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1.
J Clin Oncol ; : JCO2302172, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38900987

ABSTRACT

PURPOSE: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma. METHODS: Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria. RESULTS: ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded. CONCLUSION: The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.

2.
Pain Manag ; 14(2): 87-99, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38318666

ABSTRACT

Aim: We aimed to understand experiences with opioids and cannabis for post-treatment cancer survivors. Patients & methods: We conducted seven focus groups among head and neck and lung cancer survivors, using standard qualitative methodology to explore themes around 1) post-treatment pain and 2) utilization, perceived benefits and perceived harms of cannabis and opioids. Results & conclusion: Survivors (N = 25) experienced addiction fears, stigma and access challenges for both products. Opioids were often perceived as critical for severe pain. Cannabis reduced pain and anxiety for many survivors, suggesting that anxiety screening, as recommended in guidelines, would improve traditional pain assessment. Opioids and cannabis present complex harms and benefits for post-treatment survivors who must balance pain management and minimizing side effects.


Subject(s)
Cannabis , Chronic Pain , Neoplasms , Humans , Analgesics, Opioid/adverse effects , Pain Management/methods , Chronic Pain/drug therapy , Neoplasms/complications , Neoplasms/drug therapy , Survivors
3.
Oncologist ; 29(3): 192-199, 2024 Mar 04.
Article in English | MEDLINE | ID: mdl-37995312

ABSTRACT

The current work-up of the primary tumor site of a head and neck squamous cell carcinoma of unknown primary is not standardized and results in several time-consuming procedures that delay treatment initiation. This article seeks to consolidate contemporary strategies used to identify the primary tumor site of an unknown primary head and neck squamous cell carcinoma and offer recommendations based on current literature review.


Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Neoplasms, Unknown Primary , Humans , Squamous Cell Carcinoma of Head and Neck/diagnosis , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/therapy , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/pathology , Neck/pathology , Neoplasms, Unknown Primary/diagnosis , Neoplasms, Unknown Primary/pathology
4.
J Immunother Cancer ; 10(7)2022 07.
Article in English | MEDLINE | ID: mdl-35902131

ABSTRACT

Nonmelanoma skin cancers (NMSCs) are some of the most commonly diagnosed malignancies. In general, early-stage NMSCs have favorable outcomes; however, a small subset of patients develop resistant, advanced, or metastatic disease, or aggressive subtypes that are more challenging to treat successfully. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC). Although ICIs have demonstrated activity against NMSCs, the routine clinical use of these agents may be more challenging due to a number of factors including the lack of predictive biomarkers, the need to consider special patient populations, the management of toxicity, and the assessment of atypical responses. With the goal of improving patient care by providing expert guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their own clinical experience to develop recommendations for healthcare professionals on important aspects of immunotherapeutic treatment for NMSCs, including staging, biomarker testing, patient selection, therapy selection, post-treatment response evaluation and surveillance, and patient quality of life (QOL) considerations, among others. The evidence- and consensus-based recommendations in this CPG are intended to provide guidance to cancer care professionals treating patients with NMSCs.


Subject(s)
Carcinoma, Basal Cell , Carcinoma, Squamous Cell , Immunotherapy , Skin Neoplasms , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Clinical Trials as Topic , Guidelines as Topic , Humans , Quality of Life , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology
5.
Radiother Oncol ; 173: 32-40, 2022 08.
Article in English | MEDLINE | ID: mdl-35595174

