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Background and study aims: The 5-year survival rates for gastric cancer remain poor despite evolving therapies, and fiducial insertion via endoscopic ultrasound (EUS) is novel within this setting. We aimed to assess the feasibility of fiducial insertion for response assessment and anatomic localization in patients with gastric cancer. Patients and methods: A prospective phase II feasibility study was undertaken at Austin Health (Victoria, Australia) from February 2011 to November 2012. Consecutive adult patients were enrolled who had primary adenocarcinoma of the stomach with American Joint Committee on Cancer stage T1 – 3,N0 – 1,M0 – 1a and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. In addition, the patients were medically suitable for gastrectomy and chemotherapy/chemoradiotherapy. Gold fiducial markers were inserted under EUS guidance into the margins of the gastric cancer primary. The main outcome was successful insertion of the fiducial without complications for response assessment and anatomic localization. Results: A total of 15 fiducials were successfully inserted into 7 (88 %) of 8 patients. No immediate or delayed complications were noted. One patient proceeded to image-guided radiotherapy through the use of fiducials and is disease free at 12 months. Fiducials were used to assess treatment response in all patients who underwent computed tomographic imaging after insertion. Follow-up computed tomography with fiducial placement improved anatomic localization and estimation of the gastric cancer primary size in 3 (60 %) of 5 patients. Conclusions: Within the limitations of our small study cohort, fiducials were placed in gastric cancers under EUS guidance without complications, and placement was successful in the majority of our patients. Although potential benefits exist, there remain substantial limitations to the generalization of this technique across our patient population.

Introduction We sought to assess the cosmetic outcomes and the proportion of patients with late radiotherapy toxicity in a group of women with early-stage breast cancer treated with breast-conserving surgery (BCS) and adjuvant radiotherapy using a simultaneous integrated boost (SIB) technique. Methods and Materials Female patients with early-stage breast cancer (pT1-2 N0-1) treated with BCS and radiotherapy using an SIB technique were identified retrospectively from the departmental database. Radiotherapy consisted of 45 Gy in 25 fractions delivered to the whole breast with a simultaneous forward-planned conformal boost to the tumour bed of 60 Gy in 25 fractions. Demographic data, as well as prospectively collected measures of toxicity and cosmesis, were recorded and analysed. Results Fifty-five eligible patients were treated between 2009 and 2011. The median age was 61 years (range, 31 to 81 years). Median follow-up was 13.3 months. Late toxicities (including oedema, pigmentation, telangiectasia, fibrosis, osteonecrosis and pain) were graded using Common Terminology Criteria for Adverse Events v3.0 criteria. Grade 0, 1 and 2 toxicities were assigned to 52.8%, 43.4% and 3.8% of patients, respectively. There were no cases of grade 3 or greater toxicity. Ninety-eight per cent had a good or excellent cosmetic outcome based on independent assessment by both the patient and physician. One patient developed a second primary contralateral breast cancer. There were no cases of local recurrence. Conclusion The use of a conformal SIB technique is proposed as a mode of delivering adjuvant radiotherapy in early-stage breast cancer. This schedule is convenient for the patient given the shortened overall treatment time. Additionally, the SIB technique seems to be well tolerated, with minimal toxicity and acceptable cosmetic outcomes. Finally, there are dosimetric benefits with respect to target coverage and reduction of dose and dose per fraction to organs at risk.

Purpose: To demonstrate the technical feasibility of intensity modulated radiation therapy (IMRT) dose painting using C-11-choline positron emission tomography PET scans in patients with localized prostate cancer. Methods and Materials: This was an RT planning study of 8 patients with prostate cancer who had C-11-choline PET scans prior to radical prostatectomy. Two contours were semiautomatically generated on the basis of the PET scans for each patient: 60% and 70% of the maximum standardized uptake values (SUV60% and SUV70%). Three IMRT plans were generated for each patient: PLAN(78), which consisted of whole-prostate radiation therapy to 78 Gy; PLAN(78-90), which consisted of whole-prostate RT to 78 Gy, a boost to the SUV60% to 84 Gy, and a further boost to the SUV70% to 90 Gy; and PLAN(72-90), which consisted of whole-prostate RT to 72 Gy, a boost to the SUV60% to 84 Gy, and a further boost to the SUV70% to 90 Gy. The feasibility of these plans was judged by their ability to reach prescription doses while adhering to published dose constraints. Tumor control probabilities based on PET scan-defined volumes (TCPPET) and on prostatectomy-defined volumes (TCPpath), and rectal normal tissue complication probabilities (NTCP) were compared between the plans. Results: All plans for all patients reached prescription doses while adhering to dose constraints. TCPPET values for PLAN(78), PLAN(78-90), and PLAN(72-90) were 65%, 97%, and 96%, respectively. TCPpath values were 71%, 97%, and 89%, respectively. Both PLAN(78-90) and PLAN(72-90) had significantly higher TCPPET (P=.002 and .001) and TCPpath (P

Purpose: An anthropomorphic pelvic phantom was designed and constructed to meet specific criteria for multicenter radiotherapy dosimetric intercomparison. Methods: Three dimensional external and organ outlines were generated from a computed tomography image set of a male pelvis, forming the basis of design for an anatomically realistic phantom. Clinically relevant points of interest were selected throughout the dataset where point-dose values could be measured with thermoluminescence dosimeters and a small-volume ionization chamber. Following testing, three materials were selected and the phantom was manufactured using modern prototyping techniques into five separate coronal slices. Time lines and resource requirements for the phantom design and manufacture were recorded. The ability of the phantom to mimic the entire treatment chain was tested. Results: The phantom CT images indicated that organ densities and geometries were comparable to those of the original patient. The phantom proved simple to load for dosimetry and rapid to assemble. Due to heat release during manufacture, small air gaps and density heterogeneities were present throughout the phantom. The overall cost for production of the prototype phantom was comparable to other commercial anthropomorphic phantoms. The phantom was shown to be suitable for use as a ''patient'' to mimic the entire treatment chain formore » typical external beam radiotherapy for prostate and rectal cancer. Conclusions: The phantom constructed for the present study incorporates all characteristics necessary for accurate Level III intercomparison studies. Following use in an extensive Level III dosimetric comparison over a large time scale and geographic area, the phantom retained mechanical stability and did not show signs of radiation-induced degradation.« less

