Indira Madani

Evidence behind use of intensity-modulated radiotherapy: a systematic review of comparative clinical studies

Since its introduction more than a decade ago, intensity-modulated radiotherapy (IMRT) has spread to most radiotherapy departments worldwide for a wide range of indications. The technique has been rapidly implemented, despite an incomplete understanding of its advantages and weaknesses, the challenges of IMRT planning, delivery, and quality assurance, and the substantially increased cost compared with non-IMRT. Many publications discuss the theoretical advantages of IMRT dose distributions. However, the key question is whether the use of IMRT can be exploited to obtain a clinically relevant advantage over non-modulated external-beam radiation techniques. To investigate which level of evidence supports the routine use of IMRT for various disease sites, we did a review of clinical studies that reported on overall survival, disease-specific survival, quality of life, treatment-induced toxicity, or surrogate endpoints. This review shows evidence of reduced toxicity for various tumour sites by use of IMRT. The findings regarding local control and overall survival are generally inconclusive.

Accuracy of patient dose calculation for lung IMRT: A comparison of Monte Carlo, convolution/superposition, and pencil beam computations

The accuracy of dose computation within the lungs depends strongly on the performance of the calculation algorithm in regions of electronic disequilibrium that arise near tissue inhomogeneities with large density variations. There is a lack of data evaluating the performance of highly developed analytical dose calculation algorithms compared to Monte Carlo computations in a clinical setting. We compared full Monte Carlo calculations (performed by our Monte Carlo dose engine MCDE) with two different commercial convolution/superposition (CS) implementations (Pinnacle-CS and Helax-TMSs collapsed cone model Helax-CC) and one pencil beam algorithm (Helax-TMSs pencil beam model Helax-PB) for 10 intensity modulated radiation therapy (IMRT) lung cancer patients. Treatment plans were created for two photon beam qualities (6 and 18 MV). For each dose calculation algorithm, patient, and beam quality, the following set of clinically relevant dose-volume values was reported: (i) minimal, median, and maximal dose (Dmin, D50, and Dmax) for the gross tumor and planning target volumes (GTV and PTV); (ii) the volume of the lungs (excluding the GTV) receiving at least 20 and 30 Gy (V20 and V30) and the mean lung dose; (iii) the 33rd percentile dose (D33) and Dmax delivered to the heart and the expanded esophagus; and (iv) Dmax for the expanded spinal cord. Statistical analysis was performed by means of one-way analysis of variance for repeated measurements and Tukey pairwise comparison of means. Pinnacle-CS showed an excellent agreement with MCDE within the target structures, whereas the best correspondence for the organs at risk (OARs) was found between Helax-CC and MCDE. Results from Helax-PB were unsatisfying for both targets and OARs. Additionally, individual patient results were analyzed. Within the target structures, deviations above 5% were found in one patient for the comparison of MCDE and Helax-CC, while all differences between MCDE and Pinnacle-CS were below 5%. For both Pinnacle-CS and Helax-CC, deviations from MCDE above 5% were found within the OARs: within the lungs for two (6 MV) and six (18 MV) patients for Pinnacle-CS, and within other OARs for two patients for Helax-CC (for Dmax of the heart and D33 of the expanded esophagus) but only for 6 MV. For one patient, all four algorithms were used to recompute the dose after replacing all computed tomography voxels within the patients skin contour by water. This made all differences above 5% between MCDE and the other dose calculation algorithms disappear. Thus, the observed deviations mainly arose from differences in particle transport modeling within the lungs, and the commissioning of the algorithms was adequately performed (or the commissioning was less important for this type of treatment). In conclusion, not one pair of the dose calculation algorithms we investigated could provide results that were consistent within 5% for all 10 patients for the set of clinically relevant dose-volume indices studied. As the results from both CS algorithms differed significantly, care should be taken when evaluating treatment plans as the choice of dose calculation algorithm may influence clinical results. Full Monte Carlo provides a great benchmarking tool for evaluating the performance of other algorithms for patient dose computations.

