Immunotherapy and Modern Radiotherapy Technique for Older Patients with Locally Advanced Head and Neck Cancer: A Proposed Paradigm by the International Geriatric Radiotherapy Group.

The standard of care for locally advanced head and neck cancer is concurrent chemoradiation or postoperative irradiation with or without chemotherapy. Surgery may not be an option for older patients (70 years old or above) due to multiple co-morbidities and frailty. Additionally, the standard chemotherapy of cisplatin may not be ideal for those patients due to oto- and nephrotoxicity. Though carboplatin is a reasonable alternative for cisplatin in patients with a pre-existing hearing deficit or renal dysfunction, its efficacy may be inferior to cisplatin for head and neck cancer. In addition, concurrent chemoradiation is frequently associated with grade 3-4 mucositis and hematologic toxicity leading to poor tolerance among older cancer patients. Thus, a new algorithm needs to be developed to provide optimal local control while minimizing toxicity for this vulnerable group of patients. Recently, immunotherapy with check point inhibitors (CPI) has attracted much attention due to the high prevalence of program death-ligand 1 (PD-L1) in head and neck cancer. In patients with recurrent or metastatic head and neck cancer refractory to cisplatin-based chemotherapy, CPI has proven to be superior to conventional chemotherapy for salvage. Those with a high PD-L1 expression defined as 50% or above or a high tumor proportion score (TPS) may have an excellent response to CPI. This selected group of patients may be candidates for CPI combined with modern radiotherapy techniques, such as intensity-modulated image-guided radiotherapy (IM-IGRT), volumetric arc therapy (VMAT) or proton therapy if available, which allow for the sparing of critical structures, such as the salivary glands, oral cavity, cochlea, larynx and pharyngeal muscles, to improve the patients' quality of life. In addition, normal organs that are frequently sensitive to immunotherapy, such as the thyroid and lungs, are spared with modern radiotherapy techniques. In fit or carefully selected frail patients, a hypofractionated schedule may be considered to reduce the need for daily transportation. We propose a protocol combining CPI and modern radiotherapy techniques for older patients with locally advanced head and neck cancer who are not eligible for cisplatin-based chemotherapy and have a high TPS. Prospective studies should be performed to verify this hypothesis.

Stereotactic Body Radiotherapy and Immunotherapy for Older Patients with Oligometastases: A Proposed Paradigm by the International Geriatric Radiotherapy Group.

The standard of care for metastatic disease is systemic therapy. A unique subset of patients with limited metastatic disease defined as distant involvement of five anatomic sites or less (oligometastases) have a better chance of remission or improved survival and may benefit from local treatments such as surgery or stereotactic body radiotherapy (SBRT). However, to prevent further spread of disease, systemic treatment such as chemotherapy, targeted therapy, and hormonal therapy may be required. Older patients (70 years old or above) or physiologically frail younger patients with multiple co-morbidities may not be able to tolerate the conventional chemotherapy due to its toxicity. In addition, those with a good performance status may not receive optimal chemotherapy due to concern about toxicity. Recently, immunotherapy with checkpoint inhibitors (CPI) has become a promising approach only in the management of program death ligand 1 (PD-L1)-positive tumors. Thus, a treatment method that elicits induction of PD-L1 production by tumor cells may allow all patients with oligometastases to benefit from immunotherapy. In vitro studies have demonstrated that high dose of radiotherapy may induce formation of PD-L1 in various tumors as a defense mechanism against inflammatory T cells. Clinical studies also corroborated those observations. Thus, SBRT, with its high precision to minimize damage to normal organs, may be a potential treatment of choice for older patients with oligometastases due to its synergy with immunotherapy. We propose a protocol combining SBRT to achieve a minimum radiobiologic equivalent dose around 59.5 Gy to all tumor sites if feasible, followed four to six weeks later by CPI for those cancer patients with oligometastases. All patients will be screened with frailty screening questionnaires to identify individuals at high risk for toxicity. The patients will be managed with an interdisciplinary team which includes oncologists, geriatricians, nurses, nutritionists, patient navigators, and social workers to manage all aspects of geriatric patient care. The use of telemedicine by the team may facilitate patient monitoring during treatment and follow-up. Preliminary data on toxicity, local control, survival, and progression-free survival may be obtained and serve as a template for future prospective studies.

