In total, 5 patients with RDEB and CSCC have been treated with immunotherapy (n = 2), other systemic therapies (n = 2), or both (n = 1). Efficacy and safety results are summarized in Table 1. In our institution, we were authorized to use nivolumab and pembrolizumab, two anti-PD1 antibodies for compassionate use in two patients with RDEB and advanced CSCC. The tolerability was overall acceptable with no treatment-related serious adverse events. Radiological tumor response observed in one patient. The other patients were treated with a combination of chemotherapy and targeted therapy (EGFR inhibitors), with mixed tumor response. Patients experienced treatment-related serious adverse events, mainly myelotoxicity and febrile neutropenia. At the time of the data cut-off, the 5 patients have died. Median progression-free survival to the first systemic therapy was 3 months (range, 1 to 8) and median overall survival was 3 months (range, 1 to 11).
Table 1
Efficacy and safety results of immunotherapy and other systemic therapies in patients with RDEB and CSCC treated at our institution. CSCC, cutaneous squamous cell carcinoma; CTCAE v5.0, Common Terminology Criteria for Adverse Events version 5.0; MSSA, methicillin-sensitive staphylococcus aureus; PD, progressive disease; PR, partial response; RDEB, recessive dystrophic epidermolysis bullosa; SD, stable disease.
|
Age, years
|
Sex
|
Site of CSCC
|
Treatment
|
Tumor response
|
PFS, months
|
OS, months
|
Adverse events (CTCAE v5)
|
Case 1
|
18
|
Male
|
Right hand + ipsilateral axillary lymph node
|
Nivolumab
|
-
|
3
|
3
|
Subclinical hypothyroidism
|
Case 2
|
27
|
Male
|
Right ankle + involvement of the underlying bone
|
Pembrolizumab
|
PR
|
3
|
3
|
Subclinical hypothyroidism
|
Case 3
|
32
|
Male
|
Left feet + inguinal lymph nodes, infiltrating soft tissue and bone
|
1) Paclitaxel/cetuximab/RT
2) Cisplatin/5FU
3) Carboplatin/5FU
|
1)PR
2) -
3) -
|
1) 8
2) 1
3) 2
|
11
|
1) Rash, folliculitis G1, diarrhea G1
2) Febrile neutropenia, G3 anemia
3) Septic shock, G4 pancytopenia
|
Case 4
|
25
|
Male
|
Multifocal. Axillary + inguinal left lymph nodes, pleural, soft tissue
|
1) Cisplatin/docetaxel
2) Cetuximab/paclitaxel
|
1) SD
2)PD
|
1) 4
2) -
|
7
|
1) MSSA bacteraemia
|
Case 5
|
30
|
Male
|
Popliteal and inguinal lymph nodes
|
Cisplatin/5-fluorouracil
|
-
|
1
|
1
|
Febrile neutropenia, G3 diarrhea and G2 cutaneous toxicity
|
Case 1
Our first patient was an 18-year-old man with a well-differentiated CSCC in the back of the right hand and axillary lymph node involvement. We started therapy with paclitaxel and cetuximab. However, although, no grade 3/4 adverse events were observed, progressive disease was found after 3 months of treatment. He started on nivolumab (3mg/kg every 2 weeks) in November 2018. We found a 60% PD-L1 expression on tumor tissue. The tolerance was overall good, with no skin toxicity, only subclinical hypothyroidism and grade 1 dry mouth were reported. We continued the treatment for 5 cycles, with clinically stable disease. However, the patient was admitted to the intensive care unit of a local hospital for respiratory failure in the context of Influenza A pneumonia, confirmed with RT-PCR, and died 5 days later in January 2019. No imaging technique was performed to assess tumor response.
Case 2
Our second patient was a 27-year-old man with severe generalized RDEB that in May 2020 was diagnosed with CSCC on his right ankle with involvement of the underlying bone. The patient did not want to have his limb amputated and started pembrolizumab 2mg/kg every 3 weeks on May 2020. The tolerance of the treatment was good, with clinical improvement of the tumor (Fig. 1). Subclinical hypothyroidism was the only adverse effect reported with an adequate response to hormone replacement treatment. A PET-CT scan was performed after 3 cycles of pembrolizumab and showed a partial metabolic response in both the ankle and satellite lesions. However, the patient died in July 2020 due to massive tumoral bleeding during a cure.
Case 3
Our third patient is a 32-year-old man with history of esophageal dilation and multiple surgical intervention for syndactyly. Since 2011, he had multiple surgeries for CSCC in the left foot and left inguinal lymph nodes. In October 2014 a computed tomography (CT) scan revealed a necrotic mass that infiltrate adjacent muscle and bone. The patient started treatment with cetuximab, paclitaxel, and 5-days radiotherapy (total dose: 20Gy) to the inguinal mass. The treatment was well tolerated, only local skin dryness and cetuximab-related grade 1 papulo-pustulose skin toxicity was observed. Two months later, the patient developed sepsis of skin origin with isolation of methicillin-sensitive staphylococcus aureus. Subsequent CT scan reported partial response. In august 2015, the patient progressed and we changed therapy to cisplatin and 5-FU. He developed grade 3 anemia and febrile neutropenia with skin isolation of multi-resistant klebsiella pneumoniae. Few weeks later chemotherapy was restarted but in November 2015 the patient died due to septic shock and grade 4 pancytopenia.
Case 4
The fourth patient was diagnosed in 2013 at the age of 20 with an RDEB-related CSCC. After multiple surgeries, a PET-CT scan revealed multiple cutaneous and subcutaneous lesions with metastasis to bilateral axillary and inguinal lymph nodes, pleura and soft tissue (adjacent to L1 vertebrae). Due to the multifocal spread with high tumor burden, we started chemotherapy with cisplatin and docetaxel in June 2014. Unfortunately, after two months of treatment and progressive disease in the CT scan, the patient developed tumor-related severe hypercalcemia and sepsis of skin origin with cutaneous isolation of Pseudomonas aeruginosa and methicillin-resistant staphylococcus aureus. Therapy based on Cetuximab and paclitaxel was administered in an attempt to control hypercalcemia. However, the patient experienced a progressive clinical deterioration, and antineoplastic treatment was discontinued after a month of treatment. In November 2014 the patient died due to a severe hypercalcemia, sepsis and tumoral skin hemorrhage.
Case 5
The third case is a 30-year-old man with RDEB and a history of CSCC in the sole of the left foot since 2005. In November 2017 PET-CT scan revealed popliteal and inguinal lymph node progression. The patient declined amputation and treatment with systemic antineoplastic treatment with cisplatin/5-fluorouracil and cetuximab was offered. By that time, the patient had a low performance status and periodic red cell transfusion due to chronic anemia. Without a central venous catheter available, we started therapy with cisplatin, and docetaxel. The patient experienced febrile neutropenia, grade 3 diarrhea and grade 2 cutaneous toxicity that required hospitalization in another center. The patient presented a torpid evolution with clinical deterioration that led to the patient demise 33 days after the initiation of the therapy.