Preplanning prediction of the left anterior descending artery maximum dose based on patient, dosimetric, and treatment planning parameters.

PURPOSE: Maximum dose to the left anterior descending artery (LADmax) is an important physical constraint to reduce the risk of cardiovascular toxicity. We generated a simple algorithm to guide the positioning of the tangent fields to reliably maintain LADmax <10 Gy. METHODS AND MATERIALS: Dosimetric plans from 146 consecutive women treated prone to the left breast enrolled in prospective protocols of accelerated whole breast radiation therapy, with a concomitant daily boost to the tumor bed (40.5 Gy/15 fraction to the whole breast and 48 Gy to the tumor bed), provided the training set for algorithm development. Scatter plots and correlation coefficients were used to describe the bivariate relationships between LADmax and several parameters: distance from the tumor cavity to the tangent field edge, cavity size, breast separation, field size, and distance from the tangent field. A logistic sigmoid curve was used to model the relationship of LADmax and the distance from the tangent field. Furthermore, we tested this prediction model on a validation data set of 53 consecutive similar patients. RESULTS: A lack of linear relationships between LADmax and distance from cavity to LAD (-0.47), cavity size (-0.18), breast separation (-0.02), or field size (-0.28) was observed. In contrast, distance from the tangent field was highly negatively correlated to LADmax (-0.84) and was used in the models to predict LADmax. From a logistic sigmoid model we selected a cut-point of 2.46 mm (95% confidence interval, 2.19-2.74 mm) greater than which LADmax is <10 Gy (95% confidence interval, 9.30-10.72 Gy) and LADmean is <3.3 Gy. CONCLUSIONS: Placing the edge of the tangents at least 2.5 mm from the closest point of the contoured LAD is likely to assure LADmax is <10 Gy and LADmean is <3.3 Gy in patients treated with prone accelerated breast radiation therapy.

Postimplant dosimetry for (125)I prostate implants: definitions and factors affecting outcome.

OBJECTIVE: An analysis of CT-based dosimetry was performed to assess the efficacy of the real time method of prostate implantation, explore the relationship of various dose descriptions and determine implant factors affecting outcome. METHODS AND MATERIALS: Between 7/95 and 8/99, 297 patients underwent (125)I implants for T1-T2 prostate cancer and had CT-based dosimetry performed (TG43 formalism). Dosimetry was performed 1 month postimplant. Using a dose-volume histogram, doses delivered to 100%, 95%, 90%, and 80% of the prostate (D100, D95, D90, D80, respectively) as well as percentages of the gland receiving 240 Gy, 160 Gy, 140 Gy (V240, V160, V140, respectively) were reported. Correlations between the various dose parameters and D90 were generated. The effect of the number of seeds implanted, seeds/volume, prostate volume, experience as assessed by time (8/01/99-date of implant), ultrasound probe (mechanical sector vs. dual phased electronic), and the ratio of the CT dosimetry prostate volume/ultrasound implant volume (CT/US vol) were analyzed. RESULTS: The median D100, D95, D90, and D80 values were 10,200 cGy, 15,655 cGy, 17,578 cGy, and 19,873 cGy, respectively. The median V240, V160, and V140 were 56%, 94%, and 98%, respectively. Correlations of dose descriptions found a close relationship of D95, D80, V240, V160, and V140 with D90 with r values of 0.928, 0.973, 0.911, 0.816, and 0.733, respectively. D100 correlated poorly with D90 (r = 0.099). Using a stepwise regression analysis, CT/US vol ratio, prostate volume, and seed number were the only significant factors affecting D90 with CT/US vol ratio having the greatest effect. The dual-phased electronic probe was associated with fewer D90 values of less than 140 Gy (2%) compared to the mechanical sector probe (14%) (p = 0.02). CONCLUSION: CT-based dosimetry results reveal the real-time implant technique to be an effective method of prostate implantation. Factors associated with more precise implantation, such as decreased postimplant edema, new technology, and increased number of seeds will lead to higher D90 values.

Acute urinary morbidity following I-125 interstitial implantation of the prostate gland.