Head-and-neck cancer patients beyond 2 years of disease control: Preliminary analysis of intensity-modulated radiotherapy late-effect assessment scale.

Over a decade of intensity-modulated radiotherapy (IMRT) improved the toxicity profile among head-and-neck cancer patients and also improved the quality of life (QOL). Several parameters' few subjective and few objectives have documented various aspects related to QOL. Patients surviving beyond a certain period will have few unattended concern. A single questionnaire-based evaluation might answer few untouched issues. This brief communication formulated such an indigenous single-institution scale named IMRT late-effect assessment scale (ILEA). The preliminary analysis identified concerns related to dryness of mouth, swallowing habit change, and fear of disease recurrence. Future large-scale prospective evaluation is needed.

Use of ultrasound in image-guided high-dose-rate brachytherapy: enumerations and arguments.

Inherently, brachytherapy is the most conformal radiotherapeutic technique. As an aid to brachytherapy, ultrasonography (USG) serves as a portable, inexpensive, and simple to use method allowing for accurate, reproducible, and adaptive treatments. Some newer brachytherapy planning systems have incorporated USG as the sole imaging modality. Ultrasonography has been successfully used to place applicator and dose planning for prostate, cervix, and anal canal cancers. It can guide placement of brachytherapy catheters for all other sites like breast, skin, and head and neck cancers. Traditional USG has a few limitations, but recent advances such as 3-dimensional (3D) USG and contrast USG have enhanced its potential as a dependable guide in high-dose-rate image-guided brachytherapy (HDR-IGBT). The authors in this review have attempted to enumerate various aspects of USG in brachytherapy, highlighting its use across various sites.

Modulated Radiotherapy with Concurrent and Adjuvant Temozolomide for Anaplastic Gliomas: Indian Single-center Data.

OBJECTIVE: To evaluate early clinical outcome for anaplastic gliomas (AG) treated in the era of modulated radiotherapy (RT) and concurrent plus adjuvant temozolomide (TMZ) in an Indian setting. MATERIALS AND METHODS: Fifty-three patients with AGs treated with modulated RT and concurrent (95%) and adjuvant TMZ (90%) were analyzed. About 80% of patients had Karnofsky performance status (KPS) at least 90 with 30% seizure at presentation. Postoperative magnetic resonance imaging was available in 65% cases and RT dose was 60 Gy in 30 fractions. First posttreatment imaging was performed at 1 month and then at 3 and 6 months post-RT and then every 3 months. Kaplan-Meier analysis was used to estimate disease-free survival (DFS) and overall survival (OS), and analysis was done using SPSS version 18.0. RESULTS: With median follow-up of 25 months, 2-year DFS and OS were 75% and 88%. There were only 5% symptomatic central nerves system and 8% symptomatic hematological toxicities. At the 1st evaluation, 30.4% had complete response (CR), at 3 months 40%, and at 6 months 43%. At 6 months, only 4% had progressive disease. Forty-six patients were evaluable till the last follow-up with and 55% had stable to CR. On univariate analysis for DFS, KPS at presentation >90 (P = 0.001) and response at 6 months (P = 0.02) were significant and for OS KPS at presentation (P = 0.004) alone. CONCLUSION: Modulated RT with TMZ among Grade III glioma patients resulted in minimum treatment-related toxicities and encouraging survival. Molecular prognostic markers will determine most favorable groups in future.

Simple diagrammatic method to delineate male urethra in prostate cancer radiotherapy: an MRI based approach.

Stereotactic body radiotherapy (SBRT) is being increasingly utilized in the treatment of prostate cancer. With the advent of high-precision radiosurgery systems, it is possible to obtain dose distributions akin to high-dose rate brachytherapy with SBRT. However, urethral toxicity has a significant impact on the quality of life in patients with prostate cancer. Contouring the male urethra on a CT scan is difficult in the absence of an indwelling catheter. In this pictorial essay, we have used the MRI obtained for radiotherapy planning to aid in the delineation of the male urethra and have attempted to define guidelines for the same.

Quantification of coronary artery motion and internal risk volume from ECG gated radiotherapy planning scans.

