N.P. Joshi

Modern Image-Guided Intensity-Modulated Radiotherapy for Oropharynx Cancer and Severe Late Toxic Effects: Implications for Clinical Trial Design

ImportancenLate toxic effects are common after definitive radiotherapy and chemoradiotherapy for oropharynx cancer and are considered a significant contributor to decreased quality of life for survivors. The incidence of severe late toxic effects may be reduced by modern narrow-margin image-guided intensity-modulated radiotherapy (IG-IMRT), current supportive care improvements, and the changing epidemiology of oropharynx cancer.nnnObjectivenAssess the incidence of severe late toxic effects after modern definitive non-operative treatment for oropharynx cancer.nnnDesign, Setting, and ParticipantsnFor this single-institution retrospective review, 156 patients with stage I-IVB squamous cell carcinoma of the oropharynx treated between April 2009 and February 2015 at a tertiary-referral academic multidisciplinary head and neck practice were recruited.nnnInterventionsnDefinitive narrow-margin IG-IMRT to a dose of 66 Gy (to convert milligray to rad, multiply by 0.1) or higher with or without concurrent cisplatin.nnnMain Outcomes and MeasuresnThe primary outcome was the prospectively collected 2-year cumulative incidence of severe late toxic effects (Common Terminology Criteria for Adverse Events grade 3 or higher) occurring 3 months or more after radiotherapy. Toxic effect end points investigated included esophageal stricture requiring dilation, aspiration pneumonia hospitalization, vocal dysfunction, delayed feeding tube insertions, and osteoradionecrosis. Feeding tube dependence at 1 year was also considered a severe late toxic effect. Secondary outcomes collected include physician-reported grade 2 or higher neck fibrosis and xerostomia. The competing risks of recurrence and death were accounted for using the Gray method.nnnResultsnOne-hundred fifty-six patients (median [range] age, 58 [37-96] years) were identified; 130 patients (83%) were HPV positive. Concurrent cisplatin was delivered in 131 patients (84%) and 5 patients (3%) underwent an adjuvant neck dissection. The median (range) follow-up for survivors was 22 (4-73) months from diagnosis. The projected 2-year locoregional control was 93% (95% CI, 88.4%-97.6%) and overall survival was 88% (95% CI, 82.2%-94.0%). Thirty-eight patients (23%) required a feeding tube during treatment. The cumulative incidence of severe late toxic effects adjusted for competing risks at 2-year posttreatment was 2.3% (95% CI, 0%-5.6%). One patient required free-flap reconstruction for grade 3 osteoradionecrosis at 47 months. At 1 year, 2 patients (1%) experienced grade 2 neck fibrosis and 38 patients (23%) experienced grade 2 xerostomia.nnnConclusions and RelevancenThese results suggest that severe late toxic effects after modern definitive IG-IMRT, with or without cisplatin, for oropharynx cancer is likely uncommon. The importance of late toxic effect reduction in current and future investigational strategies, including clinical trials, should be considered.

Adjuvant Chemoradiation After Surgical Resection in Elderly Patients With High-Risk Squamous Cell Carcinoma of the Head and Neck: A National Cancer Database Analysis

