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CASE REPORT
Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 387-392

Transcatheter arterial infusion of anti-programmed cell death 1 antibody pembrolizumab combined with temozolomide or nab-paclitaxel in patient with primary anorectal malignant melanoma: Four case reports


1 Department of Minimally Invasive Interventional Therapy; Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou, China
2 Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China; Department of Biotherapy Center, Sun Yat-Sen University Cancer Center, Guangzhou, China
3 Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China; Department of Imaging Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
4 Department of Medical Imaging, Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China

Date of Submission19-Jan-2020
Date of Decision03-Feb-2020
Date of Acceptance24-Mar-2020
Date of Web Publication28-May-2020

Correspondence Address:
Weijun Fan
Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center, Guangzhou 510060, Guangdong; Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510060, Guangdong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_75_20

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 > Abstract 


Primary anorectal malignant melanoma (ARMM) is an extremely rare but aggressive tumor. We assessed the efficacy and safety of transcatheter arterial infusion (TAI) with anti-PD-1 antibody pembrolizumab at a dosage of 100 mg with 0.9% NaCl at a volume of 100 mL administered over a 30-min period every 3 weeks, combined with temozolomide or albumin-bound paclitaxel (nab-paclitaxel) in four patients with ARMM. Temozolomide was administered orally once per day at a dosage of 200 mg/m2/d for five consecutive days about every 4 weeks. Nab-paclitaxel was administered at a dosage of 200mg/m2/d once about every 3 weeks. Among four patients with a median follow-up of 8.9 months, two cases showed Murine Double Minute 2 (MDM2) amplification. Case 1 with Stage II ARMM showed pathological complete response after four cycles of TAI with pembrolizumab combined with nab-paclitaxel. Case 4 was at Stage II and showed stable disease consistently throughout the treatment. Case 2 was at stage II and Case 3 was at stage III, and they showed partial response after four or three cycles, respectively, of TAI with pembrolizumab combined with temozolomide. No Grades 3–4 adverse reactions were observed. Therefore, a combination of TAI with pembrolizumab and temozolomide or with nab-paclitaxel appears to be a promising option for treating ARMM. However, multicenter clinical trials are required to confirm the efficacy and safety of this procedure.

Keywords: Nab-paclitaxel, oral temozolomide, pembrolizumab, primary anorectal malignant melanoma, transcatheter arterial infusion


How to cite this article:
Chen S, Zhang X, Shen L, Qi H, Ma W, Cao F, Xie L, Song Z, Wu Y, Li D, Wen X, Fan W. Transcatheter arterial infusion of anti-programmed cell death 1 antibody pembrolizumab combined with temozolomide or nab-paclitaxel in patient with primary anorectal malignant melanoma: Four case reports. J Can Res Ther 2020;16:387-92

How to cite this URL:
Chen S, Zhang X, Shen L, Qi H, Ma W, Cao F, Xie L, Song Z, Wu Y, Li D, Wen X, Fan W. Transcatheter arterial infusion of anti-programmed cell death 1 antibody pembrolizumab combined with temozolomide or nab-paclitaxel in patient with primary anorectal malignant melanoma: Four case reports. J Can Res Ther [serial online] 2020 [cited 2020 Jul 16];16:387-92. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/387/285198




 > Introduction Top


Primary anorectal malignant melanoma (ARMM) is an extremely rare malignant tumor, and it is the most common primary malignant melanoma of the gastrointestinal tract. It accounts for 0.5%–4.6% of all malignant anorectal tumors, and this body region ranks third among the sites of malignant melanomas derived from mucosa.[1],[2],[3]

Programmed cell death 1 (PD-1) receptor regulates T-cell activity by binding to PD ligand 1 (PDL1) receptor, which can prevent immune responses to tumors.[4] Pembrolizumab, a PD-1 inhibitor, can restore antitumor immune responses and has, therefore, become one of the predominant therapeutic drugs for cases with advanced melanoma owing to its high efficacy and moderate toxicity;[5],[6],[7] however, most patients in the respective studies suffered from cutaneous malignant melanoma, and data on immunotherapy for mucosal malignant melanomas, particularly regarding ARMM, are still scarce. Moreover, recent studies showed that patients with mucosal malignant melanoma can benefit from intravenous administration of PD-1 inhibitors; however, objective response rates (ORR) are relatively low.[8],[9] So far, PD-1 inhibitors were typically administered by intravenous infusion. Malignant melanomas are supplied with blood predominantly via arteries, thus intravenously administered PD-1 inhibitors must be transported through arteries to reach tumor sites which may lead to blocking of PD-1 on T-cell membranes or in natural killer cells. Therefore, intravenous infusion with PD-1 inhibitors may be speculated to increase adverse effects, prolong the interval from application to initial response, and lead to reduced concentrations of the effector compound at the tumor site. In this study, we applied transcatheter arterial infusion (TAI) of anti-PD-1 antibody pembrolizumab, to deliver therapeutic drugs directly to malignant melanomas.

