Hypoxia inducible factor 1alpha signaling in fractionated radiation-induced lung injury: role of oxidative stress and tissue hypoxia.

To investigate the relationship of HIF1alpha signaling to oxidative stress, tissue hypoxia, angiogenesis and inflammation, female Fischer 344 rats were irradiated to the right hemithorax with a fractionated dose of 40 Gy (8 Gy x 5 days). The lung tissues were harvested before and at 4, 6, 10, 14, 18, 22 and 26 weeks after irradiation for serial studies of biological markers, including markers for hypoxia (HIF1alpha, pimonidazole and CA IX), oxidative stress (8-OHdG), and angiogenesis/capillary proliferation (VEGF/CD 105), as well as macrophage activation (ED-1) and cell signaling/fibrosis (NFkappaB, TGFbeta1), using immunohistochemistry and Western blot analysis. HIF1alpha staining could be observed as early as 4 weeks postirradiation and was significantly increased with time after irradiation. Importantly, HIF1alpha levels paralleled oxidative stress (8-OHdG), tissue hypoxia (pimonidazole and CA IX), and macrophage accumulation consistent with inflammatory response. Moreover, changes in HIF1alpha expression identified by immunohistochemistry assay parallel the changes in TGFbeta1, VEGF, NFkappaB and CD 105 levels in irradiated lungs. These results support the notion that oxidative stress and tissue hypoxia might serve as triggering signals for HIF1alpha activity in irradiated lungs, relating to radiation-induced inflammation, angiogenesis and fibrosis.

Timing and patterns of recurrences and deaths from prostate cancer following adjuvant pelvic radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate.

To determine the timing and patterns of late recurrence after radical prostatectomy (RP) alone or RP plus adjuvant radiotherapy (RT). Between 1970 and 1983, 159 patients underwent RP for newly diagnosed adenocarcinoma of the prostate and were found to have positive surgical margins, extracapsular extension and/or seminal vesicle invasion. Of these, 46 received adjuvant RT and 113 did not. The RT group generally received 45-50 Gy to the whole pelvis, then a boost to the prostate bed (total dose of 55-65 Gy). In the RP group, 62% received neoadjuvant/adjuvant androgen deprivation vs 17% in the RT group. Patients were analyzed with respect to timing and patterns of failure. Only one patient was lost to follow-up. The median follow-up for surviving patients was nearly 20 years. The median time to failure in the surgery group was 7.5 vs 14.7 years in the RT group (P=0.1). Late recurrences were less common in the surgery group than the RT group (9 and 1% at 10 and 15 years, respectively vs 17 and 9%). In contrast to recurrences, nearly half of deaths from prostate cancer occurred more than 10 years after treatment. Deaths from prostate cancer represented 55% of all deaths in these patients. Recurrences beyond 10 years after RP in this group of patients were relatively uncommon. Despite its long natural history, death from prostate cancer was the most common cause of mortality in this population with locally advanced tumors, reflecting the need for more effective therapy.

Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer.

BACKGROUND: The genetic events leading to initiation and/or progression of prostate cancer are not well characterized. The gene coding for the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) has recently been identified as a tumor suppressor in several types of cancer. The purpose of the present study is to determine whether the M6P/IGF2R gene is inactivated in human prostate cancer, and if so, whether this is an early or late transformational event. METHODS: In total, 43 patients with prostate cancer treated by radical prostatectomy, with archival material available for analysis, were assessed for loss of heterozygosity (LOH) in the M6P/IGF2R gene using six different gene-specific nucleotide polymorphisms. Regions of tumor, normal prostate and premalignant high-grade prostate intraepithelial neoplasia (PIN) were identified and cells were excised by laser capture microdissection (LCM). DNA segments were amplified using polymerase chain reaction (PCR). RESULTS: The M6P/IGF2R gene was polymorphic in 83.7% (36/43) of patients, and 41.7% (15/36) of these informative patients had LOH in the tumor tissue. In 11/15 patients with LOH in malignant tissue, high-grade PIN could be identified, and 63.6% (7/11) also had LOH in this premalignant tissue. CONCLUSIONS: This study is the first to find that the M6P/IGF2R gene is inactivated in prostate cancer. LOH in premalignant tissue as well suggests that mutation in the M6P/IGF2R gene is an early event in the development of prostate cancer, supporting the conclusion that it functions as a tumor suppressor gene in this disease.

What is the best postoperative treatment for patients with pT3bN0M0 adenocarcinoma of the prostate?

