Yang Yang, Nanhang Lu, Jiaqi Liu, Jianying Gu

Department of Plastic and Reconstructive Surgery, Zhongshan Hospital of Fudan University, Shanghai 200032, China

Keywords:Melanoma B-Raf gene mutation Targeted therapy Dabrafenib plus trametinib

ABSTRACT The prognosis of patients with advanced melanoma is poor.The five-year recurrence rate is approximately 70%,whereas the overall survival rate is only 4%–10%.We report the case of a 61-year-old male patient with metastatic melanoma (B-Raf+).The tumor load of the patient was significantly reduced after the application of dabrafenib plus trametinib(“D+T”)and radiotherapy.Further,it is suggested that medical staff should conduct a comprehensive analysis of the patient’s condition when dealing with adverse events (AEs) associated with such malignant tumors to provide evidence for adopting the appropriate targeted treatment or radiotherapy and nursing mode and achieve the best treatment effect.

1.Introduction

Melanoma is defined as high malignancy with poor prognosis.1For high-risk patients,postoperative adjuvant therapy is critical to reduce the risk of recurrence and metastasis and prolong the survival time.Traditional therapy, such as high-dose IFN-α, is limited.It can scarcely improve the overall survival (OS) and the toxicity is obvious.For B-Raf mutants associated with higher malignancy and worse prognosis, the application of dabrafenib plus trametinib (“D+T”) filled the gap of clinical adjuvant therapy in China, rewrote the treatment pattern, and opened a new era of double targeted therapy.In December 2019 and March 2020,the application of“D+T”was successively approved as the indication for advanced first-line treatment and adjuvant treatment,becoming the first and only targeted treatment scheme with dual indications for advanced and adjuvant treatment in China.For the unresectable or advanced mucosal melanoma,Guidelines of Chinese Society of Clinical Oncology(CSCO) in 2021 has adjusted the “D+T” treatment from grade II to grade I.2Here, we present a 61-year-old male patient with B-Raf V600E gene mutation in metastatic melanoma treated with“D+T”to reduce the tumor load,improve the condition,and relieve the adverse events.The multiple metastatic lesions of the entire body almost completely subsided within a few months,which is rare in the group of patients with advanced melanoma.This case report aimed to clarify that the “D+T” treatment may achieve curative effect in a short time in combination with radiotherapy in patients with advanced melanoma and may sustain no recurrence for a long duration.

2.Case presentation

A 61-year-old male patient had no obvious inducement two years ago.He discovered the right axillary tumor of the size of a broad bean,which did not pain, itch, or cause any other discomfort.The tumor did not subside by itself, nor did it change significantly.On the evening of December 4,2019,he was treated in Changzhou First People’s Hospital because of abdominal pain and underwent positron emission tomography-computed tomography(PET-CT)examination,which suggested that multiple metastatic lymph nodes should be considered as malignant lesions.He was admitted to Zhongshan Hospital Affiliated to Fudan University and diagnosed as having malignant metastatic tumor and abdominal pain.The physical examination by the specialist showed that the axillary mass was located under the skin,approximately 2 cm×2 cm,without obvious tenderness, redness, swelling, skin ulceration, and pulsation.The condition was diagnosed as “esophageal cancer” and the patient underwent“radical resection of left thoracic esophageal cancer”in Zhongshan Hospital Affiliated to Fudan University on December 30,2013.Postoperative pathology: esophageal uplift squamous cell carcinoma, differentiated into grade II, and the cancer tissue infiltrated the esophageal submucosa, with a depth of approximately 670 μm.No lymph node metastasis.MSH2(100%+++),MSH6(100%+++),MLH1(100%+++), PMS2 (100%+++).On January 5, 2014, owing to the diagnosis of “postoperative chylothorax of esophageal cancer”, exploratory thoracotomy was performed in Zhongshan Hospital of Fudan University.The patient reported a history of epilepsy and denied the history of hepatitis and other infectious diseases.The patient had no explicit previous history of the focal excision of pigmented diseases.The patient denied the history of drugs, food allergies, or of trauma.The family had no infectious disease and genetic history.

On December 18, 2019, the patient underwent right axillary lymph node resection under local anesthesia (4 cm× 3 cm × 2 cm of the size,Fig.1).The postoperative pathology showed metastatic melanoma.Immunohistochemistry:Ki-67(70%positive),CK5/6(-),p63(-),S-100(+), HMB-45 (small amount, +), PNL2 (±), A103/Melan A (-), p53{do7} (5% +), b-cat (100% membrane +), PTEN (-), VIM (+).Gene detection report: GTG (VAL) at codon 600 of exon 15 of the B-Raf gene was mutated into GAG(Glu).There was no mutation in exons 9,11,13,and 17 of the c-kit gene.

