Oral capecitabine plus subcutaneous interferon alpha in advanced squamous cell carcinoma of the skin

Abstract

Purpose

Squamous cell carcinoma of the skin (SSC) is a UV-damage-related skin tumor. The first-line treatment is surgery, which has a high cure rate. In advanced cases, however, the established treatment is often not curative and shows a high rate of side effects. Improved treatment modalities are necessary.

Methods

Oral capecitabine plus subcutaneous interferon alpha were used in a prospective case series in advanced SSC of the skin at an academic teaching hospital for dermatology. Four patients with advanced SCC were included. Capecitabine 950 mgm^-2 body surface on days 1 to 14 was combined with interferon alpha 3×3 mioU s.c. three times a week. The chemotherapy was repeated on day 22. Clinical response, histology, monitoring of side effects and health performance status were assessed.

Results

Four patients (two females and two males) with advanced SCC were included (age range: 19 to 75 years). Complete remission (CR) was obtained in two and partial response (PR) in two. The final outcome was CR in two and progressive disease in one. One patient died of an unknown cause. Side effects were mild. Adjuvant treatment was unnecessary. Health performance status was not affected by the treatment.

Conclusions

The treatment protocol with a combination of capecitabine and interferon alpha seems to be effective and well tolerated in patients with advanced SCC. Controlled trials are necessary to prove the benefit we observed in this case series.

Introduction

The incidence rate of UV-induced skin cancer is high and still rising in fairer skinned people. The majority of cutaneous squamous cell carcinoma (SCC) of the skin arises in actinic or solar keratoses [6]. There is persuasive evidence that the incidence of SCC is related to the total sun exposure [1]. The primary therapy of SCC is complete surgical excision. This is not always possible in cases of advanced tumor growth, in selected topography (e.g., the eyelids) and in spreading tumors [15].

Fluoropyrimidines such as 5-fluorouracil (5-FU) have been a standard treatment for advanced squamous cell carcinoma (SCC) of the skin, with common treatment-related toxicity [18, 9, 4]. There have been several attempts to optimize 5-FU-based therapy. Oral administration of the drug allows increased flexibility compared to intravenous. Capecitabine is an oral fluoropyrimidine carbamate converted predominantly in tumor cells into 5-FU. The final step is the enzymatic conversion of this compound into 5-FU by a thymidine phosphorylase (tumor-associated angiogenic factor; dThdPase). 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD) into an inactive metabolite [7, 12]. The susceptibility of tumors to 5-FU therapy correlates with the ratio of activity of dThdPase and DPD. Non-response of tumors to capecitabine would be explained by low expression of dThdPase and/or high levels of DPD [13].

Capecitabine has been approved for the treatment of spreading colo-rectal carcinoma [11] and metastatic breast cancer [16]. Phase II and phase III trials have demonstrated that capecitabine is effective and offers a favorable safety profile compared to 5-FU, particularly with a low myelosuppression rate [21].

Treatment was performed prospectively in a series of patients with advanced SCC of the skin defined as: (1) infiltrative tumor growth into subcutaneous tissue with local destruction, and/or (2) local metastases, and/or (3) tumors of a certain size that would have made complete surgical removal either impossible or have caused a significant reduction in the quality of life (e.g., leg amputation) and/or (4) relapse or non-responsiveness to previous treatment(s).

We used a combined chemo-immune therapy with oral capecitabin (Xeloda, Hoffmann-La Roche, Grenzach-Wyhlen) 950 mgm^-2 body surface on days 1 to 14 and interferon-alpha (IFNa) 2a (Roferon A, Hoffmann-La Roche, Grenzach-Wyhlen; patient nos. 1, 3 and 4) or 2a (Essex Pharma, Munich; patient no. 2) 3×3 million units (mioU) s.c. three times a week. The chemotherapy was repeated on day 22.

After three cycles, a re-staging was performed. Patients with a complete response were followed without any maintenance therapy. In case of incomplete response, the treatment was continued. Adverse effects were classified according to the Common Toxicity Criteria [19]. The general health status was assessed by the Karnofsky performance status [22]. The evaluation of response to treatment was performed according to Therasse et al. [20].

