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Multirelapse Squamed Carcinoma of the Skin

Short summary

75-year-old male with a cutaneous squamous cell carcinoma resected from the right eyebrow in 2003. In 2006, the patient underwent resection of an ipsilateral squamous cell carcinoma in the parotid bed that was presumably a nodal metastasis. He then experienced local relapse treated with resection and adjuvant radiotherapy. There was recurrent disease involving the right cheek excised in 2008. In 2009, another recurrence led to resection with orbital exenteration. Pathology showed squamous cell carcinoma, with perineural invasion, and extension into the orbital muscles. Stereotactic radiotherapy was administered to the orbital apex. Most recent MRI showed an enhancing lesion and a lymph node concerning for loco-regional recurrent disease. Neck-chest-abdomen CT was recommended, with cardiac evaluation and PORT placement in order to facilitate the administration of cisplatin, infusional 5FU and cetuximab.

Patient's questions

1) Suggested treatment?

2) International reference centres beside those already visited (European Institute of Oncology in Milan and “Ospedali Riuniti” in Trieste)?

Medical Background

75 years old , male, Italy
Diagnosis: Results of multirelapse squamed carcinoma of the skin, removed through surgery + radiotherapy (critical threshold at the orbital apex)

1999: Ischemic cardiopathy and angioplasty Allergy to NAS drugs

2003 à removal of a cell-squamed carcinoma of the right superciliary skin.

2006 à in May, exeresis of cell-squamed carcinoma of the right parotid through emptying of right laterocervical metastasis with subsequent radiotherapy.

2008 à in January, removal of right superciliary lesion: epidermoid carcinoma with unaffected edges.

March 2008 à removal of local relapse and subsequent radiotherapy.

November 2008 à Radical relapse exeresis of the right cheek (at biopsy: epidermoid carcinoma).

May 2009: skin exeresis for relapse in the right front-orbital region and right exenteratio orbitae with reconstruction with temporal rotation flap. Carcinoma with keratinized squamed cells, widely infiltrating the dermis and the sub-skin soft tissues, also including the hypodermic striated muscles, with perineural infiltration, extended to the upper periorbital muscles, to the insertion of the rectus muscles onto the optical foramen, to the endo-orbital portion of the muscle lifting the eyelid, to the trochlear portion of the upper oblique muscle, to the medial rectus muscle and its radicalization, to the radicalization of the upper rectus muscle, and to the radicalization of the eye lower edge. The neoplasia reaches the deep edge very closely (<1 mm) without infiltration, and is 1.2 mm away from the nasal edge, 2 mm from the frontal edge, radicalization of the lower edge of the right eye ypT4 ypNx.
Stereotaxic treatment at positive level for disease residual in correspondence of the left orbital apex, through 4 arches of 6 MV X photons. Localization and positioning through optoelectronic system and X-ray images acquisition. Administered daily dose. 2 Gy (session) Planned total dose: 40 Gy 05/2009: removal of 2 ulcerated subcentimetric areas, locally infiltrating at the level of the right cheek skin: diagnosis of spinocellular carcinoma.

Updated on 07/2009: MRN (7-9-09): In correspondence of the deeper portion of the surgery cavity, at the orbital apex level, a considerably hypointense tissue in the weighted T2 sequences can be noticed. It shows a lively and homogeneous contrast-enhancement, whose maximum diameter on the axial plan is approximately 18 mm. Deep inside, this tissue infiltrates at level of the optical foramen and at the lower orbital fissure, extending onto the rear region of the right cavernous sinus. In its lateral portion, near the carotideal siphon, which is partially embraced, there is a tissue provided with an extended contrast-enhancement involving the region of the Meckel’s cave. In correspondence of the subcutaneous tissues, in a cranial direction to the right cheekbone arch, there is a wide necrotic nodulation, with bilobed aspect of pathological importance, whose transversal and craniocaudal maximum diameters are approximately 2.5 x 2.6 cm. In the homolateral submandibular region there is a recognizable pathological tumefaction, probably a lymphoadenopathy. Its maximum transversal diameter on the axial plan is approximately 3.5 cm; it extends deep inside to infiltrate the mylohyoid muscle, with subsequent invasion of the adjacent sub-lingual space. In the left submandibular region there are some oval lymph nodes, the major of which has a maximum diameter of approximately 2 cm, with doubtful meaning.

In accordance to the above explanation, on the occasion of outpatient visit dated 07/2009, the conclusion is: radiological clinical diagnosis of loco-regional disease return, with local endocranial extension. On that occasion, we suggested an oncologic evaluation for possible systemic treatment.

