Download Advanced Stage of Anal Squamous Cell Carcinoma. A Case Report

Advanced Stage of Anal Squamous Cell Carcinoma.
A Case Report
Anamaria Rusu1, Tănase Timiş2, Raluca Popiţă3, Gabriel Kacsó4,5
Institute of Oncology „Ion Chiricuta”, Departments of 1) Radiation Oncology; 2) Medical Oncology, 3) Radiology,
4) Brachytherapy; 5) University of Medicine and Pharmacy „Iuliu Hatieganu” Cluj, Romania
Carcinoma of the anal canal accounts for 2% of digestive-system cancers, with squamous cell carcinoma the most common histological type. Combination
chemotherapy and radiotherapy is firmly established as the primary therapy for patients with locally advanced squamous cell anal cancer undergoing
curative-intent treatment, with anal sphincter preservation in most patients. We present the case of a 42 year old woman, T4N2Mo G3 squamous anal
carcinoma, achieving a complete response after external beam radiotherapy concomitant with Capecitabine and Cisplatin, plus interstitial brachytherapy
boost and adjuvant chemotherapy.
Key words: curative conservative therapy, squamous anal cancer
Introduction
Carcinoma of the anal canal accounts for 2% of
digestive-system cancers, with squamous cell carcinoma
the most common histological type. Five-year survival rates
range from 78% in patients with local stage disease to only
18% in patients with distant metastases (1).
Combined modality therapy consisting of concurrent
5-FluroUracil (5FU), Mitomycin C (MMC) and radiation
therapy (RT) is the standard of care for advanced stages of
anal squamous cell carcinoma (2). There is no consensus on
the optimal dose of RT and of the alternatives of concomitant
Cisplatin based regimens.
Case report
A 42 year old Caucasian woman with no history of
significant pathology complained of narrow, bloody stools
and anal pain, persisting for 3 months. At presentation
the patient had a good general condition ECOG 1 (due to
mild symptoms) without weight loss, BMI of 21.5 Kg/m2.
Clinical findings were scarce: sensibility at palpation of the
lower abdomen left colic chord with no superficial enlarged
lymph nodes. Digital rectal examination (DRE) revealed an
exophytic tumor of the posterior wall of the anal canal and
lower rectum, fixed, with sphincter invasion, which covered
a length of 6 cm from the anus, 3.5 cm large and 2 cm in
Journal of Radiotheraphy & Medical Oncology
August 2012 Vol. 18 No 1: 36-40
Address for correspondence:
Gabriel Kacsó, MD, PhD
Brachytherapy Department
“Ion Chiricuta” Cancer Center
Cluj- Napoca, Romania
Email: gabi.kacso @gmail.com
thickness. The CBC, renal and liver functions were in the
normal range as well as squamous cell carcinoma antigen
(SCC-N). The HIV antibodies were negative; HPV was not
done due to lack of reagents.
At recto-colonoscopy the patient was found to have a
5 cm maximum diameter tumor into the posterior wall of
the anal canal associated with internal hemorrhoids. The
tumor presented an irregular contour with ulcerated areas
and infiltration into the low rectum. The rest of the colon
was normal. Biopsy of the anal tumor concluded on a poor
differentiated squamous cell carcinoma (Fig. 1).
Abdominal ultrasound and chest X-ray did not show liver
or lung metastases. Enhanced Magnetic Resonance Imagery
(MRI) revealed a tumor of 5.8 cm in length /3.2 cm large /
2 cm in depth, invading the levator anal muscle, one right
internal obturator lymph node (LN) of 17 mm diameter
and several internal iliac LN with a maximum diameter
of 8 mm (Fig 2). The final diagnosis was squamous cell
carcinoma of the anal canal, T4N2M0, stage III; ECOG1,
no co-morbidities.
Fig. 1. Poor differentiated (G3) squamous cell
carcinoma at 10 x magnification, hematoxilin-eosine
(courtesy of Dr. Ferariu).
