Highlights
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The 3-year disease-free survival of locally-advanced anal carcinoma is about 60%.
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Anal carcinoma is considered an immunogenic tumor due to its association with HPV.
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The PD-L1 inhibitor durvalumab may synergize with radiochemotherapy.
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The RADIANCE trial will test durvalumab with radiochemotherapy in anal carcinoma.
Abbreviations: ASCC, anal squamous cell carcinoma; cCR, clinical complete response; RCT, radiochemotherapy; DFS, disease-free survival; MMC, mitomycin C; OS, overall survival; PD-1, programmed death receptor 1; PD-L1, programmed death receptor ligand 1; RT, radiotherapy; 5-FU, 5-fluorouracil; MRI, magnetic resonance imaging; CT, computed tomography
Keywords: Anal cancer, Durvalumab, Immunotherapy, Radiochemotherapy, Phase 2, Disease-free survival
Abstract
Purpose
Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world. The 3-year disease-free survival (DFS) in patients with locally-advanced disease is approximately 60% after primary radiochemotherapy (RCT). There is a strong rationale for combining immunotherapy with RCT in patients with ASCC due to its association with human papilloma virus (HPV) infection.
Methods/design
RADIANCE is an investigator initiated, prospective, multicenter, randomized phase II trial testing the addition of Durvalumab, a PD-L1 immune checkpoint inhibitor, to standard RCT in 178 patients with locally advanced ASCC (T2 ≥ 4 cm Nany, cT3-4 and/or cN+). In the control arm, patients will be treated with standard mitomycin C (MMC)/5-fluorouracil (5-FU)-based RCT. Intensity-modulated radiotherapy (IMRT) will be applied as follows: PTV_A (primary tumor) T1-T2 < 4 cm N+: 28 × 1.9 Gy = 53.2 Gy; or T2 ≥ 4 cm, T3-4 Nany: 31 × 1.9 Gy = 58.9 Gy; PTV_N (involved node): 28 × 1.8 Gy = 50.4 Gy ; and PTV_Elec (elective node): 28 × 1.43 Gy = 40.0 Gy over a period of 5,5–6 weeks. Concomitant chemotherapy will be administered using MMC with 5-FU during weeks 1 and 5 of radiotherapy (MMC 12 mg/m2, day 1 [maximum single dose 20 mg]; 5-FU 1000 mg/m2 days 1–4 and 29–32). In the experimental arm, Durvalmab (1500 mg absolute dose, intravenously) will be combined with the same RCT as in the control arm. Immunotherapy with Durvalumab will start 14 days before initiation of standard RCT, administered every four weeks (q4w) thereafter for a total of twelve doses. The primary endpoint is disease-free survival (DFS) after 3 years.
Discussion
As ASCC is considered an immunogenically “hot” tumor due to its association with HPV infection, the combination of RCT with Durvalumab may improve tumor control and long-term clinical outcome in this patient collective compared to RCT alone.
