Concurrent weekly cisplatin and simultaneous integrated boost intensity-modulated radiotherapy of locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Radiotherapy of locally advanced head and neck cancer represents a major clinical challenge. Any treatment intensification aiming at improved treatment outcomes poten-tially results in a higher toxicity. The search for optimal treatment schedule involving conventional or altered fractionation of radiotherapy and the frequency and dose of concomitant cisplatin or other systemic agents has been spanning over several decades. PURPOSE: To evaluate long-term outcomes and toxicity of accelerated chemoradiotherapy of locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). PATIENTS AND METHODS: Forty patients with stage III and IVA (TNM, 7th Ed.) LA SCCHN were treated with accelerated radiotherapy with a total dose of 67.5 Gy in 6 weeks delivered with simultaneous integrated boost intensity-modulated radiotherapy (SIB IMRT) and concomitant weekly cisplatin 40mg/m2. Five-year outcomes and early and late toxicity were evaluated. RESULTS: With the median follow-up of 47.8 months, a 5-year locoregional control rate (LCR) was 56.5%, distant control rate (DCR) was 87% and 5-year progression-free survival (PFS) and overall survival (OS) were 37 and 45%, respectively. Cisplatin cumulative dose of 200mg/m2 was administered in 83% of patients. Grade 2 late toxicity with dietary change was observed in 21 (53%) patients. Human papillomavirus (HPV) status determined by p16 immunohistochemistry was the only significant factor in 5-year treatment outcomes analysis with LCR 100 vs. 41% (P < 0.01), DCR 100 vs. 78% (P = 0.154), PFS 80 vs. 23% (P = 0.01) and OS 80 vs. 34% (P = 0.03) for HPV positive oropharyngeal cancer (OPC) and other HPV negative LA SCCHN. CONCLUSION: High proportion of patients with LA SCCHN received an adequate cumulative dose of concurrent cisplatin with accelerated radiotherapy with SIB IMRT. This study demonstrated that chemoradiotherapy with weekly cisplatin resulted in favorable local control rate and survival in patients with HPV+ OPC.

Patterns of practice in palliative radiotherapy in Africa - case revisited.

AIMS: To investigate patterns of practice in palliative radiotherapy in Africa. MATERIALS AND METHODS: Fifteen centres in Africa provided detailed information about radiotherapy in both metastatic and locally advanced disease via a questionnaire. Information included general information (institution status, equipment, staff, patient number), radiotherapy and other treatment characteristics in bone metastasis, brain metastasis, metastatic spinal cord compression, lung and liver metastasis, as well as locally advanced tumours. RESULTS: The number of patients annually seen/treated ranged from 285 to 5000. Breast, cervix, head and neck, gastrointestinal and prostate cancer were the top five cancers overall. Eight (53%) institutions were without linear accelerators, four (27%) had a single one, whereas one institution each had two, three and four linear accelerators. The number of cobalt machines ranged from 0 to 2 (median 1). Most centres still prefer to use fractionated radiotherapy regimens over single-fraction regimens in bone metastasis, although most centres are now using single-fraction radiotherapy in retreatments. Radiotherapy in brain metastasis and metastatic spinal cord compression mostly conform to worldwide standards. Lung and liver metastases are rarely irradiated, largely as a consequence of the lack of modern radiotherapy technology. Locally advanced disease in various tumour sites was mostly palliated, in agreement with current evidence-based practices. CONCLUSIONS: African countries still lack adequate staffing and equipment to adequately address their clinical burden, being palliative in most cases. Emphasis should also be made on more rationally using existing capacities by using more of the single-fraction radiotherapy regimens, especially in bone metastasis.

Radiosensitization by gold nanoparticles

Recent years brought increasing use of gold nano particles (GNP) as a model platform for interaction of irradiation and GNPs aiming radiosensitization. Endocytosis seems to be one of the major pathways for cellular uptake of GNPs. Internalization mechanism of GNPs is likely receptor-mediated endocytosis, influenced by GNP size, shape, its coating and surface charging. Many showed that DNA damage can occur as a consequence of metal-enhanced production of low energy electrons, Auger electrons and alike. Kilovoltage radiotherapy (RT) carries significantly higher dose enhancement factor (DEF) that is observed with megavoltage irradiations, the latter usually been at the order of 1.1-1.2. Higher gold concentrations seem to carry higher risk of toxicity, while with lower concentrations the DEF can be reduced. Adding a chemotherapeutic agent could increase level of enhancement. Clinical trials are eagerly awaited with a promise of gaining more knowledge deemed necessary for more successful transition to widespread clinical practice (AU)

Reirradiation plus EGFR inhibition in locally recurrent and unresectable head and neck cancer: final results from a single institution.