Purpose: To assess dose delivery accuracy to clinically significant points in a realistic patient geometry for two separate pelvic radiotherapy scenarios. Methods: An inhomogeneous pelvic phantom was transported to 36 radiotherapy centers in Australia and New Zealand. The phantom was treated according to Phase III rectal and prostate trial protocols. Point dose measurements were made with thermoluminescent dosimeters(TLDs) and an ionisation chamber. Comprehensive site-demographic, treatment planning, and physical data were collected for correlation with measurement outcomes. Results: Dose delivery to the prescription point for the rectal treatment was consistent with planned dose (mean difference between planned and measured dose − 0.1 ± 0.3% std err). Dose delivery in the region of the sacral hollow was consistently higher than planned (+1.2 ± 0.2%). For the prostate treatment,dose delivery to the prostate volume was consistent with planned doses (−0.49 ± 0.2%) and planned dose uniformity, though with a tendency to underdose the PTV at the prostate-rectal border. Measured out-of-field doses were significantly higher than planned. Conclusions: A phantom based on realistic anatomy and heterogeneity can be used to comprehensively assess the influence of multiple aspects of the radiotherapytreatment process on dose delivery. The ability to verify dose delivery for two trials with a single phantom was advantageous.

Introduction: The management of malignant pleural mesothelioma represents one of the most challenging issues in oncology, as there is no proven long-term benefit from surgery, radiotherapy or chemotherapy alone or in combination. Locoregional progression remains the major cause of death, but radical surgical resection may produce major postoperative morbidity. While radical or postoperative radiotherapy using conventional techniques has resulted in severe toxicity with no impact on survival, recent advances in radiotherapy delivery may be more effective. Methods: We treated patients with locally advanced mesothelioma whose tumours had been sub optimally resected with high-dose three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) to large volumes of one hemithorax, using CT and positron emission tomography (PET) scan-based treatment planning. Clinical outcomes were assessed by determining patterns of failure and metabolic changes in total glycolytic volume (TGV) between pre- and post-irradiation 18F-FDG PET/CT scans and by recording acute and late toxicity grades. Results: Fourteen patients were analysed with 40 PET scans performed before and up to 4.5 years after radiotherapy. Eleven patients had pleurectomy/decortications, one had an extrapleural pneumonectomy and two had no surgery. Four patients who received chemotherapy had all progressed prior to radiotherapy. After radiotherapy, the in-field local control rate was 71%. No progression occurred in two patients, one was salvaged with further radiotherapy to a new site, four recurred inside the irradiated volume all with concurrent distant metastases and the other seven had distant metastases only. The TGVs were reduced by an average of 67% (range 12–100%) after doses of 45 to 60 Gy to part or all of one hemithorax. There were no serious treatment-related toxicities. Median survival was 25 months from diagnosis and 17 months after starting radiotherapy. Conclusions: We have established that mesothelioma can be locally controlled with high radiation doses using 3DCRT or IMRT, and that strict normal tissue dose constraints have limited radiation toxicities. Radiotherapy should be considered to prevent or delay the local manifestations of progressive disease in suitable patients after surgery including extrapleural pneumonectomy and pleurectomy/decortication. Higher radiation doses may allow more effective palliation.

Background and Purpose Improved radiotherapy techniques in pediatric craniospinal therapy (CSRT) strive to reduce risks of late morbidity. Using a pediatric anthropomorphic phantom, this research correlated measured target and normal tissue dose to that predicted from a 3D planning system (3D-RTP). Patients and Methods A pediatric anthropomorphic phantom was planned following French Society of Pediatric Oncology (SFOP) protocols. Thermoluminescent detectors (TLDs) were used to perform dosimetric measurements during treatment. 4 and 6 MV photon fields with multi leaf collimation (MLC) or custom blocks were compared to 3D-RTP computer (ADAC Pinnacle) predictions for cranial fields. Spinal dosimetry was studied using photons (4 and 6 MV) and electrons (9 and 12 MeV). Results 3D-RTP predictions generally concurred with dose received in cranial and spinal sites. The measured dose was over-predicted significantly by the 3D-RTP in the anterior cranial fossa. Normal tissue doses were reduced when treating the spine using megavoltage electron beams instead of photons. Conclusions Treating the spinal field with electrons minimises the risk of pulmonary sequelae, however electron energy selection is critical to achieve adequate spinal field coverage. Despite adhering to a major trial protocol guideline, dose at the floor of the anterior cranial fossa remains a potential clinical problem and 3D-RTP do not predict this well.

Summary The use of fiducial markers (FM) in image-guided radiotherapy (IGRT) to increase treatment precision is emerging for upper gastrointestinal malignancies. To our knowledge there is no data beyond technical reports for the use of FMs in IGRT for gastric cancers in the current literature. We report a case of an 89-year old gentleman with localised gastric cancer who was deemed unfit for surgery and chemotherapy. He had FMs inserted endoscopically around the tumour via ultrasound guidance and received radiotherapy with a high-dose palliative intent via a two-phase technique to 54 Gy in 30 fractions with IGRT. The use of FMs allowed confidence in tumour delineation and together with IGRT enabled precise and safe delivery of a higher dose. The patient tolerated the treatment without significant toxicity and had no evidence of residual or recurrent tumour 12 months following radiotherapy. The use of FMs with IGRT in upper gastrointestinal malignancies warrants further collaborative studies.

Summary Prolonged waiting times for radiotherapy have resulted in many centres assigning priorities to various patient or diagnostic groups. A high risk of progression on a waiting list is one factor that would reasonably influence the priority. The present descriptive study of 27 patients with Merkel cell carcinoma (MCC) found that a median wait of 24 days for radiotherapy is associated with a high risk of progression. Eleven (41%) of 27 patients developed progressive disease, including five (45%) of 11 patients waiting for adjuvant radiotherapy. Patients treated adjuvantly also had longer waiting times prior to their initial radiotherapy consultation (median 41 days), which may have contributed to the rate of progression. Merkel cell carcinoma is an aggressive but curable malignancy and appropriate management should include efforts to minimize all potential delays prior to the commencement of radiotherapy.