Case reports

Case 1

A 68-year-old man presented with an exophytic, verrucous, malodorous SCC pT2 pN1 cM0, G2 of the left lower lid region involving both sides (conjunctival and cutaneous) of the lid (3×2 cm) with pre-auricular ipsilateral lymph node involvement as suggested by sonography (Fig. 1a). He suffered from hyperthyroidism, pulmonary hypertension and emphysema with global insufficiency. Surgery was denied.

Fig. 1.

Advanced squamous cell cancer (case 1): ( a) before treatment, ( b) after one cycle of combined treatment with capecitabine and interferon alpha 2a. ( c) Complete clinical remission of the exophytic lower eyelid tumor after three cycles

He was treated with combined chemo-immune therapy and responded with a PR after the first cycle, when only tumor residues on the conjunctival lid side remained (Fig. 1b). After three cycles, he showed a complete clinical response (Fig. 1c), but tumor residues in a mucosal biopsy cleared completely after four cycles. The lymph node involvement was no longer evident as shown by sonography. There were no laboratory abnormalities or adverse clinical effects. The Karnofsky performance status was 70% before and during the treatment. He was free of any tumor signs for more than 12 months before he was lost to follow-up.

Case 2

A 19-year-old woman with epidermolysis bullosa dystrophicans (Hallopeau-Siemens) presented with an exophytic tumor on the right hand (5×4 cm). A skin biospy revealed a SCC pT2 cNx cM0, G2, with lymph node enlargement in the groin. Amputation of the hand was refused by the patient. Subcutaneous injections were not possible due to an underlying genetic disorder with vulnerability of the skin and ulcer development. Since peripheral venous access was impossible, a Hickman catheter was inserted. Pre-treatment laboratory investigations showed a markedly decreased albumin level, severe anemia and renal retention. After transfusion and correction of the renal and albumin levels, we started with combined chemo-immune therapy. Because her weight was only 20 kg, the dosage of capecitabine was reduced to 2×200 mg/d (465 mg m^-2). Interferon alpha 2b was given intravenously 3×3 mio U/week.

Between the first and second cycle, she developed fever and general malaise, probably because of wound-infection-induced sepsis. She responded quickly to i.v. erythromycine. The anti-cancer treatment was continued after 1 week. The tumor showed partial remission after the first cycle. Two cycles were given. The treatment could not be continued, since the patient died for unknown reasons. Pathologic section was denied.

This patient had a Karnofsky performance status between 50 and 70%. The treatment was tolerated except for grade II nausea and grade I emesis during the first cycle. Laboratory investigations showed grade I anemia and grade II lymphopenia.

Case 3

A 75-year-old woman with chronic leg ulcers developed a relapsing squamous cell carcinoma (SCC; pT3cN0cM0, G2) of the left lower leg that was surgically treated twice with wide excision margins and mesh-graft transplantation. She presented with a verrucous, exophytic tumor with a large subcutaneous part (diameter 8 cm in MRI) on the left lower leg (Fig. 2a) and inguinal lymph node enlargements of uncertain origin. A complete ablation of the lower leg as recommended by the surgeon was refused by the patient.

Fig. 2.

Advanced squamous cell cancer on the lower leg (case 3): ( a) before treatment, ( b) after one cycle of therapy and ( c) at the end of chemo-immune therapy with complete remission

We started with a combined chemo-immune therapy that showed partial response after one cycle (Fig. 2b). The treatment was stopped after three cycles, when she showed a complete response (Fig. 2c). Lymph node enlargement was no longer seen by ultrasound. She was in complete response for more than 12 months. The Karnofsky performance status was 100% during the time of treatment. There were no laboratory abnormalities or clinical adverse effects due to treatment.