PURPOSE: For some patients with recurrent, unresectable, and previously irradiated head and neck squamous cell carcinoma (HNSCC), reirradiation (re-RT) may be a curative option. Chemotherapy with epidermal growth factor receptor (EGFR) inhibition is established as palliative management. This retrospective single-institutional study investigates feasibility, toxicity, and outcome of reirradiation (re-RT) combined with EGFR blockade for these patients. PATIENTS AND METHODS: Between June 2008 and June 2012, 23 patients with inoperable and previously irradiated HNSCC were reirradiated. Concomitant EGFR blockade (cetuximab) was given initially at 400 mg/m2 two days prior to re-RT and weekly (250 mg/m2) thereafter. PET/CT imaging was fused with planning CT in 8 patients. RESULTS: One patient died of anaphylactic shock during the first cetuximab administration; two discontinued treatment on their own request. In all, 20 patients completed re-RT (50.4-66.6 Gy) and received cetuximab as prescribed. Grade 3 acute side effects were documented for dermatitis (35%), dysphagia (30%), acneiform rash (30%), and mucositis (15%). The 1-year overall survival rate was 34.8% Median overall and progression-free survival times were 9 and 4.3 months, respectively. A multivariable analysis using the Cox regression model showed significant positive impact of acneiform rash (hazard ratio [HR] 0.1531, 95% confidence interval [CI] 0.0383-0.6111), while a period from first radiation to re-RT longer than 120 months negatively (HR 0.1633, 95% CI 0.0305-0.8734) influenced patient survival. CONCLUSION: re-RT with concurrent cetuximab was feasible. Compared to platinum-based chemotherapy with fluorouracil and cetuximab, this therapeutic approach did not demonstrate survival benefit. Prolonged intervals from first treatment to re-RT seem to be unfavorable.

Radiotherapy alone versus radiochemotherapy in patients with stage IIIA adenocarcinoma (ADC) of the lung.

PURPOSE: To evaluate the outcome of radiotherapy (RT) versus radiochemotherapy (RT-CHT) in patients with locally advanced (stage III) inoperable adenocarcinoma of the lung. PATIENTS AND METHODS: 146 patients with these characteristics were among 600 patients enrolled into five prospective trials and were treated with either hyperfractionated (Hfx) RT (64.8 and 69.6 Gy using 1.2 Gy bid) alone (n = 33) or with Hfx RT (64.8 and 69.6 Gy using 1.2 Gy bid and 67.6 Gy using 1.3 Gy bid) and concurrent carboplatin-etoposide or paclitaxel-carboplatin (n = 113). RESULTS: The median times and 5-year overall survival (OS), local progression-free survival (LPFS) and the distant metastasis-free survival (DMFS) rates for all 146 patients were 17, 20 and 20 months, respectively, and 15, 26 and 33, respectively. RT-CHT was superior to RT alone in terms of both OS (MST 19 vs. 12 months, respectively, 5-year OS 18 vs. 6 %, respectively; p = 0.003) and LPFS (MTLP 21 vs. 15 months, respectively, 5-year LPFS 28 vs. 0 %; p = 0.06), but not the DMFS (p = 0.43). In all 146 patients, the most frequent acute high-grade toxicity was esophageal, bronchopulmonary and hematological (each 12 %), while the most frequent late high-grade toxicity was bronchopulmonary (4 %) and esophageal (3 %). RT-CHT caused significantly more frequent acute high-grade (>3) esophageal (15 %), and hematological (15 %), while late high-grade toxicity was similar between RT and RT-CHT groups of patients. CONCLUSION: RT-CHT achieved excellent results (MST 19 months, 5-year survival 18 %) in this patient population accompanied with low toxicity, comparing favorably to results of other similar studies.

Radiosensitization by gold nanoparticles.