The course of the postoperative treatment was as follows (Fig.2).From December 20, 2019 to January 10, 2020, the patient was treated with pembrolizumab (200 mg, ivgtt, q3w) twice in Zhongshan Hospital Affiliated to Fudan University,and the symptoms of abdominal pain were relieved.On January 31, 2020, the patient was treated once with pembrolizumab (200 mg, ivgtt) at the Department of Dermatology and Oncology of a hospital in Australia.On February 26,2020,the patient’s abdominal pain worsened.PET-CT showed tumor progression (evaluation effect:PD),and scalp lesions were found.On February 28,2020,the patient began treatment with “D+T” (dabrafenib 150 mg, po, bid; trametinib 2 mg,po,qd)in Australia.From March 2 to 6,2020,the patient received additional head radiotherapy (Fig.3), and the abdominal pain was significantly relieved.On March 8,2020,the patient returned home.On March 10,the abdominal pain was basically relieved,but he began to have fever, which lasted for 4 days.On March 22, 2020, the patient developed fever and epilepsy.The CT examination showed pulmonary inflammation.The fever lasted for 10 days.On April 10,2020,the patient underwent PET-CT examination, which showed that the original tumor focus decreased, partially disappeared, and the metabolic activity disappeared or significantly decreased (Fig.4).As on April 20, 2020, the patient had fever symptoms again and the platelet count decreased on April 21,the administration of drug was stopped for 2 weeks.On May 11,2020,the platelet count was normal and the medication was resumed.On March 26,2021,the latest follow-up,the patient underwent PET-CT.The results showed that the original lesion did not progress further, and the metabolic activity disappeared or decreased(Fig.4).

Fig.1. Right axillary lymph node during operation.

3.Discussion

It is estimated that there were 62 260 melanoma male cases and 43 850 female cases in America in 2021.The incidence of melanoma in China is relatively lower than that in European and American countries, but has also shown an upward trend with an annual growth rate of 3%–5% in recent years,and the number of new cases is approximately 20 000 every year.3Presently in China, because of the relative lack of awareness of melanoma,many patients do not opt for the best treatment option when they seek medical advice.The prognosis of patients with advanced melanoma is poor,and the 5-year overall survival rate is only 4%–10%.1

The case we reported above had no exact history of excision of acral melanoma.It is speculated that it belongs to the late metastasis of mucosal patients, which accounts for 20% of the Chinese melanoma cases.The patient was subjected to targeted drug therapy and radiotherapy during the entire treatment process.The PET-CT results showed that the multiple metastatic lesions of the whole body almost completely subsided within a few months,and there was no recurrence during a long follow-up time, which is rare in the group of patients with advanced melanoma.Additionally, it provided a new understanding for our treatment concept of advanced melanoma.It is still not quite clear whether the application of “D+T” plays the main role in targeted therapy,radiotherapy plays the main role in sensitization,or the synergy formed by the two complements each other in the process.The authors’team has made some assumptions about the mechanism and conducted corresponding basic research and clinical trials, which are also the research orientations of our team in recent years.

It has been acknowledged in recent studies that radiotherapy not only mediates DNA damage and leads to cancer cell death,but also produces immunogenicity and adjuvants by triggering the release of proinflammatory mediators,increasing immune stimulation,inhibiting tumor cell infiltration, and enhancing the expression of new antigens.4,5Generally, the positive immune stimulation shown by radiotherapy can be changed from“cold”tumor to“hot”tumor to some extent.By driving the immune cell infiltration and enhancing immunogenicity, radiotherapy may increase the immune response of tumors.Studies have shown that the internal event of tumor cell DNA damage after radiotherapy is the key to driving immune regulation.4Additionally, radiotherapy can induce micronuclei in tumor cells, thereby activating cytosolic DNA/RNA sensors, the most important of which is the cyclic GMP-AMP synthase (cGAS)-STING pathway.6–8After radiotherapy, the tumor cells can also affect immune monitoring through the expression of new antigens,9which may also provide a microenvironment basis for the effectiveness of targeted therapy.

