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Camrelizumab for the treatment of advanced cervical adenocarcinoma: a case report and literature review

Cervical adenocarcinoma belongs to an invasive subtype of cervical carcinoma, presenting poorly prognostic status. Chemotherapy treatment for recurrent cervical carcinoma are thought to be limited and supposed to be noncurative. Because of the poor prognosis of patients with recurrent cervical carcinoma, however, the benefits of second-line chemotherapy have not yet reached a consensus. Immunotherapy is a split-new tactic of overwhelming carcinomas that relies on the instinct of the immune system to recognize and directly kill neoplasm cells. Here, we reported a 55-year-old female patient with clinical stage IVB cervical adenocarcinoma. The patient received four cycles of systematic therapy, with the regimen of docetaxel plus carboplatin in combined with bevacizumab anti-vascular therapy. The progressive disease (PD) was assessed by imaging evaluation and PD was confirmed once more after four cycles of chemotherapy of albumin paclitaxel plus cisplatin. The patient exhibited a good response during the twelve-cycle of immunotherapy of Camrelizumab, whereas PD was observed upon termination of her immunotherapy. This case with the treatment of PD-1 inhibitor Camrelizumab exhibits a good curative effect and tolerable adverse reactions. In addition, some clinical markers and biomarkers expression levels can be served as the predictors of the effect of anti-PD-1 immunotherapy.


Introduction
Cervical cancer is the fourth most common malignancy in women, and its incidence ranks first among female reproductive system tumors, with 604,000 new cases and 342,000 deaths recorded worldwide in 2020. The incidence of cervical adenocarcinoma has been increasing in recent years, accounting for about 10-20% of new cases of cervical cancer (1). Most cervical adenocarcinomas originate in the cervical canal and are classified by International Endocervical Adenocarcinoma Criteria and Classification (IECC) as human papillomavirus (HPV)associated adenocarcinomas (HPVAs) and non-HPVassociated adenocarcinomas (NHPVAs). The HPVAs can be classified as common type, mucinous type, infiltrative laminar mucinous type, and so on, whereas NHPVAs can be classified as gastric type, clear cell type, mesonephric ductal type, and so forth (2). Cervical adenocarcinoma has the following particular behaviors compared to squamous carcinoma (2): (I) various pathological types, (II) insidious onset and difficult to diagnose at the early stage, (III) stronger invasiveness and endogenous growth, vascular invasion, and lymph node metastasis, (IV) less sensitive to radiotherapy. Therefore, it is generally accepted that the prognosis of cervical adenocarcinoma is less favorable than that of squamous carcinoma, and the prognosis of poorly differentiated cervical adenocarcinoma is less favorable than that of highly differentiated. At present, the treatment of cervical adenocarcinoma is no different from that of Case Report Camrelizumab for the treatment of advanced cervical adenocarcinoma: a case report and literature review squamous carcinoma. Surgical treatment is available for stage I to stage IIA cervical cancer. For advanced stage cervical cancer (stage IIB and beyond), its treatment is mainly systemic treatment (platinum-based chemotherapy) ± local management (radiotherapy of lesions and lymph nodes), but there are few options for patients whose disease progresses after first-line chemotherapy. Immunotherapy against PD-1/PD-L1 is the current hot spot in cervical cancer treatment and is expected to improve the treatment outcome of cervical adenocarcinoma. Camrelizumab, a humanized monoclonal antibody against PD-1, has been used in a variety of solid tumors such as nasopharyngeal carcinoma and hepatocellular carcinoma due to its favorable clinical activity and safety profile, but has fewer studies in cervical cancer. We report a patient with cervical adenocarcinoma with stage IVB, and the patient is deserving of being reported for the following reasons: (I) the patient was diagnosed with advanced ADC, a subtype of cervical cancer with a poor prognosis, (II) effective control of tumor with only camrelizumab immunotherapy after failure of both first-and second-line chemotherapy, and at least 10 months of PFS, (III) the patient has PD-L1-negative which is considered unfavorable for immunotherapy, but has MLH1 gene mutation, which could be a target for predicting immunotherapy efficacy. We present the following article in accordance with the CARE reporting checklist (available at https://atm.amegroups.com/article/ view/10.21037/atm-22-67/rc).

Case presentation
A 55-year-old female patient presented with "irregular vaginal fluid for more than 1 year" at the Affiliated Hospital of Qingdao University in May 2019. Gynecologic examination indicated cauliflower-like swelling of the cervix (approximately 4×5 cm in diameter), thickening of the anterior fornix of the cervix, bilateral thickening of the primary sacral ligament, and invasion of the pelvic wall. The pathology of cervical biopsy showed poorly differentiated adenocarcinoma, and the results of immunohistochemical (IHC) examination showed that the lesion was cytokeratin  Table 1.
Based on the International Federation of Gynecology and Obstetrics (FIGO) cervical cancer staging (2018 edition), the clinical diagnosis of this case was poorly differentiated cervical adenocarcinoma of stage IVB with metastasis to non-regional lymph nodes and lung.