Oncologic visit performed on 07/2009 with the following schedule: - Restaging with neck-thorax-abdomen CAT scan with contrast medium (upon premedication) - ECG + angiocardioscintigraphy with EF (ejection fraction) evaluation - PORT positioning - Chemotherapy with CDDP (60 mg/mq) g1 + 5-fluorouracil (600 mg/m2 ic) gg1-4 + weekly Cetuximab (400 mg/mq loading dose, followed by 250 mg/mq maintenance) - Symptomatic therapy: Omeprazen 20 mg 1 tablet; Medrol 16 mg 1/2 tablet x 2 (on a full stomach); Durogesic 25 micrograms, plaster to be replaced every 72 hours; Toradol 20 gtt if needed, in case of uncontrolled pain (max once a day)

Medical opinion

The inquiry specifically asks about suggested treatment and other referral centers.

This elderly man has a history of heart failure and advanced loco-regionally recurrent cutaneous squamous cell carcinoma that is widely infiltrative and involves the base of skull. This is clearly an unresectable tumor, and the prior radiotherapy precludes any consideration of further radiation-based treatment. The approach up to this point seems quite appropriate and aggressive in keeping with the nature of this tumor. Unfortunately, the disease has won the battle, and is now recurrent with only palliative systemic approaches remaining. I would agree that platinum/5FU/cetuximab as per the EXTREME study is a reasonable approach at this point. The patient is chemotherapy-naïve, and platinum/5FU has known activity in cutaneous squamous cell carcinoma. Moreover, there are a few case reports in the literature of cutaneous squamous cell carcinoma responding to cetuximab. So, like mucosal squamous cell carcinoma of the head and neck, it is possible that platinum/5FU/cetuximab is better than platinum/5FU in the cutaneous variant of this disease. I would, however, consider substituting carboplatin for cisplatin in this regimen based upon the patient’s age and comorbid heart failure.

Other standard chemotherapies that have demonstrated some activity in cutaneous squamous cell carcinoma are methotrexate and capecitabine. These would be reasonable second-line approaches. An alternative would be a trial of erlotinib or gefitinib, if available, based upon the abstract below, presented at this year’s ASCO meeting from MD Anderson in Texas:

Gefitinib for advanced cutaneous squamous cell carcinoma of head and neck: Phase II trial.
J Clin Oncol 27:15s, 2009 (suppl; abstr 6054)

R. S. Weber, R. A. Lustig, A. K. El-Naggar, D. I. Rosenthal, E. S. Kim, I. I. Wistuba, X. M. Tang, F. F. Wan, S. A. Taylor, B. S. Glisson; UT M. D. Anderson Cancer Center, Houston, TX; Hospital of the University of Pennsylvania, Philadelphia, PA; University of Texas M. D. Anderson Cancer Center, Houston, TX

: Advanced head and neck cutaneous squamous cell carcinoma (HN cSCC) carries a 30-40% risk of death by 2 years with standard therapies. Small molecular inhibitors of the epidermal growth factor receptor (EGFR) may have an impact. We evaluated gefitinib as an induction therapy in a high-risk patient (pt) group prior to definitive therapy to determine efficacy, toxicity and feasibility. Correlative studies of EGFR expression, gene mutation, and ploidy may serve as predictors of response. Methods: Eligible pts must have HN cSCC >2cm, regional nodal metastases, peri-neural invasion, or deep invasion and must be candidates for definitive locoregional therapy with surgery and/or radiation. Two 30-day induction cycles of gefitinib (250mg po qd). Pts are assessed clinically after 15 days. If a response is noted, gefitinib is continued. For pts with stable disease, the dose is escalated to 500mg qd. Pts with progressive disease go off study. Total and phosphorylated (p) EGFR protein expression was analyzed by immunohistochemistry and gene copy number by fluorescent in-situ hybridization (FISH).

Results: To date, 23 pts are enrolled and 22 are evaluable for responses and toxicities. Complete responses (CR) were noted in 3 pts, partial response (PR) 7, stable disease (SD) 5, and progressive disease (PD) 7 (68.1% response per RECIST criteria). Minimal side effects are associated with gefitinib (cutaneous and GI related). EGFR and p-EGFR protein overexpression were observed in 5 of 11 (45.5%) pts tested thus far. Eight of the pts were FISH negative with respect to EGFR gene expression: 7 had low trisomy and 1 had low polysomy. Two were FISH positive and expressed high polysomy. No gene amplification was detected. No statistically significant correlations between EGFR gene or protein expression and responses to administration of gefitinib were found at this point in the analysis. Protein and gene expression analyses are ongoing.

Conclusions: The preliminary results from our study are encouraging and suggest that anti-EGFR therapy may have a role in the adjuvant treatment of HN cSCC. Correlative studies may help identify pts most likely to respond to anti-EGFR therapy.