Regarding targeted therapy, the B-Raf mutations are the most common type of gene mutations in melanoma,of which more than 90%are BRaf V600 site mutations.10The distribution type of melanoma patients in China is different from that in European and American countries,thus the B-Raf mutation rate is different.The former is mainly the acral and mucosal type, the latter is mainly the chronic solar injury type with higher mutation rate of B-Raf.11–13From the five-year follow-up data of the “D+T” treatment for advanced melanoma in 2020,14870 patients with B-Raf mutation received oral dabrafenib(at a dose of 150 mg twice daily)plus trametinib(2 mg once daily)or two matched placebos for 12 months.At five years,the percentage of patients who were alive without relapse was 52%(95%confidence interval(CI),48–58)with dabrafenib plus trametinib and 36%(95%CI,32–41)with placebo(hazard ratio for relapse or death, 0.51; 95% CI, 0.42–0.61).The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61–71)with dabrafenib plus trametinib and 54%(95%CI,49–60)with placebo(hazard ratio for distant metastasis or death,0.55;95%CI,0.44–0.70).11This suggests that more than half of the patients with B-Raf mutation can obtain 5-year long-term survival through “D+T” treatment, which was unimaginable in the past,and fully proves the curative effect advantage of “D+T”combination compared to a single drug.15

Fig.2. Treatment process and follow-up details.

Fig.3. Radiation induced alopecia.

When combined drugs improve the efficacy, it is inevitable that incidence of adverse events(AEs)will increase in varying degrees,which is also the case for all antitumor drugs.Although there is no clinically meaningful difference between the combination-therapy group and placebo group in the incidence or severity of serious AEs reported during the follow-up period in most clinical studies, the occurrence of AEs is often an important factor leading to patients’inability to adhere to medication.Good patient compliance and a full dose and adequate treatment are the premise to ensure the curative effect,which is expected to maximize the survival benefit.Therefore, it is important for clinicians to predict the occurrence of AEs and deal with it effectively and timely.Many side effects of “D+T” are mild (grades 1–2), mainly including fever, chills, fatigue, gastrointestinal symptoms (such as nausea, vomiting, loss of appetite),and skin toxicity.16

The new fever management process can improve fever related outcomes and medication compliance.Many patients experience fever after receiving“D+T”combined treatment,but in 80%–90%cases,the fever is mild(grades 1–2).Previously,the treatment suggestion based on China’s drug instructions was to conduct layered treatment according to the severity of the fever;38.5°C and 40°C were the critical values of stratification.Generally,the single drug was stopped first.The clinical study of COMBI-Aplus published at the annual meeting of the American Society of Clinical Oncology(ASCO)this year established a new fever management process,suggesting that once the patient has a fever exceeding 38°C,the“D+T” drug administration should be stopped immediately.If nonsteroidal anti-inflammatory drugs and other drugs are used for symptomatic treatment and a small amount of glucocorticoids are used, the fever symptoms of the patient can be controlled effectively.When the body temperature drops below 38°C for more than 24 h, the restart process will be initiated, and the original dose of both drugs will be restored simultaneously.If the fever is not well controlled and repeated,a new step can be considered to adjust the dose of the two drugs.For example,dalafenib is reduced from 150 mg bid to 100 mg bid and then to 75 mg bid.In addition to fever,other adverse reactions of“D+T”such as antiemetic or appetite improving drugs can be well controlled.

4.Conclusion

This study aimed to clarify that the “D+T” treatment may achieve a curative effect in a short time in combination with radiotherapy in patients with advanced melanoma and may sustain no recurrence for a long duration.Additionally, we can still safely realize the survival benefits from targeted therapeutic drugs as long as we fully evaluate the benefit and risk, detection,and intervention common to AEs at the earliest.

Fig.4. PET-CT during the development of the patient’s disease.(A)PET-CT image on December 4,2019;(B)PET-CT image on April 10,2020;(C)PET-CT image on July 28, 2020; (D) PET-CT image on March 26, 2021.

Ethics declarations

Ethics approval and consent to participate

The need for ethical approval and written informed consent was waived as it is a case report.

Consent for publication

The patient gave written informed consent to publish the data contained within this study.

Competing interest

The authors declare that they have no competing interests.

Authors’contributions

Yang Y:Writing-Original draft.Lu N:Supervision,Writing-Reviewing and Editing.Liu J: Data curation, Writing-Reviewing and Editing.Gu J:Writing-Reviewing and Editing.

Acknowledgments

We appreciate the patient who provided informed consent for the publication of his case.