ABSTRACT

BACKGROUND: Limited data exists regarding the efficacy of curative hypofractionated radiotherapy (hypo-RT) regimens compared to conventionally-fractionated radiotherapy (conv-RT) for Merkel cell carcinoma (MCC). METHODS: A retrospective analysis of 241 patients diagnosed with non-metastatic MCC from 2005-2021 and who received RT at Dana-Farber/Brigham & Women's Cancer Center. The primary outcome was cumulative incidence of in-field locoregional relapse using Gray's test with competing risks of death and isolated out-of-field recurrence. Secondary outcomes included overall survival (OS) and MCC-specific survival using log-rank tests, and risk factors of recurrence using Cox-proportional hazards regression. RESULTS: There were 50 (20.6 %) and 193 (79.4 %) courses of hypo-RT and conv-RT, respectively. The hypo-RT cohort was older (≥73 years at diagnosis: 78.0 % vs 41.5 %, p < 0.01), and received a lower equivalent total RT dose in 2 Gy per fraction (<50 Gy: 58.0 % vs 5.2 %, p < 0.01). Median follow-up was 65.1 months (range: 1.2-194.5) for conv-RT and 25.0 months (range: 1.6-131.3) for hypo-RT cohorts. Two-year cumulative incidence of in-field locoregional relapse was low in both groups (1.1 % conv-RT vs 4.1 % hypo-RT, p = 0.114). While two-year OS was lower for the hypo-RT group (62.6 % vs 84.4 %, p = 0.0008), two-year MCC-specific survival was similar (84.7 % vs 86.6 %, p = 0.743). On multivariable analysis, immunosuppression, clinical stage III disease, and lymphovascular invasion were associated with any-recurrence when controlling for sex, age, and hypo-RT. CONCLUSIONS AND RELEVANCE: There was no difference in cumulative incidence of in-field locoregional relapse or MCC-specific survival between hypo-RT and conv-RT. Prospective studies are needed to confirm hypo-RT as an efficacious treatment option for MCC.


Subject(s)
Carcinoma, Merkel Cell , Skin Neoplasms , Carcinoma, Merkel Cell/pathology , Carcinoma, Merkel Cell/radiotherapy , Female , Humans , Neoplasm Recurrence, Local , Radiation Dose Hypofractionation , Retrospective Studies , Skin Neoplasms/radiotherapy
6.
Head Neck ; 44(5): 1213-1222, 2022 05.
Article in English | MEDLINE | ID: mdl-35243719

ABSTRACT

BACKGROUND: Submandibular gland (SMG) transfer decreased radiation-associated xerostomia in the 2/3-dimensional radiotherapy era. We evaluated the dosimetric implications of SMG transfer on modern intensity modulated radiotherapy (IMRT) plans. METHODS: Eighteen oropharynx cancer patients underwent SMG transfer followed by IMRT; reoptimized plans using the baseline SMG location were generated. Mean salivary gland, oral cavity, and larynx doses were compared between clinical plans and reoptimized plans. RESULTS: No statistically significant difference in mean SMG dose (27.53 Gy vs. 29.61 Gy) or total salivary gland dose (26.12 Gy vs. 26.41 Gy) was observed with or without SMG transfer (all p > 0.05). Mean oral cavity and larynx doses were not statistically different. Neither tumor site, target volume crossing midline, stage, nor salivary gland volumes were associated with mean doses. CONCLUSIONS: Salivary gland doses were similar with or without SMG transfer. IMRT likely decreases the benefit of SMG transfer on the risk of radiation-associated xerostomia.


Subject(s)
Head and Neck Neoplasms , Oropharyngeal Neoplasms , Radiotherapy, Intensity-Modulated , Xerostomia , Humans , Oropharyngeal Neoplasms/radiotherapy , Radiotherapy Dosage , Radiotherapy, Intensity-Modulated/adverse effects , Radiotherapy, Intensity-Modulated/methods , Submandibular Gland , Xerostomia/etiology , Xerostomia/prevention & control
8.
JID Innov ; 1(4): 100045, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34909742

ABSTRACT

Cutaneous squamous cell carcinoma is the second most common skin cancer in the United States. Currently, there is no standardized management approach for patients with cutaneous squamous cell carcinoma who develop metastatic or locally advanced disease and are not candidates for curative surgery or curative radiation. To address this issue, the Expert Cutaneous Squamous Cell Carcinoma Leadership program convened an expert steering committee to develop evidence-based consensus recommendations on the basis of a large, structured literature review. Consensus was achieved through modified Delphi methodology. The steering committee included five dermatologists, three medical oncologists, two head and neck surgeons, one radiation oncologist, and a patient advocacy group representative. The steering committee aligned on the following clinical topics: diagnosis and identification of patients considered not candidates for surgery; staging systems and risk stratification in cutaneous squamous cell carcinoma; the role of radiation therapy, surgery, and systemic therapy in the management of advanced disease, with a focus on immunotherapy; referral patterns; survivorship care; and inclusion of the patient's perspective. Consensus was achieved on 34 recommendations addressing 12 key clinical questions. The Expert Cutaneous Squamous Cell Carcinoma Leadership steering committee's evidence-based consensus recommendations may provide healthcare professionals with practically oriented guidance to help optimize outcomes for patients with advanced cutaneous squamous cell carcinoma.