Adaptive Dose Painting by Numbers for Head-and-Neck Cancer

PURPOSE To investigate the feasibility of adaptive intensity-modulated radiation therapy (IMRT) using dose painting by numbers (DPBN) for head-and-neck cancer. METHODS AND MATERIALS Each patients treatment used three separate treatment plans: fractions 1-10 used a DPBN ([(18)-F]fluoro-2-deoxy-D-glucose positron emission tomography [(18)F-FDG-PET]) voxel intensity-based IMRT plan based on a pretreatment (18)F-FDG-PET/computed tomography (CT) scan; fractions 11-20 used a DPBN plan based on a (18)F-FDG-PET/CT scan acquired after the eighth fraction; and fractions 21-32 used a conventional (uniform dose) IMRT plan. In a Phase I trial, two dose prescription levels were tested: a median dose of 80.9 Gy to the high-dose clinical target volume (CTV(high_dose)) (dose level I) and a median dose of 85.9 Gy to the gross tumor volume (GTV) (dose level II). Between February 2007 and August 2009, 7 patients at dose level I and 14 patients at dose level II were enrolled. RESULTS All patients finished treatment without a break, and no Grade 4 acute toxicity was observed. Treatment adaptation (i.e., plans based on the second (18)F-FDG-PET/CT scan) reduced the volumes for the GTV (41%, p = 0.01), CTV(high_dose) (18%, p = 0.01), high-dose planning target volume (14%, p = 0.02), and parotids (9-12%, p < 0.05). Because the GTV was much smaller than the CTV(high_dose) and target adaptation, further dose escalation at dose level II resulted in less severe toxicity than that observed at dose level I. CONCLUSION To our knowledge, this represents the first clinical study that combines adaptive treatments with dose painting by numbers. Treatment as described above is feasible.

Maximum tolerated dose in a phase I trial on adaptive dose painting by numbers for head and neck cancer

PURPOSE To determine the maximum tolerated dose (MTD) in a phase I trial on adaptive dose-painting-by-numbers (DPBN) for non-metastatic head and neck cancer. MATERIALS AND METHODS Adaptive intensity-modulated radiotherapy was based on voxel intensity of pre-treatment and per-treatment [(18)F]fluoro-2-deoxy-d-glucose positron emission tomography ((18)F-FDG-PET) scans. Dose was escalated to a median total dose of 80.9 Gy in the high-dose clinical target volume (dose level I) and 85.9 Gy in the gross tumor volume (dose level II). The MTD would be reached, if ≥ 33% of patients developed any grade ≥ 4 toxicity (DLT) up to 3 months follow-up. RESULTS Between February 2007 and August 2009, seven patients at dose level I and 14 at dose level II were treated. All patients completed treatment without interruption. At a median follow-up for surviving patients of 38 (dose level I) and 22 months (dose level II) there was no grade ≥ 4 toxicity during treatment and follow-up but six cases of mucosal ulcers at latency of 4-10 months, of which five (36%) were observed at dose level II. Mucosal ulcers healed spontaneously in four patients. CONCLUSIONS Considering late mucosal ulcers as DLT, the MTD of a median dose of 80.9 Gy has been reached in our trial.

Intensity-Modulated Radiotherapy for Sinonasal Tumors: Ghent University Hospital Update

PURPOSE To report the long-term outcome of intensity-modulated radiotherapy (IMRT) for sinonasal tumors. METHODS AND MATERIALS Between July 1998 and November 2006, 84 patients with sinonasal tumors were treated with IMRT to a median dose of 70 Gy in 35 fractions. Of the 84 patients, 73 had a primary tumor and 11 had local recurrence. The tumor histologic type was adenocarcinoma in 54, squamous cell carcinoma in 17, esthesioneuroblastoma in 9, and adenoid cystic carcinoma in 4. The tumors were located in the ethmoid sinus in 47, maxillary sinus in 19, nasal cavity in 16, and multiple sites in 2. Postoperative IMRT was performed in 75 patients and 9 patients received primary IMRT. RESULTS The median follow-up of living patients was 40 months (range, 8-106). The 5-year local control, overall survival, disease-specific survival, disease-free survival, and freedom from distant metastasis rate was 70.7%, 58.5%, 67%, 59.3%, and 82.2%, respectively. No difference was found in local control and survival between patients with primary or recurrent tumors. On multivariate analysis, invasion of the cribriform plate was significantly associated with lower local control (p = 0.0001) and overall survival (p = 0.0001). Local and distant recurrence was detected in 19 and 10 patients, respectively. Radiation-induced blindness was not observed. One patient developed Grade 3 radiation-induced retinopathy and neovascular glaucoma. Nonocular late radiation-induced toxicity comprised complete lacrimal duct stenosis in 1 patient and brain necrosis in 3 patients. Osteoradionecrosis of the maxilla and brain necrosis were detected in 1 of the 5 reirradiated patients. CONCLUSION IMRT for sinonasal tumors provides low rates of radiation-induced toxicity without blindness with high local control and survival. IMRT could be considered as the treatment of choice.