Recent years brought increasing use of gold nano particles (GNP) as a model platform for interaction of irradiation and GNPs aiming radiosensitization. Endocytosis seems to be one of the major pathways for cellular uptake of GNPs. Internalization mechanism of GNPs is likely receptor-mediated endocytosis, influenced by GNP size, shape, its coating and surface charging. Many showed that DNA damage can occur as a consequence of metal-enhanced production of low energy electrons, Auger electrons and alike. Kilovoltage radiotherapy (RT) carries significantly higher dose enhancement factor (DEF) that is observed with megavoltage irradiations, the latter usually been at the order of 1.1-1.2. Higher gold concentrations seem to carry higher risk of toxicity, while with lower concentrations the DEF can be reduced. Adding a chemotherapeutic agent could increase level of enhancement. Clinical trials are eagerly awaited with a promise of gaining more knowledge deemed necessary for more successful transition to widespread clinical practice.

Relapsing high grade mucoepidermoid carcinoma. Long-lasting complete response following reirradiation and EGFR blockade.

BACKGROUND AND PURPOSE: The treatment strategy for inoperable recurrent mucoepidermoid carcinoma (MEC) is not well established. Here, we present a case of a relapsed high grade MEC of the salivary glands of the hard palate that was successfully treated with a reirradiation (re-RT) and cetuximab, an antibody against epidermal growth factor receptor (EGFR). CASE REPORT: Twelve years after resection and adjuvant radiotherapy for high grade MEC of the salivary glands, a patient presented with inoperable recurrent disease. She received another 59.4 Gy. In addition, 400 mg/m(2) cetuximab was administered in the first week, followed by six additional weekly courses at 250 mg/m(2). RESULTS: Treatment was well tolerated. The patient is doing well and continuous radiological complete response (CR) is documented for 25 months after completion of the combined treatment. CONCLUSION: Combined re-RT and targeted inhibition of EGFR with cetuximab may be a valuable therapeutic strategy in patients with recurrent localized high grade MEC who are not candidates for radical surgery.

Palliative radiation therapy practice for advanced esophageal carcinoma in Africa.

While numerous surveys of pattern of practices of palliative radiotherapy (RT) in advanced esophageal cancers have been published in developed countries, there is no such survey in African countries. During and after a regional training course by the International Atomic Energy Agency (IAEA) in palliative cancer care, a questionnaire was distributed to African RT centers to gather information about infrastructure and human resources available, and the pattern of practice of palliative RT for esophageal cancers. Twenty-four of the 35 centers (60%) completed the questionnaire. Twenty out of 23 (87%) centers treat patients with esophageal cancer presenting with dysphagia using external beam RT (16 centers external beam RT alone and 4 centers also use brachytherapy as a boost). Twelve (60%) centers prescribe RT doses of 30 Gy in 10 fractions and 2 centers 20 Gy in 5 fractions. Eighteen centers (78%) have low dose rate (LDR) brachytherapy, and 9 (39%) centers have high dose rate (HDR) brachytherapy. One center only used HDR brachytherapy alone to a dose of 16 Gy in 2 fractions over 8 days. RT remains a major component of treatment of patients with esophageal cancers in African countries. Still, there is a great variety among centers in both indications for RT and its characteristics for a treatment indication.

Radiochemotherapy for lung cancer in developing countries.

Radiochemotherapy has become a standard approach in locally advanced non-small cell lung cancer and limited disease small cell lung cancer. Most of the data supporting this observation come from the developed world and only extremely rarely have good-quality clinical trials been carried out in developing countries. It is therefore of paramount importance to put the experience of the developed world into the context of the limited resources and other health care problems of developing countries. In this overview, the problems with the implementation of such data are discussed. The necessity of carrying out clinical trials specifically designed to address the needs of developing countries is emphasised. The research on cheaper ways of radiochemotherapy combination should be encouraged. The specific national guidelines for local needs should be created and followed. The availability of radiotherapy equipment is of major importance, as radiotherapy has a pivotal role in non-surgical treatment of lung cancer, especially in the developing world.

The role of external beam radiotherapy in the management of bone metastases.

External beam radiotherapy is effective in the management of bone metastases for both local and more widespread pain. It is effective in spinal canal compression and pathological fracture where it also may have a prophylactic role. Single dose radiotherapy for bone metastases is a highly cost effective palliative treatment.

Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients.