1. Background
Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world. There is a strong rationale for combining the PD-L1 immune checkpoint inhibitor Durvalumab with radiochemotherapy (RCT) in patients with ASCC. First, although primary RCT with concurrent mitomycin C and 5-fluorouracil (MMC/5-FU) is the standard treatment for ASCC, the 3-year disease-free survival (DFS) in patients with locally-advanced disease is approximately 60% [1], [2], [3], [4]. Notably, despite several randomized trials aiming at treatment optimization, the standard therapy has not changed over the past 30 years. Second, approximately 80–90% of patients with ASCC are human papilloma virus (HPV)-positive, which is associated with higher tumor “immunogenicity” in this malignancy that is known to correlate with better response to RCT as well as PD-1/PD-L1 immune checkpoint inhibitors [5], [6]. Also, PD-L1 expression was observed in 33%-62% of patients with locally advanced non-metastatic ASCC that correlated with tumor stage [5], [7]. Third, inhibition of the PD-1/PD-L1 axis showed encouraging responses in recurrent/metastatic ASCC in two phase Ib/II trials [8], [9]. Fourth, several data indicate complementary roles between R(C)T and immunotherapy: R(C)T can, via immunogenic cell death, lead to upregulation of major histocompatibility class I (MHC I) molecules, induction of the CD95 Fas receptor, release of various cytokines and danger signals (ATP, calreticulin, High-Mobility-Group-Protein B1), activation of prophagocytic signals and increased antigen presentation with subsequent enhanced antigen presentation, recruitment of dendritic cells and activation of cytotoxic CD8+ T-cells [10], whereas immune checkpoint inhibition can reinvigorate T-cells by enhancing their cytotoxic function and motility [11], [12]. Accordingly, numerous preclinical studies have demonstrated enhanced radiosensitization using immune checkpoint inhibitors in melanoma, breast, pancreatic, colorectal cancer and glioblastoma multiforme [13], [14], [15], [16], [17]. Fifth, R(C)T can induce PD-L1 upregulation with resulting dysfunction in CD8+ T-cells, and addition of anti-PD-L1 to RCT can overcome T-cell suppression to reinvigorate immune surveillance [18]. Thus, based on the above data, RCT combined with Durvalumab is expected to be more effective than primary RCT alone. In a large randomized phase III trial in patients with locally-advanced non-small cell lung cancer, the addition of Durvalumab to RCT led to significant improvement of approximately 20% in progression free survival (PACIFIC trial) [19]. Altogether, the RADIANCE multicenter, randomized phase II trial aims to improve the current standard treatment by incorporating Durvalumab to the primary MMC/5-FU-based RCT in patients with locally-advanced ASCC.
2. Methods/design
2.1. Study setting
The RADIANCE trial is a prospective, multicenter, randomized phase II trial. Only patients with histologically-confirmed, locally-advanced (T2 ≥ 4 cm Nany: stage IIA, stage IIB-IIIC: cT3-4 and/or cN+, according to the American Joint Committee on Cancer TNM Staging Classification, 8th ed., 2017) ASCC will be screened for this trial. Of note, previous studies [20], [21], [22] have demonstrated worse survival rates in patients with tumors ≥4 cm, which consisted the rationale for including patients T2 ≥ 4 cm Nany in the RADIANCE trial. After signing informed consent, all patients will be prospectively randomized to either control or experimental arm in a 1:1 ratio. Altogether 22 centers throughout Germany (21) and Switzerland (1) will participate in this trial with an anticipated minimum recruitment of 3–5 patients per year and a maximum of 15 patients per year and center. The study overview with the treatment schedule in both arms is shown in Fig. 1. The inclusion and exclusion criteria are summarized in Table 1.
Fig. 1.
Overview of the RADIANCE trial. In the control arm (upper row), patients with ASCC will be treated with standard primary 5-FU/MMC RCT, as indicated. In the experimental arm (lower row), 5-FU/MMC RCT will be combined with the PD-L1 immune checkpoint inhibitor Durvalumab. Of note, Durvalumab will be initiated 14 days prior to RCT start, and will be administered every 4 weeks thereafter (q4w) for a total of 12 doses. The x-axis indicates the time in days. Abbreviations: R, randomization; ASCC, anal squamous cell carcinoma; 5-FU, 5, fluorouracil; MMC, mitomycin C; RCT, radiochemotherapy;
Table 1.
Main inclusion and exclusion criteria of the RADIANCE trial.
Inclusion criteria |
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Exclusion criteria |
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2.2. Clinical endpoints
DFS is the primary endpoint of the study. DFS is defined as the time between randomization and the first of the following events: (a) non-complete clinical response at restaging magnetic resonance imaging (MRI) and proctoscopy, including biopsies of suspicious findings, 26 weeks after initiation of RCT, (b) loco-regional recurrence after initial complete clinical response (cCR), (c) distant metastases, (d) second primary cancer, or (e) death from any cause, whichever occurs first. Patients without any of these events are censored at the time point of last observation. The primary aim is to improve DFS by adding the PD-L1 immune checkpoint inhibitor Durvalumab to standard MMC/5-FU-based RCT in patients with locally-advanced (T2 ≥ 4 cm Nany, stage IIB-IIIC: cT3-4 and/or cN+) ASCC. Our hypothesis is that addition of Durvalumab to primary RCT will increase the 3-year DFS rate from 60% (control arm) to 80% (experimental arm).