Does ionizing radiation stimulate cancer invasion and metastasis

Radiotherapy (RT) is a form of local treatment used mainly for malignant tumors. Such tumors originate from mutated stem cells. During their development they do attract a variety of host cells, coined tumor-associated host cells. Malignant tumors are characterized by uncontrolled growth, invasion and metastasis, the latter being the major cause of death of patients, even when their primary tumor is under control. RT inhibits growth. There are, however, clinical data suggesting that, under some circumstances, it may stimulate metastasis. DNA is a target of ionizing radiation (IR), though not the only one. IR produces cascades of growth factors and chemokines; it activates molecules initiating multiple signaling pathways that modulate several cellular functions. We consider cancer as a network of ecosystems, including at least the founder primary tumor, the site of metastasis and the bone marrow. As these ecosystems are in continuous communication, it is not surprising that RT of the primary tumor influences metastasis. Indeed, experiments with cells in culture and with animal tumors have shown that IR stimulates invasion and metastasis and activates pro-invasive and prometastatic cellular activities through upregulation of key molecules. At certain doses and within certain time frames, IR enhances the activities of the tumor-associated host cells that support invasion and metastasis, namely: endothelial cells building new vessels; leucocytes and macrophages causing inflammation; myofibroblasts initiating desmoplasia; osteoblasts and osteoclasts establishing bone metastasis; nerve cells producing efferent growth- and invasion-promoting molecules. Techniques such as spatially fractioned radiotherapy and hadron therapy may have different effects on metastasis. Taking into consideration the dose- and time-dependency of the IR-induced tumor-associated host cell reactions, these techniques, as well as the conventional ones, should be combined with repetitive biological imaging, reevaluation of planning and eventual replanning during the course of the treatment.

Three-phase adaptive dose-painting-by-numbers for head-and-neck cancer: initial results of the phase I clinical trial

PURPOSE To evaluate feasibility of using deformable image co-registration in three-phase adaptive dose-painting-by-numbers (DPBN) for head-and-neck cancer and to report dosimetrical data and preliminary clinical results. MATERIAL AND METHODS Between November 2010 and October 2011, 10 patients with non-metastatic head-and-neck cancer enrolled in this phase I clinical trial where treatment was adapted every ten fractions. Each patient was treated with three DPBN plans based on: a pretreatment 18[F]-FDG-PET scan (phase I: fractions 1-10), a per-treatment 18[F]-FDG-PET/CT scan acquired after 8 fractions (phase II: fractions 11-20) and a per-treatment 18[F]-FDG-PET/CT scan acquired after 18 fractions (phase III: fractions 21-30). A median prescription dose to the dose-painted target was 70.2 Gy (fractions 1-30) and to elective neck was 40 Gy (fractions 1-20). Deformable image co-registration was used for automatic region-of-interest propagation and dose summation of the three treatment plans. RESULTS All patients (all men, median age 68, range 48-74 years) completed treatment without any break or acute G≥4 toxicity. Target volume reductions (mean (range)) between pre-treatment CT and CT on the last day of treatment were 72.3% (57.9-98.4) and 46.3% (11.0-73.1) for GTV and PTV(high_dose), respectively. Acute G3 toxicity was limited to dysphagia in 3/10 patients and mucositis in 2/10 patients; none of the patients lost ≥20% weight. At median follow-up of 13, range 7-22 months, 9 patients did not have evidence of disease. CONCLUSIONS Three-phase adaptive 18[F]-FDG-PET-guided dose painting by numbers using currently available tools is feasible. Irradiation of smaller target volumes might have contributed to mild acute toxicity with no measurable decrease in tumor response.