BACKGROUND: Radiotherapy for carcinoma of breast and thoracic structures involves inadvertent radiation to heart and coronary arteries (CA). Coronary artery stenosis in high radiation dose segments has been documented. Cardiac and respiratory motion induced displacement of CA and internal risk volume (IRV) margin remains inadequately quantified. MATERIAL AND METHODS: Twenty cases of carcinoma breast, lung and lung metastasis were enrolled in this study. ECG gated intravenous contrast enhanced computed tomography (CECT) scans were performed in inspiratory breath hold (IBH) and expiratory breath hold (EBH). The images were segregated into inspiratory systole (IS), inspiratory diastole (ID), expiratory systole (ES) and expiratory diastole (ED) sets. Left anterior descending (LAD), limited segment of LAD close to chest wall (short LAD), right coronary artery (RCA), Left circumflex artery (LCX) and left ventricle (LV) were delineated in all four sets. Mean displacements in systole versus diastole and inspiration versus expiration were calculated in three co-ordinates [anterio-posterior (Z), left-right (X) and cranio-caudal (Y)]. RESULTS: Mean of displacement (mm) between systole and diastole (IS versus ID; and ES versus ED) in X, Y, Z co-ordinates were: LAD 3.0(±1.6), 2.8(±1.5), 3.6(±2.0); Short-LAD 3.0(±1.1), 0.8(±0.4), 2.4(±0.6); LV 2.4(±1.6), 1.7(±1), 5.0(±1.5); LCX 4.9(±1.6), 2.9(±1.3), 5.1(±1.9); RCA 6.6(±2.2), 3.6(±2.1), 5.9(±2.2). Mean displacement between inspiration and expiration (IS versus ES; and ID versus ED) in X, Y, Z axes were: LAD 3.3(±1.5), 8.0(±3.4), 3.8(±1.8); Short-LAD 2.7(±1), 12.2(±4.4), 3.3(±1.5); LV 2.9(±1.4), 9.8(±3.3), 4.7(±1.9); LCX 2.9(±.8), 9.7(±3.2), 6.2(±2.5); RCA 2.6(±1.3), 7.6(±2.5), 3.8(±1.7). CONCLUSION: Radial (RM), cranio-caudal margin (CC) of 7mm, 4mm in breath-hold radiotherapy whereas RM, CC of 7mm, 13mm respectively in free breath radiotherapy will cover the range of motions of CA, LV and can be recommended as IRV for these structures.

Need of collaborative radiology-radiation oncology workshops in decision making for head and neck cancer (HNC) management in India: Perspectives of the radiation oncologists.

BACKGROUND: In India, head and neck cancer (HNC) has always been a challenge to treatment due to its various disease., treatment., and patient.related factors. Recent developments in the field of both radiology and radiation oncology brings us to a stage where combined collaborative efforts are required for proper management of HNC. The article identifies the potential areas of such need through online survey. MATERIALS AND METHODS: This anonymous online survey with specific questions and their responses from radiation oncology community identifies potential areas of radiology expertise as perceived by a radiation oncologist. The questions were simple Likert-type and the best possible response was sought for. RESULTS: There were 57 email responses and majority (37) agreed upon the extreme importance of such collaborative efforts. The major areas where a radiation oncologist would seek help are target volume delineation and response evaluation posttreatment in HNC, though other areas are also important albeit to a lesser degree. CONCLUSION: There is urgent need of radiology.radiation oncology workshops in managing HNC in the modern era of image.based and image-guided treatment. Future larger hospital.based survey would determine need on a large scale basis at resolving these issues.

Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers.

Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor), RAS (rat sarcoma) oncogene or loss of PTEN (phosphatase and tensin homologue) which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K)/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells), it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies.

Clinical outcomes of adaptive radiotherapy in head and neck cancers.