Background and Aims Radiotherapy is an accepted modality in the treatment of esophageal cancers and is currently being evaluated in conjunction with chemotherapy for the neoadjuvant treatment of gastric cancers. Our aim was to assess whether a novel endoscopically inserted marker can be used to improve radiological assessment of the primary cancer and allow for image-guided radiotherapy. Methods A phase II feasibility study was conducted at a tertiary-care center. Twenty-six consecutive adult patients with esophagogastric cancers underwent endoscopic marking of the tumor margins with a novel radiopaque marker (mixture of lipiodol and n-butyl 2-cyanoacrylate). The main outcome measure was the successful insertion of the marker based on a combination of radiological, endoscopic, and histological assessment. Results A total of 92 markers were inserted in 26 patients. Twenty-two (88%) had follow-up imaging to assess the 81 markers inserted, 79 of which (97.5%) were visible. There were no postprocedural adverse events noted in our cohort. Radiological assessment of tumor size improved such that it was in line with the endoscopic evaluation after marker placement in 18 of 21 patients (85.7%) who had appropriate follow-up radiology imaging. Ten patients (38.5%) from our cohort underwent image-guided radiotherapy (IGRT) by using the endoscopically inserted markers. Conclusion Within the limitations of our small pilot study, endoscopic placement of our novel marker was successful in the majority of our cohort without significant adverse events. Marker placement resulted in improved radiological localization in the majority of our cohort and allowed for IGRT. (Australian New Zealand Clinical Trials Registry: ACTRN12613000239763.)

The acute and late toxicities of synchronous carboplatin, etoposide, and radiation therapy were prospectively assessed in a group of patients with high-risk Merkel cell carcinoma of the skin.Forty patients from six different centers throughout Australia were entered into a Phase II study under the auspices of the Trans-Tasman Radiation Oncology Group. The trial was activated in 1996 and continues to accrue. Patients are eligible if they have disease localized to the primary site and nodes and are required to have at least one of the following high-risk features: recurrence after initial therapy, involved nodes, primary size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks, and synchronous carboplatin (area under curve [AUC] 4.5) and etoposide (80 mg/M(2) i.v.) were given on days 1-3 during weeks 1, 4, 7, and 10. The median age of the group was 67 years (43-78).The median duration of follow-up was 22 months (2-45). There were no treatment-related deaths. Grade 3 or 4 skin toxicity occurred in 63% of patients (95% CI 48, 78). The most serious acute effect was on neutrophils with Grade 3 or 4 (neutrophils1 x 10(9)/L), occurring in 60% (95% CI 45, 75) of cases. Complications from neutropenia (fever and sepsis) occurred in 16 patients (40% of cases). The median time for neutropenic complications was 27 days (9-35), and 10/16 (62%) cases of neutropenic fever occurred after the second cycle of chemotherapy. The probability of Grade 3 or 4 late effects on platelets (50 x 10(9)/L) and hemoglobin (8 g/dl) was 10% (95% CI 1, 20) and 6% (95% CI 2, 15), respectively. Of the 40 patients, 35 were able to complete 4 cycles of chemotherapy. There were no factors predictive for neutropenic toxicity at a p value0.05.The protocol has acceptable toxicity, and the treatment has been deliverable in a multi-institutional trial setting. Neutropenia is likely to occur with synchronous carboplatin/etoposide and radiation in this population of patients. The risk of a febrile neutropenia was greatest at the time of the second cycle of chemotherapy, when there was moist desquamation of skin or mucosal membranes that provided a portal for infection. This should be considered in the design of subsequent protocols with chemoradiotherapy.

Cutaneous oedema is a relatively frequent complication in patients treated conservatively for breast cancer. The factors that contribute to this complication have not been precisely determined. We performed a pilot study to assess the usefulness of high-frequency ultrasound as a quantitative measure of cutaneous oedema. Eleven patients undergoing breast-conserving therapy for breast cancer were studied. Both the treated and untreated breasts were examined. Total cutaneous thickness provided a useful measure of cutaneous oedema. The treated breast was significantly thicker than the untreated breast (P < 0.001). The medial aspect of the breast was thicker than the lateral aspect in both the treated and untreated breast (P < 0.001). The increase in cutaneous thickness predated radiotherapy in those patients who had undergone an axillary dissection. Intrapatient variation in skin thickness was much less than interpatient variation in skin thickness (coefficient of variation 6.4% vs. 18.2% for the untreated breast; coefficient of variation 13.9% vs. 30.9% for the treated breast). Increasing cutaneous thickness was associated with decreasing cutaneous echodensity. We were unable to derive quantitative estimates of echodensity. Cutaneous oedema is an important outcome variable following conservative treatment of breast cancer. High-frequency ultrasound is able to quantify this accurately. It can readily detect changes invisible to the naked eye. High-frequency ultrasound should enable the effects of different treatment options (e.g., extent of surgery, radiotherapy, and chemotherapy) on cutaneous oedema to be differentiated and for the time course of oedema to be accurately characterised.

The purpose of the present paper was to evaluate treatment outcome after conservative breast surgery or mastectomy followed by simultaneous adjuvant radiotherapy and cyclophosphamide, methotrexate and fluorouracil (CMF) therapy. Two hundred and sixty eight (268) patients were treated at two Australian and two New Zealand centres between 1981 and July 1995. One hundred and sixty-nine patients underwent conservation surgery and 99 had mastectomies. Median follow-up was 53 months. Conventionally fractionated radiation was delivered simultaneously during the first two cycles of CMF, avoiding radiation on the Fridays that the intravenous components of CMF were delivered. In conservatively treated patients, 5-year actuarial rates of any recurrence, distant recurrence and overall survival were 34.5 +/- 5.2%, 25.4 +/- 4.5% and 75.5 +/- 4.8%, respectively. Crude incidence of local relapse at 4 years was 6.3% and at regional/distant sites was 26.3%. Highest grades of granulocyte toxicity (< 0.5 x 10(9)/L), moist desquamation, radiation pneumonitis and persistent breast oedema were recorded in 10.7, 8.5, 8.9 and 17.2%, respectively. In patients treated by mastectomy, 5-year actuarial rates of any recurrence, distant recurrence and overall survival were 59.7 +/- 7.3%, 56.7 +/- 7.4% and 50.1 +/- 7%. The crude incidence of local relapse at 4 years was 5.6% and at regional/distant sites it was 45.7%. The issue of appropriate timing of adjuvant therapies has become particularly important with the increasing acknowledgement of the value of anthracycline-based regimens. For women in lower risk categories (e.g. 1-3 nodes positive or node negative), CMF may offer a potentially better therapy, particularly where breast-conserving surgical techniques have been used. In such cases CMF allows the simultaneous delivery of radiotherapy with the result of optimum local control, without compromise or regional or systemic relapse rates. Further randomized trials that directly address the optimal integration of the two modalities, such as the one carried out in Boston, are clearly necessary.