The purpose of this paper to identify the optimal therapy after radical prostatectomy (RP) for patients with adenocarcinoma of the prostate invading the seminal vesicles (pT3bN0M0 or SVI). A PubMed search using the keywords 'prostate', 'seminal vesicle', 'prostatectomy', 'radiotherapy', 'androgen blockade' was performed to identify literature regarding rates of disease failure in patients with SVI who are observed or treated with androgen blockade (AB), radiotherapy (RT) or RT + AB after RP. The outcome of 68 patients treated at Duke University with post-operative AB, RT or RT + AB for pT3bN0M0 is also presented. More than 70% of patients with SVI develop disease recurrence after surgery. For many, recurrence occurs within 2 y after RP. These patients have poor control rates with postoperative RT alone. While experience with AB and RT+AB is limited, control rates are generally superior to RT alone. At Duke University, after a median follow-up of nearly 4 y, patients treated with RT + AB or AB alone for pT3bN0M0 achieved better 5-y progression-free survival (PFS) compared with those who received RT alone (78 and 68 vs 30%, P = 0.03 and 0.046, respectively). There was no PFS difference between those who received AB alone or RT + AB (68 vs 78%, P=0.5). Seminal vesicle invasion confers a poor prognosis after RP. SVI is a consistent predictor of poor outcome after RT. The limited data available examining AB and RT + AB in pT3bN0M0 disease, including data from Duke University, are encouraging. Nonetheless, postoperative AB, RT and RT + AB for pT3bN0M0 disease require prospective evaluation, as RP alone is rarely curative.

Radiation-induced pulmonary toxicity: a dose-volume histogram analysis in 201 patients with lung cancer.

PURPOSE: To relate lung dose-volume histogram-based factors to symptomatic radiation pneumonitis (RP) in patients with lung cancer undergoing 3-dimensional (3D) radiotherapy planning. METHODS AND MATERIALS: Between 1991 and 1999, 318 patients with lung cancer received external beam radiotherapy (RT) with 3D planning tools at Duke University Medical Center. One hundred seventeen patients were not evaluated for RP because of <6 months of follow-up, development of progressive intrathoracic disease making scoring of pulmonary symptoms difficult, or unretrievable 3D dosimetry data. Thus, 201 patients were analyzed for RP. Univariate and multivariate analyses were performed to test the association between RP and dosimetric factors (i.e., mean lung dose, volume of lung receiving >or=30 Gy, and normal tissue complication probability derived from the Lyman and Kutcher models) and clinical factors, including tobacco use, age, sex, chemotherapy exposure, tumor site, pre-RT forced expiratory volume in 1 s, weight loss, and performance status. RESULTS: Thirty-nine patients (19%) developed RP. In the univariate analysis, all dosimetric factors (i.e., mean lung dose, volume of lung receiving >or=30 Gy, and normal tissue complication probability) were associated with RP (p range 0.006-0.003). Of the clinical factors, ongoing tobacco use at the time of referral for RT was associated with fewer cases of RP (p = 0.05). These factors were also independently associated with RP according to the multivariate analysis (p = 0.001). Models predictive for RP based on dosimetric factors only, or on a combination with the influence of tobacco use, had a concordance of 64% and 68%, respectively. CONCLUSIONS: Dosimetric factors were the best predictors of symptomatic RP after external beam RT for lung cancer. Multivariate models that also include clinical variables were slightly more predictive.

Using plasma transforming growth factor beta-1 during radiotherapy to select patients for dose escalation.

PURPOSE: The ability to prescribe treatment based on relative risks for normal tissue injury has important implications for oncologists. In non-small-cell lung cancer, increasing the dose of radiation may improve local control and survival. Changes in plasma transforming growth factor beta (TGFbeta) levels during radiotherapy (RT) may identify patients at low risk for complications in whom higher doses of radiation could be safely delivered. PATIENT AND METHODS: Patients with locally advanced or medically inoperable non-small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved nodes to a dose of 73.6 Gy (1.6 Gy twice daily). If the plasma TGFbeta level was normal after 73.6 Gy, additional twice daily RT was delivered to successively higher total doses. The maximum-tolerated dose was defined as the highest radiation dose at which < or = one grade 4 (life-threatening) late toxicity and < or = two grade 3 to 4 (severe life-threatening) late toxicities occurred. RESULTS: Thirty-eight patients were enrolled. Median follow-up was 16 months. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGFbeta levels. Fourteen patients whose TGFbeta levels were normal after 73.6 Gy were escalated to 80 Gy (n = 8) and 86.4 Gy (n = 6). In the 86.4-Gy group, dose-limiting toxicity was reached because there were two (33%) grade 3 late toxicities. CONCLUSION: It is feasible to use plasma TGFbeta levels to select patients for RT dose escalation for non-small-cell lung cancer. The maximum-tolerated dose using this approach is 86.4 Gy.

