Phase I Trial of Cetuximab, Radiotherapy, and Ipilimumab in Locally Advanced Head and Neck Cancer.

PURPOSE: Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4-positive (CTLA-4+) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti-CTLA-4 mAb, to cetuximab-radiotherapy. PATIENTS AND METHODS: A (3 + 3) design was used to establish the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, every-3-week doses to fixed, standard cetuximab-radiotherapy. Eligible subjects had stage III to IVb, high-risk [human papillomavirus-negative (HPV-)] or intermediate-risk HPV-positive (HPV+)] HNSCC. Dose-limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or immune-related (ir) AE requiring ≥2 weeks of systemic steroids. Baseline tumor and serial blood specimens were collected for immune correlatives. RESULTS: From July 2013 to May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering deescalation of ipilimumab to 1 mg/kg. Dose level -1 was expanded to N = 12 without DLT. irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1), and grade 1 hyperthyroidism (1). Three-year disease-free survival (DFS) and overall survival were 72% [90% confidence interval (CI), 57-92] and 72% (90% CI, 56-92). High expression of coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg was associated with worse DFS (HR = 5.6; 95% CI, 0.83-37.8; P = 0.08). CONCLUSIONS: The RP2D for ipilimumab plus standard cetuximab-radiotherapy is 1 mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy.

Phase 1 study of EGFR-antisense DNA, cetuximab, and radiotherapy in head and neck cancer with preclinical correlatives.

BACKGROUND: Cetuximab combined with radiation therapy (RT) is an evidence-based treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, locoregional failure remains the primary cause of cancer-related death in this disease. Intratumoral injection of epidermal growth factor receptor (EGFR)-antisense plasmid DNA (EGFR-AS) is safe and has been associated with promising lesional responses in patients who have recurrent/metastatic HNSCC. For the current study, the authors investigated the antitumor effects of cetuximab and EGFR-AS in preclinical HNSCC models and reported their phase 1 experience adding intratumoral EGFR-AS to cetuximab RT. METHODS: Antitumor mechanisms were investigated in cell line and xenograft models. Phase 1 trial eligibility required stage IVA through IVC HNSCC and a measurable lesion accessible for repeat injections. Patients received standard cetuximab was for 9 weeks. EGFR-AS was injected weekly until they achieved a lesional complete response. RT was delivered by conventional fractionation for 7 weeks, starting at week 3. Research biopsies were obtained at baseline and week 2. RESULTS: When added to cetuximab, EGFR-AS decreased cell viability and xenograft growth compared with EGFR-sense control, partially mediated by reduced EGFR expression. Six patients were enrolled in the phase 1 cohort. No grade 2 or greater EGFR-AS-related adverse events occurred. The best lesional response was a complete response (4 patients), and 1 patient each had a partial response and disease progression. EGFR expression decreased in 4 patients who had available paired specimens. CONCLUSIONS: In preclinical models, dual EGFR inhibition with cetuximab and EGFR-AS enhanced antitumor effects. In a phase 1 cohort, intratumoral EGFR-AS injections, cetuximab, and RT were well tolerated. A phase 2 trial is needed to conduct an extended evaluation of safety and to establish efficacy.

Local control and visual acuity following treatment of medium-sized ocular melanoma using a contact eye plaque: a single surgeon experience.

PURPOSE: To evaluate the outcomes of choroidal melanoma in (CM) patients treated with (125)I episcleral plaque brachytherapy and to compare our single surgeon results with the multi-institutional Collaborative Ocular Melanoma Study (COMS). METHODS AND MATERIALS: A review was performed of all CM patients treated with (125)I episcleral plaque brachytherapy by ophthalmologist in accordance with established COMS guidelines. RESULTS: The records of 35 patients were reviewed. The median longest basal tumor diameter and apical tumor height was 13.5 and 7.8mm, respectively. Median dose to the apex was 8609 cGy at a median dose rate of 92 cGy/h. At a median followup of 45 months, 35 patients had local control and 33 had successful organ preservation. At 5 years, the local control rate was 100%, and the eye preservation rate was 94%. Five patients developed hepatic metastasis at a median of 58 months, and 2 succumbed from disease. The 5-year survival rate was 84%, and the 5-year rate of death with histopathologically confirmed metastasis was 15%. Of the 22 patients with at least 3 years of followup, 68% had a visual acuity in the treated eye of 20/200 or worse. CONCLUSION: Excellent local control, eye preservation rates, and survival outcomes following (125)I episcleral plaque application for CM can be optimized by having an experienced ophthalmologist place the plaques. Additionally, hepatic metastasis can occur more than 5 years postimplant regardless of local control; therefore, longer systemic staging should be considered.