Intensity-modulated radiotherapy for recurrent and second primary head and neck cancer in previously irradiated territory☆

PURPOSE To evaluate re-irradiation using IMRT for recurrent and second primary head and neck cancer in previously irradiated territory. MATERIALS AND METHODS Between 1997 and 2008, 84 patients with recurrent and second primary head and neck cancer were treated with IMRT to a median dose of 69 Gy. Median time interval between initial radiotherapy and re-irradiation was 49.5 (5.2-298.3) months. Salvage surgery preceded re-irradiation in 19 patients; 17 patients received concurrent chemotherapy. RESULTS Median follow-up of living patients was 19.8 (1.9-76.1) months. Five-year locoregional control and overall survival were 40% and 20%, respectively. Five-year disease-specific survival and disease-free survival were 29% and 15%, respectively. Stage T4 (p=0.015), time interval between initial treatment and re-irradiation (p=0.011) and hypopharyngeal cancer (p=0.013) were independent prognostic factors for worse overall survival in multivariate analysis. Twenty-six and 11 patients developed Grade 3 acute and late toxicity, respectively. No Grade 5 acute toxicity was encountered. There were 2 fatal vascular ruptures during follow-up. CONCLUSIONS High-dose IMRT for recurrent and second primary head and neck cancer in previously irradiated territory leads to approximately 20% long-term survival in a non-selected patient population. Identification of patients who would benefit most of curative IMRT is warranted.

Intensity-modulated radiotherapy for cervical lymph node metastases from unknown primary cancer

PURPOSE To compare the effectiveness of intensity-modulated radiotherapy (IMRT) and conventional (two-dimensional) radiotherapy in the treatment of cervical lymph node metastases from unknown primary cancer (UPC). METHODS AND MATERIALS Between February 2003 and September 2006, 23 patients with UPC of squamous cell carcinoma were treated with IMRT. Extended putative mucosal and bilateral nodal sites were irradiated to a median dose of 66 Gy. In 19 patients, IMRT was performed after lymph node dissection, and in 4 patients primary radiotherapy was given. The conventional radiotherapy group (historical control group) comprised 18 patients treated to a median dose of 66 Gy between August 1994 and October 2003. RESULTS Twenty patients completed treatment. As compared with conventional radiotherapy, the incidence of Grade 3 acute dysphagia was significantly lower in the IMRT group (4.5% vs. 50%, p = 0.003). By 6 months, Grade 3 xerostomia was detected in 11.8% patients in the IMRT group vs. 53.4% in the historical control group (p = 0.03). No Grade 3 dysphagia or skin fibrosis was observed after IMRT but these were noted after conventional radiotherapy (26.7%, p = 0.01) and 26.7%, p = 0.03) respectively). With median follow-up of living patients of 17 months, there was no emergence of primary cancer. One patient had persistent nodal disease and another had nodal relapse at 5 months. Distant metastases were detected in 4 patients. The 2-year overall survival and distant disease-free probability after IMRT did not differ significantly from those for conventional radiotherapy (74.8% vs. 61.1% and 76.3% vs. 68.4%, respectively). CONCLUSIONS Use of IMRT for UPC resulted in lower toxicity than conventional radiotherapy, and was similar in efficacy.

Cancer invasion and metastasis: interacting ecosystems

Malignant tumors invade and metastasize. They consist of cancer cells, evolving through genetic and epigenetic modulation, mixed with tumor-associated host cells, emerging from resident or bone marrow-derived precursors. These cells establish ecosystems to activate cellular programs for local invasion and distant metastasis. Characteristic of such malignancy-related activities is communication inside ecosystems between cells, ligands, receptor protein complexes, and signaling pathways as well as between ecosystems comprising the primary tumor, lymph node and distant metastasis, bone marrow and blood and lymph circulation. Complexity is another characteristic, resulting from: heterogeneity of the cell populations; the numbers of promoter and suppressor genes, their levels of regulation, and the pleiotropic activities of their products; biological redundancy of the molecular mechanisms underpinning invasion-related activities. Clinical attention is paid to putative new targets, namely host cells, individual molecules and their signaling pathways, as well as the effects of current treatment on invasion and metastasis.