An Improvement of Exertional Dyspnea by the Reintroduction of Anti-EGFR Antibody in Patients with Metastatic Rectal Cancer Who Developed Cancerous Lymphangiopathy: A Case Report

Reexposure to anti-EGFR antibodies has attracted considerable attention for the treatment of metastatic colorectal cancer (mCRC). Reexposure includes a rechallenge after the acquisition of resistance to anti-EGFR antibodies and reintroduction after discontinuation due to severe adverse events or according to the patient’s wishes, and both have shown good therapeutic outcomes [1].

In particular, a reintroduction has shown far better therapeutic outcomes than a rechallenge, as most patients eligible for reintroduction discontinued treatment due to adverse events despite a good treatment response during the front-line treatment [2]. A rechallenge with anti-EGFR antibodies is not an established treatment strategy, as there is no evidence based on the results of large prospective randomized trials. However, some phase 2 studies have shown relatively good therapeutic outcomes for a rechallenge with anti-EGFR antibodies [3, 4]. Given the above, reexposure to anti-EGFR antibodies via either a reintroduction or rechallenge is expected to be a useful treatment option in daily clinical practice.

A 68-year-old man who had undergone laparoscopic low anterior resection and lymph node dissection for stage IIIB rectal cancer followed by adjuvant chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) was found to have multiple lung tumors 6 years after surgery. These tumors were diagnosed as lung metastases (RAS, wild-type; BRAF, wild-type; MSI, negative) from rectal cancer by means of a computed tomography-guided biopsy.

Considering his history of allergy to oxaliplatin during adjuvant chemotherapy, 5-fluorouracil + leucovorin + irinotecan (FOLFIRI) + cetuximab was selected as the first-line treatment. However, despite the diagnosis of a partial response at the initial evaluation, the patient requested discontinuation of cetuximab due to acneiform eruptions. Therefore, the patient continued taking only FOLFIRI for the next 7 months.

Nine months after the initiation of the first-line treatment, the patient was diagnosed with progressive disease. Subsequently, he received trifluridine/tipiracil as a second-line treatment. The stable disease persisted for 5 months with the second-line treatment, but eventually, multiple lung metastases increased. Regorafenib was introduced as a third-line treatment, but within 3 months, respiratory failure developed due to multiple lung metastases and cancerous lymphangiopathy (Fig. 1). Therefore, home oxygen therapy and supportive care were initiated.

Although his performance status was poor, irinotecan (150 mg/m², every 2 weeks) + cetuximab (loading dose of 400 mg/m² followed by weekly 250 mg/m²) were introduced as a reintroduction of anti-EGFR antibody based on his strong desire to continue intensive treatment. Surprisingly, 2 months after the reintroduction of the anti-EGFR antibody, his exertional dyspnea improved (Fig. 2), similar to the imaging findings (Fig. 3). Although the same doses of irinotecan and cetuximab were used as those administered in the first-line treatment, the patient was able to maintain a level of only mild skin damage due to careful supportive care with topical steroids and oral minomycin.

Anti-EGFR antibodies dramatically prolong the survival of mCRC patients. In the phase 3 PARADIGM clinical trial, the median overall survival time reached 37.9 months in patients with RAS-wild-type left-sided mCRC who were treated with an anti-EGFR antibody in combination with mFOLFOX6 as the first-line treatment [5]. However, anti-EGFR antibodies often cause severe skin toxicity, such as acneiform eruptions, which often reduce the patients’ quality of life [6]. Therefore, it is not uncommon for patients to have no choice but to discontinue treatment with anti-EGFR antibodies despite a good treatment response in daily clinical practice.

A reintroduction is a strategy for reexposure to anti-EGFR antibodies in such cases. Since the administration of anti-EGFR antibodies is discontinued despite a good treatment response, as expected, the therapeutic outcome of reintroduction is better than that of rechallenge, in which administration is repeated after acquiring tolerance. Karani et al. [2] reported that in 51 patients who underwent the re-induction of anti-EGFR antibody, the median progression-free survival time was 6.6 months and the median overall survival time was 33.4 months [2], which is an excellent outcome for second- or third-line treatments. Although it has been reported that a poor performance status is associated with poor treatment outcomes in cancer treatment [7], in our case, the reintroduction of anti-EGFR antibody during late-line treatment dramatically improved the patient’s respiratory failure, which was extremely meaningful in terms of improving his quality of life. As some reports have described that a higher efficacy can be expected in cases of skin toxicity [6], it may be necessary to actively consider the reintroduction of anti-EGFR antibody in patients who discontinued treatment with anti-EGFR antibody due to skin toxicity despite a good treatment response.

However, it is also necessary to take appropriate measures to prevent any adverse events. In cancer treatment, inappropriate drug doses may lead to permanent discontinuation, dose interruptions, and dose reductions, thus resulting in an inability to receive the full benefit of the drug [8]. Patients who develop severe skin toxicity during frontline treatment are likely to experience similar adverse events upon reexposure. If the previous skin toxicity was grade ≤2, there may be no need to reduce the dose; however, in cases where adverse events of grade ≥3 occurred, it may be necessary to restart the anti-EGFR antibody at a reduced dose. It is also necessary to take strict measures to prevent any side effects by using topical and oral medications. In this case, by providing strict supportive care, no serious adverse events occurred, and the patient benefited from anti-EGFR antibodies. In rechallenge therapy, both the RAS status and anti-EGFR antibody-free interval are important, but in reintroduction therapy, countermeasures against adverse events may hold the key to success.

The appropriate timing for reexposure to anti-EGFR antibodies differs between a rechallenge and reintroduction. It has been reported that in rechallenge therapy, the efficacy of anti-EGFR antibody is better in patients with long anti-EGFR antibody-free intervals than in those with short anti-EGFR antibody-free intervals, as acquired resistance to anti-EGFR antibody decreases over time [9]. However, the appropriate timing of a reintroduction may be earlier than that of a rechallenge, as therapeutic efficacy is not affected by oncological factors. Karani et al. [2] reported that a rechallenge was often performed as a fourth-line treatment, whereas a reintroduction was often used as a second- or third-line treatment.

In conclusion, the reintroduction of anti-EGFR antibody to patients who have discontinued anti-EGFR antibody therapy due to skin toxicity despite a good treatment response is a very useful treatment option for mCRC. The CARE checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000538235).

We thank the patient and his family for allowing us to publish these findings. We thank Brian Quinn, who provided medical writing services on behalf of Japan Medical Communication, K.K.

This article does not contain any studies involving human participants or animals performed by any of the authors. Ethical approval was not required for this case study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of this case report and accompanying images.

The authors have no conflicts of interest to declare.

The authors have no funding to any research relevant to this case report.

M.S. and H.T. collected clinical data and drafted the manuscript. T.F., H.K., and S.K. critically revised the manuscript. K.M. critically reviewed the article. All authors have reviewed and approved the final manuscript.

All data underlying the results are available as part of the article, and no additional source data are required. Further inquiries can be directed to the corresponding authors.