Stereotactic radiosurgery boost to the resection bed for oligometastatic brain disease: challenging the tradition of adjuvant whole-brain radiotherapy.

OBJECT: Whole-brain radiation therapy (WBRT) has been the traditional approach to minimize the risk of intracranial recurrence following resection of brain metastases, despite its potential for late neurotoxicity. In 2007, the authors demonstrated an equivalent local recurrence rate to WBRT by using stereotactic radiosurgery (SRS) to the operative bed, sparing 72% of their patients WBRT. They now update their initial experience with additional patients and more mature follow-up. METHODS: The authors performed a retrospective review of all cases involving patients with limited intracranial metastatic disease (< or = 4 lesions) treated at their institution with SRS to the operative bed following resection. No patient had prior cranial radiation and WBRT was used only for salvage. RESULTS: From November 2000 to June 2009, 52 patients with a median age of 61 years met inclusion criteria. A single metastasis was resected in each patient. Thirty-four of the patients each had 1 lesion, 13 had 2 lesions, 3 had 3 lesions, and 2 had 4 lesions. A median dose of 1500 cGy (range 800-1800 cGy) was delivered to the resection bed targeting a median volume of 3.85 cm(3) (range 0.08-22 cm(3)). With a median follow-up of 13 months, the median survival was 15.0 months. Four patients (7.7%) had a local recurrence within the surgical site. Twenty-three patients (44%) ultimately developed distant brain recurrences at a median of 16 months postresection, and 16 (30.7%) received salvage WBRT (8 for diffuse disease [> 3 lesions], 4 for local recurrence, and 4 for diffuse progression following salvage SRS). The median time to WBRT administration postresection was 8.7 months (range 2-43 months). On univariate analysis, patient factors of a solitary tumor (19.0 vs 12 months, p = 0.02), a recursive partitioning analysis (RPA) Class I (21 vs 13 months, p = 0.03), and no extracranial disease on presentation (22 vs 13 months, p = 0.01) were significantly associated with longer survival. Cox multivariate analysis showed a significant association with longer survival for the patient factors of no extracranial disease on presentation (p = 0.01) and solitary intracranial metastasis (p = 0.02). Among patients with no extracranial disease, a solitary intracranial metastasis conferred significant additional survival advantage (43 vs 10.5 months, p = 0.05, log-rank test). No factor (age, RPA class, tumor size or histological type, disease burden, extent of resection, or SRS dose or volume) was related to the need for salvage WBRT. CONCLUSIONS: Adjuvant SRS to the metastatic intracranial operative bed results in a local recurrence rate equivalent to adjuvant WBRT. In combination with SRS for unresected lesions and routine imaging surveillance, this approach achieves robust overall survival (median 15 months) while sparing 70% of the patients WBRT and its potential acute and chronic toxicity.

Single session stereotactic radiosurgery boost to the post-operative site in lieu of whole brain radiation in metastatic brain disease.

PURPOSE: Whole brain radiation (WBXRT) reduces the incidence of local and distant recurrence following resection of metastatic brain disease but does not prolong life and may entail neurocognitive decline. We employed a novel treatment modality of providing a single-session stereotactic radiosurgery (SRS) boost to the surgical resection site to achieve local control without the risk of cognitive effects. METHODS: We reviewed all patients at our institution that were treated with SRS to the post-operative bed following resection of a metastatic brain deposit. RESULTS: There were 32 patients identified (16 F) and median age was 60 years. One lesion was resected in all patients of whom 21 were solitary (eight with two lesions, three with three). Median survival was 16.4 months with a 14 month median follow-up. Factors which improved survival were solitary tumor, age <65 and RPA 1, although none achieved statistical significance. In the Cox multivariate analysis only smaller post-operative treatment volume correlated with survival (P = .04). There were two local recurrences (6.25%) to the surgical site and four patients required SRS for new lesions. Nine patients ultimately required salvage WBXRT (3/21 solitary v. 6/11 multiple lesions, P = .03 chi(2)), two for local recurrence post resection and seven for diffuse new disease. CONCLUSION: The use of SRS to the surgical site results in local recurrence rates comparable to WBXRT and is associated with excellent survival. Over 70% of patients managed this way were spared WBXRT. The presence of multiple lesions on presentation is predictive of the need for subsequent salvage WBXRT.