Secondary endpoints are acute toxicities, rate of complete remissions 26 weeks after initiation of RCT, overall survival (OS), colostomy free-survival (CFS), cumulative incidence of local and distant recurrences, Quality of Life according to EORTC QLQ–C30 (version 3.0) and functional outcome per EORTC QLQ-ANL27, and various translational and biomarker studies as part of a translational research program including analyses of primary tumor and blood samples.
2.3. Treatment schedule
The prescribed radiotherapy doses are based on the UK guidelines for IMRT in anal canal for primary tumors T1-T2 < 4 cm, and involved lymph nodes as well as elective lymph nodes [23]. However, for large tumors i.e. T2 ≥ 4 cm and T3-4, a fractionation regimen with higher total radiotherapy dose of approximately 60 Gy is used considering the NCCN/RTOG guidelines, and previous and recent literature indicating better local control for higher doses close to 60 Gy in those large tumors [21], [24]. Chemotherapy prescription is according to the ESMO guidelines [25] that is also similar to the NCCN guidelines [26].
In the control arm, patients will be treated with standard MMC/5-FU-based RCT. Intensity-modulated radiotherapy (IMRT) will be applied as follows: PTV_A (primary tumor) T1-T2 < 4 cm N+: 28 × 1.9 Gy = 53.2 Gy; or T2 ≥ 4 cm, T3-4 Nany: 31 × 1.9 Gy = 58.9 Gy; PTV_N (involved node): 28 × 1.8 Gy = 50.4 Gy ; and PTV_Elec (elective node): 28 × 1.43 Gy = 40.0 Gy over a period of 5,5–6 weeks. Concomitant chemotherapy will be administered using MMC with 5-FU during weeks 1 and 5 of radiotherapy (MMC 12 mg/m2, day 1 [maximum single dose 20 mg]; 5-FU 1000 mg/m2 days 1–4 and 29–32).
Patients randomized in the experimental arm will receive the same RCT as in the control arm but with the first Durvalumab application within 14 days after randomization. Immunotherapy with Durvalumab (1500 mg absolute dose, intravenously) will start 14 days before initiation of RCT and will be given every four weeks (q4w) thereafter for a total of twelve doses i.e. to a total duration of 1 year. The rationale for administering Durvalumab 14 days before initiation of RCT in the experimental arm is preclinical evidence showing that immune checkpoint inhibition can reinvigorate the immune system and enhance response to RCT. This delay is not clinically relevant. Patients will receive Durvalumab unless there is unacceptable toxicity, withdrawal of consent or another discontinuation criterion is met (e.g., an individual patient will not receive any further Durvalumab if their weight falls to 30 kg or less). The first fraction of radiotherapy has to be applied within 14 days for the control arm and 21 days for the experimental arm (±3 days) after randomization.
2.4. Pilot phase
A first safety analysis will be performed after the inclusion of 10 patients in the experimental arm. The toxicity evaluation period for the pilot phase starts from the onset of treatment and continues up to 16 weeks upon initiation of treatment with Durvalumab (time of first follow-up examination after RCT). If one of the first 10 patients develops predefined toxicity levels up to 16 weeks from initiation of Durvalumab treatment, an additional 10 patients will be treated. Predefined toxicity is summarized in Table 2. The trial will be held if predefined toxicity levels occur in ≥ 2 of 20 patients up to 16 weeks from initiation of Durvalumab, and discussed with the Data Safety Monitoring Board for possible amendments.
Table 2.
Predefined toxicity criteria for the pilot Phase I part of the RADIANCE trial.
