C.C. Ling

High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer

PURPOSE We present the long-term outcome and tolerance of 3-dimensional (D) conformal and intensity modulated radiation therapy for localized prostate cancer. MATERIALS AND METHODS Between October 1988 and December 1998, 1,100 patients with clinical stages T1c-T3 prostate cancer were treated with 3-D conformal or intensity modulated radiation therapy. Patients were categorized into prognostic risk groups based on pretreatment prostate specific antigen (PSA), Gleason score and clinical stage. Sextant biopsies were performed 2.5 years or greater after treatment to assess local control. PSA relapse was defined according to the consensus guidelines of the American Society for Therapeutic Radiation Oncology. Late toxicity was classified according to the Radiation Therapy Oncology Group morbidity grading scale. Median followup was 60 months. RESULTS At 5 years the PSA relapse-free survival rate in patients at favorable, intermediate and unfavorable risk was 85% (95% confidence interval [CI] +/- 4), 58% (95% CI +/- 6) and 38% (95% CI +/- 6), respectively (p <0.001). Radiation dose was the most powerful variable impacting PSA relapse-free survival in each prognostic risk group. The 5-year actuarial PSA relapse-free survival rate for patients at favorable risk who received 64.8 to 70.2 Gy. was 77% (95% CI +/- 8) compared to 90% (95% CI +/- 8) for those treated with 75.6 to 86.4 Gy. (p = 0.04) [corrected]. The corresponding rates were 50% (95% CI +/- 8) versus 70% (95% CI +/- 6) in intermediate risk cases (p = 0.001), and 21% (95% CI +/- 8) versus 47% (95% CI +/- 6) in unfavorable risk cases (p = 0.008) [corrected]. Only 4 of 41 patients (10%) who received 81 Gy. had a positive biopsy 2.5 years or greater after treatment compared with 27 of 119 (23%) after 75.6, 23 of 68 (34%) after 70.2 and 13 of 24 (54%) after 64.8 Gy. The incidence of toxicity after 3-D conformal radiation therapy was dose dependent. The 5-year actuarial rate of grade 2 rectal toxicity in patients who received 75.6 Gy. or greater was 14% (95% CI +/- 2) compared with 5% (95% CI +/- 2) in those treated at lower dose levels (p <0.001). Treatment with intensity modulated radiation therapy significantly decreased the incidence of late grade 2 rectal toxicity since the 3-year actuarial incidence in 189 cases managed by 81 Gy. was 2% (95% CI +/- 2) compared with 14% (95% CI +/- 2) in 61 managed by the same dose of 3-D conformal radiation therapy (p = 0.005). The 5-year actuarial rate of grade 2 urinary toxicity in patients who received 75.6 Gy. or greater 3-D conformal radiation therapy was 13% compared with 4% in those treated up to lower doses (p <0.001). Intensity modulated radiation therapy did not affect the incidence of urinary toxicity. CONCLUSIONS Sophisticated conformal radiotherapy techniques with high dose 3-D conformal and intensity modulated radiation therapy improve the biochemical outcome in patients with favorable, intermediate and unfavorable risk prostate cancer. Intensity modulated radiation therapy is associated with minimal rectal and bladder toxicity, and, hence, represents the treatment delivery approach with the most favorable risk-to-benefit ratio.

Radiation-induced apoptosis: Relevance to radiotherapy

Radiation-induced apoptosis is reviewed in terms of: (a) the identification of apoptotic and necrotic cells, (b) observations in vitro and in vivo of radiation-induced apoptosis, (c) genes controlling apoptosis, (d) evidence that the target may be the plasma membrane or nuclear DNA, (e) quantitative comparisons of apoptotic death and reproductive (clonogenic) death, (f) the importance of radiation-induced apoptosis in radiotherapy, and (g) studies of radiation-induced apoptosis that are needed. High priority should be placed on determining the molecular pathways that are important in the expression and modulation of radiation-induced apoptosis. Specifically, the events that modulate the apoptosis that occurs in interphase before the cell can divide should be distinguished from the events before division that modulate the misrepair of DNA damage, that results in chromosomal aberrations observed in mitotic cells, which in turn cause the progeny of the dividing cell with aberrations to die by either apoptosis or necrosis. Then, molecular events that determine whether a cell that divides with or without a chromosomal aberration will produce progeny that apoptose or necrose need to be identified. These considerations are important for determining how modulation of radiation-induced apoptosis will affect the ultimate clonogenic survival, and possibly genomic instability in the surviving progeny.