The Trans-Tasman Radiation Oncology Group (TROG) initiated a randomized trial, testing accelerated (twice daily) radiotherapy against conventional radiotherapy for stage III and stage IV squamous cell carcinoma of the head and neck in 1991. In 1996, the Trial Management Committee arranged for a technical audit of 76 cases from 11 institutions, conducted by investigators from interstate institutions. A 10% unacceptable protocol violation rate was detected, which compares favourably with initial Radiation Therapy Oncology Group (RTOG) experience in the late 1970s. Infrastructural deficits with poor quality of documentation, incomplete retrieval of films and document return have been demonstrated in some cases. The Trans-Tasman Radiation Oncology Group is actively pursuing procedural and resourcing issues in order to redress this and is actively expanding its Quality Assurance (QA) Programme with an intercentre dosimetry study. Ultimately, comprehensive clinical and technical QA site visits are planned.

Background and purpose : Regeneration of the aerodigestive mucosa is known to occur during conventionally fractionated radiotherapy. The circumstances surrounding its time of onset and magnitude are not well understood, however. Material and methods : Mucosal reactions were observed in 100 patients undergoing conventionally fractionated treatment at 2 Gy/day over 7 weeks and 88 receiving accelerated treatment at 1.8 Gy twice daily over 312 weeks on the Trans Tasman Radiation Oncology Group head and neck cancer trials. Similar observations in 61 patients treated palliatively at dose rates between 0.8 and 240 Gy/h using ten 3.0–4.2 Gy fractions over 2 weeks are compared. Results : Several findings emerged from these studies: 1. Reactions evolved more quickly at oropharyngeal sites than in the hypopharynx. 2. Reactions at both sites evolved more rapidly at greater rates of dose accumulation. 3. The timing of reactions suggested the presence of a strong regenerative mucosal response that started before the manifestation of ‘patchy' (grade II) mucosal reactions. 4. The regenerative response was strong enough to ‘make good' damage accumulated at a rate of 2 Gy/day in over a third of cases. 5. The linear quadratic model without time correction failed to provide an adequate prediction of the frequency or intensity of mucosal reactions produced by any of the regimes. A simple model of the regenerative response is presented. Conclusions : This study suggests that the timing and magnitude of the regenerative response vary between sites and individuals but are linked to the amount of epithelial cellular depletion occurring during treatment.

The aim of this study was to compare live and photographic methods of assessing variables which can influence cosmetic outcome following breast conserving treatment. This study was undertaken in 47 patients who had previously received breast conserving surgery, radiotherapy and simultaneous chemotherapy for stage I and II breast cancer and a matched group of patients who had received surgery and radiotherapy alone. The assessment consisted of patient and spouse self-assessment, a live assessment by two trained observers and a photographic assessment by five observers, two trained and three untrained. Patients rated their outcome more favourably than their spouses, and both rated the outcomes above those of the other observers. Quantitative variables such as measurement of nipple retraction were assessed by different observers more consistently than qualitative variables such as overall perception of assessed cosmetic outcome. Upward retraction of the nipple emerged as the most powerful determinant of cosmetic outcome in the eyes of both the patient and the trained observers and was reproducibly measured by both live and photographic techniques. The distinction between post-surgical effects and post-radiation effects was more readily made by live assessment. Photographic assessment is as effective as live assessment in post-surgical cosmetic assessment. It provides reliable information about all of the factors which were important to both the patient and observers in formulating an overall cosmetic outcome score. The effects of surgery, which include nipple retraction, need to be taken into account in future trials of adjuvant therapy in which cosmesis is an important outcome measure. Stratification using upward retraction of the nipple is a possibility.

Background and purposes . To define new directions, the Trans Tasman Radiation Oncology Group (TROG) has conducted a detailed analysis of its unrandomised experience with radio-chemotherapy in oesophageal cancer. Methods and patients . Since 1984, 373 patients with oesophageal cancer have been treated on three prospective, but unrandomised, protocols involving radiation with concurrent cisplatin and infusional fluorouracil. Centres in Australia and New Zealand have contributed patients. Reasons for case selection have been examined in detail and prognostic models have been examined in the light of biases exposed. Results . Cause specific survival in 92 patients treated pre-operatively with 35 Gy, infusional fluorouracil and cisplatin was 25.5 ± 6.0% at 5 years and similar to the 5 year expectations of 169 patients treated with 60 Gy and two courses of the same chemotherapy (23.8 ± 4.7%). Analysis of failure in these groups suggests that local relapse precedes the development of metastases and competes as a cause for ultimate failure. Although patients treated surgically were less likely to relapse locally, survival was no better because more developed metastases. Some of the 112 patients treated ‘palliatively' with 30–35 Gy concurrent with chemotherapy without surgery have become long-term survivors with 5 year survival figure in this group 7.7 ± 3.4%. Apart from variables related to disease stage and performance status at presentation, tumour site emerged as a strong predictor of outcome. Prognosis worsens the nearer the tumour is to the stomach. In addition, indications of a radiation dose response relationship emerged. Conclusions . Concurrent radio-chemotherapy protocols can improve outcome in patients fit enough to tolerate these approaches. New strategies remain necessary, however.