The objective of this paper was to evaluate the acute urinary morbidity associated with I-125 interstitial implantation of the prostate gland. From 1991-1995, 117 patients underwent ultrasound (U/S)-guided implantation of the prostate gland. Median dose to 90% of the gland (d90) was 14.68 Gy (range = 1.65-21.75 Gy). The patients' urinary symptoms were recorded pre-implantation and at regular intervals after implantation using the International Prostate Symptom Score (IPSS), a self-assessment questionnaire in which patients scored 7 symptoms: incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia. Median follow-up was 12 months. The natural history of implant-related urinary symptoms was assessed in this manner. In addition, dosimetric factors including U/S prostate volume, total activity, activity per seed, dose volume histogram (DVH) values for dose to gland, and dose area histogram (DAH) values for dose to urethra and bladder were examined for correlation to the severity of each symptom as well as to total IPSS (sum of the individual symptom scores). Total IPSS peaked at 1 month post-implant and gradually returned to approximately baseline at 24 months. Total IPSS directly correlated with total activity and DVH for the prostate. Total IPSS, however, did not correlate with bladder or urethral DAH. With the exception of frequency, individual symptoms did not correlate with dose to gland, bladder, or urethra. Frequency scores did, however, correlate not only with dose to prostate gland but also dose to urethra. The acute urinary side effects of I-125 prostate implantation are transient and peak at 1 month post-implant. The severity of the urinary irritative symptoms developed are closely related to total dose to the gland. Urethral dose appears to affect frequency most significantly. Urinary symptoms, therefore, may be a limiting factor when considering dose escalation with I-125.

A dose-response study for I-125 prostate implants.

PURPOSE: No dose-response study has ever been performed for I-125 prostate implants using modern techniques of implant evaluation and modern treatment outcome end points. The amount of activity per volume implanted was increased over time based on review of postimplant dosimetry. This resulted in different delivered dose levels. This study explores the relationship between dose, biochemical failure, and biopsy results. MATERIALS AND METHODS: 134 patients with T1-T2 prostate cancer were implanted with I-125 radioactive seeds and followed from 12 to 74 months (median: 32) postimplant. No patient received external beam irradiation or hormonal therapy. All patients implanted with I-125 had Gleason scores < or =6. One month postimplant, a CT-based three-dimensional dosimetric evaluation was performed on all patients. Using TG43 guidelines, dose-volume histograms were calculated. The dose delivered to the gland was defined as the D90 (dose delivered to 90% of prostate tissue as defined by CT). The D90s ranged from 26.8 to 256.3 Gy (median: 140.8 Gy). Biochemical failure was defined as two consecutive rises in prostate specific antigen (PSA) or a nadir level above 1.0 ng/ml. Posttreatment prostate biopsies (six to eight core samples) were routinely performed at 2 years postimplant. RESULTS: Improvements in freedom from biochemical failure (FFBF) rates were seen with increasing D90 levels. The 4-year FFBF rates for patients with D90 values < 100 Gy, 100-119.9 Gy, 120-13.9 Gy, 140-159.9 Gy, and > or =160 Gy were 53, 82, 80, 95, and 89%, respectively (p = 0.02). Patients receiving a D90 < 140 Gy (65 patients) were similar with respect to presenting disease prognostic factors to those receiving a D90 > or =140 Gy (69 patients). Patients receiving a D90 < 140 Gy had a 4-year FFBF rate of 68% compared to a rate of 92% for those receiving a D90 > or =140 Gy (p = 0.02). Two-year posttreatment biopsies were negative in 70% (33 of 47) of patients with a D90 < 140 Gy compared to a rate of 83% (24 of 29) in patients with a D90 > or =140 Gy (p = 0.2). A multivariate analysis using dose, PSA, score, and stage revealed that dose was the most significant predictor of biochemical failure (p = 0.001). This dose response was more pronounced in patients presenting with PSA levels > 10 ng/ml. In these patients, the 4-year FFBF rates were 51 and 100% for the low and high dose groups, respectively (p = 0.009) and the negative biopsy rates were 64% (14 of 22) and 100% (8 of 8), respectively (p = 0.05). In patients with presenting PSA <10 ng/ml, the 4-year FFBF rates were 82 and 88% for the low and high dose groups, respectively (p = 0.29). CONCLUSION: A dose response was observed at a level of 140 Gy. Adequate I-125 implants should deliver a dose of 140-160 Gy using TG43 guidelines.

A new technique for performing Syed-Neblett template interstitial implants for gynecologic malignancies using transrectal-ultrasound guidance.