Locally advanced anal squamous carcinoma
The case was discussed in multidisciplinary round table
and concurrent chemo-radiation (CRT) was decided. After
informed consent, the patient received conformal external
beam radiation (EBRT) 45Gy / 25fr / 33day to the posterior
pelvis in a prone position, concomitant with daily oral
Capecitabine 825 mg/sqm twice daily (daily dose of 1650
mg) and weekly iv. Cisplatin 30mg/sqm. We used a 3 field
technique with wedges on the transversal fields in order
to minimize the urinary and sexual toxicity (to lower the
irradiation of the bladder, the vulva and the vagina). The
internal iliac and obturator LN received additional 10Gy/5fr
conformal RT and the inguinal LN were boosted bilaterally
in a supine position by direct anterior fields with electrons,
12 MeV (according to the depth of the femoral vessels on
the scanner), 3Gy/fr, 2 fr/ wk to achieve a total dose of 45
Gy. Using the CTCAEv.3.0 scale, we recorded a G3 perineal
acute toxicity (skin) which healed within 15 days after the
end of the EBRT; G1 gastrointestinal toxicity (diarrhea) and
G1 leukopenia.
Two weeks after CRT, the MRI concluded on a
major partial remission of 90%. One week later we
delivered a radiation boost by interstitial HDR Iridium 192
brachytherapy (BT). In spinal anesthesia, 9 needles were
implanted, 2 hemi-circumferential parallel rows (5 inner
and 4 outer).The external arch was justified by the initial
distal infiltration into the levator anal muscle. The needle
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was loaded on 5 cm length and she received DT=12 Gy /3fr
/2 days (Fig. 4).The patient subsequently had three cycles
of adjuvant chemotherapy Capecitabine 2000mg/sqm daily,
D1-14/q21 plus Cisplatin 75mg/sqm/D1/q21, with upper
digestive tract toxicity G3 (vomiting) and mild hematologic
toxicity (leukopenia- G2, neutropenia- G1).
Three months after the end of chemotherapy, she was
in complete remission (clinically, at ultrasound and MRI Fig. 3), with excellent anal and bladder continence and no
late toxicity > G1. She was offered hormonal replacement
therapy for alleviating the symptoms of radiation induced
menopause.
Discussion
The incidence of anal squamous cell carcinoma has
increased both in men and women during the last three
decades, associated with HIV and human papilloma viruses
(HPV), with the diagnosis at younger age (as was our patient
but not HIV related). We did not perform a HPV genotyping.
There is no data concerning the possible favorable prognosis
of HPV related anal carcinoma treated by chemoradiation,
as it is demonstrated for the same histological type in head
and neck cancers (3).
Local and lymphatic extension are the most common
routes of spread, the vascular dissemination being less
Fig. 2. Transversal, coronal and sagital MRI view before treatment (arrows indicating the tumor).
Fig. 3. Transversal, coronal and sagital MRI view showing complete remission after chemoradiation,
brachytherapy and adjuvant chemotherapy.
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Rusu et al
Fig. 4. Oblique radiography of palisade of hollow 9 needles in 2 plans surrounding
the anus and lower rectum with related dosimetry (in red is the100% prescription
isodose).
common, although the latter is higher among patients with
advanced disease. Direct invasion into the sphincter muscles
and perianal connective tissue occurs early in the course
of the disease, and about one-half of patients present with
tumor invasion of the rectum, peri-anal region or both. This
was one of the reasons why we delivered a radiation boost
by interstitial HDR brachytherapy with needles in 2 plans.
Tumors in the distal canal drain to the inguinal–femoral,
the external and common iliac nodal regions. About 15%
of patients have clinical evidence of inguinal lymphnodes
(LN) at presentation and involvement is usually unilateral.
However, microscopic invasion into the inguinal LN occurs
in up to 60 % of advanced stages. It was not surprising
therefore that we did not find clinically enlarged inguinal
LN but we designed the RT plan in order to cover them as
elective target volume.