9.
Clin Cancer Res ; 27(19): 5236-5247, 2021 10 01.
Article in English | MEDLINE | ID: mdl-34301750

ABSTRACT

PURPOSE: We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by mouse double minute 2 (MDM2) and MDMX to induce cell-cycle arrest or apoptosis in TP53-wild-type (WT) tumors. PATIENTS AND METHODS: Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor effects in patients with solid tumors or lymphomas. In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B was twice-weekly for 2 weeks every 21 days. RESULTS: Seventy-one patients were enrolled: 41 in arm A (0.16-4.4 mg/kg) and 30 in arm B (0.32-2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg. CONCLUSIONS: ALRN-6924 was well tolerated and demonstrated antitumor activity.


Subject(s)
Antineoplastic Agents , Lymphoma , Neoplasms , Animals , Antineoplastic Agents/adverse effects , Dose-Response Relationship, Drug , Fatigue , Humans , Lymphoma/drug therapy , Lymphoma/genetics , Maximum Tolerated Dose , Mice , Neoplasms/drug therapy , Neoplasms/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/genetics
10.
Curr Oncol ; 28(2): 1537-1543, 2021 04 18.
Article in English | MEDLINE | ID: mdl-33919580

ABSTRACT

Recurrent meningiomas remain a substantial treatment challenge given the lack of effective therapeutic options aside from surgery and radiation therapy, which yield limited results in the retreatment situation. Systemic therapies have little effect, and responses are rare; the search for effective systemic therapeutics remains elusive. In this case report, we provide data regarding significant responses in two radiographically diagnosed intracranial meningiomas in a patient with concurrent thyroid carcinoma treated with cabozantinib, an oral multitarget tyrosine kinase inhibitor with potent activity against MET and VEGF receptor 2. Given the clinical experience supporting the role of VEGF agents as experimental therapeutics in meningioma and the current understanding of the biological pathways underlying meningioma growth, this may represent a new oral therapeutic alternative, warranting prospective evaluation.


Subject(s)
Meningeal Neoplasms , Meningioma , Anilides/therapeutic use , Humans , Meningeal Neoplasms/drug therapy , Meningioma/drug therapy , Neoplasm Recurrence, Local , Pyridines
11.
Laryngoscope Investig Otolaryngol ; 5(6): 1063-1069, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33364395

ABSTRACT

BACKGROUND: Circulating tumors cells (CTCs) are considered an early step towards metastasis and have been linked to poor prognosis in several types of cancer. CTCs in squamous cell carcinoma of the head and neck (SCCHN) have an unclear role. METHODS: In this prospective study, patients with locally advanced or metastatic SCCHN had CTC counts assessed before starting systemic treatment using the CellSearch System. Select cases also had sequential CTC evaluation. Presence of CTCs was correlated with patient characteristics and outcomes. RESULTS: Forty-eight patients enrolled, and 36 had evaluable clinical data and baseline CTC counts. Twenty-five patients had locally advanced disease (LAD) and 11 had metastatic disease. ≥1 CTCs were detected in six patients with LAD (24%) and four with metastatic disease (36%). On univariate analysis, smoking was associated with CTCs. CONCLUSION: CTCs are not associated with prognosis in patients with LAD and metastatic disease; however, they are present in this patient population, and ≥1 CTCs is associated with a history of smoking. LEVEL OF EVIDENCE: 1b; individual prospective cohort study.