The deep inspiration breath-hold technique in the treatment of inoperable non–small-cell lung cancer☆

PURPOSE Conventional radiotherapeutic techniques are associated with lung toxicity that limits the treatment dose. Motion of the tumor during treatment requires the use of large safety margins that affect the feasibility of treatment. To address the control of tumor motion and decrease the volume of normal lung irradiated, we investigated the use of three-dimensional conformal radiation therapy (3D-CRT) in conjunction with the deep inspiration breath-hold (DIBH) technique. METHODS AND MATERIALS In the DIBH technique, the patient is initially maintained at quiet tidal breathing, followed by a deep inspiration, a deep expiration, a second deep inspiration, and breath-hold. At this point the patient is at approximately 100% vital capacity, and simulation, verification, and treatment take place during this phase of breath-holding. RESULTS Seven patients have received a total of 164 treatment sessions and have tolerated the technique well. The estimated normal tissue complication probabilities decreased in all patients at their prescribed dose when compared to free breathing. The dose to which patients could be treated with DIBH increased on average from 69.4 Gy to 87.9 Gy, without increasing the risk of toxicity. CONCLUSIONS The DIBH technique provides an advantage to conventional free-breathing treatment by decreasing lung density, reducing normal safety margins, and enabling more accurate treatment. These improvements contribute to the effective exclusion of normal lung tissue from the high-dose region and permit the use of higher treatment doses without increased risks of toxicity.

Treatment planning and delivery of intensity-modulated radiation therapy for primary nasopharynx cancer

PURPOSE To implement intensity-modulated radiation therapy (IMRT) for primary nasopharynx cancer and to compare this technique with conventional treatment methods. METHODS AND MATERIALS Between May 1998 and June 2000, 23 patients with primary nasopharynx cancer were treated with IMRT delivered with dynamic multileaf collimation. Treatments were designed using an inverse planning algorithm, which accepts dose and dose-volume constraints for targets and normal structures. The IMRT plan was compared with a traditional plan consisting of phased lateral fields and a three-dimensional (3D) plan consisting of a combination of lateral fields and a 3D conformal plan. RESULTS Mean planning target volume (PTV) dose increased from 67.9 Gy with the traditional plan, to 74.6 Gy and 77.3 Gy with the 3D and IMRT plans, respectively. PTV coverage improved in the parapharyngeal region, the skull base, and the medial aspects of the nodal volumes using IMRT and doses to all normal structures decreased compared to the other treatment approaches. Average maximum cord dose decreased from 49 Gy with the traditional plan, to 44 Gy with the 3D plan and 34.5 Gy with IMRT. With the IMRT plan, the volume of mandible and temporal lobes receiving more than 60 Gy decreased by 10-15% compared to the traditional and 3D plans. The mean parotid gland dose decreased with IMRT, although it was not low enough to preserve salivary function. CONCLUSION Lower normal tissue doses and improved target coverage, primarily in the retropharynx, skull base, and nodal regions, were achieved using IMRT. IMRT could potentially improve locoregional control and toxicity at current dose levels or facilitate dose escalation to further enhance locoregional control.