Relating radiation-induced regional lung injury to changes in pulmonary function tests.

PURPOSE: To determine whether the sum of radiotherapy (RT)-induced reductions in regional lung perfusion is quantitatively related to changes in global lung function as assessed by reductions in pulmonary function tests (PFTs). METHODS AND MATERIALS: Two hundred seven patients (70% with lung cancer) who received incidental partial lung irradiation underwent PFTs (forced expiratory volume in 1 s and diffusion capacity for carbon monoxide) before and repeatedly after RT as part of a prospective clinical study. Regional lung function was serially assessed before and after RT by single photon emission computed tomography perfusion scans. Of these, 53 patients had 105 post-RT evaluations of changes in both regional perfusion and PFTs, were without evidence of intrathoracic disease recurrence that might influence regional perfusion and PFT findings, and were not taking steroids. The summation of the regional functional perfusion changes were compared with changes in PFTs using linear regression analysis. RESULTS: Follow-up ranged from 3 to 86 months (median 19). Overall, a significant correlation was found between the sum of changes in regional perfusion and the changes in the PFTs (p = 0.002-0.24, depending on the particular PFT index). However, the correlation coefficients were small (r = 0.16-0.41). CONCLUSIONS: A statistically significant correlation was found between RT-induced changes in regional function (i.e., perfusion) and global function (i.e., PFTs). However, the correlation coefficients are low, making it difficult to relate changes in perfusion to changes in the PFT results. Thus, with our current techniques, the prediction of changes in perfusion alone does not appear to be sufficient to predict the changes in PFTs accurately. Additional studies to clarify the relationship between regional and global lung injury are needed.

Radiation-induced hypoxia may perpetuate late normal tissue injury.

PURPOSE: The purpose of this study was to determine whether or not hypoxia develops in rat lung tissue after radiation. METHODS AND MATERIALS: Fisher-344 rats were irradiated to the right hemithorax using a single dose of 28 Gy. Pulmonary function was assessed by measuring the changes in respiratory rate every 2 weeks, for 6 months after irradiation. The hypoxia marker was administered 3 h before euthanasia. The tissues were harvested at 6 weeks and 6 months after irradiation and processed for immunohistochemistry. RESULTS: A moderate hypoxia was detected in the rat lungs at 6 weeks after irradiation, before the onset of functional or histopathologic changes. The more severe hypoxia, that developed at the later time points (6 months) after irradiation, was associated with a significant increase in macrophage activity, collagen deposition, lung fibrosis, and elevation in the respiratory rate. Immunohistochemistry studies revealed an increase in TGF-beta, VEGF, and CD-31 endothelial cell marker, suggesting a hypoxia-mediated activation of the profibrinogenic and proangiogenic pathways. CONCLUSION: A new paradigm of radiation-induced lung injury should consider postradiation hypoxia to be an important contributing factor mediating a continuous production of a number of inflammatory and fibrogenic cytokines.

Predicting the risk of symptomatic radiation-induced lung injury using both the physical and biologic parameters V(30) and transforming growth factor beta.

