of-care of all, but the
smallest, non-metastatic anal cancers
• Capecitabine may substitute for FU
• Cisplatin is less effective than mitomycin
• Optimal timing for response assessment is week 26
• No one knows for sure what is the optimal rescue therapy
• Cisplatin + FU (?)
• Paclitaxel + Carbo (?)
• Bevacizumab (?)
• Unclear role of anti-EGFR therapy in anal cancer
• Anal cancer may benefit from anti-PD1/anti-PD-L1 therapy
• Non-random genomic alterations in anal cancer may be amenable to targeted therapy
• HPV-directed therapy may be effective for some anal cancer patients

ACHO 2017 - Anal Cancer - Version 3

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ACHO 2017 - Anal Cancer - Version 3