Purpose: Thii report updates local control and survival experience and focuses on treatment toxicity in 294 patients with esophageal cancer who have been treated at six Australasian centers using three prospective unrandomized protocols that used concurrent radiation, cisplatin, and modest dose infusional fluorouracii. Methods and Materials: Protocol l--“ definitive” chemoradiation. One hundred and thirty-seven patients have been treated with “definitive” radiation to 60 Gy in 6 weeks plus two courses of cisplatin (80 mg/m’) and infusional fluorouracil (800 mg/m’/day over 4 days) during the first and fourth weeks of radiation. Protocol 2--” preoperative” chemoradiation and surgery. Seventy-eight patients received chemoradiation using the same chemotherapy, but 30-35 Gy in 3-4 weeks prior to surgery. Protocol 3-“palliative” chemoradiation. Seventy-nine patients deemed incurable were treated “palliatively” with the same chemoradiation protocol without surgery. Follow-up ranges from 6 months to 7 years (mean 22 months) in live patients. Results: Durable palliation of dysphagia in all three treatment groups has been reflected by encouraging 3-year survival expectations of 43.2 + 5 % in dethtitively treated patients, 40.3 2 7.65% in surgically treated patients, and 8.5% ? 3.9% in the palliatively treated patients. There are early indications that female patients have fared better than males. Toxicity levels were modest in all three groups. Following definitive treatment, severe myelotoxicity (World Health Organization grades 3 and 4) occurred in 19%, severe esophagitis (World Health Organization grade 3) in ll%, and moderate or severe benign stricture in 17%, depending upon age and sex of the patient (being worse in female patients). Conclusions: These studies demonstrate that the concurrent addition of modest dose cisplatin and infusional dose fluorouracil to radiation in the definitive, preoperative, and palliative settings contribute to high rates of durable dysphagia-free survival, with overall survival comparable to (and possibly better than) the chemoradiation arm of the recently reported Intergroup Study, but at the cost of less morbidity. Esophageal cancer, Combined modality therapy, Chemoradiation.

In a patterns of practice study 14 Australasian radiation oncologists were invited to define tumour and target volumes in 12 sample cases of non-small cell carcinoma of the lung (NSCCL) firstly using orthogonal simulator AP and lateral radiographic views, then using computed tomography (CT) slices obtained in the treatment position. In addition, they were asked to complete questionnaires addressing their criteria for determining treatment policy and their reasons for choosing specific tumour and target volume boundaries in individual cases. Significant variations in choice of size and position of both tumour and target volume were apparent between clinicians. These variations, however were no greater for simulator planned volumes than for CT planned volumes, except in cases selected for palliative treatment, were CT planned volumes were significantly larger. Failure to include tumour extensions, the mistaken inclusion of normal structures as tumour, and major differences in allowance for microscopic tumour spread were identified as the most significant cause for variation in the size and positioning of target volumes between clinicians. Differences over margins to allow for factors such as variation in day-to-day set-up, patient movement, equipment-related factors, etc, were also apparent. CT and simulator planned target volumes were equally successful in adequate tumour coverage; 79162 (49%), and 80162 (49%) respectively. Gross miss of tumour was more common in simulator planned target volumes than CT planned target volumes; 70162 (43%) and 55162 (34%), respectively. This study supports the integration of diagnostic expertise into the planning process for simulator and CT planning, but suggests that substantial practice variation would still exist in planning for radiotherapy in NSCCL.

Thirty-two patients with locally advanced head and neck cancer have been treated with concurrent weekly carboplatin and conventional radiation therapy (RT) (2 Gy fractions 4-5 days/week to a total dose of 64-70 Gy over 7-8 weeks) in a Phase I/II study. Carboplatin was administered weekly during RT at doses of 75-150 mg/m2/wk as a 1-hour infusion. The maximum tolerated dose of carboplatin was 130 mg/m2/wk, with myelosuppression, predominantly neutropenia, being dose limiting. Other systemic toxicities were insignificant and no overlapping toxicity was evident. Ultimate locoregional control and survival probabilities were disappointing. It is suggested that either further studies using radiation and carboplatin at the dose 130 mg/m2/wk, or variations on dose and scheduling be performed prior to the instigation of Phase III studies.

A unifying approach to cumulative dose-volume histogram (CDVH) reduction analysis is presented, utilising two weighted linear interpolation models (VWD, DWV), two weighted probability models (VWP, DWP) and a novel integral probability model (IPM). As a test of their predictive value these algorithms were applied to CDVH data generated from lung doses, measured by TLD arrays in a female anthropomorphic phantom. Three arbitrary configurations of breast size and location of “target volume” within the breast were “treated”, using an appropriate electron field (Varian Clinac 1800) or double-plane iridium-192 implant. Calculated effective doses from each of the reduction algorithms showed the iridium implant to be dosimetrically the most favourable in two the three configurations. Likewise, complication probabilities, based on a logistic dose-volume response function showed lung complication probabilities to be lower for the interstitial technique in the same situations. All algorithms tested showed reasonable consistency, with the exception of the VWD. The rationale and value of comparative rather than absolute dose-volume histogram analyses are discussed.

To identify factors that can influence breast edema in women undergoing breast-conserving therapy. Breast edema was assessed clinically and via high frequency ultrasound (HFUS) prior to, during and following radiotherapy. Fifty-four women were assessed. Breast edema was present prior to radiotherapy in patients who had undergone level 2 node dissection or had wound infection after sentinel node dissection. Edema increased during and after radiotherapy and peaked at 4–6 months. The time course of breast edema was related to the extent of nodal dissection, postoperative wound infection and regional radiotherapy. HFUS prior to irradiation was found to be no better than clinical assessment in predicting prolonged parenchymal breast edema but was significantly better at the end of irradiation. Breast edema levels are minimal in patients who do not undergo axillary node dissection or have an uncomplicated sentinel node dissection. Most edema is due to compromise of the draining lymphatics, which relates largely to the extent of axillary node dissection. HFUS appears to be a useful in the research setting in quantifying the effect of techniques that aim to reduce complications such as edema.