BACKGROUND: Despite several randomised trials comparing radiotherapy alone with concomitant radio-chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC), it is not clear whether the addition of chemotherapy improves survival. PATIENTS AND METHODS: This meta-analysis was based on individual patient data from published and unpublished randomised trials which compared radiotherapy alone with the same radiotherapy combined with concomitant cisplatin- or carboplatin-based chemotherapy. Trials with accrual completed after 2000 were excluded. Trials were sought in electronic databases, clinical trial registries and by additional manual searches. The primary endpoint was overall survival analysed using the log-rank test stratified by trials. RESULTS: There were twelve eligible trials that included a total of 1921 patients. The data from 3 trials were not available. Therefore, the analysis was based on 9 trials including 1764 patients. Median follow-up was 7.2 years. The hazard ratio of death among patients treated with radio-chemotherapy compared to radiotherapy alone was 0.89 (95% confidence interval, 0.81-0.98; P = 0.02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. There was some evidence of heterogeneity among trials and sensitivity analyses did not lead to consistent results. The combination of platin with etoposide seemed more effective than platin alone. CONCLUSIONS: Concomitant platin-based radio-chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.

Sequential and/or concurrent hypofractionated radiotherapy and concurrent chemotherapy in neoadjuvant treatment of advanced adenocarcinoma of the pancreas. Outcome and patterns of failure.

BACKGROUND/AIMS: To investigate treatment outcome and patterns of failure of sequential chemotherapy (CHT) and/or concurrent hypofractionated radiotherapy (RT) and CHT followed by surgery in locally advanced non-metastatic pancreatic adenocarcinoma. METHODOLOGY: Seven patients with locally advanced but marginal resectable tumors (close contact but no signs of infiltration of the mesenteric vessels and/or vena portae) were treated with hypofractionated RT (5x3 Gy per week) and concurrent continuous infusion (300 mg/sqm/24 h, 7 days per week) of 5-fluorouracil (FU). Ten patients with locally advanced disease with radiologically suspected infiltration of the mesenteric vessels and/or v. portae were treated with 2 cycles of Cisplatin (75 mg/sqm) and Gemcitabine (2x1250 mg/sqm), and patients without tumor progression received the same concurrent RT/CHT as group 1. Four weeks after RT/CHT radical pancreatectomy was planned for patients with stable disease or remission. RESULTS: Toxicity was low in both groups, with no CTC grade 4 toxicity. In group 1, RT/CHT was completed in all patients. There was no radiological remission, but stable disease in 5 out of 7 patients. All 5 patients underwent resection of the primary tumor with a R0-resection in 3 patients. In group 2, 8 patients completed CHT and RT/CHT treatment as planned. There were 3 with partial remission. Operation was done in 4 patients, but only one R0 resection was achieved. The median survival time for all 17 patients is 13 months, with 1- and 2-year survival being 53% and 18%, respectively. Local progression was observed in 9, peritoneal seeding in 7 and distant metastasis (mostly liver and lung) in 8 patients. CONCLUSIONS: The neoadjuvant therapy could be administered with low toxicity. Results of this study warrant further investigation aiming at optimal tailoring in of this treatment approach in these two subgroups of patients.

Stereotactic fractionated irradiation of optic nerve sheath meningioma: a new treatment alternative.

BACKGROUND: Primary optic nerve sheath meningioma (ONSM) is a rare but almost invariably blinding tumour when its natural history is observed in a "wait and see" strategy. Surgery has hitherto only been advocated in case of progressive disease involving intracranial structures, as it leads to iatrogenic blindness in the overwhelming majority of cases. Therefore, treatment options bearing lesser risk of functional deterioration are highly desirable, both in cases of intracranial involvement as well as during earlier phases of the disease which are currently generally left untreated. The authors report the outcome of the largest series of patients to date treated by stereotactic fractionated irradiation as a new treatment approach in ONSM at all stages. METHODS: 15 patients (16 nerves) underwent stereotactic fractionated conformal irradiation with a total dose of 54 Gy, using standard fractionation. Main outcome parameters included visual acuity and visual field, as well as three dimensional remission as documented by imaging. RESULTS: Tumour control was confirmed in all 15 patients undergoing stereotactic fractionated conformal irradiation (mean follow up 37 (range 12-71) months). No patient developed functional deterioration during or after treatment. Moreover, visual acuity improved by more than two lines in one patient and the visual field improved in six cases. Visual outcome in the other patients remained unchanged. There were no significant side effects of radiation therapy. CONCLUSION: These data provide convincing evidence that stereotactic fractionated conformal irradiation is an effective treatment option for primary ONSM with minimal treatment related morbidity. It should therefore be considered as therapeutic option both in early stage ONSM where surgery cannot be justified as well as in later stages, where surgery is so far considered the first line approach.