Advances in radiation techniques and seminal studies
combining chemotherapy and radiation have led to their
use as standard definitive treatment for advanced stages of
anal squamous carcinoma, reserving surgery for recurrent or
persistent disease. The ability of radiation or chemoradiation
treatment over surgery alone in achieving local tumor control
while preserving the ano-rectal function without sacrificing
survival has served as a model for organ preservation in
other types of cancer (4).
In a trial conducted by the UK Coordinating Committee
for Cancer Research (5), patients were randomized to
receive radiation alone or combined-modality therapy. The
total dose (TD) was 45Gy in 20 to 25 fractions over 4 or 5
weeks. The combined-modality group was given radiation in
combination with 5-FU and Mitomycin C on the first day of
each course of chemotherapy. If the tumor had not regressed
by at least 50% at 6 weeks after the CRT, surgery or further
radiation (15Gy /6 fr to a perineal field or an interstitial
implant of 25Gy/ 2-3 day) was considered. The local
recurrence rates were 36% in the combined-modality group
and 59% in the radiation-only group. Another trial conducted
by EORTC (6) that compared radiation alone versus CRT.
Radiation was given to a total dose of 45Gy over 5 weeks;
chemotherapy included 5-FU given as a continuous infusion
during the first and fifth week of radiation and Mitomycin C
given as an intravenous bolus on the first day of each course
of chemotherapy. After 6 weeks, a boost dose of radiation
by EBRT or interstitial techniques was given (15 Gy for
complete response and 20 Gy for partial response).Tumor
regression rates were significantly higher in the CRT group.
The colostomy-free survival rate at 5 years was 70% for
the CRT group and only 52% for the treated with radiation
alone. These trials have shown significant improvements
from the addition of chemotherapy to radiation in terms of
primary tumor control and colostomy-free survival rate but
not in terms of overall survival rate.
Concerns over the hematologic toxicity of Mitomycin
C and its long-term effect have led to the use of cisplatin
with 5-FU for the treatment of anal cancer. This combination
showed complete response rates of 90% to 95% and
colostomy-free survival rates of 86% at 3 years. The toxicity
of Cisplatin and 5-FU seemed to be more limited (7).
A phase III Gastrointestinal Intergroup study (RTOG 9811) compared radiation therapy with concurrent 5-FU and
MMC versus two courses of induction 5-FU and Cisplatin
followed by concurrent radiation with 5-FU and Cisplatin
(8). Radiation doses up to 59 Gy were allowed for patients
with T3-T4 or node positive disease. Rate of loco regional
control, disease-free survival, overall survival, acute nonhematologic toxicity and long–term toxicity were similar in
both treatment groups. Severe acute hematologic toxicity
was significantly worse in the MMC group (61% versus
42%). However, the cumulative colostomy rate was lower in
the MMC than in the Cisplatin group (10% versus 19%).
Results from the ACCORD-03 randomized phase
III clinical trial also suggest that there is no benefit of
chemotherapy given prior to chemoradiation. In this study
patients with locally advanced anal cancer were randomized
to receive induction therapy with 5-FU/cisplatin or no
induction therapy followed by chemoRT (they were further
randomized in order to receive an additional radiation
boost or not). No differences were observed between
tumor complete response, tumor partial response, 3-year
colostomy-free survival, local control, event-free survival,
or 3-year overall survival (9).
Results from recent phase III trials in anal cancer have
Locally advanced anal squamous carcinoma
failed to show any benefit for neoadjuvant chemotherapy
(NACT) with cisplatin, or cisplatin-based consolidation CT
compared to CRT alone for loco-regional control, diseasefree survival (DFS) and overall survival (OS). In total, for
CRT, 103 retrospective/observational studies, four phase
I/II studies, 16 phase II prospective studies, two randomised
phase II studies, and six phase III trials of CRT in anal
cancer were identified (10). Only three phase II CT studies
in metastatic disease were identified. Few retrospective
studies were consistent in their use of CT or radiation
doses, and long-term follow-up (> 3 years) was rare. In
anal cancer T3/T4 lesions fare badly (3 year DFS 40-68%).