12.
Front Med (Lausanne) ; 7: 198, 2020.
Article in English | MEDLINE | ID: mdl-32582722

ABSTRACT

Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer. Prior to the advent of immunotherapy, treatment options were limited. In our study, we evaluate the impact of tumor cell PD-L1 expression and tumor immune microenvironment on survival in MCC patients who were not treated with immune checkpoint inhibitors. Methods: Clinical data and tissue samples were collected from 78 patients with confirmed MCC treated at Dana-Farber Cancer Institute. Specimens were analyzed for the distribution of PD-L1 by immunohistochemistry staining (IHC) and standardized analysis. Results were correlated with survival data. Results: In this study, membrane and cytoplasmic MCC tumor cell staining for PD-L1 was detected in 22.4% (15 of 67) of cases and PD-L1 staining of intratumoral microvessels and PD-L1 positive immune cells at the infiltrative margins of the tumor in 92.5% (62 of 67) of cases. In patients untreated with immune checkpoint inhibitors, median overall survival was not different for patients based on PD-L1 expression (PD-L1+ 64 months vs. PD-L1- not reached; HR = 1.26, 95% CI: 0.46-3.45; p = 0.60). Conclusion: PD-L1 expression is frequently detected in MCC tumor cells and tumor microenvironment. PD-L1 expression did not affect prognosis in this cohort that had not received PD-1/L1 blockade.

13.
Genome Med ; 12(1): 30, 2020 03 18.
Article in English | MEDLINE | ID: mdl-32188490

ABSTRACT

BACKGROUND: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin caused by either the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet-induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. However, it has been challenging to reliably distinguish between virus positive and UV damaged MCC. METHODS: In this study, we assembled a cohort of 71 MCC patients and performed deep sequencing with OncoPanel, a clinically implemented, next-generation sequencing assay targeting over 400 cancer-associated genes. To improve the accuracy and sensitivity for virus detection compared to traditional PCR and IHC methods, we developed a hybrid capture baitset against the entire MCPyV genome and software to detect integration sites and structure. RESULTS: Sequencing from this approach revealed distinct integration junctions in the tumor genome and generated assemblies that strongly support a model of microhomology-initiated hybrid, virus-host, circular DNA intermediate that promotes focal amplification of host and viral DNA. Using the clear delineation between virus-positive and virus-negative tumors from this method, we identified recurrent somatic alterations common across MCC and alterations specific to each class of tumor, associated with differences in overall survival. Finally, comparing the molecular and clinical data from these patients revealed a surprising association of immunosuppression with virus-negative MCC and significantly shortened overall survival. CONCLUSIONS: These results demonstrate the value of high-confidence virus detection for identifying molecular mechanisms of UV and viral oncogenesis in MCC. Furthermore, integrating these data with clinical data revealed features that could impact patient outcome and improve our understanding of MCC risk factors.


Subject(s)
Carcinoma, Merkel Cell/genetics , Mutation , Polyomavirus Infections/genetics , Skin Neoplasms/genetics , Tumor Virus Infections/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Merkel Cell/pathology , Carcinoma, Merkel Cell/virology , Child , DNA, Neoplasm/genetics , DNA, Viral/genetics , Female , Genetic Testing/methods , Humans , Male , Middle Aged , Polyomavirus/genetics , Polyomavirus/pathogenicity , Polyomavirus Infections/pathology , Polyomavirus Infections/virology , Skin Neoplasms/pathology , Skin Neoplasms/virology , Survival Analysis , Tumor Virus Infections/pathology , Tumor Virus Infections/virology
14.
Future Oncol ; 16(4): 11-19, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31951149

ABSTRACT

In 2018, cemiplimab-rwlc became the first systemic treatment approved by the US FDA for patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. In 2019, conditional approvals were granted by Health Canada and the European Commission for the same indications. Limited data exist pertaining to the clinical characteristics, disease progression and survivorship of patients with advanced CSCC in real-world clinical practice. CemiplimAb-rwlc Survivorship and Epidemiology (CASE) is a prospective Phase IV, noninterventional, survivorship and epidemiology study that will enroll patients with advanced CSCC who have recently initiated or who plan to receive cemiplimab in a real-world setting. Trial registration number: NCT03836105.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/epidemiology , Clinical Protocols , Skin Neoplasms/drug therapy , Skin Neoplasms/epidemiology , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/mortality , Female , Humans , Male , Molecular Targeted Therapy , Neoplasm Metastasis , Neoplasm Staging , Prognosis , Skin Neoplasms/diagnosis , Skin Neoplasms/mortality , Treatment Outcome
15.
Int J Radiat Oncol Biol Phys ; 105(1): 132-139, 2019 09 01.
Article in English | MEDLINE | ID: mdl-31082494