Evaluation of respiratory movement during gated radiotherapy using film and electronic portal imaging

PURPOSE To evaluate the effectiveness of a commercial system(1) in reducing respiration-induced treatment uncertainty by gating the radiation delivery. METHODS AND MATERIALS The gating system considered here measures respiration from the position of a reflective marker on the patients chest. Respiration-triggered planning CT scans were obtained for 8 patients (4 lung, 4 liver) at the intended phase of respiration (6 at end expiration and 2 at end inspiration). In addition, fluoroscopic movies were recorded simultaneously with the respiratory waveform. During the treatment sessions, gated localization films were used to measure the position of the diaphragm relative to the vertebral bodies, which was compared to the reference digitally reconstructed radiograph derived from the respiration-triggered planning CT. Variability was quantified by the standard deviation about the mean position. We also assessed the interfraction variability of soft tissue structures during gated treatment in 2 patients using an amorphous silicon electronic portal imaging device. RESULTS The gated localization films revealed an interfraction patient-averaged diaphragm variability of 2.8 +/- 1.0 mm (error bars indicate standard deviation in the patient population). The fluoroscopic data yielded a patient-averaged intrafraction diaphragm variability of 2.6 +/- 1.7 mm. With no gating, this intrafraction excursion became 6.9 +/- 2.1 mm. In gated localization films, the patient-averaged mean displacement of the diaphragm from the planning position was 0.0 +/- 3.9 mm. However, in 4 of the 8 patients, the mean (over localization films) displacement was >4 mm, indicating a systematic displacement in treatment position from the planned one. The position of soft tissue features observed in portal images during gated treatments over several fractions showed a mean variability between 2.6 and 5.7 mm. The intrafraction variability, however, was between 0.6 and 1.4 mm, indicating that most of the variability was due to patient setup errors rather than to respiratory motion. CONCLUSIONS The gating system evaluated here reduces the intra- and interfraction variability of anatomy due to respiratory motion. However, systematic displacements were observed in some cases between the location of an anatomic feature at simulation and its location during treatment. Frequent monitoring is advisable with film or portal imaging.

Effect of respiratory gating on reducing lung motion artifacts in PET imaging of lung cancer

Positron emission tomography (PET) has shown an increase in both sensitivity and specificity over computed tomography (CT) in lung cancer. However, motion artifacts in the 18F fluorodioxydoglucose (FDG) PET images caused by respiration persists to be an important factor in degrading PET image quality and quantification. Motion artifacts lead to two major effects: First, it affects the accuracy of quantitation, producing a reduction of the measured standard uptake value (SUV). Second, the apparent lesion volume is overestimated. Both impact upon the usage of PET images for radiation treatment planning. The first affects the visibility, or contrast, of the lesion. The second results in an increase in the planning target volume, and consequently a greater radiation dose to the normal tissues. One way to compensate for this effect is by applying a multiple-frame capture technique. The PET data are then acquired in synchronization with the respiratory motion. Reduction in smearing due to gating was investigated in both phantoms and patient studies. Phantom studies showed a dependence of the reduction in smearing on the lesion size, the motion amplitude, and the number of bins used for data acquisition. These studies also showed an improvement in the target-to-background ratio, and a more accurate measurement of the SUV. When applied to one patient, respiratory gating showed a 28% reduction in the total lesion volume, and a 56.5% increase in the SUV. This study was conducted as a proof of principle that a gating technique can effectively reduce motion artifacts in PET image acquisition.

Probability of radiation-induced complications in normal tissues with parallel architecture under conditions of uniform whole or partial organ irradiation

A biologically based model is developed for normal tissue complication probability as a function of dose and irradiated volume fraction for organs such as the kidney and the lung. The organ is assumed to be composed of functional subunits (FSUs) which are arranged in a parallel architecture. The complication is produced only if a sufficiently large fraction of the FSUs are inactivated by radiation and an FSU is inactivated only when all the clonogenic cells within it are killed. The linear-quadratic model is used for the dose-response of individual cells within an FSU. The predictions of this model are compared with those of an empirical power law function for uniform whole and partial organ irradiation.

Cone-beam CT with megavoltage beams and an amorphous silicon electronic portal imaging device: potential for verification of radiotherapy of lung cancer.

