Efficacy and Safety of Chemoradiation with Cisplatin plus Capecitabine in Localized Squamous Cell Anal Cancer

doi:10.21203/rs.3.rs-4964999/v1

Background

Localized Squamous Cell Anal Cancer (SCCAC) is a rare disease. The standard of care treatment with curative intent is chemoradiation (CRT) with mitomycin (MMC) or cisplatin (CDDP) plus infusional 5-Fluoracil (5-FU). Capecitabine may replace 5-FU in MMC doublet. However, MMC and infusional pumps are frequently unavailable in underdeveloped countries. CCDP and capecitabine are widely available, but there is no prospective data about the feasibility and efficacy of this combination in a definitive SCCAC CRT setting.

Methods

A Prospective cohort study aimed to evaluate the safety and efficacy of treatment with chemoradiation with CDDP 60mg/m2 D1 and D29 plus Capecitabine 825mg/m2 BID in a population without MMC and infusional pump access. Eligible patients (pts) had T2-4, N0-3, and M0 disease candidates for a full curative CRT regimen. The study data were prospectively collected using REDCap. The primary endpoint was the response by RECIST v.1.1 at 24 weeks(w). The secondary endpoints included toxicity by CTCAE v.5.0, PFS, and OS.

Results

We enrolled 40 consecutive pts between Aug/2019-Dec/2022 in a tertiary cancer center in Brazil. The median age was 61.6y, the majority were stage III (n = 31, 77.5%) and ECOG 1 (n = 20, 50%). HIV + serology was observed in 11 pts (27,5%). All patients received CRT, with a median dose of 54Gy in the primary tumor and 45Gy in the elective nodes. At 8w, 35% (n = 14) had a complete response (CR), 50% (n = 20) partial response (PR), and 2.5% (n = 1) progressive disease (PD). Considering the 35 participants evaluable for response at 24 weeks months by RECIST v.1.1, the disease control rate was 88.5% (n = 31). CR was observed in 47,5% (n = 19), PR in 20% (n = 8), and PD in 12,5% (n = 5). 11 pts had disease recurrence, and six died. The 1y estimated OS was 94.7% (IC95%: 80.7–98.6%), and 1y estimated PFS was 75.3% (IC95%:57.8–86.3%). Colostomy-free survival at one year was 89.6% (IC95%: 74.7–95.9%). Regarding toxicities, any grade 3/4 toxicity was present in 45% (n = 18) being the main G3/4 clinical toxicity radiodermatitis.

Conclusions

The CRT regimen with C + CDDP represents an alternative treatment for localized anal canal tumors in a population that does not have access to MMC and 5-FU infusion pumps. Further studies in this population are encouraged to confirm these findings.

anal cancer

chemoradiation

capecitabine

Squamous

Anal cancer is a rare disease, corresponding to about 2% of all gastrointestinal tract malignancies [1, 2]. However, its incidence and death are growing worldwide [2, 3], with an annual increase in the incidence by 2.7% and a mortality rate of 3.1% [2]. Squamous cell cancer is the most common histology, the majority related to HPV infection. SCCAC is highly prevalent in females and immunosuppressed populations [4, 5].

The curative standard of care treatment for non-metastatic cancer remains chemoradiation definitive therapy (CRT) with mitomycin (MMC) plus 5-fluorouracil (5-FU)[7, 8]. Due to commercial reasons, MMC is not readily available worldwide, and other drugs have been studied in SCCAC management, such as cisplatin (CDDP) [6, 9–11]. The ACT II trial showed similar complete response rates, disease-free survival, and overall survival in the group receiving concurrent CDDP plus 5-FU during CRT compared to the MMC plus 5-FU group[10]; however, the continuous infusional 5-FU requires hospitalization or an infusion pump availability. In this context, a retrospective analysis of 67 patients treated with CDDP plus capecitabine (C) concurrently with intensity-modulated radiation therapy (IMRT) evaluated the safety and efficacy of a capecitabine oral regimen replacing endovenous infusional 5-FU, showing > 90% objective response rate (ORR) with 85% disease-free survival (DFS) rates [6].

