The purpose of this study was to compare the effectiveness and safety of intralesional versus intramuscular MTX in the treatment of different NMSC types. Up to our knowledge, no study comparing intralesional and systemic MTX is currently present in the literature. Moreover, the efficacy of systemic MTX in different types of NMSCs has never been previously explored.
In the current study, NMSC response of greater than 50% was significantly higher in the IL MTX group (53.3%) as compared to the IM MTX group (26.67%) (P = 0.04). This higher success rate of IL MTX might be attributed to the direct injection of the drug into the tumor.
In the IL MTX group, 88.9% of patients with KA were responders, as compared to 42.8% of BCC, and 28.6% of cSCC. The mechanism of action of MTX, which suppresses DNA synthesis during cell replication(5), may explain the differences in therapeutic response across the three forms of NMSC. As compared with SCC and BCC, KA is more vulnerable to this chemotherapeutic action due to its rapid growth.(4)
In a retrospective study peformed by Gualdi ei al.(4) on 35 patients with NMSCs (21 SCC,12 KA, 2 BCC) who were intralesionally injected with MTX, KA had shown a higher response rate than SCC and BCC. For KA, 92% of patients responded by greater than 50%, and 8% only partially. These results are very close to our KA results of IL MTX where 88.9% were responders and 11.1% were partial responders.
A review found that IL MTX was highly effective at treating KA in 94% of 86 patients.(10) Moreover, Moss and Weber(11) reported resolution in 88% of 157 KAs with IL MTX injection.
Our results for KA are also quite similar to those of Patel and Cervino(12), who demonstrated that IL MTX injection following surgical debulking of the KA resulted in 88.9% resolution rate after 1–4 injections of 12.5–25 mg MTX.
Furthermore, our results are close to those of Annest et al.(13) and Yoo and Kim(14) who reported a cure rate of 92% and 91% of KAs, respectively, with IL MTX.
Our KA outcomes are less favourable than those of Melton et al.(15) and Scalvenzi et al.(6) who reported complete resolution of KA lesions in 100% of their patients (9 and 11 patients, respectively) after a mean of 1.7 and 5.3 intralesional MTX injections, respectively. According to several case studies(16–18), intralesional injection of MTX successfully resolved KAs.
Regarding BCC, the current study showed that 42.8% of patients affected with BCC were responders, 28.6% were partial responders, and 28.6% non-responders. This response rate is too much higher than Gualdi et al.(4), where none of the BCC in their study responded. This difference may be attributed to higher number of cases (14 versus 2 BCC) and sessions (8 versus 6) in our study.
The result of our responder BCC patients was also too much higher than that of Balighi et al.(19) who treated 11 patients with BCC by a single dose of IL-MTX injection with no improvement. This may be attributed to the use of only one session in their study versus 8 sessions in our study.
Our study shows that IL MTX was effective for about 28.6% of cases of cSCC (2 of 7 SCC). However, there aren't many research on the effectiveness of MTX for cSCC. Additionally, the majority assessed MTX's effectiveness as an adjuvant therapy rather than a stand-alone treatment.
For SCC, 47.6% of patients studied by Gualdi et al.(4) were responders. The number of responders in that study was higher than our study (28.6%). This difference may be simply because their study included higher number of SCC patients (21 versus 7 in our study). Several treatment protocols, doses (20–50 mg/session) and sessions (up to 6) were compared in their patients.
Notably, SCC and KA of the lips seemed more responsive than tumors of other areas as reported by previous studies.(16, 17, 20) Similarly, Bergón-Sendín et al.(20) demonstrated significant reduction in the size of lip SCCs by 68.18% for the minor axis and 57.28% for the major after 2 IL MTX injections 50 days prior to surgery. Our study showed higher response rate of 100% (> 50% decrease in size) for both SCC and KA of lips in the IL MTX group and 75% of lip NMSCs in the IM MTX group.
However, in invasive SCC of the lip, Salido-Vallejo et al.(21) reported a 23% reduction in lesion size with IL MTX injected prior to surgery and an average increase of 19% in the lesion size in patients treated with surgery alone. This low response rate may be explained by the invasive behaviour of SCCs treated in their study.
The lack of a defined standardised treatment protocol is one of the key problems with the use of IL MTX. Our findings imply that 8 sessions of weekly administration of 25 mg/ml of MTX may be an effective strategy.
Intralesional MTX is noted in the literature as an effective, well-tolerated and less invasive treatment for solitary NMSC, particularly KA. However, this approach may not be practical in multiple NMSCS, especially if it is believed that a predisposition exists for the development of additional lesions, such as field cancerization or a cancer-predisposition syndrome.(22, 23)
Some literature supports the use of parenteral methotrexate as a method to ensure uniform and predictable bioavailability, particularly in doses ≥ 15 mg.(24, 25) Moreover, injectable MTX has been found to be more effective than the oral form with greater bioavailability.(26, 27) That is why we chose the parenteral route for MTX administration.
Regarding the results of IM MTX, 26.67% of the patients were responders, where 71.4% of patients with KA showed tumor regression by < 50%, as compared to 30% of BCC, and none of the SCC patients.
There aren't many studies on the use of systemic MTX for the treatment of NMSCs. Additionally, the majority of them assessed the efficacy of MTX as an adjuvant polychemotherapy, with higher overall response rate for polychemotherapy than monotherapy, but the latter is generally more tolerated and minimally toxic.(7–9)
Our result for KA is in agreement with that of Bieber et al.(23) who described a case series of 3 patients with multiple KAs who successfully switched from cyclosporine, acitretin, and topical 5-fluorouracil to subcutaneous methotrexate, which caused a significant improvement in KAs with a reduced risk of developing new lesions. Despite cyclosporine's immunosuppressive properties, new KA lesions developed, and existing KAs failed to involute in their patients.(23,28−30)
Methotrexate's antiproliferative effects make it less likely to induce cancer.(31) Low-dose MTX has anti-inflammatory properties by blocking specific pathways, which increases adenosine level.(32) Despite its antiproliferative effects, high-dose MTX therapy is linked to an increased incidence of SCC.(33) In patients receiving low-dose MTX (5–25 mg/week), as in our study, no such lesions appeared during treatment.
To date, no systemic chemotherapeutic drug has been approved for advanced cSCC. Mono- or poly-chemotherapy regimens have included MTX and other agents.(7–9, 34) A review of various systemic treatments for BCC and cSCC stated response rates that were not higher than 20–30% and response durations of typically 2–3 months. Only case series have reported the use of systemic chemotherapy for locally advanced BCC and metastatic BCC, and the majority of patients with metastatic SCC received treatment with platinum-based regimens.(7–9, 35, 36)
It's noteworthy that MTX can be a beneficial treatment option to treat tumors for which surgery could not be indicated or to preoperatively debulk tumors and thus preserve function and provide acceptable cosmetic results.