PURPOSEnTo determine the patterns of adjuvant chemoradiotherapy use in elderly patients treated with definitive surgical resection for squamous cell carcinoma of the head and neck with extracapsular extension (ECE) or positive margins and determine whether an association with overall survival (OS) exists with adjuvant concurrent chemoradiotherapy (CRT).nnnMETHODS AND MATERIALSnThe National Cancer Database was queried to identify patients with SCC of the oral cavity, oropharynx, larynx, and hypopharynx who were treated with primary definitive surgery and adjuvant radiation therapy between 2004 and 2012. For elderly patients (aged >70xa0years) with pathology revealing ECE or positive margin, the benefit of concurrent chemotherapy was explored using multivariable Cox proportional hazards modeling.nnnRESULTSnA total of 7349 patients were identified meeting study criteria, of whom 1187 were elderly (aged >70xa0years) with a median follow-up of 30.6xa0months. Of these elderly patients, 445 had ECE or positive margin and represent the study population, of whom 187 (42%) received CRT. Delivery of CRT in this cohort increased over the study period, and intensity modulated radiation therapy was associated with increased use of CRT (odds ratio 2.07; P=.004). Increasing age was associated with reduced use of CRT (odds ratio 0.88; P<.001). Chemoradiotherapy was associated with a significant improvement in OS on multivariable analysis (hazard ratio 0.74; P=.04) and a trend toward significance on inverse propensity score analysis (hazard ratio 0.78; P=.051). Three-year OS was 53.8% in the CRT group, compared with 44.6% in the adjuvant radiation therapy-alone patients.nnnCONCLUSIONSnThe use of adjuvant CRT is increasing among elderly patients with resected squamous cell carcinoma of the head and neck exhibiting ECE or positive margins. Chemoradiotherapy was associated with an improvement in OS on multivariable analysis but not propensity-weighted analysis. Among fit elderly patients with ECE or positive margins after definitive surgical resection, concurrent chemotherapy can be carefully considered.

Adjuvant radiotherapy in high-risk cutaneous squamous cell cancer of the head and neck in immunosuppressed patients

Head and neck cutaneous squamous cell carcinoma (HNCSCC) is a growing problem in the immunosuppressed population, and the behavior of these cancers can be unexpectedly aggressive. The role of adjuvant radiation therapy (RT) in the management of high-risk HNCSCC has been an area of much debate. We present a case of HNCSCC with perineural invasion (PNI) successfully treated with surgery and adjuvant RT to prevent recurrence.

Temporally feathered intensity‐modulated radiation therapy: A planning technique to reduce normal tissue toxicity

Purpose Intensity‐modulated radiation therapy (IMRT) has allowed optimization of three‐dimensional spatial radiation dose distributions permitting target coverage while reducing normal tissue toxicity. However, radiation‐induced normal tissue toxicity is a major contributor to patients’ quality of life and often a dose‐limiting factor in the definitive treatment of cancer with radiation therapy. We propose the next logical step in the evolution of IMRT using canonical radiobiological principles, optimizing the temporal dimension through which radiation therapy is delivered to further reduce radiation‐induced toxicity by increased time for normal tissue recovery. We term this novel treatment planning strategy “temporally feathered radiation therapy” (TFRT). Methods Temporally feathered radiotherapy plans were generated as a composite of five simulated treatment plans each with altered constraints on particular hypothetical organs at risk (OARs) to be delivered sequentially. For each of these TFRT plans, OARs chosen for feathering receive higher doses while the remaining OARs receive lower doses than the standard fractional dose delivered in a conventional fractionated IMRT plan. Each TFRT plan is delivered a specific weekday, which in effect leads to a higher dose once weekly followed by four lower fractional doses to each temporally feathered OAR. We compared normal tissue toxicity between TFRT and conventional fractionated IMRT plans by using a dynamical mathematical model to describe radiation‐induced tissue damage and repair over time. Results Model‐based simulations of TFRT demonstrated potential for reduced normal tissue toxicity compared to conventionally planned IMRT. The sequencing of high and low fractional doses delivered to OARs by TFRT plans suggested increased normal tissue recovery, and hence less overall radiation‐induced toxicity, despite higher total doses delivered to OARs compared to conventional fractionated IMRT plans. The magnitude of toxicity reduction by TFRT planning was found to depend on the corresponding standard fractional dose of IMRT and organ‐specific recovery rate of sublethal radiation‐induced damage. Conclusions TFRT is a novel technique for treatment planning and optimization of therapeutic radiotherapy that considers the nonlinear aspects of normal tissue repair to optimize toxicity profiles. Model‐based simulations of TFRT to carefully conceptualized clinical cases have demonstrated potential for radiation‐induced toxicity reduction in a previously described dynamical model of normal tissue complication probability (NTCP).