Toxicity criteria |
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2.5. Follow-up
The follow-up will include clinical and radiological assessment of tumor status as well as clinical and laboratory examination. Tumor response and staging will be assessed using digital rectal examination (DRE) and proctoscopy, inguinal node palpation, pelvic MRI, abdomen sonography and chest X-ray/(computed tomography (CT)). The follow-up schedule for both arms is summarized in Table 3. If a DFS event occurs, treatment within the clinical trial will be stopped. In that case, treatment of local and/or distant recurrence will be performed according to the in-house and international guidelines following discussion at the multidisciplinary tumor board.
Table 3.
Follow-up schedule in both arms of the RADIANCE trial.
Evaluation | Time Since Completion of Radiochemotherapy |
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weeks |
Months (±1 week) |
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6–8 w | 20 w | 9 | 11* | 12 | 15 | 18 | 21 | 24 | 27 | 30 | 36 | |
Physical examinationa | X | X | X | X | X | |||||||
Urine hCG or serum βhCGb | X | |||||||||||
Vital signs (temperature, respiratory rate, blood pressure, pulse) | X | |||||||||||
Weight | X | X | X | X | ||||||||
AE/SAE assessment | X | X | X | X | X | X | X | X | X | X | X | |
ECOG performance status | X | X | X | X | X | X | X | X | ||||
Hematology | X | X | X | X | ||||||||
Serum chemistry | X | X | X | |||||||||
Thyroid function testsc | X | X | ||||||||||
DRE, inguinal node palpation | X | X | X | X | X | X | X | X | X | X | ||
Proctoscopy | X | X | X | X | X | X | X | |||||
Pelvic MRI | X | X | X | X | X | X | ||||||
Abdomen and thorax CT (or abdomen sonography and thorax X-ray) | X | X | X | |||||||||
EORTC QLQ-C30 and QLQ-ANL27 | X | X | X | X | ||||||||
Survival status: | phone contact every 6 months with patients who refuse to return for evaluations and agree to be contacted |
Abbreviations: HCG, human chorionic gonadotropin; AE/SAE, adverse events/ serious adverse events; DRE, digital rectal examination; MRI, magnetic resonance imaging; CT, computer tomography.
11 months applies only to the experimental arm and should be performed 30 days after the last dose of durvalumab. It has to be recalculated, if durvalumab has been discontinued earlier.
Full physical exam.
Pre-menopausal female patients of childbearing potential only.
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to the endocrine system.
2.6. Sample size and statistical considerations
The sample size is driven by the primary efficacy outcome (DFS). The 3-year DFS after RCT for locally-advanced ASCC is approximately 60% [2]. In the PACIFIC randomized phase III trial examining the possible benefit of RCT combination with Durvalumab compared with RCT plus placebo in patients with NSCLC, a highly significant improvement in the PFS rate of approximately 20% after 12 months and 18 months was reported [19]. Therefore, we hypothesize that the 3-year DFS rate will show an improvement from 60% in the control arm to 80% in the experimental arm, which would clearly be considered as clinically relevant. In order to detect a difference of this magnitude with a power of 80%, a sample size of 178 patients (89 in each arm using a 1:1 randomization; a drop-out rate of 10% included) is required to reject the null hypothesis of no improvement on a one-sided type I error level of 2.5%. This calculation is based on the application of a logrank test, on an assumed exponential shape of the survival curves and the drop-out process, as well as a minimum follow-up period of three years for all patients.