OBJECTIVE: The present study evaluated the efficacy and toxicity of adaptive radiotherapy (RT) among patients with head and neck cancer. METHODS: 36 patients eligible for radical RT underwent RT planning scans and were planned for 54-Gy dose to both high-risk and low-risk target volumes in Phase I. All patients underwent a second (adaptive) scan during the fifth week of RT. Phase II plans for 16 Gy to high-risk planning target volume were developed on these mid-treatment scans. The primary end point was local response. Disease-free survival (DFS), overall survival (OS) and treatment-related morbidity were secondary end points. RESULTS: Median reductions in gross primary and nodal disease volumes on mid-treatment scans were 34% and 43.2%, respectively. 16 patients experienced grade 3 acute mucositis. No patient had grade 3 or above haematologic toxicity. Four patients developed local recurrences, all within the RT field. Median DFS and OS were 17.5 and 23.5 months, respectively. CONCLUSION: Adaptation to changes in the anatomic and tumour volume or shape may help tilt the balance towards more efficient dose delivery as well as better normal tissue sparing. ADVANCES IN KNOWLEDGE: This study supports the need for adaptive replanning for minimizing normal tissue toxicity without compromising local control and adds to the existing body of literature.

Simple diagrammatic approach to delineate duodenum on a radiotherapy planning CT scan.

In recent years, there has been increasing application of intensity-modulated radiotherapy and stereotactic body radiotherapy for the treatment of abdominal malignancies (stomach, pancreas, liver, spinal metastases). This warrants accurate delineation of organs at risk, especially the duodenum. The tortuous and curvy anatomy of duodenum often indistinguishable from adjoining organs is a practical challenge. Radiation Therapy Oncology Group (RTOG) has already published upper abdominal normal structure contouring guidelines to ease the delineation process. This pictorial essay following the RTOG guideline elaborates the step-by-step identification of the different parts of duodenum in relation to the adjoining important structures.

Analysis of intrafraction motion in CyberKnife-based stereotaxy using mask based immobilization and 6D-skull tracking†.

Purpose: Analysis of intrafraction motion in patients with intracranial targets treated with frameless, mask based stereotactic radiosurgery / radiotherapy using standard couch and 6D-skull tracking on CyberKnife. Materials and methods: Twenty-seven treatment datasets of fifteen patients were analyzed. For each sequential pair of images, the correction to the target position (position "offset") in six-degrees of motion was obtained. These offsets were used to calculate intrafraction shifts, and their statistical distribution. PTV margins were calculated, based on Van Herk formula. Results: The mean ± 1 SD intrafraction translationals were 0.27±0.61mm in left-right, 0.24±0.62mm in antero-posterior and 0.14±0.24mm in supero-inferior direction, and rotations were 0.13±0.21 degrees roll, 0.18±0.25 degrees pitch and 0.28±0.44 degrees yaw. Most intrafraction shifts were ≤ 1mm and 1 degree. Fourteen instances of intrafraction shifts exceeding the robotic correction threshold were noted. Calculated PTV margins were 1mm, 1mm and 0.4mm for for left-right, antero-posterior and supero-inferior directions, respectively. Conclusions: CyberKnife 6D-skull tracking with 1mm PTV margin effectively compensates for intrafraction motion. The occasional large intrafraction movements may assume significance for techniques not employing intrafraction motion management.

Factors influencing response to neoadjuvant chemoradiation and outcomes in rectal cancer patients: tertiary Indian cancer hospital experience.

BACKGROUND: In the treatment of rectal cancers several randomized trials have demonstrated benefits of neoadjuvant chemoradiotherapy (NACRT) in downstaging as well as survival among these patients. We investigated the patient and tumor related variables dictating the outcomes in these patients. METHODS: Biopsy proven treatment naive 182 rectal cancer patients underwent NACRT from June 2006 to December 2010. The entire patients received long course conventionally fractionated external beam radiotherapy with concurrent oral Capecitabine. At 6 weeks from completion of NACRT clinico-radiological assessment was carried out for surgical feasibility. All patients were given postoperative adjuvant chemotherapy either single agent or multi drug regimen depending upon biopsy report. RESULTS: Among 182 patients, 131 (72%) underwent surgery and initial T stage and signet ring cell morphology were major determinant of operability. Among the 131 operated patients at median follow up of 36 months, 94 (72%) are alive and disease free. With a median follow up of 42 months the 5-year disease free survival (DFS) and overall survival (OS) was 60% and 77%. The majority of the failures were distal but with more advanced disease at presentation both local and distal failures were similar. While assessing survival by multivariate analysis patients having positive nodes post-surgery had a significantly poorer DFS (P=0.001), while signet ring cell morphology and pre-treatment carcino-embryonic antigen (CEA) levels strongly influenced OS (P=0.03). CONCLUSIONS: The outcome of our patients were similar to World Literature and signet ring cell morphology, pre-treatment CEA level, and pathological nodal staging all were influential in determining survival. Besides this, the study also highlights the fact that tumours with signet ring cell morphology appearing in younger population with poor survival needs prospective evaluation for more intense CRT regimen and aggressive surgical resections.