A matched comparison of human papillomavirus–induced squamous cancer of unknown primary with early oropharynx cancer

Patients with human papillomavirus (HPV)–induced cancer of unknown primary (CUP) are generally excluded from clinical trials, despite surgical series reporting detection rates of occult oropharynx primaries of >80%. We performed a matched‐pair analysis to compare outcomes between T0N1‐3M0 HPV+ CUP and T1‐2N1‐3M0 HPV+ oropharynx known primary (OPX).

Definitive chemoradiation in locally advanced squamous cell carcinoma of the hypopharynx: Long-term outcomes and toxicity

Background/Aim: Definitive chemoradiation (CRT) is a common approach for locally advanced hypopharyngeal squamous cell carcinoma (SCC) with the goal of organ preservation. Reports on long-term oncologic and functional outcomes have been limited. This study reports on outcomes utilizing this approach at a single institution over 30 years. Materials and Methods: Medical records for patients with stage III-IVB SCC of the hypopharynx were retrospectively reviewed. Patient and disease-related factors were identified and analyzed for impact on overall survival (OS), cancer-specific survival (CSS), disease-free survival, distant failure, and locoregional failure. Results: A total of 54 patients were identified who were treated with definitive CRT to a mean dose of 72 Gy. With a median follow-up period of 49.8 months, 5- and 10-year OS was 62% and 43% respectively. Five and 10-year CSS were 74% and 72% respectively. Ten-year local control was 78%. Of the 37 patients with no treatment failure, 29% experienced a grade 3 or higher late toxicity, with the majority resolving during continued long-term follow-up. Conclusion: This study demonstrates good outcomes with long-term follow-up with acceptable rates of late toxicities. The findings here represent the longest published median follow-up in this population and validate the strategy of organ preservation.

SU-F-T-224: Importance of Timely Review of Daily Cone-Beam CTs: Dosimetric Evaluation of Rejected CBCTs for Head and Neck Patients

PURPOSEnTo dosimetrically evaluate the importance of timely reviewing daily CBCTs for patients with head and neck cancer.nnnMETHODSnAfter each fraction daily cone-beam CT (CBCT) for head and neck patients are reviewed by physicians prior to next treatment. Physician rejected image registrations of CBCT were identified and analyzed for 17 patients. These CBCT images were rigidly fused with planning CT images and the contours from the planning CT were transferred to CBCTs. Because of limited extension in the superior-inferior dimension contours with partial volumes in CBCTs were discarded. The treatment isocenter was placed by applying the clinically recorded shifts to the volume isocenter of the CBCT. Dose was recalculated at the shifted isocenter using a homogeneous dose calculation algorithm. Dosimetrically relevant changes defined as greater than 5% deviation from the clinically accepted plans but with homogeneous dose calculation were evaluated for the high dose (HD), intermediate dose (ID), and low dose (LD) CTVs, spinal cord, larynx, oropharynx, parotids, and submandibular glands.nnnRESULTSnAmong seventeen rejected CBCTS, HD-CTVs, ID-CTVs, and LD-CTVs were completely included in the CBCTs for 17, 1, and 15 patients, respectively. The prescription doses to the HD-CTV, ID-CTV, and LD-CTV were received by < 95% of the CTV volumes in 5/17, 1/1, and 5/15 patients respectively. For the spinal cord, the maximum doses (D0.03cc) were increased > 5% in 13 of 17 patients. For the oropharynx, larynx, parotid, and submandibular glands, the mean dose of these organs at risk was increased > 5% in 7/17, 8/12, 11/16 and 6/16 patients, respectively.nnnCONCLUSIONnTimely review daily CBCTs for head and neck patients under daily CBCT guidance is important, and uncorrected setup errors can translate to dosimetrically relevant dose increases in organsat- risk and dose decreases in the clinical target volumes.