Temozolamide is an oral analog of dacarbazine, and a phase-3 clinical study revealed that temozolamide showed potential advantages in patients with metastatic malignant melanoma.[10] Paclitaxel (Abraxane) can produce noncovalent bonds with stable albumin particles, forming a complex compound termed nab-paclitaxel, and both phase-2 and phase-3 clinical studies revealed that nab-paclitaxel is a potential therapeutic drug for patients with advanced melanoma.[11],[12] Here, we report four cases of ARMM patients treated with TAI with pembrolizumab combined with temozolomide or nab-paclitaxel.


 > Case Reports: Clinical Characteristics of Four Patients With Anorectal Malignant Melanoma Top


Four female patients (median age, 49 years) were diagnosed with ARMM after pathological and immunohistochemical examination from December 2018 to July 2019. In two cases, primary lesions occurred in the anorectal region, and in the rectum in the other two cases; mean tumor size was 4.0 ± 1.0 cm. Three of the four patients had reached or exceed stage T3 in the T staging of the TNM staging system. None of the patients showed BRAF V600E/V600K mutations. Each of the four patients showed only a single primary lesion. The median minimum distance of the tumor from the anus was 1.68 cm (Q1-Q3 of quartile: 1.60–3.13 cm). Cases 1, 2, and 4 were diagnosed at stage II, and case 3 was diagnosed at stage III.[13] Cases 1 and 4 also showed MDM2 amplification, which can be related to poor clinical outcome and hyperprogression after immunotherapy [Table 1].[14] The study was conducted in accordance with the declaration of Helsinki and was approved by the SYSUCC Hospital Ethics Committee.
Table 1: Clinical characteristics of four patients with anorectal malignant melanoma

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Case 1

The patient was a 41-year-old woman diagnosed with rectal malignant melanoma with multiple pelvic lymph node metastases, according to pelvic magnetic resonance imaging (MRI), chest and abdomen computed tomography (CT), and positron-emission tomography– CT (PET/CT) produced by a different hospital in February 2019. The largest metastatic lymph node, measuring approximately 5.0 cm × 5.0 cm, was situated in front of the sacrum. First, treatment with temozolomide combined with nab-paclitaxel was administered between March 8 and March 13, 2019.

On March 13, 2019, pelvic CT was performed at Sun Yat-Sen University Cancer Center, revealing rectal malignant melanoma [Figure 1]a with multiple regional lymph node metastases, and the largest metastatic lymph node with necrosis was observed in front of the sacrum [Figure 1]b.
Figure 1: Efficacy of transcatheter arterial infusion with pembrolizumab combined with nab-paclitaxel in the treatment of case 1. (a-c) Pelvic computed tomography of a 41-year-old woman showed rectal malignant melanoma with multiple pelvic lymph node metastases, with the largest metastatic lymph node situated in front of the sacrum and measuring approximately 5.0 cm × 5.0 cm. Conspicuous tumor staining was observed during the second transcatheter arterial infusion procedure with pembrolizumab. (d-f) After two transcatheter arterial infusion treatments with pembrolizumab combined with two treatments with nab-paclitaxel treatment, a lower abdomen and pelvic magnetic resonance imaging showed no obvious mass in the rectum, and metastatic lymph nodes in front of the sacrum had disappeared. No tumor staining was observed during the third transcatheter arterial infusion procedure with pembrolizumab showed no tumor staining

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Between March 13 and April 30, 2019, the patient underwent two treatments with nab-paclitaxel and two TAI treatments with pembrolizumab, and conspicuous tumor staining was shown during the second TAI with pembrolizumab [Figure 1]c. The patient also received a temozolomide treatment on March 28, 2019, but subsequently suffered from fever and chills, which was attributed to temozolomide due to the absence of signs of infection; this treatment was, therefore, discontinued.