ABSTRACT

PURPOSE: To determine the maximum tolerated dose and tolerability of (1) afatinib in combination with postoperative radiation therapy (PORT) for patients with intermediate-risk squamous cell carcinoma of the head and neck (SCCHN) and (2) afatinib in combination with PORT and weekly docetaxel for high-risk SCCHN. METHODS AND MATERIALS: An open-label, multicenter, 2-cohort, phase 1 dose-escalation trial was conducted using a 3 + 3 design. Eligible patients had definitive surgery for SCCHN, including the oral cavity, oropharynx, larynx, or hypopharynx and had intermediate- or high-risk pathologic features. Afatinib was given for a 1-week lead in before PORT and daily during 6 to 6.5 weeks of PORT with or without weekly docetaxel. The starting dose was 30 mg and could be escalated to 40 mg or de-escalated to 20 mg. The primary objective was to determine the maximum tolerated dose of afatinib with PORT or PORT + docetaxel. RESULTS: Between April 2013 and November 2017, 27 patients were enrolled and started study treatment, including 16 intermediate-risk patients and 11 high-risk patients, all with Eastern Cooperative Oncology Group performance status of 0 to 1. Most patients (n = 25) had oral cavity cancer and were treated to a median total dose of 60 Gy in the intermediate-risk arm and 65 Gy in the high-risk arm. There was 1 grade 4 event, but no deaths. The maximum tolerated dose was not established owing to dose-limiting toxicities (DLTs) in both arms. In the high-risk arm, DLTs were grade 3 mucositis (n = 3) and grade 3 diarrhea/hypokalemia (n = 1). In the intermediate-risk arm, DLTs were grade 3 mucositis (n = 4) and grade 3 diarrhea (n = 2). CONCLUSIONS: Afatinib in combination with PORT for mucosal SCCHN was difficult to tolerate because of grade 3 toxicity, mostly mucositis, in a cohort of patients requiring high-dose PORT to the oral cavity. This regimen may be better tolerated for a non-oral cavity site or if given in a different schedule.


Subject(s)
Afatinib/administration & dosage , Antineoplastic Agents/administration & dosage , Carcinoma, Squamous Cell/therapy , Head and Neck Neoplasms/therapy , Adult , Afatinib/adverse effects , Aged , Antineoplastic Agents/adverse effects , Carcinoma, Squamous Cell/pathology , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , Diarrhea/etiology , Disease-Free Survival , Docetaxel/administration & dosage , Drug Administration Schedule , Female , Head and Neck Neoplasms/pathology , Humans , Hypokalemia/etiology , Male , Maximum Tolerated Dose , Middle Aged , Mouth Neoplasms/therapy , Mucositis/etiology , Postoperative Period , Prospective Studies , Radiotherapy Dosage
16.
Eur J Cancer ; 113: 1-9, 2019 05.
Article in English | MEDLINE | ID: mdl-30954880

ABSTRACT

AIMS: The activity that the immune checkpoint inhibitor (ICI) cemiplimab has recently demonstrated has led to a paradigm shift in the management of patients with advanced cutaneous squamous cell carcinoma (cSCC). To identify predictive biomarkers of response to ICIs in advanced cSCC, we studied 33 patients who received ICI therapy at the Dana-Farber/Harvard Cancer Center (DF/HCC) and analysed sequencing data for a subset of these patients. METHODS: We collected clinical data using electronic health records and genomic data using the institutional OncoPanel platform of the DF/HCC. We compared tumour genomics with data from previously sequenced cSCC cohorts. RESULTS: We observed high tumour mutational burden regardless of smoking status and response to ICI and longer median overall survival among those patients who achieved an ICI response. We compared the genetic data from our cohort with data from other cohorts that included fewer patients with distant metastatic disease. Although our cohort had a similar genetic landscape to those of comparator cohorts, mutations in PIK3C2B were more common in our study. In our cohort, copy number alterations (CNAs) in the 3q chromosomal arm appeared to predict response to ICI therapy. CONCLUSION: CNAs in the 21-27 bands of chromosome arm 3q, a region that includes PIK3CA, ETV5 and BCL6, may represent predictors of response to ICI and may be candidates for drug targeting in combination or sequence with ICI agents.