Cisplatin appears an effective drug, but novel strategies
have not allowed progress against MMC, infusional 5FU
and radiotherapy. New substances such as capecitabine and
oxaliplatin have been tested in phase II trials. Because anal
cancer overexpresses the epidermal growth factor receptor
(EGFR) and a KRAS wild type is usually present, treatment
with the EGFR antibody cetuximab is potentially interesting.
Phase I trials have shown that the combination with RCT
is practicable; however, phase II trials have not yet been
carried out (11).
EBRT with 5 FU and cisplatin and an interstitial
implant has been effective in treating anal cancer. In a
long–term study conducted in France, this strategy resulted
in colostomy-free survival rates of 71% at 5 years and 67%
at 8 years (12).
There is an increasing body of literature suggesting that
toxicity can be reduced with advanced radiation delivery
techniques. There is considerable interest in the use of
IMRT for anal cancer. A dosimetric comparison of IMRT
and conventional radiation-treatment plans showed that
using IMRT resulted in a reduction of dose to the femoral
head and neck and to the external genitalia, with comparable
coverage of tumor volume (13-15).
Based on results of three recent randomized phase
III trials, neither induction chemotherapy (RTOG 98-11,
ACCORD 03) or RT dose escalation (ACCORD 03)
improved the outcome of concurrent 5-FU/MMC-CRT. A
randomized phase II trial (EORTC 22011-40014) compared
concurrent 5-FU/MMC-CRT with cisplatin/ MMC-CRT.
The response rate of cisplatin/MMC-CRT was promising,
but compliance to this regimen was limited. Current phase
I/II studies are evaluating the use of capecitabine, oxalipatin,
and the EGFR (epidermal growth factor receptor) inhibitor
cetuximab. Concurrent 5-FU/MMC-CRT without induction
or maintenance chemotherapy remains the standard of care
for anal cancer patients (19).
In this case, the particularities are the chemotherapy
regimen and the brachytherapy technique in 2 plans. We
combined EBRT to chemotherapy with daily Capecitabine
and weekly iv. Cisplatin to maximally increase the
radiosensitivity. Capecitabine has proven equivalent efficacy
to 5-FU in colon and rectal adenocarcinoma. We adjusted
the doses according to the data published for rectal cancers
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and on the published phase II studies in anal squamous
carcinoma. Weekly Cisplatin concomitant to RT is standard
for cervix squamous carcinoma. We used a prone position 3
field conformal RT technique with wedges on the transversal
fields in order to minimize the urinary and sexual toxicity
(to lower the irradiation of the bladder, the vulva and the
vagina). The brachytherapy implant was optimized on the
shrinkage volume after CRT but the depth of the 100%
coverage isodose to the initial infiltration into the levator
anal muscle was adapted. Consequently, a two plan implant
was required, which is rather unusual for this topography.
The adjuvant chemotherapy, although not standard care for
advanced stages, has not yet been properly assessed and
there is a suggestion that N2 patients (as our case) might
benefit more than the T3-4No ones (16). After the end of
treatment, a complete remission (clinically, ultrasound and
MRI) with a mild profile of toxicity was achieved. Further
follow-up is required .
Conclusion
Combination chemotherapy and radiotherapy is
firmly established as a primary therapy for patients with
squamous cell anal cancer undergoing curative-intent
treatment, with anal sphincter preservation in most patients.
Surgery should not be pursued unless clinical evidence of
disease progression is shown. Treatment-related toxicity
can be significant, causing interruption in treatment that
can compromise local control. Strategies to minimize
toxic effects and improve rates of local control are being
investigated, such as our scheme with brachytherapy boost
(instead of EBRT) and the Capecitabine- Cisplatin regimen
(instead of 5FU-MMC).