This study was aimed to prospectively evaluate patients with SCCAC treated with curative intent using concurrent CRT with CDDP 60 mg/m2 on Days 1 and 29 plus C 825 mg/m2 twice daily on radiotherapy days.

This prospective cohort study enrolled consecutive SCCAC patients treated between Aug/2019 and Dec/2022 at São Paulo Câncer Institute, São Paulo, Brazil. Inclusion criteria included histologically confirmed invasive anal squamous cell carcinoma, stage I-III by AJCC VIII Ed, age > 18 years, and clinical eligibility for complete curative-intent treatment with concurrent chemoradiotherapy (CRT). All patients were planned to be staged and have local clinical assessments at baseline, 8 weeks, and 24 weeks post-CRT, with chest/abdominal computed tomography (CT) and pelvic magnetic resonance (IMR). As our standard of care, the chemotherapy regimen included oral capecitabine at 825 mg/m2 every 12 hours on radiotherapy days and endovenous cisplatin 60 mg/m2 D1 and D29. Radiotherapy was planned to be 50.4–54 Gy and administered in 28–30 fractions. Patients are monitored with laboratory and clinical evaluation bi-weekly or weekly, according to physician choice and toxicity reported by CTCAE v.5.0. Acute toxicity was reported based on the maximum grade of toxic effect observed for each patient and event type. We use RedCap software to manage all study data. The primary endpoint was response rate at 24 weeks post-treatment, defined by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 [13]. Secondary endpoints included response evaluation at 8 weeks, toxicities, PFS, and overall survival (OS) at 1, 3, and 5 years. Data analyses were performed using STATA software version 9.4 (SAS Institute, Cary, NC, USA) [14]. A p-value less than 0.05 was considered statistically significant.

We included 40 patients in the study. The median age was 61.6 years (range 40.5 – 82.9 years). The majority of the population had ECOG 0-1 (n=39, 97.5%) and were female. Regarding race, 40% (n=16) were black or mixed race. The initial stage was III in 77.5% (n=31), being 67.5% with T3/T4 tumors and 77.5% (n=31) with positive lymph nodes. 11 patients were known HIV-positive, being 8 with a medical history of acquired immunodeficiency syndrome, AIDS (Table 1 and 2).

Table 1: characteristics of the population

Characteristics of population
Number of patients included (n)	40
Sex
Female	28 (70%)
Male	12 (30%)
Race
White	24 (60%)
Mixed Race	12 (30%)
Black	4 (10%)
Smoking Medical History
Yes	18 (45%)
No	22 (55%)
Median age (years)	61,6 years (40,5 - 82,9 years)
Comorbidities
Hypertension	19 (47,5%)
Diabetes	11 (27,5%)
Infections Medical History
HIV	11 (27,5%)
AIDS	8
Hepatitis B	4 (10%)
Hepatitis C	4 (10%)

Table 2: staging by AJCVIII Ed.

Staging
T
T1	2 (5%)
T2	11 (27,5%)
T3	13 (32,5%)
T4	14 (35%)
N
N0	8 (20%)
N1a	11 (27,5%)
N1b	6 (15%)
N1c	14 (35%)
Nx	1 (2,5%)
M
M0	40 (100%)
M1	0
I	2 (5%)
IIA	5 (12,5%)
IIB	2 (5%)
IIIA	10 (25%)
IIIB	7 (17,5%)
IIIC	14 (35%)
IV	0

All patients started CRT with curative intent, but three patients had cisplatin omissions by physician choice, after an initial plan of full CRT treatment. The median follow-up time was 30.1 months. At 8w, 35% (n = 14) had a complete response (CR), 50% (n = 20) partial response (PR), and 2.5% (n = 1) progressive disease (PD). Considering the 35 participants evaluable for response at 24 weeks by RECIST v.1.1, the disease control rate was 88.5% (n=31). CR was observed in 47,5% (n = 19), PR in 20% (n = 8), and PD in 12,5% (n = 5). At 8w, 37.5% (n = 15) had a CR , 45% (n = 18) PR, and 5% (n = 2) PD. At 24 weeks, CR was observed in 47.5% (n = 19), PR in 20% (n = 8), and PD in 12.5% (n = 5) (Table 3).