On May 7, 2019, MRI of the lower abdomen and pelvic region showed no obvious mass in the rectal area [Figure 1]d, and metastatic lymph node in front of the sacrum was almost disappeared [Figure 1]e.

Between May 8 and June 23, 2019, the patient underwent two treatments with nab-paclitaxel and two TAI treatments with pembrolizumab, and no obvious tumor staining was observed during the third TAI treatment with pembrolizumab [Figure 1]f. On May 27, 2019, a PET/CT showed no obvious mass in the rectal area; however, metabolic lesions in front of the sacrum appeared to be active, suggesting residual activity of metastases.

On June 24, 2019, an abdominoperineal mass resection (also termed the Miles' resection) was performed. Postoperative pathological examination suggested pathological complete response (pCR). After the surgery, the patient continuously received temozolomide adjuvant chemotherapy combined with intravenous pembrolizumab. Reexamination of the chest and the upper and lower abdomen and pelvic CT on December 19, 2019, showed no signs of recurrence.

Case 2

The patient was a 41-year-old woman who had been hospitalized in March 2019 due to a local mass in the anorectal area. In April 2019, CT of the chest and the upper and lower abdomen and pelvic MRI and PET/CT were performed, showing ARMM with multiple regional lymph node metastases [Figure 2]a-d].
Figure 2: A 41-year-old female patient (case 2) with multiple lymph node metastases from ARMM accompanied by symptoms such as repeated occurrence of blood in the stool. (a-d) Pretreatment positron emission tomography/computed tomography and pelvic magnetic resonance imaging showed AMRR with a tumor measuring approximately 3.8cm × 3.1 cm and a mesorectal lymph node metastasis measuring approximately 2.2 cm × 1.8 cm. (e-f) After four transcatheter arterial infusion treatments with pembrolizumab and four treatments with temozolomide, pelvic magnetic resonance imaging showed that the tumor measured approximately 2.3 × 1.2 cm and the mesorectal lymph node metastasis measured approximately 1.1 × 0.9 cm

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Between April and July 2019, the patient underwent five TAI treatments with pembrolizumab and four treatments with temozolomide. After four cycles of TAI with pembrolizumab combined with temozolomide treatment, pelvic MRI showed significant reduction in the size of the tumor and of the largest metastatic lymph node [Figure 2]e and [Figure 2]f.

In August 2019, a Miles' resection was performed. A total of 14 lymph nodes were removed, and an ARMM metastasis was found in only one lymph node adjacent to the intestine (no shown). After surgery, the patient continued to receive temozolomide adjuvant chemotherapy combined with intravenous pembrolizumab. Reexamination by CT in November 2019 showed no signs of recurrence.

Case 3

The patient was a 57-year-old woman who had been hospitalized in January 2019 due to a local mass in the anorectal area. In December 2018, CT of the chest and the upper and lower abdomen and pelvic MRI were performed, revealing ARMM with multiple regional lymph node metastases and right anterior diaphragmatic horn lymph node metastases [Figure 3]a and [Figure 3]b.
Figure 3: 57-year-old female patient (case 3), who accepted transcatheter arterial infusion treatment with pembrolizumab combined with temozolomide treatment, with regional and distant lymph node metastases from ARMM accompanied by symptoms of change in bowel habits and inside tenesmus. Panels a-e show that the size of her primary lesion of ARMM and distant metastasis of lymph nodes was significantly reduced, but multiple metastases in the lungs (c and f) and mediastinal multiple lymph node metastases nodules were suspected (not shown). (a-c) Pretreatment pelvic magnetic resonance imaging and CT of the chest and abdomen showed ARMM with a tumor measuring approximately 4.3 cm × 4.3 cm and a distant lymph node metastasis measuring approximately 1.9 cm × 1.5 cm. (d-f) Until the eighth cycle of transcatheter arterial infusion with pembrolizumab, the size of the primary lesion from ARMM and distant metastases in lymph nodes shrank to a minimum of 1.6 cm × 0.9 cm and 1.2 cm × 0.8 cm, respectively. Multiple metastatic nodules in the lungs and mediastinal multiple lymph node metastases were suspected (not shown)

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Between January and June 2019, the patient underwent eight TAI treatments with pembrolizumab and four treatments with temozolomide. The size of the primary lesion of the ARMM, of the largest regional metastatic lymph node, and of the distant metastatic lymph nodes had significantly decreased until the eighth TAI treatment with pembrolizumab [Figure 3]d and [Figure 3]e. However, the patient was suspected to have multiple metastatic nodules in the lungs [Figure 3]c and [Figure 3]f and multiple mediastinal lymph node metastases (no shown).