3. Discussion
The main hypothesis of the RADIANCE trial is that incorporation of Durvalumab into standard RCT for patients with locally-advanced ASCC will improve the 3-year DFS in a way that the DFS rate after 3 years is increased to 80% compared to an expected rate of 60% on standard therapy, i.e. RCT [2]. In contrast to other malignancies, no substantial progress in the treatment of ASCC has been made since implementation of RCT in the 1980s [27]. Importantly, the addition of either induction, or consolidation chemotherapy to primary RCT, concurrent chemotherapy other than MMC/5-FU, or any dose escalation of radiotherapy, failed to improve the clinical outcome as shown in large phase III trials [2], [3], [28]. The optimal timing for combination of CRT with immunotherapies still remains unclear. In line to preclinical evidence [13], the post hoc analysis of the PACIFIC trial [19] suggests that starting the durvalumab within 14 days after CRT (rather than ≥14 days) is associated with a higher benefit to OS and PFS. As such, we hypothesized that administration of Durvalumab before CRT could, potentially, prime the immune system towards a more immunogenic phenotype to facilitate increased response to CRT. This consisted the rationale for the combination schedule in our trial.
Recently, PD-1/PD-L1 pathway blockade proved to be a feasible and efficient treatment for recurrent/metastatic ASCC [8], [9]. The response rate to this treatment was between 17% and 24%, and some responses were long-lasting, despite the advanced stage of the tumors treated and the negative selection due to progression after first-line therapy. So far, there is no reliable predictive marker for response to PD-1/PD-L1 blockade available. In this trial, the efficacy and toxicity of a combined RCT and PD-L1 blockade will be studied. It is expected that toxicity will be tolerable as data so far do not show any exceptional or unexpected toxicities by the combination of RT and PD-1/PD-L1 blockade [29], [30], [31]. Another novelty in this trial compared to most other trials in ASCC is the inclusion of HIV positive patients, if they are on a stable medication without measurable viral load and adequate CD4 counts as defined per protocol. The current NCCN guidelines also state that patients living with HIV should be treated with standard RCT [26]. With regard to possible side effects of immune checkpoint inhibition in this cohort, a recent study with the PD-1 inhibitor Pembrolizumab in HIV positive patients showed an acceptable safety profile [32]. With regard to efficacy, immunohistochemical and gene expression analysis revealed no differences in the composition of the tumor microenvironment between HIV positive and negative patients [33].
As standard MMC/5-FU-based RCT for ASCC is safely used for over 30 years, the main risks of the combination with durvalumab in this trial are the possible immunological toxicities attributed to durvalumab. However, the safety of durvalumab has already been tested in many published clinical trials and for various indications. Common toxicities were diarrhea, fatigue, vomiting, pain and skin reactions. Serious adverse events occurred in less than 5% of the treated patients. Intensity-modulated RT-techniques lower toxicity rates in modern series; especially the frequency of enteritis is relatively low. In retrospective studies, no increase in severe toxicities occurred following combination of RT with either CTLA-4 blockade, PD-1 blockade or PD-L1 blockade [34]. Importantly, in the recent PACIFIC phase III randomized trial in NSCLC, the combination of RCT with durvalumab was well-tolerated without any significant increase in the incidence of serious adverse effects compared to control arm that received RCT plus placebo (Grade 3–4 pneumonitis: 3.4% vs 3%; dyspnea 1.5% vs 2.6%; diarrhea 0.6% vs 1.3%; hypothyroidism: 0.2% vs 0%; fatigue 0.8% vs 1.3%) [19], [35]. Adverse events leading to death were seen in 4.4% of patients given durvalumab and 5.6% of those given placebo [35].
We decided to use 26 weeks as timepoint for the evaluation of clinical response based on the findings of the ACT2 trial [36]. In that trial, clinical response was assessed prospectively 11, 18 and 26 weeks after initiation of RCT in patients with ASCC. In total, n = 691 patients attended all three assessments, and a cCR was observed in 64%, 80% and 85% at 11, 18 and 26 weeks, respectively, indicating a delayed tumor response. As expected, patients with cCR at 26 weeks post-RCT initiation had a superior 5-year OS compared to patients without cCR. Thus, these results provided high-level evidence to justify 26 weeks after initiation of RCT (i.e. 20 weeks after completion of RCT) as the ideal time point for evaluating clinical response after RCT.