Table 3: Response assessment at 6-8 weeks and at 24 weeks according to RECIST v.1.1 criteria

Response RECIST v.1.1	Post-Treatment Evaluation Period
Response RECIST v.1.1	6-8 weeks	24 weeks
Partial	18 (45%)	8 (20%)
Complete	15 (37,5%)	19 (47,5%)
Progression	2 (5%)	5 (12,5%)
Not evaluable/Not assessed	5 (12,5%)	8 (20%)

In secondary endpoint assessments, 11 pts had disease recurrence, and six died - 5 due progression of oncological disease, and one due to toxicities related to treatment. The median progression-free survival was not reached, with estimated rates of 75% (95% CI 57 - 86%) and 69% (95% CI 51 - 81%) at 1 and 2 years, respectively (Graph 1). The median of overall survival was not reached, with an overall survival estimated rate of 94% (95% CI 80–98%), 84% (95% CI 65–93%), and 80% (95% CI 61–90%) at 1, 2, and 3 years, respectively (Graph 2).

No impact was observed in PFS or OS regarding HIV status.The 3-year progression-free survival was 88.8% (95% CI: 43.4% - 98.3%) in the HIV-positive group and 62.0% (95% CI: 40.7% - 77.5%) in the HIV-negative group.The 3-year overall survival was 83.3% (95% CI: 27.3% - 97.4%) in the HIV-positive group and 79.7% (95% CI: 57.7% - 91.1%) in the HIV-negative group (Graph 3 and 4).No difference in PFS was observed between the groups, HR 1.26, p 0.72, and CI 0.335 - 4.776. The 3-year progression-free survival was 69.5% (95% CI: 47.9% - 83.5%) in the group under 70 years old and 66.7% (95% CI: 28.1% - 87.8%) in the group aged 70 years or older.

The main clinical toxicities of any grade were radiodermatitis and nausea in 95% (n = 38). Other clinical toxicities of any grade were vomiting in n=22 (55%), mucositis in n=21 (52.5%), asthenia in 50% (n=20) and diarrhea in 62.5% (n = 25) (Table 4). Radiodermatitis grade 3 or higher was present in n=9 (24%) patients. Any grade 3/4 toxicity was present in 45% (n=18). Hospitalization due to toxicity was seen in 17.5% (n=7), the majority 57.1% (n=4) related to perineal infection.Among hematological toxicities, anemia was present in 65% of patients (n=26), neutropenia in 47.5% of patients (n=18), lymphopenia in 35% (n=14), and thrombocytopenia in 12.5% of patients (n=5) (Table 4,5). One grade 5 event (n=1) occurred in 83-year-old women with multiple comorbidities. She was hospitalized ten days after starting CRT treatment and developed severe mucositis, diarrhea, dehydration, and abdominal sepsis refractory to clinical support. There was no significant difference in the occurrence of toxicities between HIV + and HIV- groups (Table 4,5).

Table 4: clinical toxicities

Toxicities
Overall population (n=40)		HIV positive (n=11)	HIV negative (n=29)
Radiodermatitis
G1/G2	28 (70%)	8 (73%)	20 (69%)
G3/G4	10 (25%)	3 (27%)	7 (24%)
Any grade	38 (95%)	11 (100%)	27 (93%)
HIV+ vs. HIV- evaluation by Fisher's exact test p=1
Vomiting
G1/G2	18 (45%)	6 (54%)	12 (42%)
G3/G4	4 (10%)	0	4 (14%)
Any grade	22 (55%)	6 (54%)	16 (56%)
HIV+ and HIV- evaluation by Fisher's exact test p=0.676
Mucositis
G1/G2	20 (50%)	8 (72%)	12 (42%)
G3/G4	1 (2,5%)	0	1 (3%)
Any grade	21 (52,5%)	8 (72%)	13 (45%)
HIV+ and HIV- evaluation by Fisher's exact test p=0.18
Asthenia
G1/G2	20 (50%)	5 (45%)	15 (52%)
G3/G4	0	0	0
Any grade	20 (50%)	5 (45%)	15 (52%)
HIV+ and HIV- evaluation by Fisher's exact test p=0.1
Diarrhea
G1/G2	24 (60%)	7 (63%)	17 (59%)
G3/G4	1 (2,5%)	0	1 (3%)
Any grade	25 (62,5%)	7 (63%)	18 (62%)
HIV+ and HIV- evaluation by Fisher's exact test p=0.1