Subject(s)
Carcinoma, Squamous Cell/genetics , Chromosomes, Human, Pair 3/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , DNA-Binding Proteins/genetics , Proto-Oncogene Proteins c-bcl-6/genetics , Skin Neoplasms/genetics , Squamous Cell Carcinoma of Head and Neck/genetics , Transcription Factors/genetics , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , DNA Copy Number Variations , Female , High-Throughput Nucleotide Sequencing , Humans , Logistic Models , Male , Middle Aged , Mutation , Prognosis , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/pathology
17.
Front Oncol ; 9: 106, 2019.
Article in English | MEDLINE | ID: mdl-30863722

ABSTRACT

Background: Anaplastic thyroid cancer (ATC) is a very aggressive disease and accounts for over 50% of thyroid-cancer related deaths. mTOR inhibition has shown anti-tumor activity in ATC. We report our experience treating patients with ATC with everolimus off-protocol. Methods: Patients with confirmed ATC and treated with everolimus at DFCI were identified and reviewed retrospectively. NexGen sequencing was performed, and radiologic responses were correlated with mutational profile. Results: Five patients were treated from 2013 to 2016. Three patients had a response, which included one patient who achieved a partial response for 27.9 months, and two patients who had stable disease for 3.7 and 5.9 months, respectively. Genomic analysis was available in two patients and revealed that the partial responder had mutations involving the PI3K/mTOR pathway. Conclusion: Everolimus has anti-tumor activity in ATC, and responses may correlate with mutations involving the PI3K/mTOR pathway. Further studies are warranted.

18.
Head Neck ; 41(7): 2111-2115, 2019 07.
Article in English | MEDLINE | ID: mdl-30697925

ABSTRACT

BACKGROUND: Data evaluating outcomes and patterns of recurrence following radiation therapy (RT) for cutaneous squamous cell carcinoma (cSCC) of the head and neck are limited. METHODS: We performed a retrospective analysis of 111 head and neck cSCC patients treated with RT at 4 affiliated institutions. RESULTS: With median follow-up of 7 months, there were 29 (26%) recurrences, 73% of which were nodal (n = 21). Immunosuppression (IS) was the only factor associated with recurrence (47% in IS, 22% in non-IS, P = .04), and also with time to recurrence in multivariate analysis (HR 5.5; P = .03). No factors were associated with recurrence among patients who received definitive RT. The majority of patients who recurred were salvaged with surgery (n = 20, 69%). CONCLUSION: In a cohort of cSCC treated with radiotherapy, there was an association between IS and increased failure risk. The majority of failures were salvaged surgically.


Subject(s)
Carcinoma, Squamous Cell/therapy , Immunocompromised Host , Neoplasm Recurrence, Local , Skin Neoplasms/therapy , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/pathology , Female , Follow-Up Studies , HIV Infections/complications , Hematologic Neoplasms/complications , Humans , Immunologic Factors/adverse effects , Male , Middle Aged , Multivariate Analysis , Radiotherapy Dosage , Radiotherapy, Adjuvant , Retrospective Studies , Skin Neoplasms/pathology , Transplant Recipients
19.
Head Neck ; 41(4): 959-966, 2019 04.
Article in English | MEDLINE | ID: mdl-30620435

ABSTRACT

BACKGROUND: Radiation therapy for squamous cell cancer of the head and neck with unknown primary (head and neck CUP) has been associated with significant levels of swallowing toxicity. We examined the effect of changes in mucosal dose on development of laryngeal strictures and percutaneous endoscopic gastrostomy (PEG) dependence. METHODS: Retrospective analysis of 58 patients with head and neck CUP treated with intensity-modulated radiation therapy (IMRT) at the Dana Farber Cancer Institute from August 2004 through July 2013. RESULTS: There were no significant differences between any recurrences for groups treated to 56 versus ≥60 Gy to the mucosal surfaces. However, mucosal dose and chemotherapy type were associated with stricture on multivariable analysis; median PEG dependence was decreased for patients treated to 56 Gy. A larynx-sparing approach was associated with improved outcomes for strictures and PEG use. CONCLUSION: In this single institution study, a 56 Gy IMRT-based mucosal dose demonstrated significant improvements in swallowing toxicity. Additional benefit was seen with larynx-sparing IMRT.