The patient started first-line treatment with "paclitaxel + carboplatin (TC) combined with bevacizumab" in May 2019 at the following dosage: docetaxel 100 mg day 1 + carboplatin 400 mg day 1 + bevacizumab 500 mg day 1, intravenous drip, repeated every 3 weeks. After 2 cycles of chemotherapy, the patient underwent CT examination (9 July 2019), and the efficacy was evaluated as partial remission (PR) for both primary and metastatic foci. This regimen of chemotherapy was continued. After 4 cycles of chemotherapy, pelvic CT (26 August 2019), showed an enlarged cervical tumor with invasion of the uterine body, vagina, and left ureter, and a progressive metastasis in both lungs compared to after cycle 2 (9 July 2019), which was evaluated as tumor progressive disease (PD). The 5th cycle of chemotherapy was switched to "albumin paclitaxel + cisplatin (TP)" regimen (bevacizumab was discontinued due to the patient's financial constraints) at the following dose: albumin paclitaxel 300 mg day 1 + cisplatin 50 mg day 1 and 2, intravenous drip, repeated every 3 weeks. Efficacy was evaluated as PR after 2 cycles of second-line chemotherapy (18 October 2019) and re-evaluated as PD after 4 cycles (17 December 2019), compared to the CT on 18 October 2019, for both primary and pulmonary metastatic foci. Considering resistance to the second-line regimen, after adequate communication with the patient, she agreed to a trial of the PD-1 inhibitor camrelizumab. After 2 cycles (25 March 2020), both primary cervical focus and metastatic foci were evaluated as PR by enhanced CT; after 5 cycles (26 May 2020), the primary focus was evaluated as stable disease (SD) and pulmonary foci were evaluated as complete remission (CR); after 8 cycles (14 August 2020) the primary focus was evaluated as SD and pulmonary foci evaluated as CR. At that time, the patient was advised to receive pelvic radiotherapy, but she refused and continued immunotherapy. The last evaluation of the primary cervical  focus was on 12 October 2020, with a result of SD, and the evaluation of the pulmonary foci was on 14 December 2020, with a result of CR. At this time of treatment, the patient, and her family were aware of the illness and actively cooperated with the doctors. The patient had no significant discomfort, the adverse effects did not affect her daily life, and the treatment effect was considered to exceed expectation.
The patient stopped immunotherapy of her own accord in November 2020, after a total of 12 cycles of immunotherapy. The patient's CT and magnetic resonance (MR) results were reviewed on 20 January 2021: the primary focus was PD with enlarged lymph nodes in the retroperitoneum, and the pulmonary metastases remained CR, compared to the MR on 12 October 2020, and CT on 14 December 2020. At that time, the patient agreed to receive pelvic radiotherapy and continue immunotherapy.
The main immune-related adverse reaction during immunotherapy was reactive cutaneous capillary hyperplasia (RCCEP), which occurred after 2 cycles of immunotherapy, mainly in her neck and chest, in "red nevus type" and "pearl type", with an evaluation of grade 1 (diameter <1 cm and no infection), no special treatment was performed because there was no rupture or bleeding, and it gradually subsided after 5 cycles, as shown in Figure 2.
The concentration of CA125 in venous blood during the patient's treatment appeared to change accordingly during the treatment, as shown in Figure 3. The images of the patient's successive evaluations during the treatment are shown in Figures 4-6. The patient's treatment timeline is shown in Figure 7.
All procedures performed in this patient were in  (6) reported progressionfree survival of 6 and 10 months in 2 patients with liver metastases from cervical cancer treated with camrelizumab, respectively. In addition, Boussios et al. (7) reported that bevacizumab could enhance the anti-tumor effect of PD-1 inhibitors through neovascularization. However, Friedman et al. (8) did not achieve the desired effect in the study of PD-L1 inhibitor atezolizumab combined with bevacizumab in the treatment of cervical cancer. A study of melanoma by Xiao et al. (9) showed that effective anti-PD-1/PD-L1 therapy was strongly associated with high PD-L1 expression, while Borghaei et al. (10) reported that PD-L1-negative patients also had a good prognosis.
The expression rate of PD-L1 in cervical cancer ranged from 53% to 88% (11), suggesting that immunotherapy may benefit most cervical cancer patients. However, conversely, the high expression rate of PD-L1 also suggests that using it as a marker to predict clinical benefits may be imprecise. Although all PD-L1-negative cervical cancer patients in the KEYNOTE-158 study did not respond to PD-1 inhibitors, the sample was small and needed to be validated in a more extensive scale. In this case, although the patient had low PD-L1 expression, she received a good clinical efficacy, so the impact of PD-L1 expression on the clinical efficacy of cervical adenocarcinoma is still worth further exploration.
The TP53 gene is a tumor suppressor, about 20% of patients harbor TP53 mutation (12), and its mutation rate is higher in patients with cervical adenocarcinoma than squamous. Piha-Paul and Biton et al. (3,13) reported that mutations of this gene in lung adenocarcinoma were strongly associated with good efficacy of PD-1 inhibitors, while the effects were opposite in ovarian, esophageal, and colon cancers. No clinical study has confirmed the effect in cervical cancer, but basic research by Tornesello et al. (14) showed that TP53 plays an essential role in cervical adenocarcinoma, and high expression of this gene is also considered a predictor of poor prognosis in cervical cancer (15).