Routine testing for PD-L1 expression will not be routinely performed to enroll patients but will be assessed as part of an extensive translational research program of the RADIANCE trial. The correlation between PD-L1 expression and efficacy remains a topic of discussion. Several studies have indicated that patients can benefit from PD-L1 immune checkpoint inhibition independently of the baseline PD-L1 expression in primary tumor [37], [38]. Similarly, in the phase 3 randomized trial that tested durvalumab with RCT in NSCLC, the PFS benefit was observed irrespectively of PD-L1 expression [19]. In addition, high mutational burden (e.g., in bladder carcinoma [39]) or viral tumor etiology that is linked with an activated immune response as seen in anal cancer [5] may contribute to the responses seen with immune therapy.
In conclusion, the RADIANCE trial will assess whether the combination of RCT with immunotherapy using durvalumab may improve tumor control and long-term clinical outcome in patients with locally advanced ASCC compared to RCT alone.
Ethics approval and consent to participate
The study protocol (v. 2.0, 31.10.2019) and informed constent form have been reviewed and approved by the local ethics committee of the Goethe University Frankfurt (19-374-AMG) and the responsible German federal institute for vaccines and biomedicines (Paul Ehrlich Institute).
Funding
The trial is funded by the German Cancer Aid (Deutsche Krebshilfe, DKH; Funding Project Number: 70113615; PI: Emmanouil Fokas). The study drug and the pharmacy costs (Funding Project Number: ESR-17-13077) are provided by Astra Zeneca.
Trial registration
EudraCT: 2018-003005-25; ClinicalTrials.gov: NCT04230759; Date of registration: 15.01.2020.
Declaration of Competing Interest
The trial is funded by the German Cancer Aid (Deutsche Krebshilfe, DKH; Funding Project Number: 70113615; PI: Emmanouil Fokas). The study drug and the pharmacy costs (Funding Project Number: ESR-17-13077) are provided by Astra Zeneca. The authors have no further conflicts of interest to declare.
Acknowledgements
We would like to thank Dr Margarita Diaz and Mrs Atefeh Nateghian from the clinical trials coordination office, Department of Radiation Oncology, University of Frankfurt.
References
- 1.Martin D., Balermpas P., Winkelmann R., Rödel F., Rödel C., Fokas E. Anal squamous cell carcinoma – state of the art management and future perspectives. Cancer Treat Rev. 2018;65:11–21. doi: 10.1016/j.ctrv.2018.02.001. [DOI] [PubMed] [Google Scholar]
- 2.Gunderson L.L., Winter K.A., Ajani J.A., Pedersen J.E., Moughan J., Benson A.B. 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. J Clin Oncol. 2012;30:4344–4351. doi: 10.1200/JCO.2012.43.8085. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.James R.D., Glynne-Jones R., Meadows H.M., Cunningham D., Myint A.S., Saunders M.P. 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. Lancet Oncol. 2013;14:516–524. doi: 10.1016/S1470-2045(13)70086-X. [DOI] [PubMed] [Google Scholar]
- 4.Northover J., Glynne-Jones R., Sebag-Montefiore D., James R., Meadows H., Wan S. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I) Br J Cancer. 2010;102:1123–1128. doi: 10.1038/sj.bjc.6605605. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Balermpas P., Martin D., Wieland U., Rave-Fränk M., Strebhardt K., Rödel C. Human papilloma virus load and PD-1/PD-L1, CD8+ and FOXP3 in anal cancer patients treated with chemoradiotherapy: rationale for immunotherapy. OncoImmunology. 2017;6 doi: 10.1080/2162402X.2017.1288331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.De Vuyst H., Clifford G.M., Nascimento M.C., Madeleine M.M., Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer. 2009;124:1626–1636. doi: 10.1002/ijc.24116. [DOI] [PubMed] [Google Scholar]
- 7.Govindarajan R., Gujja S., Siegel E.R., Batra A., Saeed A., Lai K. Programmed cell death-ligand 1 (PD-L1) expression in anal cancer. Am J Clin Oncol. 2016 doi: 10.1097/COC.0000000000000343. [DOI] [PubMed] [Google Scholar]