Case 4

The patient was a 60-year-old woman who had been hospitalized in July 2019 with chief complaints due to a local mass in the rectum. In June 2019, CT of the chest and the upper and lower abdomen and pelvic MRI were performed, revealing a rectal malignant melanoma with suspected multiple regional lymph node metastases.

Between July 2019 and November 2019, the patient underwent seven TAI treatments with pembrolizumab and six treatments with temozolomide. During this period, the size of the primary tumor was reduced from the initial 2.8 cm to 2.3 cm. Approximately 3 weeks after the seventh TAI treatment with pembrolizumab, pelvic MRI showed that the size of the primary lesion had increased from 2.3 cm to 3.1 cm. However, the size of the suspected regional metastatic lymph nodes had not changed significantly.

Drugs administration and adverse effects

All four patients received targeted TAI into the tumor-feeding artery with anti-PD-1 antibody pembrolizumab at a dosage of 100 mg with 0.9% NaCl at a volume of 100 mL, administered over about a 30-min period every 3 weeks. Temozolomide was administered orally once per day at a dosage of 200 mg/m2/d for five consecutive days about every 4 weeks. Nab-paclitaxel was administered at a dosage of 200mg/m2 once about every 3 weeks. No adverse reactions of Grade 3–4 occurred. No adverse effects were observed in case 2; however, fever, chills, and Grade 2 leukopenia occurred in case 1. Cases 3 and 4 showed adverse reactions of Grade 1–2 such as fatigue, rash, nausea, vomiting, diarrhea, colitis, and itching.


 > Discussion Top


ARMM is an extremely rare and highly malignant tumor that accounts for only 0.05% of all malignant colorectal tumors.[15] Analysis of a large number of studies showed that mucosal melanoma occurred in only 1.3% of 85,000 melanoma patients, 24% of which were ARMM.[3] At present, surgery is the method of choice to treat primary anorectal melanoma; however, some previous studies reported a median overall duration of survival in primary ARMM patients of 8–19 months, which may be affected by gender, infiltration depth of the anorectal wall, perineural invasion, lymph node metastasis, and distant metastases.[16],[17],[18] Therefore, improved treatment methods of ARMM are urgently required.

Immune checkpoint inhibitors (nivolumab, pembrolizumab, and ipilimumab) administered by intravenous infusion are a promising group of drugs for the treatment of advanced malignant cutaneous melanomas.[5],[6],[7] However, data on immunotherapy of mucosal malignant melanomas, particularly of ARMM, are considerably scarce. Recently, D'Angelo et al. conducted a pooled analysis on nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma and found that patients who received nivolumab monotherapy experienced 3.0 months of progression-free survival (PFS) with ORR of 23.3%, and patients treated with nivolumab combined with ipilimumab showed 5.9 months of PFS with ORR of 37.1%.[9] Furthermore, Moya-Plana et al. examined immunotherapy of nonresectable mucosal melanomas in 20 patients with mucosal malignant melanomas (on the head and neck in nine cases, in the vulvovaginal area in six cases, and in the anorectal area in five cases) treated withfirst-line pembrolizumab delivered at 2 mg/kg every 3 weeks had ORR of 35% and a local control rate of 45%.[19] However, PD-1 inhibitors were administered via intravenous infusion, which may be speculated to prolong the interval from application to initial response, reduce its local concentrations, requiring increased doses of PD-1 inhibitors which would increase adverse effects. Temozolamide and nab-paclitaxel are also promising drugs for patients with advanced malignant melanoma. Two randomized phase III studies showed that patients with advanced metastatic melanomas treated with oral temozolomide or nab-paclitaxel experienced 1.9 months of median PFS, with 7.7 months of median overall survival (OS)[10] or 4.8 months of median PFS, with 12.6 months of median OS,[11] respectively.