Single fraction external beam radiation therapy in the treatment of localized metastatic bone pain. A review.

Bone metastases are a frequent complication of cancer, and frequently cause pain. Indications for radiotherapy for bone metastases include pain, risk for pathologic fracture, and neurological complications arising from spinal cord compression, nerve root pain or cranial nerve involvement. There are numerous fractionation patterns of external beam radiation therapy for painful bone metastasis, both fractionated schedules and single fraction regimens. All prospective randomized trials that evaluated differences in the outcomes associated with various fractionated regimens versus single fraction regimens unequivocally showed that single fraction regimens (mostly 8 Gy) are at least equal with various fractionated regimens. The single fraction regimens have an additional advantage of being more convenient to both patients and hospitals. However, there are still numerous questions that are left unanswered in these trials, such as the "optimal" single fraction that should be used, the possibility for retreatment, and prognostic factors that may help identify those patients more likely to respond to a single fraction radiation therapy in the treatment of painful bone metastasis.

Absence of cervical radiation myelitis after hyperfractionated radiation therapy with and without concurrent chemotherapy for locally advanced, unresectable, nonmetastatic squamous cell carcinoma of the head and neck.

PURPOSE: To evaluate the risk of developing radiation myelitis after a cervical spinal cord dose of 50.6 Gy given via 1.1 Gy b.i.d. fractionation during a prospective, randomised trial of hyperfractionated radiation therapy (HFX RT) to a total dose of 77 Gy given in 70 fractions of 1.1 Gy b.i.d., with and without concurrent low-dose, daily cisplatin (CDDP) for head and neck cancer. METHODS: Of 130 patients with locally advanced, unresectable, nonmetastatic squamous cell carcinoma of the head and neck (SCC H&N) who entered a prospective, randomised trial, 101 patients received 50.6 Gy to a portion of their spinal cord and survived > 1 year following the beginning of therapy. Forty-five patients were treated with HFX RT alone and fifty-six patients also received CDDP. RESULTS: None of these 101 patients developed cervical radiation myelitis. Therefore, it was not possible to investigate the influence of potentially contributing factors on the occurrence of radiation myelitis, such as interfraction interval, cord length, and administration of concurrent CDDP. CONCLUSIONS: Given the increasing number of studies with both altered fractionated regimens and concurrent radio-chemotherapy in SCC H&N, new studies with more patients are needed to gain better insight into the risks of developing cervical radiation myelitis.

Concurrent accelerated hyperfractionated radiation therapy and carboplatin/etoposide in patients with malignant glioma: long-term results of a phase II study.

PURPOSE: Feasibility, antitumor activity and toxicity of accelerated hyperfractionated radiation therapy (Acc Hfx RT) and concurrent carboplatin/etoposide (CBDCA/VP 16) chemotherapy were investigated in patients with malignant glioma. MATERIAL AND METHODS: Seventy-nine patients with either glioblastoma multiforme (GBM) (n = 61) or anaplastic astrocytome (AA) (n = 18) entered into a phase II study on the use of Acc Hfx RT with 60 Gy in 40 fractions in 20 treatment days over 4 weeks and concurrent CBDCA, 200 mg/m2, and VP 16, 200 mg/m2, both given once weekly during the RT course. RESULTS: The median survival time for all 79 patients was 14 months (11 and 44 months for GBM and AA patients, respectively), while the 2- and 4-year survival was respectively 33% and 11% for all patients, 13% and 1.6% for GBM patients, and 100% and 44% for AA patients (p < 0.0001). The median time to progression for all patients was 12 months (9 and 40 months for GBM and AA, respectively), while the 2- and 4-year progression-free survival (PFS) was respectively 28% and 10% (all patients), 10% and 1.7% (GBM) and 89% and 39% (AA) (p < 0.0001). Multivariate analysis showed that age, performance status, and preoperative size of tumor influenced survival in GBM. Only 5 (6%) patients experienced grade 3 leukopenia and 6 (8%) patients experienced grade 3 thrombocytopenia. No late RT-induced toxicity was observed to date. CONCLUSIONS: Although Acc Hfx RT/CBDCA + VP 16 was feasible and little toxic, it failed to improve survival/progression-free survival over that obtained with other currently used regimens. These results do not justify the investigation of this regimen in a phase III trial.