Purpose: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy in improving survival was evaluated by comparison of a matched set of historic control subjects with patients treated in a prospective Phase II study that used synchronous chemotherapy and radiation and adjuvant chemotherapy. Patients and Methods: Patients were included in the analysis if they had disease localized to the primary site and nodes, and they were required to have at least one of the following high-risk features: recurrence after initial therapy, involved nodes, primary size greater than 1 cm, or gross residual disease after surgery. All patients who received chemotherapy were treated in a standardized fashion as part of a Phase II study (Trans-Tasman Radiation Oncology Group TROG 96:07) from 1997 to 2001. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks, and synchronous carboplatin (AUC 4.5) and etoposide, 80 mg/m(2) i.v. on Days 1 to 3, were given in Weeks 1, 4, 7, and 10. The historic group represents a single institution's experience from 1988 to 1996 and was treated with surgery and radiation alone, and patients were included if they fulfilled the eligibility criteria of TROG 96:07. Patients with occult cutaneous disease were not included for the purpose of this analysis. Because of imbalances in the prognostic variables between the two treatment groups, comparisons were made by application of Cox's proportional hazard modeling. Overall survival, disease-specific survival, locoregional control, and distant control were used as endpoints for the study. Results: Of the 102 patients who had high-risk Stage I and II disease, 40 were treated with chemotherapy (TROG 96:07) and 62 were treated without chemotherapy (historic control subjects). When Cox's proportional hazards modeling was applied, the only significant factors for overall survival were recurrent disease, age, and the presence of residual disease. For disease-specific survival, recurrent disease was the only significant factor. Primary site on the lower limb had an adverse effect on locoregional control. For distant control, the only significant factor was residual disease. Conclusions: The multivariate analysis suggests chemotherapy has no effect on survival, but because of the wide confidence limits, a chemotherapy effect cannot be excluded. A study of this size is inadequately powered to detect small improvements in survival, and a larger randomized study remains the only way to truly confirm whether chemotherapy improves the results in high-risk MCC. (c) 2006 Elsevier Inc.

Purpose To describe the natural history of mucosal changes, in particular the development of telangiectases in the rectum, after radiotherapy (RT) for prostate cancer. Methods and materials Twenty patients undergoing local-field, nonconformal RT for prostate cancer underwent flexible sigmoidoscopy every 6 months for up to 3 years after RT completion. Telangiectasis was scored as absent, single, multiple, or multiple confluent. The site and circumferential extent were also documented. The patients filled in a diary to document the symptoms they were experiencing, including rectal bleeding. Results Of the 20 patients, 12 developed multiple telangiectases, and 10 of these had rectal bleeding, which in all cases was mild. Telangiectasis was most commonly seen between 4 (anorectal junction) and 8 cm from the anal verge. In 5 patients, 4 of whom had multiple telangiectases, spontaneous resolution occurred. Conclusion Late radiation effects in the rectum do not appear to be permanent in all cases. This first prospective prolonged evaluation may provide an explanation for the observation that rectal bleeding resolves in a large proportion of patients with mild symptoms after RT. The reasons for improvement in the late radiation changes in the rectum compared with the permanent changes seen in organs such as the skin are unknown.

Purpose: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy was prospectively assessed in a group of patients with high-risk Merkel cell carcinoma (MCC) of the skin. Patients and Methods: Patients were eligible if they had disease localized to the primary site and nodes, and were required to have at least one of the following high risk features: recurrence after initial therapy, involved nodes, primary tumor size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks and synchronous carboplatin (area under the curve, 4.5) and intravenous etoposide 80 mg/m2 days 1 to 3 was given in weeks 1, 4, 7, and 10. The median age of the group was 67 (range, 43–86) years, and there were 39 males and 14 females. Involved nodes (stage II) were present in 33 cases (62%). The sites involved were head and neck (22 patients), occult primary (13 patients), upper limb (eight patients), lower limb (eight patients), and trunk (two patients). Results: Fifty-three patients were entered between 1996 and 2001. The median potential follow-up was 48 months. There were no treatment related deaths. The 3-year overall survival, locoregional control, and distant control were 76%, 75%, and 76%, respectively. Tumor site and the presence of nodes were factors that were predictive for local control and survival. Multivariate analysis indicated that the major factor influencing survival was the presence of nodes; however, this was not a significant factor in locoregional control. Conclusion: High levels of locoregional control and survival have been achieved with the addition of chemotherapy to radiation treatment for high-risk MCC of the skin. The role of chemoradiotherapy for high-risk MCC warrants further investigation.

The aims of this analysis were to determine the effect of anaemia on loco-regional control, relapse-free survival, cause-specific survival, overall survival, and acute and late radiation therapy toxicity in patients with Stage III and IV squamous cell carcinoma of the head and neck treated with radiotherapy.Between 1991 and 1998, 350 patients were randomly assigned to either conventional radiotherapy, (70 Gy in 35 fractions in 49 days) or to accelerated radiotherapy (59.4 Gy in 33 fractions in 24 days). Patients were divided into two groups according to their haemoglobin level: a normal haemoglobin group (/=13 g/dl in males,/=12 g/dl in females) and a low haemoglobin group (13 g/dl in males,12 g/dl in females). The influence of anaemia on cause-specific survival and the development of confluent mucositis independent of other variables was tested using Cox proportional hazards model.Of 350 patients recruited to the trial, 238 had haemoglobin measurements and were eligible for inclusion in this secondary analysis. One hundred and ninety-three were considered to have normal haemoglobin, and 45 patients were considered to be anaemic. There were significant differences between the groups in loco-regional control, relapse-free survival, cause-specific survival and overall survival, with hazards ratios of 0.56 (95% confidence interval (CI) 0.34-0.94), 0.57 (95% CI 0.35-0.92), 0.49 (95% CI 0.29-0.85) and 0.43 (95% CI 0.26-0.70) in favour of the normal haemoglobin group. Using Cox proportional hazards modelling, haemoglobin level was a significant predictor of cause-specific survival in addition to disease site, stage, and Eastern Cooperative Oncology Group status. There were no statistically significant differences between the groups in the development of acute or late reactions.Significant reductions in loco-regional control, disease-free survival, cause-specific survival and overall survival occur in the presence of anaemia. No significant differences in normal tissue toxicity have been identified in this analysis.

Introduction Fatigue is commonly reported in patients receiving radiotherapy for breast conservation, but the underlying mechanisms remain unclear. Methods Patients with early breast cancer participating in a prospective study of the impact of inflammatory processes on early and delayed breast morbidity were assessed for fatigue levels using the Functional Assessment of Cancer Therapy (FACT) fatigue subscale before and at intervals during and after radiotherapy. Blood for analysis of a variety of circulating cytokines, coagulation factors, peripheral blood indices and biochemical factors was collected at the same time points. Results Fifty-two eligible patients were assessed. Twenty-one patients (43%) developed significant fatigue during radiotherapy, whereas 28 (54%) developed minimal or no fatigue. Fatigue appeared to plateau between week 4 of treatment and 2 weeks after treatment. The fatigue was beginning to settle by 6 weeks after treatment. Significant fatigue was predicted by a higher baseline fatigue score, red cell count, neutrophil count, and D-dimer level. Baseline fatigue correlated with higher body mass index, C-reactive protein, soluble thrombomodulin, tissue plasminogen activator, von Willebrand factor antigen, interleukin-6, ICAM-1, hemoglobin and red cell, monocyte, and neutrophil counts. There were also significant correlations between body mass index and tissue plasminogen activator, C-reactive protein, interleukin-6, ICAM-1, and red cell count. After these factors were controlled for, baseline fatigue was seen to be associated with higher body mass index, soluble thrombomodulin, tissue plasminogen activator, von Willebrand factor antigen, monocyte count, and neutrophil count. Multiple logistic regression procedures indicated that the most predictive factors for fatigue during radiotherapy were higher baseline fatigue level and higher baseline neutrophil and red cell counts. Conclusion This study has shown that significant fatigue is common in patients receiving breast irradiation and is precipitated during radiotherapy in some patients but not others. The factors shown to be associated with fatigue in this study will be helpful in shaping future studies.