Subject(s)
Head and Neck Neoplasms/radiotherapy , Neoplasms, Unknown Primary/pathology , Radiation Injuries/prevention & control , Radiotherapy, Intensity-Modulated/methods , Squamous Cell Carcinoma of Head and Neck/radiotherapy , Squamous Cell Carcinoma of Head and Neck/secondary , Adult , Aged , Cancer Care Facilities , Disease-Free Survival , Female , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/secondary , Humans , Induction Chemotherapy , Kaplan-Meier Estimate , Male , Middle Aged , Mucous Membrane/radiation effects , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Proportional Hazards Models , Quality Improvement , Radiotherapy Dosage , Retrospective Studies , Risk Assessment , Squamous Cell Carcinoma of Head and Neck/mortality , Survival Analysis , Treatment Outcome
20.
Int J Radiat Oncol Biol Phys ; 102(1): 137-145, 2018 09 01.
Article in English | MEDLINE | ID: mdl-29960819

ABSTRACT

PURPOSE: Programmed death-1 (PD-1) inhibitors are approved for the treatment of patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN). Ongoing and planned randomized phase 3 trials are testing the benefit of combining PD-1/programmed death-ligand 1 (PD-L1) inhibitors with chemoradiation for patients with locoregionally confined SCCHN. Few studies have investigated relationships among potential predictive pathologic biomarkers such as PD-L1, PD-L2, and PD-1 in this population and associations between these markers and clinical characteristics. METHODS AND MATERIALS: We retrospectively reviewed records and pathology from 81 patients with locoregional oropharynx SCCHN treated with curative intent. Samples were analyzed for PD-L1, PD-L2, PD-1, CD8, and CD56 expression using immunohistochemistry. Human papilloma virus (HPV) status was determined by p16-immunohistochemistry and confirmed by in situ hybridization or polymerase chain reaction-based HPV typing. Correlations between HPV status, clinical features, and recurrence status with immune markers in both tumor and tumor-associated stroma were determined. Hazard ratios were estimated via Cox proportional hazards model. RESULTS: Tumor PD-L1 expression was inversely associated with age (P = .01) and the highest levels of expression (>30% of tumor cells) were observed in HPV-associated tumors. There was a correlation between tumor and stromal PD-L1 expression (P = < .0001). PD-1 and CD8 expression within tumor deposits was associated with HPV status (P = 0.003 and P = .008, respectively) and decreased local recurrence (P = .001 and P < .001, respectively). In addition to the association between tumor and stromal PD-1 (P < .0001), PD-1 was also correlated with tumor PD-L1 expression (P < .001). CD56+ natural killer cell infiltrates correlated with PD-L1 expression. CONCLUSIONS: In patients with untreated oropharyngeal SCCHN, HPV-associated tumors displayed the highest levels of PD-L1 expression and PD-1+ and CD8+ immune cells. Locally recurrent tumors had lower levels of PD-L1, PD-1, and CD-8 positivity. Whereas almost all SCCHN tumors had CD56+ infiltrating natural killer cells, most tumors didn't have PD-L2 expression. These associations may help predict which patients may benefit most from immunotherapeutic approaches.


Subject(s)
Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/metabolism , Oropharyngeal Neoplasms/immunology , Oropharyngeal Neoplasms/metabolism , Programmed Cell Death 1 Receptor/metabolism , Aged , Aged, 80 and over , B7-H1 Antigen/metabolism , CD56 Antigen/metabolism , CD8-Positive T-Lymphocytes/immunology , Female , Gene Expression Regulation, Neoplastic , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male , Middle Aged , Programmed Cell Death 1 Ligand 2 Protein/metabolism , Retrospective Studies
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