PURPOSE: Interstitial brachytherapy plays an important role in the treatment of advanced and recurrent gynecologic malignancies. Unfortunately, the inability to visualize the tumor and surrounding normal structures during the implant has hampered the accuracy and safety of the implant. Transrectal ultrasound guided Syed-Neblett template implantation is a new technique for performing interstitial implants under direct visualization. The details of the technique are presented to demonstrate the ability to accurately guide needle placement into tumor and avoid needle insertion into critical surrounding normal structures. METHODS AND MATERIALS: The transrectal ultrasound is positioned so that it can visualize the tumor, and normal surrounding structures in both transverse and longitudinal planes. The Syed-Neblett template is positioned and sutured into the perineum. Needles are inserted into the target area under direct visualization through transverse imaging. The bladder and rectum can be directly imaged and thus avoided. Longitudinal imaging is then used to guide the needles to the appropriate depth. In addition, it can be used to assess the length of the target volume and aid in determining the active length of the sources. RESULTS: A total of 12 procedures have been performed on seven patients from August 30, 1995 to April 12, 1996. The presenting diseases included: Stage IIIb cervical cancer in four cases, recurrent endometrial cancer in two cases, and Stage III vaginal cancer in one case. The total length of time for implantation of the needles ranged from 45 to 165 min (median--130 min). CONCLUSION: Transrectal ultrasound guidance provides real-time visualization of the target volume and normal tissues during interstitial implantation of gynecologic malignancies and allows for accurate needle placement.

Enhanced radiosensitization with interferon-alpha-2b and cisplatin in the treatment of locally advanced cervical carcinoma.

PURPOSE: To evaluate the efficacy and toxicity of interferon-alpha-2b (IFN-alpha) and cisplatin given concomitantly with radiation therapy (RT) in the treatment of locally advanced cervical carcinoma. MATERIALS AND METHODS: Twenty-one patients with stage bulky Ib-IIIb (Ib, 2; IIa, 2; IIb, 8; IIIb, 9) cervical carcinoma were treated with combined IFN-alpha (5 million IU) subcutaneously three times per week and cisplatin (25 mg/m2) i.v. infusion over 2 h weekly for 7 weeks, given concomitantly with RT (4500 cGy of external beam plus 2 brachytherapy procedures). Total radiation doses delivered ranged from 7500 to 9960 cGy (median, 9300 cGy). Follow-up ranged from 16 to 33 months (median, 25 months). RESULTS: The 2-year local control rate was 100%. The only sites of disease recurrence were distant. Freedom from distant metastases, disease-free survival, and overall survival at 2 years was 76%. Late complication rates were high. Grade 4 rectosigmoid, bladder, and small bowel complication rates were 49, 18, and 23% at 2 years. Late toxicity was seen earlier than expected with rectosigmoid complications observed 5 to 11.5 months (median, 8 months) after completion of treatment. CONCLUSION: Combination IFN-alpha and cisplatin produced a marked effect of enhanced radiosensitization as evidenced by 100% local tumor control and high late normal tissue complication rates. Due to the unacceptable late toxicity, its routine clinical use cannot be recommended. Further investigation is needed to determine whether a therapeutic window exists such that the use of lower doses of IFN-alpha, cisplatin, or RT can increase tumor control with more acceptable normal tissue toxicity.

Prostate specific antigen findings and biopsy results following interactive ultrasound guided transperineal brachytherapy for early stage prostate carcinoma.

BACKGROUND: Interactive, transrectal, ultrasound-guided transperineal implantation is a new technique for performing permanent brachytherapy implants of the prostate. Prostate specific antigen (PSA) findings, biopsy results, and morbidity are examined to demonstrate its efficacy and safety in treating early stage prostate carcinoma. METHODS: Ninety-seven patients underwent permanent implants for classifications T1 to T2 adenocarcinoma of the prostate gland with a median follow-up of 18 months (range: 6-51 months). Seventy-nine patients had negative laparoscopic pelvic lymph node dissections prior to implantation. Patients with positive lymph nodes were not implanted. The radioactive isotope used was I-125 in 71 patients and Pd-103 in 26 patients. RESULTS: PSA failure was defined as two consecutive increases in PSA above the nadir level. The actuarial freedom from PSA failure (FFPF) at 2 years was 76% for the entire group. Stage significantly affected FFPF. Patients classified as T1b to T2a (35) had a FFPF of 91% at 2 years compared with 68.5% for patients classified as T2b to T2c (62) (P = 0.04). The pre-treatment PSA also significantly affected FFPF. Patients with PSA values of < or = 10 ng/mL (44) had a FFPF of 83% at 2 years. A similar rate of 82% was found in patients with PSA values of 10.1 to 20 ng/mL (29). Patients with PSA values > 20 ng/mL (24) had a significantly poorer FFPF at 2 years of 58% (P = 0.02). The PSA values of patients free from a PSA failure (82) ranged from 0.1 to 12.9 ng/mL with a median of 0.8 ng/mL. Transrectal prostate biopsies were performed 18 to 36 months posttreatment in 39 patients. Negative biopsies were found in 74% (29/39) of cases. The procedure was associated with an actuarial preservation of erectile function rate and sexual potency at 2 years of 96% and 79%, respectively. There were no cases of urinary incontinence or radiation cystitis. Associated morbidity included urinary retention requiring catheterization in 4% of the patients, outlet obstruction requiring a transurethral resection of the prostate in 2% and Grade 2 rectal complications in 1%. CONCLUSIONS: Interactive, ultrasound-guided transperineal brachytherapy results in a low PSA failure rate, high negative biopsy rate, and is associated with low morbidity and preservation of erectile function.