Purpose: To quantify the oral mucosal cell density and proliferation rate during conventional radiotherapy of head-and-neck tumors and to compare these parameters with clinical scoring of oral mucositis. Methods and Materials: Between 1996 and 1999, 22 patients were included in this study. Mucosal biopsies were taken before or during the radiotherapy course (5 × 2 Gy/wk). Biopsies were incubated in vitro with tritiated thymidine immediately after excision to label DNA-synthesizing cells. Results: Epithelial cell density followed a biphasic radiation response. A steep decrease to about 50% of the preirradiation value (1000 cells/mm epithelium) during Week 1 was followed by a more gradual loss to about 400 cells at the end of treatment. The initial phase was based on the depression of proliferation, with 5–10 labeled cells/mm at the end of Week 1 vs. 60 labeled cells/mm in controls. Subsequently, proliferation was partially restituted at 20 labeled cells/mm. A significant difference in cell numbers was seen between Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Grade 0 (∼850 cell/mm) and Grade 2 (325/mm) or Grade 3 (370/mm). No significant differences were observed between reaction grades 1, 2, and 3. Conclusion: Conventionally fractionated radiotherapy induces a rapid suppression in cell production in Week 1, which results in a prompt reduction in cell numbers. Subsequently, a partial restoration of proliferation significantly reduces the rate of cell loss. These processes clearly precede the clinical response. Regeneration, defined as restoration of cellularity, is already under way when the maximal clinical response is observed. Clinical reaction grading corresponds poorly to cellular density measures during conventional fractionation.

Background : Two prospective trials were designed to determine whether there may be a role for inflammatory mediators in human skin erythema at both high and low doses per fraction and for `out of field' effects. Methods : Trial 1 . Effects of topical indomethacin (1%) and hydrocortisone (1%) applied before and during radiotherapy were compared for erythema induced by 20 Gy in four fractions ( n =26, 6 MV). Trial 2 . Effects of topical hydrocortisone (1%) applied before and during radiotherapy and no medication were compared for erythema induced by 1, 3, 5 and 7 Gy in five fractions ( n =21, 120 kV). Erythema was measured using reflectance spectrophotometry (RFS) and laser Doppler (LD) on a weekly basis. Results : Trial 1 . A bi-phasic reaction time course was suggested in two-thirds of the cases. The first phase did not appear to be influenced by hydrocortisone cream but the second was significantly attenuated. Indomethacin had no effect on either reaction phase. Erythema measured several centimetres outside of the field was reduced by hydrocortisone but not by indomethacin. Trial 2 . Trial 2 confirmed the presence of measurable erythema, invisible to the eye, that coincided in its time course to the first phase of erythema noted in trial 1. This reaction was more intense than predicted by the LQ formula and was non-significantly attenuated by topical hydrocortisone. RFS readings proved to be less subject to inter- and intra-patient variations than the LD unit used. Conclusion : Inflammatory responses may play a role in the mediation of the erythematous response to radiation in human skin. Further studies are warranted.

Background: Development of bone marrow support techniques has altered the standard chemotherapeutic management of haematological malignancies, and these techniques are now being increasingly utilized in solid tumours. In breast cancer, survival benefits have resulted from conventional dose adjuvant chemotherapy, but outcomes remain poor in many women with high-risk disease. Improved response rates with high-dose chemotherapy (HDC) in metastatic disease have led to the investigation of these techniques in adjuvant therapy of high-risk localized disease. In some high-risk patient subgroups survival is extremely poor, with 5-year rates below 30%. Improved adjuvant strategies for patients in these subgroups are therefore urgently required. In Australasia, oncology departments are currently considering accrual of women with high-risk disease into the International Breast Cancer Study Group (IBCSG) 15–95 Trial investigating HDC/stem cell transplantation. Methods: The present paper reviews the available data on the efficacies and toxicities of currently available high-dose chemotherapeutic strategies; discussing methodological considerations relevant to their introduction and safe use in the adjuvant setting in Australia and New Zealand. Results: Although response rates with HDC in metastatic disease are encouraging, the clinical effectiveness of current HDC regimens in adjuvant management has not been established and is limited by significant toxicity. Conclusions: The introduction of HDC strategies for high-risk breast cancer in Australia encounters difficulties both in trial design and potential clinical practice.

Hair cortical cell counting (HCCC) represents a non-invasive, in-vivo measure of cell kill in the human integument. Sixty-six patients undergoing conventionally fractionated, external beam radiotherapy for early stage carcinoma of the prostate had groin hair samples counted. This technique is a sensitive and reproducible measure of radiation effect and may have applicability as an in-vivo prediction tool or in the field of biological dosimetry. A repopulative follicular response occurring at 3-4 weeks may explain flattening of the dose response curve.

Background and purpose . The erythematous response of human skin to radiotherapy has proven useful for testing the predictions of the linear quadratic (LQ) model in terms of fractionation sensitivity and repair half time. No formal investigation of the response of human skin to doses less than 2 Gy per fraction has occurred. This study aims to test the validity of the LQ model for human skin at doses ranging from 0.4 to 5.2 Gy per fraction. Materials and methods . Complete erythema reaction profiles were obtained using reflectance spectrophotometry in two patient populations: 65 patients treated palliatively with 5, 10, 12 and 20 daily treatment fractions (varying thicknesses of bolus, various body sites) and 52 patients undergoing prostatic irradiation for localised carcinoma of the prostate (no bolus, 30–32 fractions). Results and conclusions . Gender, age, site and prior sun exposure influence pre- and post-treatment erythema values independently of dose administered. Out-of-field effects were also noted. The linear quadratic model significantly underpredicted peak erythema values at doses less than 1.5 Gy per fraction. This suggests that either the conventional linear quadratic model does not apply for low doses per fraction in human skin or that erythema is not exclusively initiated by radiation damage to the basal layer. The data are potentially explained by an induced repair model.