Table 5: hematological toxicities

Toxicities
Overall population (n=40)		HIV positive (n=11)	HIV negative (n=29)
Anemia
G1/G2	26 (65%)	7 (63%)	19 (66%)
G3/G4	0	0	0
Any grade	26 (65%)	7 (63%)	19 (66%)
HIV+ and HIV- evaluation by Fisher's exact test p=0.1
Neutropenia
G1/G2	17 (42,5%)	6 (54%)	11 (38%)
G3/G4	1 (2,5%)	0	1 (3%)
Any grade	18 (45%)	6 (54%)	12 (41%)
HIV+ and HIV- evaluation by Fisher's exact test p=0.625
Lymphopenia
G1/G2	11 (27,5%)	4 (36%)	7 (24%)
G3/G4	3 (7.5%)	1 (9%)	2 (7%)
Any grade	14 (35%)	5 (45%)	9 (31%)
HIV+ and HIV- evaluation by Fisher's exact test p=0.63
Thrombocytopenia
G1/G2	5 (12.5%)	3 (27%)	2 (7%)
G3/G4	0	0	0
Any grade	5 (12.5%)	3 (27%)	2 (7%)
HIV+ and HIV- evaluation by Fisher's exact test p=0.11

Seven (17.5%) patients required colostomy, five before the start of treatment, and two after recurrence in a rescue surgery setting. The Colostomy-free survival at one year was 89.6% (95% CI 74.7 - 95.9%), and at 2 years, 82.9% (95% CI 65.6 - 92%) (Graph 5).

Retrospective studies showed cisplatin and capecitabine as options for CRT with curative intent in localized anal cancer [6, 11]. However, due to the rarity of SCCAC [2], no prospective data are available with this combination.CRT treatment for SCCAC with MMC and 5-FU presents operational restrictions in many countries, considering the lack of MMC and infusional pumps in real-world scenarios in underdeveloped countries [15, 16, 17]. In agreement with the literature, our data showed a predominance of females, 70%, with a median age of 61.6 years [6, 11]. We included representative subjects in terms of diversity, with 40% of black/mixed race. Most randomized trials do not have participants in this group or even report this information.

This study showed a high percentage of HIV+, 27.5%. In other studies with CDDP plus C, the rate of HIV + was 1% and 0%, respectively [6, 11]. Our data also contain a significant representation of T3 and T4 with tumors larger than 5 cm, 67.5%, and with positive nodes, 77,5%. These findings could explain our lower objective response rate compared to data from the ACT II study (67.5% versus 95.2%), probably influenced by the higher-risk population included in our sample [10]. The previous randomized clinical trials in localized SCCAC had lower rates of localized advanced disease, with a prevalence of tumors > 5 cm of 51% in the ACT-I, 44% in the ACT-II, and 28% in the RTOG-9811 study. Positive nodes were observed in 18% in the ACT-I (nodes palpable), 38% in the ACT-II, and 30% in the RTOG-9811 study [9, 10, 18].

The high rate of localized advanced disease in this cohort impacted progression-free survival and overall survival rates. Our results show an estimated progression-free survival rate of 69% at 2y, with an overall survival estimated rate of 84% at 2y. Specific studies, such as Li et al., showed a disease-free survival rate (95% CI 85–92%) and an overall survival rate of 90% at two years [11]. Rotundo et al. presented a disease-free survival rate of 89%, 87%, and 85% at 1, 2, and 3 years, respectively, while the overall survival rates at 1 and 2 years were 100% and 95% [6]. On the other hand, considering the American Joint Committee on Cancer expectation 5y OS of 85.5% for stage I, 78.5% for stage IIA,73.7% for stage IIB, 62.2% for stage IIIA, 59.3% for stage IIIB and 57.2% for stage IIIC [19] our findings are consistent with expected outcomes for stage III disease, being necessary a longer follow up to reach 5y OS evaluation.