In the cases reported in the current study, four patients with ARMM were treated with chemotherapy (temozolomide or nab-paclitaxel) and TAI with lower doses of pembrolizumab than used in intravenous infusions. Of these four patients, case 1 showed pCR, cases 2 and 3 showed partial response, and case 4 showed stable disease consistently. Moreover, cases 1 and 4 also showed MDM2 amplification, which can be associated with poor clinical outcome and hyperprogression after immunotherapy.[14] Surprisingly, hyperprogression was not observed in any patient, and one of them showed pCR, suggesting that TAI with pembrolizumab combined with chemotherapy reduces the likelihood of hyperprogression caused by MDM2 amplification. Moreover, a previous study showed that, based on surgical treatments, the prognosis of patients at T3 in the T staging system was significantly poorer than that of patients at T2.[18] However, we found that compared with case 1 (Stage II), case 2 (Stage II), and case 3 (Stage III), the infiltration depth of the anorectal wall in case 4 (Stage II) was most superficial, and tumor size was also the smallest; however, treatment efficacy was the lowest, which may be associated with MDM2 amplification related to poor clinical outcome and hyperprogression after immunotherapy.[14] Taken together, this suggests that for patients with MDM2 amplification, TAI with pembrolizumab combined with nab-paclitaxel may achieve better results than TAI with pembrolizumab combined with temozolomide. Of these four patients, case 1 and case 2 underwent surgical treatment (Miles' resection), and no signs of recurrence was found by the latest follow-up time, which suggested that TAI combined with chemotherapy (nab-paclitaxel and temozolomide) may be a safe and effective neoadjuvant combination therapy for ARMM. Regarding treatment safety, no adverse effects of Grade 3–4 were observed.


 > Conclusions Top


Our results indicate that temozolomide or nab-paclitaxel combined with a lower dose of pembrolizumab administered via TAI into the target artery may achieve higher treatment efficacy with few adverse effects. To confirm these results, multicenter clinical trials examining TAI with pembrolizumab combined with temozolomide or nab-paclitaxel for ARMM treatment on a larger sample size are required.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgements

We would like to thank Ms Binyan Shen for her support of Shuanggang Chen.

Financial support and sponsorship

This work was funded by the National Natural Science Foundation of China (grant number 81771954).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 2017;390:1853-62.  Back to cited text no. 5
    
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Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol 2019;20:1239-51.  Back to cited text no. 6
    
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Koppolu V, Rekha Vasigala VK. Checkpoint immunotherapy by nivolumab for treatment of metastatic melanoma. J Cancer Res Ther. 2018;14:1167-75.  Back to cited text no. 7
    
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Shoushtari AN, Munhoz RR, Kuk D, Ott PA, Johnson DB, Tsai KK, et al. The efficacy of anti-PD-1 agents in acral and mucosal melanoma. Cancer 2016;122:3354-62.  Back to cited text no. 8
    
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D'Angelo SP, Larkin J, Sosman JA, Lebbé C, Brady B, Neyns B, et al. Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: A pooled analysis. J Clin Oncol 2017;35:226-35.  Back to cited text no. 9
    
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Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000;18:158-66.  Back to cited text no. 10
    
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Hersh EM, O'Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, et al. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer 2010;116:155-63.  Back to cited text no. 11
    
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Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, et al. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol 2015;26:2267-74.  Back to cited text no. 12
    
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Singer M, Mutch MG. Anal melanoma. Clin Colon Rectal Surg 2006;19:78-87.  Back to cited text no. 13
    
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Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: Analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res 2017;23:4242-50.  Back to cited text no. 14
    
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Cagir B, Whiteford MH, Topham A, Rakinic J, Fry RD. Changing epidemiology of anorectal melanoma. Dis Colon Rectum 1999;42:1203-8.  Back to cited text no. 15
    
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Siegal B, Cohen D, Jacob ET. Surgical treatment of anorectal melanomas. Am J Surg 1983;146:336-8.  Back to cited text no. 16
    
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Ross M, Pezzi C, Pezzi T, Meurer D, Hickey R, Balch C. Patterns of failure in anorectal melanoma. A guide to surgical therapy. Arch Surg 1990;125:313-6.  Back to cited text no. 17
    
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19.
Moya-Plana A, Herrera Gómez RG, Rossoni C, Dercle L, Ammari S, Girault I, et al. Evaluation of the efficacy of immunotherapy for non-resectable mucosal melanoma. Cancer Immunol Immunother 2019;68:1171-8.  Back to cited text no. 19
    


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