PURPOSE: To establish the toxicity profile of simultaneously administered postoperative radiation therapy and CMF chemotherapy as a prelude to a randomized controlled study addressing the sequencing of the two modalities. METHODS AND MATERIALS: One hundred and thirty eight breast cancer patients at high risk of locoregional, as well as systemic relapse, who were referred to three centers in Australia and New Zealand were treated with postoperative radiation therapy and chemotherapy simultaneously. Acute toxicity and dose modifications in these patients were compared with 83 patients treated over the same time frame with chemotherapy alone. In a separate study the long-term radiation and surgical effects in 24 patients treated simultaneously with radiation therapy and chemotherapy at Newcastle (Australia) following conservative surgery were compared with 23 matched patients treated at Newcastle with radiation therapy alone. RESULTS: Myelotoxicity was increased in patients treated simultaneously with radiation therapy and chemotherapy. The effect was not great, but may have contributed to chemotherapy dose reductions. Lymphopenia was observed to be the largest factor in total white cell depressions caused by the simultaneous administration of radiation therapy. Postsurgical appearances were found to so dominate long-term treatment effects on the treated breast that the effect of radiation therapy dose and additional chemotherapy was difficult to detect. CONCLUSION: Studies addressing the sequencing of radiation therapy and chemotherapy will necessarily be large because adverse effects from administering the two modalities simultaneously are not great. The present study has endorsed the importance in future studies of stratification according to the extent and type of surgery and adherence to a single strict policy of chemotherapy dose modification.

SUMMARY Modern radiotherapy planning and treatment techniques allow the delivery of treatment with considerable geographic and dosimetric precision. Uncertainties and variability in the radiotherapy process prior to this stage, that is, localization of the target volume, has received little systematic study. The results of a planning study in non-small cell carcinoma of the lung are presented to highlight the possible variability in the planning process, both at an inter-clinician and intra-clinician level. The implications of this survey, both in terms of treatment outcome and training issues, are discussed.

Well-known inadequacies in currently available electron planning systems, and two cases of temporal lobe necrosis following electron therapy of the parotid stimulated a comprehensive head and neck phantom dosimetric study of the use of high energy electrons for parotid treatments. A typical electron field employed for the treatment of parotid malignancy was examined in an anthropomorphic head phantom from which air cavities had been excavated. Thermoluminescent dosimeter measurements were compared with predicted point doses obtained from a Theraplan Treatment planning system (V05). Data was examined for three different electron energies: 12, 16 and 20 MeV and with the addition of contoured bolus for 20 MeV. A number of significant discrepancies between the measured and predicted dose were observed. Measured doses were seen to exceed predicted doses by up to 23% in the temporal lobe. Further under-predictions of dose were found behind the mandible and in the nasal cavity. Over-predictions of dose by the planning algorithm of up to 22% were observed beside the oropharynx. Some of these discrepancies were found to relate to Theraplan under-estimation of the dose in the fall-off region. Other errors are attributable to the difficulties in predicting dose at density interfaces. Localised over- and under-predictions of this magnitude must be accounted for by the clinician prescribing treatment in terms of possible late effects on the temporal lobe and, in particular, the nominated dose specification point.

Combined modality treatment for cancer of the rectum has been shown to reduce recurrences and improve overall survival. We wished to find out if we could safely give concurrent radiotherapy and 5-fluorouracil (5-FU) modulated by leucovorin (LV) in 3 settings: pre-operatively, adjuvantly and in recurrent disease. A total of 39 patients were treated, 11 preoperatively, 17 adjuvantly and 11 with recurrent disease. There were 26 males and 13 females with a median age of 64 years. The median radiotherapy (RT) dose was 45 Gy/25 fractions/1.8 Gy per fraction (range 25-63 Gy). Chemotherapy consisted of LV 80 mg/m2 i.v. infusion over 1.5 hours followed by 5-FU 400 mg/m2 i.v. bolus, both given once a week. The median number of cycles was 8 (range 3-12). Diarrhoea was the main toxicity, and was encountered in 30 patients (77%): grade 1 in 3 (8%), grade 2 in 12 (30%), grade 3 in 11 (28%), and grade 4 in 4 (10%). This required 18 (46%) patients to have modifications to their RT (20% had breaks and 26% ceased at doses45 Gy). Nine patients (23%) had modifications in the chemotherapy (10% had breaks and 13% received6 cycles). Encouraging responses were seen in the preoperative setting. Concurrent RT and 5-FU/LV, as given in this schedule, results in an unacceptable incidence of diarrhoea, limiting both the total dose of RT and chemotherapy that can be delivered, particularly in patients who have had previous surgery.

This paper examines how physical factors such as the depth of the excision cavity below the skin surface and its distance from the underlying lung may impact upon the choice between the use of an electron field (from a Varian Clinac 1800) or an implant (using a double plane of iridium-192 wires). Data have been derived from a phantom dosimetry experiment simulating different permutations of breast size and depth of excision cavity. An anthropomorphic female phantom with two different-sized wax breast phantoms has been used to simulate the clinical circumstances envisaged and iso-dose distributions have been estimated from an array of TLD readings. The biological significance of doses measured in skin and lung have been examined using the linear-quadratic (LQ) model. Both on physical and biological grounds, the results favour the implant under the experimental conditions adopted. The use of the electron beam to definitively treat the excision cavity (omitting breast tangents) to 60 Gy would result in unacceptable late effects in the skin and an observable incidence of pneumonitis if the excision cavity were near the chest wall. Small carcinogenic risks, particularly to the lung, are apparent with each modality, but may be moderated for the iridium-192 implant by a reduced carcinogenic potential associated with low-dose rate radiation. The use of the newer radionuclides iodine-125 and samarium-145, with less penetrating gamma ray emissions, might be preferred to iridium-192 from the point of view of bronchial carcinogenesis if definitive treatment of the exision cavity became widespread practice.