A modified technique allowing interactive ultrasound-guided three-dimensional transperineal prostate implantation.

PURPOSE: Ultrasound-guided transperineal prostate implantation is a new technique for performing permanent isotope implants of the prostate. The details of the technique are presented to demonstrate its ability to place radioactive seeds three-dimensionally within the prostate gland to achieve uniform dose distribution without the need for complicated preplanning. METHODS AND MATERIALS: An accurate measurement of the prostate volume is made using biplanar transrectal ultrasound. The total activity to be implanted is derived from a look-up table based on prostate volume. The basic plan is to implant 60-70% of the total activity in the periphery of the gland and the remaining activity in the interior of the gland. The ultrasound transducer provides visualization of the prostate through transverse, longitudinal and oblique cuts and allows for accurate placement of implant needles, approximately 1 cm apart. In addition, these needles can be moved through the prostate under constant visualization, thus allowing for precise seed placement. RESULTS: The setup of the transrectal ultrasound device as well as prostate volume measurements are performed in 10 to 15 min. The actual placement of the needles and seed implantation takes 1 to 1.5 h to perform. Postimplantation dosimetric evaluation is performed using orthogonal x-ray films and 3 mm thick CT slices taken at 3 mm intervals. This evaluation has confirmed accurate seed placement within the prostate gland. CONCLUSION: Interactive ultrasound guided transperineal prostate implantation is a fast and accurate method of performing permanent radioactive isotope prostate implants.

Transmission block to simplify combined pelvic and inguinal radiation therapy.

A homogeneous dose distribution of radiation to inguinal lymph nodes and deep pelvic structures can be achieved with use of a transmission block over the central portion of a large anterior pelvic-inguinal portal, together with a smaller posterior field. This relatively simple technique permits individualization of isodose distributions and eliminates the problems of matching abutting portals. Reproducibility of daily setup and optimization of machine utilization are both improved.

Scatter dose summation for irregular fields: speed and accuracy study.

Using program IRREG as a standard, we have compared speed and accuracy of several algorithms that calculate the scatter dose in an irregular field. All the algorithms, in some manner, decompose the irregular field into component triangles and obtain the scatter dose as the sum of the contributions from those triangles. Two of the algorithms replace each such component triangle with a sector of a certain "effective radius": in one case the average radius of the triangle, in the other the radius of the sector having the same area as the component triangle. A third algorithm decomposes each triangle further into two right triangles and utilizes the precalculated "equivalent radius" of each, to find the scatter contribution. For points near the center of a square field, all the methods compare favorably in accuracy to program IRREG, with less than a 1% error in total dose and with approximately a factor of 3-5 savings in computation time. Even for extreme rectangular fields (2 cm X 30 cm), the methods using the average radius and the equivalent right triangles agree to within 2% in total dose and approximately a factor of 3-4 savings in computation time.

Scatter integration with right triangular fields.

The concept of the equivalent field is used extensively in radiotherapy dose calculation algorithms. The rationale for using equivalent fields is to allow dose calculations for a wide variety of field shapes, while maintaining dose calculational data for only a few, very regularly shaped fields. A common example is the table of equivalent squares of rectangular fields presented by Day in the British Journal of Radiology. Recently, in searching for fast dose calculation algorithms for irregular fields, we introduced the concept of the equivalent square of a right triangular field. It is shown that an arbitrary irregular field of N vertices may be decomposed into 2N right triangular fields, each with a precalculated equivalent square. The scatter at the point of calculation due to the irregular field is then obtained as a sum of the scatter contributions from the equivalent squares. The scatter integration with right triangles is compared with scatter integration using program IRREG.

Thermal survival characteristics of cell subpopulations isolated from a heterogeneous human colon tumor.