We investigate the potential of megavoltage (MV) cone-beam CT with an amorphous silicon electronic portal imaging device (EPID) as a tool for patient position verification and tumor/organ motion studies in radiation treatment of lung tumors. We acquire 25 to 200 projection images using a 22 x 29 cm EPID. The acquisition is automatic and requires 7 minutes for 100 projections; it can be synchronized with respiratory gating. From these images, volumetric reconstruction is accomplished with a filtered backprojection in the cone-beam geometry. Several important prereconstruction image corrections, such as detector sag, must be applied. Tests with a contrast phantom indicate that differences in electron density of 2% can be detected with 100 projections, 200 cGy total dose. The contrast-to-noise ratio improves as the number of projections is increased. With 50 projections (100 cGy), high contrast objects are visible, and as few as 25 projections yield images with discernible features. We identify a technique of acquiring projection images with conformal beam apertures, shaped by a multileaf collimator, to reduce the dose to surrounding normal tissue. Tests of this technique on an anthropomorphic phantom demonstrate that a gross tumor volume in the lung can be accurately localized in three dimensions with scans using 88 monitor units. As such, conformal megavoltage cone-beam CT can provide three-dimensional imaging of lung tumors and may be used, for example, in verifying respiratory gated treatments.

Relative profile and dose verification of intensity-modulated radiation therapy

PURPOSE To develop a quality assurance (QA) procedure to assess the intensity profile and dosimetry for intensity-modulated (IM) treatment fields using electronic portal imaging devices (EPIDs). METHODS AND MATERIALS A series of rapidly acquired (approximately 1/sec) portal images are summed and converted to dose. For relative intensity QA, the intended profile is subtracted point-by-point from the measured profile forming a series of error values. The standard deviation, sigma, of the errors, a measure of the goodness of the match, is minimized by applying a normalization and uniform scatter subtraction from the measured profile. For dose verification (dose to isocenter), an empirically determined phantom-correction factor is added to incorporate the effect of patient presence on EPID readings. Seventy prostate treatment fields were used in a phantom study to verify these approaches. Sensitivity was studied by creating artificial mismatches. RESULTS The average sigma for relative profile verification is 3.3% (percentage of average intended intensity) whereas artificial mismatches resulted in sigma values from 5% to 27%. The average isocentric dose calculated from EPID readings is 1.001 relative to the planned dose with a standard deviation of 0.018. CONCLUSIONS An EPID can be used for profile verification and absolute isocentric dose measurement for IM fields.

Apoptosis in Heat-Induced Cell Killing: The Protective Role of hsp-70 and the Sensitization Effect of the c-myc Gene

We studied heat-induced apoptosis and loss of clonogenicity in Rat-1 fibroblasts, thermotolerant Rat-1 (TT Rat-1), Rat-1 transfected with the human hsp-70 gene (M21) and Rat-1 transfected with the human c-myc proto-oncogene (Rat-1:myc). Relative to Rat-1, TT Rat-1 and M21 cells are heat-resistant, but Rat-1:myc cells are heat-sensitive, in terms of both apoptosis and clonogenic survival. The apoptotic fractions assayed 24 h after a heat treatment of 60 min at 44 degrees C, are about 20% for Rat-1, 7% for TT Rat-1, 10% for M21 and 70% for Rat-1:myc cells, respectively. Most of the apoptotic cells detach from substratum within 1 day of heat treatment and exhibit morphological changes, chromatin condensation and DNA fragmentation. The results of this study suggest that (1) apoptosis is an important mechanism of heat-induced cell killing in some cell lines, (2) apoptosis-mediated cell killing manifests rapidly (relative to clonogenic assay) after a heat treatment, and (3) overexpression of the human hsp-70 gene reduces, whereas expression of the human c-myc proto-oncogene enhances, heat-induced apoptosis. Lastly, the effects of the hsp-70 and c-myc genes on the thermosensitivity of cells are correlated with their modulation of apoptosis.