Mutations in the MLH1 gene, which plays a role in DNA mismatch repair, result in mismatch repair deficiency There are also other genes predictive of immune efficacy: Kato et al. (19) concluded that patients with solid tumors with mutations of TERT, PTEN, NF1, and NOTCH1 had better results with anti-PD-1/PD-L1 immunotherapy and those with mutations of MDM2, MDM4, and DNMT3A had more unsatisfactory efficacy. Pore et al. (20) found that SKT11 mutation was unfavorable for anti-PD-1/PD-L1 immunotherapy but could be reversed by STAT3targeted therapy. Lau et al. (21) concluded that patients with POLE mutation were susceptible to anti-PD-1/PD-L1 immunotherapy.
The use of each biomarker alone to predict the efficacy of PD-1 inhibitors is currently controversial, and there is no consensus on the predictivity of multiple markers in combination (22).
Our decision to treat this patient with camrelizumab was based on a combination of these factors: (I) she had advanced cervical adenocarcinoma and was resistant to both first-and second-line therapies, leaving few treatment options; (II) clinical studies have shown that PD-L1negative patients may also benefit from anti-PD-1/ PD-L1 immunotherapy; (III) the patient had an MLH1 gene mutation, and fundamental studies support the use of this mutation in patients with anti-PD-1/PD-L1 Camrelizumab triggers a high proportion of AEs (97%, of which 24% ≥ grade 3), among which RCCEP, anemia, fever, fatigue, hypothyroidism, cough, and proteinuria are the most common complications. Most of these AEs are reversible, and prevention and early recognition are the most important factors in treating these side effects. The RCCEP is a typical adverse reaction of camrelizumab (23), which occurs in around 1 month after drug administration, is self-limiting (healing after 3-6 months without scarring), and occurs only on the skin, rather than in visceral mucosa. Morphologically, RCCEP is mainly classified as red nevus, pearl, mulberry, patchy, and tumor-like type. Mechanism of RCCEP occurrence may be that camrelizumab reactivates the immune response by blocking the immunosuppressive pathway, and the overactivation of this process stimulates CD4+ and Th2 cells to secrete interleukin (IL)-4 and macrophage colony-stimulating factor (M-CSF), which promote the differentiation and expansion of macrophages in the skin toward the M2 type and release vascular endothelial growth factor (VEGF)-A, ultimately causing abnormal capillary proliferation. The treatment of RCCEP is mainly symptomatic, and the traditional Chinese medicine (TCM) formula Yunnan Baiyao or antibiotics can be used externally in the event of ulceration. A study by Wang et al. (24) in patients with hepatocellular carcinoma showed that those who developed RCCEP had better clinical efficacy and survival benefit, and the development of RCCEP in cervical cancer may also serve as a clinical marker for predicting the efficacy of camrelizumab.  This case shows that patients with progressive advanced cervical adenocarcinoma are well treated with the PD-1 inhibitor camrelizumab, with a long duration of disease control and mild adverse effects. Unfortunately, this patient̓ s tumor progressed again after self-discontinuation of immunotherapy, mainly due to progression of the primary focus. Based on this case, we suggest the following for the treatment of advanced cervical adenocarcinoma: (I) early detection of immune checkpoints such as PD-L1 to clarify the possibility of immunotherapy; (II) even if patients have low PD-L1 expression, PD-1/PD-L1 inhibitor such as camrelizumab can be tried; (III) for patients with effective immunotherapy, maintenance therapy and supplementation with local radiotherapy may allow patients to obtain longer PFS.
We draw the following conclusions from the case: (I) • First-line treatment: paclitaxel + carboplatin (TC) combined with bevacizumab. Total 4 cycles. • PR after 2 cycles but PD after 4 cycles.
• PD of primary cervical focus. • The patient agreed to receive pelvic radiotherapy and continue immunotherapy.
• Immunotherapy: PD-1 inhibtor camrelizumab, stopped on patient̕ s own. Total 12 cycles. • PR after two cycles and SD after 12 cycles of primary cervical focus; CR of pulmonary foci.
• Diagnosed with stage IVB cervical adenocarcinoma.

Figure 7
Timeline of the patient's treatment. PD, progressive disease; PR, partial response; SD, stable disease; CR, complete response. immunotherapy with camrelizumab after resistance to first-line chemotherapy is effective and can be used as a reference for subsequent line treatment in advanced cervical adenocarcinoma; (II) detection of PD-L1, TMB, MSI, and other immune-related genes is recommended to predict the effect of immunotherapy; (III) MLH1 mutation or RECCP appearing in the process of immunotherapy may be the positive markers of the curative effect of camrelizumab. In addition, the progression-free survival time of this patient may increase with the addition of pelvic radiotherapy when immunotherapy achieves better control. Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this patient were in accordance with the ethical standards of the institutional and national research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. Due to the retrospective and non-interventional nature of the study, permission by the local ethics committee was not required.
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