Objectives To report on our institutional experience of palliative radiotherapy (RT) of cancers in the head and neck by the RTOG 8502 ‘QUAD SHOT’ regimen. Methods Seventy-five patients completed at least 1 cycle of palliative RT to the head and neck for primary or metastatic disease based on the RTOG 8502 regimen (3.7 Gy twice daily over 2 consecutive days at 4 week intervals per cycle) between 2/2005 and 7/2014. Results Median patient age was 76 years (range 23 to 97). The most common histologies were squamous cell carcinoma (55%), non-anaplastic thyroid carcinoma (10%) and salivary gland carcinoma (9%). Thirty patients (40%) received prior RT at the palliative site. Twenty-eight patients (37%) completed at least three RTOG 8502 cycles. Sixty-five percent of all patients had a palliative response. Median overall survival was 5.67 months (range, 0.20 - 34.5). Grade 3 toxicity in 4 patients (5%) consisted of acute dermatitis and functional mucositis. Palliative response was significantly correlated with increasing number of RTOG 8502 cycles (p=0.012), but not KPS, prior RT, palliative chemotherapy, prior surgery, histology or stage. On survival analysis, palliative response (p<0.001), KPS ≥70 (p=0.001), and greater number of RTOG 8502 cycles (p=0.022) remained independent predictors of improved survival. Conclusions For patients with incurable malignant disease in the head and neck, the palliative RTOG 8502 ‘QUAD SHOT’ regimen provides excellent rates of palliative response with minimal associated toxicity. Patients who are able to complete greater number of RT cycles have higher rates of palliative response and overall survival.

In the era of cancer immunotherapy, there is significant interest in combining conventional cancer therapies, such as radiotherapy, with drugs that stimulate the immune system. The observation that ionizing radiation applied to murine tumors delays the growth of distant tumors (“abscopal effect”) and that this effect is potentiated by immunostimulatory drugs, led to clinical trials in which often only one lesion is irradiated in combination with immunotherapy drugs. The results of these initial clinical trials combining radio therapy and immunotherapy show that a meaningful abscopal effect is still infrequent. Recent preclinical data suggest that preexistent intratumoral T cells can survive radiation and contribute to its therapeutic effect. In this review, we discuss possible mechanisms underlying the preclinical/clinical discrepancies regarding the abscopal effect, and we propose the irradiation of multiple or all tumor sites in combination with systemic immunotherapy as a possible avenue to increase the efficacy of radio-immunotherapy.

Earlier and more accurate detection of oral squamous cell carcinoma (OSCC) is essential to improve the prognosis of patients and to reduce the morbidity of surgical therapy. Here, we demonstrate that the nuclear enzyme Poly(ADP-ribose)Polymerase 1 (PARP1) is a promising target for optical imaging of OSCC with the fluorescent dye PARPi-FL. In patient-derived OSCC specimens, PARP1 expression was increased 7.8 ± 2.6-fold when compared to normal tissue. Intravenous injection of PARPi-FL allowed for high contrast in vivo imaging of human OSCC models in mice with a surgical fluorescence stereoscope and high-resolution imaging systems. The emitted signal was specific for PARP1 expression and, most importantly, PARPi-FL can be used as a topical imaging agent, spatially resolving the orthotopic tongue tumors in vivo. Collectively, our results suggest that PARP1 imaging with PARPi-FL can enhance the detection of oral cancer, serve as a screening tool and help to guide surgical resections.

Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02–2.63, p = 0.041) and OS (MVA-HR 2.08, 95% CI 1.21–3.49, p = 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months; p = 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months; p = 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%; p = 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.

Nanomaterials have been shown to have physical and chemical properties that have opened new avenues for cancer diagnosis and therapy. Nanoconstructs that enhance existing treatments for cancer, such as radiation therapy, are being explored in several different ways. Two general paths toward nanomaterial-enabled radiosensitization have been explored: (1) improving the effectiveness of ionizing radiation and (2) modulating cellular pathways leading to a disturbance of cellular homeostasis, thus rendering the cells more susceptible to radiation-induced damage. A variety of different agents that work via one of these two approaches have been explored, many of which modulate direct and indirect DNA damage (gold), radiosensitivity through hyperthermia (Fe), and different cellular pathways. There have been many in vitro successes with the use of nanomaterials for radiosensitization, but in vivo testing has been less efficacious, predominantly because of difficulty in targeting the nanoparticles. As improved methods for tumor targeting become available, it is anticipated that nanomaterials can become clinically useful radiosensitizers for radiation therapy.