Postoperative interstitial brachytherapy in eyelid cancer: long term results and assessment of Cosmesis After Interstitial Brachytherapy scale.

PURPOSE: To analyse feasibility and safety of postoperative interstitial brachytherapy (IBRT) in patients of eyelid cancer treated primarily by surgical excision. MATERIAL AND METHODS: In this series, 8 patients with eyelid cancer were treated using postoperative interstitial brachytherapy. Patients were followed up for local control, cosmetic outcome, and acute and late toxicities. Cosmetic outcome was measured using a 6 point indigenous Cosmesis After Interstitial Brachytherapy (CAIB) scale. RESULTS: The patients were between 23-82 years (median: 71 years). There were 3 females and 5 males, and 3 patients had lesions in upper eyelid. Postoperative high-dose-rate brachytherapy was used in all with 2 catheters implanted in most of them (6 out of 8). Local control was calculated from end of treatment to last follow-up. At last follow-up, all patients remained locally controlled. Two patients had nodal recurrence 6 months after interstitial brachytherapy and were salvaged effectively by external beam radiotherapy. At last follow-up, 7 patients were loco-regionally controlled and one was lost to follow up. All patients had Radiation Therapy Oncology Group (RTOG) grade 1 acute toxicity and 2 had grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version.3 late toxicities. The cosmesis score for the whole group ranged between 0-1 indicating excellent to very good cosmesis. CONCLUSIONS: Postoperative high-dose-rate brachytherapy resulted in excellent disease control and cosmesis without significant acute or late toxicities. It is an effective modality for treatment of eyelid cancers in selected patients. Future prospective studies with the validation of CAIB scale would give us more insight to this effective yet often ignored modality of IBRT.

Chemoradiation in elderly patients with head and neck cancers: a single institution experience.

AIMS: To evaluate the efficacy and toxicity of concurrent chemoradiation in patients with head and neck cancers aged 65 and older. MATERIALS AND METHODS: Thirty-two elderly patients were treated with radical chemoradiation. Twenty-six (81.3%) out of thirty-two patients had stage III-IV disease. Twenty-nine (90.6%) patients received concurrent weekly cisplatin or carboplatin, 3 (9.4%) patients received concurrent cetuximab or nimotuzumab. Total dose of radiotherapy ranged from 66Gy to 70Gy. RESULTS: Twenty-nine patients (90.6%) completed at least 5cycles of concurrent chemotherapy. Twenty-four (77.6%) patients achieved complete response. Fourteen (45.2%) patients experienced grade 3 mucositis. None of our patients developed grade 3 or above hematological toxicity. Loco-regional control and overall survival at 2year were 71.6% and 88.9%, respectively. CONCLUSIONS: Chemoradiation in elderly patients with high precision radiotherapy is a feasible option.

Toxicity with radiotherapy for oral cancers and its management: a practical approach.

Radiotherapy-induced damage in the oral mucosa is the result of the deleterious effects of radiation, not only on the oral mucosa itself but also on the skin, adjacent salivary glands, bone, dentition, and masticatory apparatus. From basic skin care to dental and oral health maintenance, several ointments and lotions, oral and parenteral medications, biological response modifiers, cytoprotective drugs, newer radiation techniques and surgery have been introduced to combat and more importantly to prevent the development of these complications. Radiotherapy-induced oral complications involve complex and dynamic pathobiological processes. This in the immediate- and long-term course lowers the quality of life and predisposes patients to serious clinical disorders. Here, we focus on these oral complications of radiotherapy, highlight preventive and therapeutic developments, and review the current treatment options available for these disorders.