References
1. Jemal A, Siegel R, Ward E, et al. Cancer Statistics. CA Cancer J
Clin 2008;58(2):71–9
2. Ryan DP, Compton CC, Mayer RJ et al. Carcinoma of the anal. N
Engl J Med 2000; 34:792-800.
3. Stina Syrjänen. Human Papillomaviruses in Head and Neck
Carcinomas. N Engl J Med 2007; 356:1993-95.
4. Weber DC, Kurtz JM, Allal AS et al. The impact of gap duration
on local control in anal canal carcinoma treated by split-course
radiotherapy and concomitant chemotherapy. Int J Radiat Oncol
Biol Phys 2001; 50:675–80.
5. Glynne-Jones R, Sebag-Montefiore D, Adams R, McDonald
A, Gollins S, James R, Northover JM, Meadows HM, Jitlal M;
UKCCCR Anal Cancer Trial Working Party. the impact of variations
in the duration of the treatment gap and overall treatment time in the
first UK Anal Cancer Trial (ACT I).Int J Radiat Oncol Biol Phys.
2011; 81:1488-94.
6. Matzinger O, Roelofsen F, Mineur L, Koswig S, Van Der SteenBanasik EM, Van Houtte P, Haustermans K, Radosevic-Jelic L,
Mueller RP, Maingon P, Collette L, Bosset JF; EORTC Radiation
Oncology and Gastrointestinal Tract Cancer Groups. Eur J Cancer.
2009; 45: 2782-91.
40
7. Créhange G., Bosset M., Lorchel F., et al: Combining cisplatin and
mitomycin with radiotherapy in anal carcinoma. Dis Colon Rectum
2007; 50:43-49.
8. Ajani JA, Winter KA, Gunderson LL et al. Mitomycin, and
radiotherapy vs. fluorouracil, cisplatin, and radiotherapy for
carcinoma of the anal canal: a randomized controlled trial. JAMA.
2008; 299:1914-21.
9. T. Conroy, M. Ducreux, C. Lemanski, E. Francois, M. Giovannini, F.
Cvitkovic, X. Mirabel, O. Bouché, C. Montoto-Grillot, D. Peiffert.
France Treatment intensification by induction chemotherapy (ICT)
and radiation dose escalation in locally advanced squamous cell
anal canal carcinoma (LAAC): Definitive analysis of the intergroup
ACCORD 03 trial. J Clin Oncol 2009; 27:15s.
10. Lim F, Glynne-Jones R. Chemotherapy/chemoradiation in anal
cancer: a systematic review. Cancer Treat Rev. 2011;37:520-32.
11. Fraunholz I, Rabeneck D, Weiss C, Rödel C. Combined-modality
treatment for anal cancer: current strategies and future directions.
Strahlenther Onkol. 2010;186: 361-6.
Rusu et al
12. Gerard JP, Ayzac L, Hun D, et al. Treatment of anal canal carcinoma
with high dose radiation therapy concomitant fluorouracilcisplatinum. Long term results in 95 patients. Radiother Oncol 1998;
41:169-76.
13. Salama J.K., Mell L.K., Schomas D.A., et al. Concurrent
chemotherapy and intensity-modulated radiation therapy for anal
canal cancer patients: a multicenter experience. J Clin Oncol 2007;
25:4581- 86.
14. Milano MT, Jani AB., Farrey KJ, et al: Intensity-modulated radiation
therapy (IMRT) in the treatment of anal cancer: toxicity and clinical
outcome. Int J Radiat Oncol Biol Phys 2005; 63:354-61.
15. Devisetty K., Mell .K., Salama JK., et al: Anal cancer treated with
intensity modulated radiation therapy (IMRT) and concurrent
chemotherapy: a dosimetric analysis of acute gastrointestinal
toxicity. Int J Radiat Oncol Biol Phys 2006; 66:S287.
16. Das P, Bhatia S, Eng C, et al. Predictors and patterns of recurrence
after definitive chemoradiation for anal cancer. Int J Radiat Oncol
Biol Phys 2007; 68:794-800.