Responses of a heterogeneous human colon adenocarcinoma model tumor system to in vitro hyperthermic treatment at various temperatures have been studied. This model tumor system consists of an original tumor line (DLD-1) obtained from surgical biopsy, and two derivative subpopulations termed clones A and D. These 3 tumor cell populations differ in many properties, including karyotype and DNA content, production of specific antigens, and sensitivities to other cytotoxic agents such as chemotherapeutic drugs and X-irradiation. In these experiments, exponentially growing tumor cells were exposed to hyperthermia (42.2, 42.5, 43.0, 44.0, or 45.0 degrees) for graded time periods. A single-hit, multitarget equation was used to express the dependence of survival on time at a given temperature, and values for extrapolation numbers, quasi-threshold time (min), and T0 (mean lethal time; min) were obtained for the initial regions of survival. At the lower temperatures of 42.2 and 42.5 degrees, biphasic survival curves were obtained for all three tumor lines and, as a consequence, a second mean lethal time (T0,f) was also determined for the final thermal-resistant portion of the survival curves. Using the T0 values as an index of relative resistance, values at 42.2 and 42.5 degrees indicated that, in this temperature region, the parent (DLD-1) line was the most sensitive, the clone A line showed intermediate sensitivity, and the clone D line was the most resistant. In the thermally resistant portion of the survival curve, T0 values indicated that the clone A subpopulation was the most sensitive, the DLD-1 line showed intermediate sensitivity, and the clone D tumor subpopulation remained the most resistant. At the higher temperatures of 43, 44, and 45 degrees, in which thermotolerance is not observed during heat treatment, values for T0 indicated the parent (DLD-1) tumor line was still the most sensitive tumor line, and the clone A and clone D lines showed approximately equal resistance. These data indicate that significant differences may exist among subpopulations of heterogeneous tumors in their survival responses to hyperthermia.

Survival responses of cell subpopulations isolated from a heterogeneous human colon tumour after combinations of hyperthermia and X-irradiation.

In summary, this research has investigated the effects of combined modality treatment (i.e., low linear energy transfer ionizing radiation and hyperthermia at 42.5 degrees C) on the survival responses of two tumour subpopulations (designated clones A and D) obtained from a heterogeneous human colon adenocarcinoma. A constant hyperthermic exposure (2 hours at 42.5 degrees C) was given either 3 min before or 3 min after graded exposure to X-rays. An isobologram analysis (Steel and Peckham 1979) of the clonogenic survival responses of the two tumour subpopulations showed that the clone A responses were within the envelope of additivity for either sequence of application. In contrast, the responses of the clone D tumour subpopulation exhibited a supra-additive response to the combined treatments with the sequence of heat followed by X-irradiation being somewhat more effective than the sequence of X-irradiation followed by heat. These data indicate that the responses of tumour subpopulations obtained from heterogeneous solid tumours to combined modality treatments may vary in an, at present, unpredictable manner.

Differential responses to x-irradiation of subpopulations of two heterogeneous human carcinomas in vitro.

The responses of two heterogeneous human cancer cell lines and their derivative clones to graded single doses of X-rays were examined in vitro. One system consisted of the human colon carcinoma line DLD-1 and two subpopulations (clones A and D). The second system consisted of the human lung carcinoma line (LX1) and four subpopulations (LX1-1, LX1-2, LX1-3, and LX1-9). These subpopulations have previously been shown to be markedly heterogeneous in terms of such characteristics as karyotype, morphology, drug sensitivity, tumorigenicity, and expression of membrane glycoproteins (such as carcinoembryonic antigen and tumor colonic mucoprotein antigen). Exponentially growing cultures were irradiated with graded single doses of 100-kVp X-rays. Survival was assessed using colony formation as the end point, and responses from multiple experiments were fitted to the single-hit, multitarget equation of cell survival. Values for the mean lethal dose (D0, grays), quasithreshold dose (Dq, grays), and extrapolation number (n) were obtained. For the human colon adenocarcinoma system, these values for the three tumor lines were: DLD-1, 0.95, 2.34, and 11.7; clone A, 1.06, 2.23 and 8.20; and clone D, 1.08, 1.89, and 5.80. For the human lung carcinoma system, these values for the five sublines were: LX1, 1.14, 0.19, and 1.20; LX1-1, 0.96, 2.06, and 8.54; LX1-2, 0.98, 0.88, and 2.48; LX1-3, 0.68, 2.05, and 20.3; and LX1-9, 1.12, 0.00, and 1.00. These two human tumor systems therefore exhibit variability in their intrinsic sensitivity to X-irradiation. The data indicate that failure of some human carcinomas to respond to physical treatment modalities can be due to preexisting resistant subpopulations.