Case 4

A 72-year-old man presented with a large ulcerated (30×40 cm) SCC (pT3, Nx, M0; G1, Stage III) of the pre-sacral region, mimicking a chronic pre-sacral pressure sore. He suffered from incomplete paresis after spine trauma and diabetes mellitus. Pretreatment included a palliative radiotherapy with partial response after formation of a colostoma and a percutaneous nephrostoma (because of pyonephrosis). Two years later, however, there was a local relapse and an ongoing infiltration of the pelvis. An MRI investigation revealed enlarged pelvic lymph nodes, an infiltration of the rectal and anal sphincter musculature and the sacral spine by the tumor growth.

He was treated with combined chemo-immune therapy. Treatment was well tolerated. A clinical response was noted during the first cycle. During chemo-immune therapy, we observed a marked improvement of granulation and a significant decrease of the wound diameter and depth. He received four cycles with a PR as best response. Lymph node involvement did not show a significant change. A tumor progression was noted by MRI after 18 weeks. The Karnofsky performance status was 50% before and during treatment. The final outcome is shown in Table 1. The response rate (CR+PR) after three cycles was 100%, with two CR and two PR.

Table 1.

Outcome in combined chemo-immune therapy with capecitabine plus interferon alpha 2a

Patient no.	No. of cycles	Best response	Final outcome
1	4	CR	CR
2	2	PR (clinical)	✝
3	3	CR	CR
4	4	PR	PD

Discussion

Advanced SCC of skin is a therapeutic challenge. Non-resectable or spreading tumors have been treated with mono- or polychemotherapy either alone or in combination with radiotherapy. The response rate for systemic 5-FU is around 15% in SCC. 5-FU is mainly used in polychemotherapy protocols [18, 9, 4].

In a recent prospective trial in 14 patients with progressive SCC, oral 5-FU was administered at a daily dose of 175 mg m^-2 for 3 weeks every 5 weeks. Two partial remissions and three minimal remissions were observed [4]. Cisplatin 100 mg m^-2 on day 1 combined with a continuous 24-h 5-FU infusion of 1,000 mg m^-2 for 4 days was used in patients with metastatic SCC of unknown origin. The regimen was repeated every 21 days. Responses were seen in 8 of 15 patients (1 CR, 7 PR) [9]. In another phase I trial combining capecitabine with cisplatin in locally recurrent or metastatic head and neck cancer, 21 patients were included. Objective response was obtained in seven patients with three CR [17].

Advanced SCC of the head and neck was treated in a neoadjuvant protocol with paclitaxel (225 mg m^-2), carboplatin (area under the curve of six) and four 80 cGy fractions of radiotherapy on days 1 and 2. The sequence was repeated on days 22 and 23. Of 40 patients enrolled in the study, 39 were assessable, with an overall response rate of 82%. Eleven patients (28%) had a CR. Grade 3 or worse toxicities were common with neutropenia (50%) and infection (13%), among others [2].

Capecitabine offers a comparable or even better efficacy than 5-FU and an improved safety profile [21, 8]. The rationale for a combination of capecitabine and IFN is a synergistic effect. IFN stimulates dThdPase, leading to a forced accumulation of 5-FU in tumor cells [14].

Adverse effects of capecitabine and IFN are dose-dependent. In a phase I study in metastatic renal cancer with 2×1,000 mg capecitabine m^-2 on days 1 to 14 and 22 to 36 combined with 3×3 mioU IFN-alpha s.c. per week, side effects included mild nausea and vomiting (70%), hand-foot syndrome (67%), diarrhea (63%) and mild neutropenia [5]. Mucositis may be treatment-limiting [3]. The lower dosages used in the previous study did not cause severe adverse effects. Recently, an inflammation of actinic keratoses, potential SCC precursors, during capecitabine therapy has been reported [10].

We treated four patients with local advanced or regional SCC with a combination of oral capecitabine and subcutaneous interferon-alpha 2a with dramatic responses to inoperable tumors. An advantage of the treatment is the the oral application mode of capecitabine, in particular for older patients affected by SCC. The small number of patients in this case series, however, warrants further validation by a prospective trial.

Abbreviations

CR

complete remission

5-FU

5-fluorouracil

IFN

interferon

PD

progressive disease

PR

partial remission

s.c.

subcutaneous

SCC

squamous cell carcinoma