- 8.Morris V.K., Salem M.E., Nimeiri H., Iqbal S., Singh P., Ciombor K. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18:446–453. doi: 10.1016/S1470-2045(17)30104-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ott P.A., Piha-Paul S.A., Munster P., Pishvaian M.J., van Brummelen E.M.J., Cohen R.B. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol Off J Eur Soc Med Oncol. 2017;28:1036–1041. doi: 10.1093/annonc/mdx029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sharabi A.B., Lim M., DeWeese T.L., Drake C.G. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015;16:e498–e509. doi: 10.1016/S1470-2045(15)00007-8. [DOI] [PubMed] [Google Scholar]
- 11.Topalian S.L., Taube J.M., Anders R.A., Pardoll D.M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016;16:275–287. doi: 10.1038/nrc.2016.36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–264. doi: 10.1038/nrc3239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Dovedi S.J., Adlard A.L., Lipowska-Bhalla G., McKenna C., Jones S., Cheadle E.J. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74:5458–5468. doi: 10.1158/0008-5472.CAN-14-1258. [DOI] [PubMed] [Google Scholar]
- 14.Demaria S., Kawashima N., Yang A.M., Devitt M.L., Babb J.S., Allison J.P. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11:728–734. [PubMed] [Google Scholar]
- 15.Deng L., Liang H., Burnette B., Beckett M., Darga T., Weichselbaum R.R. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687–695. doi: 10.1172/JCI67313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Sharabi A.B., Nirschl C.J., Kochel C.M., Nirschl T.R., Francica B.J., Velarde E. Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol Res. 2015;3:345–355. doi: 10.1158/2326-6066.CIR-14-0196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Azad A., Yin Lim S., D’Costa Z., Jones K., Diana A., Sansom O.J. PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med. 2017;9:167–180. doi: 10.15252/emmm.201606674. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Pauken K.E., Wherry E.J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36:265–276. doi: 10.1016/j.it.2015.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Antonia S.J., Villegas A., Daniel D., Vicente D., Murakami S., Hui R. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377:1919–1929. doi: 10.1056/NEJMoa1709937. [DOI] [PubMed] [Google Scholar]
- 20.Touboul E., Schlienger M., Hadjrabia S., Laugier A. Cancer of the anal canal; role of radiotherapy and combinations of chemotherapy and radiotherapy. Rev Med Interne. 1993;14:340–349. doi: 10.1016/s0248-8663(05)81312-8. [DOI] [PubMed] [Google Scholar]
- 21.Faivre J.-C., Peiffert D., Vendrely V., Lemanski C., Hannoun-Levi J.-M., Mirabel X. Prognostic factors of colostomy free survival in patients presenting with locally advanced anal canal carcinoma: a pooled analysis of two prospective trials (KANAL 2 and ACCORD 03) Radiother Oncol J Eur Soc Ther Radiol Oncol. 2018;129:463–470. doi: 10.1016/j.radonc.2018.08.008. [DOI] [PubMed] [Google Scholar]
- 22.Johnsson A., Leon O., Gunnlaugsson A., Nilsson P., Höglund P. Determinants for local tumour control probability after radiotherapy of anal cancer. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2018;128:380–386. doi: 10.1016/j.radonc.2018.06.007. [DOI] [PubMed] [Google Scholar]
- 23.Anal IMRT Guidance n.d. http://analimrtguidance.co.uk/ (accessed September 26, 2019).
- 24.Muirhead R., Partridge M., Hawkins M.A. A tumor control probability model for anal squamous cell carcinoma. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2015;116:192–196. doi: 10.1016/j.radonc.2015.07.014. [DOI] [PubMed] [Google Scholar]
- 25.Glynne-Jones R., Nilsson P.J., Aschele C., Goh V., Peiffert D., Cervantes A. Anal cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Eur J Surg Oncol EJSO. 2014;40:1165–1176. doi: 10.1016/j.ejso.2014.07.030. [DOI] [PubMed] [Google Scholar]
- 26.Al-Hawary MM, Arain MA, Cooper HS. NCCN Guideline Anal Cancer 2019. https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf (accessed September 26, 2019).