Regarding toxicity, the main clinical toxicities observed were radiodermatitis of any grade in 95% of patients (n = 38), with 45% (n = 18) experiencing grade 3 or higher. Key laboratory abnormalities included anemia in 65% of patients (n = 26), neutropenia in 47.5% (n = 18), lymphopenia in 35% (n = 14), and thrombocytopenia in 12.5% (n = 5). The ACT II trial described 8 deaths related to oncologic treatment, with any adverse event grade 3/4 in 72% at the CDDP treatment arm [11]. The grade 5 event occurred in an elderly patient and adults with > 70 years may experience more toxicities with capecitabine treatment, including life-threatening diarrhea [20]. The leading cause for fluoropyrimidine-related toxicity is dihydropyrimidine dehydrogenase (DPD) enzyme deficiency [21]. Unfortunately, the DPYD gene evaluation test is not widely available in clinical practice, and none of the participants of our cohort had access to DPYD evaluation.

As a limitation, this is a single-center cohort with a limited number of subjects and a shorter follow-up to access 5y PFS and OS. However, SCCAC is a rare disease, and this cohort is representative of patients seen in daily practice, including a diverse population in terms of race, stage, and presence of immunosuppression.

In the present study, we evaluated prospective patients with SCCAC treated with curative intent using concurrent CRT comprising CDDP plus C, showing the feasibility of this regimen. To your knowledge, this is the first prospective analysis using this approach.

CRT with C + CDDP scheme is feasible in clinical practice. Disease control rate, estimated PFS and OS post-definitive CRT were consistent with expected outcomes for stage III disease with positive nodes. The CRT with C + CDDP represents an alternative in populations with no access to MMC and infusional pumps. Elderly patients should be closely monitored due C toxicity risk. Further studies are needed to confirm this cohort findings.

Conflict of interest

The authors declare that there is no conflict of interest related to this paper.

Ethical considerations

This study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice (ICH GCP) protocol and applicable local laws and regulatory requirements. The study was also in accordance with the Declaration of Helsinki (Tokyo, Venice, Hong Kong, Somerset West and Edinburgh amendments) or with the laws and regulations of the country providing greater patient protection.

The informed consent form was drawn up by the investigator and the IRB and was in accordance with ICH GCP guidelines and legal requirements.

It was ensured that all study patients, or their legal representatives, were fully informed about the nature and objectives of the study and also about the possible risks associated with participation. The investigator obtained written informed consent from each patient prior to any activity and retained a copy of each signed consent form.

The protocol was written and the study was conducted in accordance with the International Conference on Harmonization Tripartite Guidelines for Good Clinical Practice (http://www.ifpma.org/pdfifpma/e6.pdf). The protocol was approved by the national and local ethics committees. All patients were informed about the intentions of the study and the possible risks. They were informed about the strict confidentiality of their data and that their medical records could be reviewed by the study investigators. It was emphasized that participation was voluntary and that the patient had the right to refuse further participation in the protocol at any time and that this would not jeopardize the subsequent care of the patient at the institution. Documented informed consent was obtained from all patients included in this study before they were enrolled in the study.

Funding

The Sao Paulo Cancer Institute supported this Investigator Initiated study.

Author Contribution

Abraão Dornellas, Renata Bonadio, Priscila Moraes, Denis Galhera, Carolina Victor, Andre Chen, Carolina Muratori, Cinthia Ortega, Henrique Alves, Karim Ibrahim, Caio Nahas, Carlos Frederico Marques, Luciana Alban, Maria Ignez Braghiroli, Paulo Marcelo Hoff, Camila Moniz contributed equally to the production and preparation of the research and the article. All authors reviewed the manuscript.

Availability of data and materials:

not applicable.

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No competing interests reported.

Efficacy and Safety of Chemoradiation with Cisplatin plus Capecitabine in Localized Squamous Cell Anal Cancer

Status:

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Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

Results

Discussion

Conclusion

Declarations

Conflict of interest

Ethical considerations

Funding

Author Contribution

Availability of data and materials:

References

Additional Declarations

Status:

Version 1