Contemporary management of large-volume arteriovenous malformations: a clinician’s review

Arteriovenous malformations (AVMs) represent a heterogeneous group of lesions, and as such, there exist several treatment options and approaches depending on size, location, grading, and symptoms. Large-volume AVMs represent a particularly challenging subset of AVMs with controversy over the very classification with definitions based on size, volume, and Spetzler-Martin grade. With regards to treatment paradigms, the natural history of these lesions is an important foundation upon which management principles have been built. At this time, management options range from observation with medical management to interventions including radiosurgery, microsurgery, embolization, or a combination of these approaches. In light of the challenges facing clinicians, we performed a literature review of AVMs with a specific focus on the management of large-volume AVMs with respect to outcomes, toxicity, and future treatment options. Based on the review, we have proposed a comprehensive risk-based treatment algorithm for the management of large-volume AVMs.

Measuring impact of survivorship care plans on head and neck cancer patients.

73 Background: At our institution, patients who have completed treatment for a locoregionally confined head and neck cancer are followed in a multidisciplinary head and neck survivorship clinic initiated by the administration of a formal, patient specific survivorship care plan (SCP). We sought to assess the impact of these SCP visits on patient understanding of their disease, its treatment, and potential late effects and follow up plans.nnnMETHODSnAn IRB approved survey was administered by an uninvolved third party, to an unselected sequential series of head and neck cancer survivorship patients at the time of a regularly scheduled follow up visit. The survey focused on the knowledge recalled from the SCP, and whether this changed over time. We analyzed two cohorts of patients, based on whether the SCP had been given to them within the last 18 months or not.nnnRESULTSnPreliminary results from the first 20 patients surveyed are presented. These patients received their SCP 3-27 months before being surveyed. Primary tumor sites included oropharynx (16) and larynx (4) and most patients had been treated with intensity modulated radiation therapy (19) and concurrent cisplatin (11).nnnCONCLUSIONSnAlthough patients recall about receiving a formal SCP appeared to diminish over time, the information provided by this SCP plan and subsequent survivorship visits was retained. Whether this reflected the SCP itself, or the reinforcement of continued close follow up survivorship visits cannot be determined, but merits further investigation. [Table: see text].

Triple-negative breast cancer: A single-institution retrospective analysis.

e11543 Background: Triple negative breast cancer (TNBC) is a distinct entity associated with adverse outcomes. We explore our institutional results.nnnMETHODSnWe retrospectively analysed our database between 2000 & 2010. The estrogen receptor (ER) & progesterone receptor (PR) status was negative by immunohistochemistry (IHC) while Her2 status was negative by IHC or confirmed negative by fluorescent in-situ hybridisation for equivocal cases. Adjuvant radiation was 50 Gy in 25 fractions after modified radical mastectomy (MRM) or 66 Gy equivalent after wide local excision (WLE). Adjuvant chemotherapy was anthracycline or taxane-anthracycline based. Treatment at relapse consisted of chemotherapy, surgery & radiation as required. Palliative chemotherapy included single agent or combination chemotherapy with paclitaxel, carboplatin, gemcitabine, ixabepilone & capecitabine. Survival outcomes (overall [OS] & disease free survival [DFS]) were calculated using the Kaplan Meier method. These were correlated with age, menopausal status, clinical & pathological T & N stage (T1 & T2 vs. T3 &T4 or N0 vs. Node positive disease) lymphovascular space invasion, extracapsular spread & type of chemotherapy. Log-rank test was used to compare survival distribution. The data was analysed using SPSS 16.nnnRESULTSnOne ninety six patients were analysed. TNBCs formed 22% of all breast cancer cases noted. Median follow up was 19.4 months (range: 1-135) Median age at presentation was 45 years (range: 27-58 years). The 5 year OS was 73% & 5 year DFS was 60%. Earlier clinical T & N stage (p=0.054 & p=0.095) & taxane chemotherapy (p=0.06) showed a trend for better coverall survival. Earlier pathological T stage (p=0.004) & taxane chemotherapy (p=0.006) had significantly better DFS while there was a trend for earlier pathological N stage (p=0.076). Other variables did not correlate significantly with survival data.nnnCONCLUSIONSnClinical and pathological stage remain important predictors of survival for this disease defined on the basis of ER, PR & Her2 status. Taxanes seem to offer better disease free as well as overall survival.