- 27.Nigro N.D., Seydel H.G., Considine B., Vaitkevicius V.K., Leichman L., Kinzie J.J. Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer. 1983;51:1826–1829. doi: 10.1002/1097-0142(19830515)51:10<1826::aid-cncr2820511012>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
- 28.Peiffert D., Tournier-Rangeard L., Gérard J.-P., Lemanski C., François E., Giovannini M. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:1941–1948. doi: 10.1200/JCO.2011.35.4837. [DOI] [PubMed] [Google Scholar]
- 29.Levy A., Massard C., Soria J.-C., Deutsch E. Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: single centre subset analysis from a phase 1/2 trial. Eur J Cancer Oxf Engl. 1990;2016(68):156–162. doi: 10.1016/j.ejca.2016.09.013. [DOI] [PubMed] [Google Scholar]
- 30.Bang A., Wilhite T.J., Pike L.R.G., Cagney D.N., Aizer A.A., Taylor A. Multicenter evaluation of the tolerability of combined treatment with PD-1 and CTLA-4 immune checkpoint inhibitors and palliative radiation therapy. Int J Radiat Oncol Biol Phys. 2017;98:344–351. doi: 10.1016/j.ijrobp.2017.02.003. [DOI] [PubMed] [Google Scholar]
- 31.Aboudaram A., Modesto A., Chaltiel L., Gomez-Roca C., Boulinguez S., Sibaud V. Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination. Melanoma Res. 2017;27:485–491. doi: 10.1097/CMR.0000000000000386. [DOI] [PubMed] [Google Scholar]
- 32.Uldrick T.S., Gonçalves P.H., Abdul-Hay M., Claeys A.J., Emu B., Ernstoff M.S. Assessment of the safety of pembrolizumab in patients with HIV and advanced cancer – a phase 1 study. JAMA Oncol. 2019 doi: 10.1001/jamaoncol.2019.2244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Yanik E.L., Kaunitz G.J., Cottrell T.R., Succaria F., McMiller T.L., Ascierto M.L. Association of HIV status with local immune response to anal squamous cell carcinoma: implications for immunotherapy. JAMA Oncol. 2017 doi: 10.1001/jamaoncol.2017.0115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Hwang W.L., Pike L.R.G., Royce T.J., Mahal B.A., Loeffler J.S. Safety of combining radiotherapy with immune-checkpoint inhibition. Nat Rev Clin Oncol. 2018;15:477–494. doi: 10.1038/s41571-018-0046-7. [DOI] [PubMed] [Google Scholar]
- 35.Antonia S.J., Villegas A., Daniel D., Vicente D., Murakami S., Hui R. PACIFIC, Investigators. Overall survival with durvalumab after chemoradiotherapy in Stage III NSCLC [published online September 25, 2018] N Engl J Med. 2018 doi: 10.1056/NEJMoa1809697. [DOI] [Google Scholar]
- 36.Glynne-Jones R., Sebag-Montefiore D., Meadows H.M., Cunningham D., Begum R., Adab F. 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. Lancet Oncol. 2017;18:347–356. doi: 10.1016/S1470-2045(17)30071-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Rittmeyer A., Barlesi F., Waterkamp D., Park K., Ciardiello F., von Pawel J. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet Lond Engl. 2017;389:255–265. doi: 10.1016/S0140-6736(16)32517-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Massard C., Gordon M.S., Sharma S., Rafii S., Wainberg Z.A., Luke J. Safety and Efficacy of Durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34:3119–3125. doi: 10.1200/JCO.2016.67.9761. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Zielinski C.C. A phase I study of MEDI4736, NNT-PD-L1 antibody in patients with advanced solid tumors. Transl Lung Cancer Res. 2014;3:406–407. doi: 10.3978/j.issn.2218-6751.2014.08.07. [DOI] [PMC free article] [PubMed] [Google Scholar]