PURPOSE: To correlate the volume of lung irradiated with changes in plasma levels of the fibrogenic cytokine transforming growth factor beta (TGFbeta) during radiotherapy (RT), such that this information might be used to predict the development of symptomatic radiation-induced lung injury (SRILI). METHODS AND MATERIALS: The records of all patients with lung cancer treated with RT with curative intent from 1991 to 1997 on a series of prospective normal tissue injury studies were reviewed. A total of 103 patients were identified who met the following inclusion criteria: (1) newly diagnosed lung cancer of any histology treated with RT +/- chemotherapy with curative intent; (2) no evidence of distant metastases or malignant pleural effusion; (3) no thoracic surgery after lung RT; (4) no endobronchial brachytherapy; (5) follow-up time more than 6 months; (6) plasma TGFbeta1 measurements obtained before and at the end of RT. The concentration of plasma TGFbeta1 was measured by an enzyme-linked immunosorbent assay. Seventy-eight of the 103 patients were treated with computed tomography based 3-dimensional planning and had dose-volume histogram data available. The endpoint of the study was the development of SRILI (modified NCI [National Cancer Institute] common toxicity criteria). RESULTS: The 1-year and 2-year actuarial incidence of SRILI for all 103 patients was 17% and 21%, respectively. In those patients whose TGFbeta level at the end of RT was higher than the pre-RT baseline, SRILI occurred more frequently (2-year incidence = 39%) than in patients whose TGFbeta1 level at the end of RT was less than the baseline value (2-year incidence = 11%, p = 0.007). On multivariate analysis, a persistent elevation of plasma TGFbeta1 above the baseline concentration at the end of RT was an independent risk factor for the occurrence of SRILI (p = 0.004). The subgroup of 78 patients treated with 3-dimensional conformal radiotherapy, who consequently had dose-volume histogram data, were divided into groups according to their TGFbeta1 kinetics and whether their V(30) level was above or below the median of 30%. Group I (n = 29), with both a TGFbeta1 level at the end of RT that was below the pre-RT baseline and V(30) < 30%; Group II (n = 35), with a TGFbeta1 level at the end of irradiation that was below the baseline but a V(30) > or = 30% or with a TGFbeta1 level at the end of RT that was above the pre-RT baseline but V(30) < 30%; Group III (n = 14), with both a TGFbeta1 level at the end of RT that was above the baseline and V(30) > or = 30%. A significant difference was found in the incidence of SRILI among these three groups (6.9%, 22.8%, 42.9%, respectively, p = 0.02). CONCLUSIONS: (1) An elevated plasma TGFbeta1 level at the end of RT is an independent risk factor for SRILI; (2) The combination of plasma TGFbeta1 level and V(30) appears to facilitate stratification of patients into low, intermediate, and high risk groups. Thus, combining both physical and biologic risk factors may allow for better identification of patients at risk for the development of symptomatic radiation-induced lung injury.

Acute urinary toxicity following transperineal prostate brachytherapy using a modified Quimby loading method.

PURPOSE: To examine the acute urinary toxicity following transperineal prostate implant using a modified Quimby loading method with regard to time course, severity, and factors that may be associated with a higher incidence of morbidity. METHODS AND MATERIALS: One hundred thirty-nine patients with prostate adenocarcinoma treated with brachytherapy from 1997 through 1999 had follow-up records available for review. Patients considered for definitive brachytherapy alone included those with prostate specific antigen (PSA) < or = 6, Gleason score (GS) < or = 6, clinical stage < T2b, and prostate volumes generally less than 40 cc. Patients with larger prostate volumes were given neoadjuvant antiandrogen therapy. Those with GS > 6, PSA > 6, or Stage > T2a were treated with external beam radiation therapy followed by brachytherapy boost. Sources were loaded according to a modified Quimby method. At each follow-up, toxicity was graded based on a modified RTOG urinary toxicity scale. RESULTS: Acute urinary toxicity occurred in 88%. Grade I toxicity was reported in 23%, grade II in 45%, and grade III in 20%, with 14% requiring prolonged (greater than 1 week) intermittent or indwelling catheterization. Overall median duration of symptoms was 12 months. There was no difference in duration of symptoms between patients treated with I-125 or Pd-103 sources (p = 0.71). After adjusting for GS and PSA, multivariate logistic regression analysis showed higher incidence of grade 3 toxicity in patients with larger prostate volumes (p = 0.002), and those with more seeds implanted (p < 0.001). Higher incidence of prolonged catheterization was found in patients receiving brachytherapy alone (p = 0.01), with larger prostate volumes (p = 0.01), and those with more seeds implanted (p < 0.001). CONCLUSION: Interstitial brachytherapy for prostate cancer leads to a high incidence of acute urinary toxicity, most of which is mild to moderate in severity. A prolonged need for catheterization can occur in some patients. Patients receiving brachytherapy alone, those with prostate volumes greater than 30 cc, and those implanted with a greater number of seeds have the highest incidence of significant toxicity.

Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience.

OBJECTIVE: To examine clinical outcomes in patients receiving neoadjuvant chemoradiation for locally advanced rectal adenocarcinoma. SUMMARY BACKGROUND DATA: Preoperative radiation therapy, either alone or in combination with 5-fluorouracil-based chemotherapy, has proven both safe and effective in the treatment of rectal cancer. However, data are lacking regarding which subgroups of patients benefit from the therapy in terms of decreased local recurrence and increased survival rates. METHODS: A retrospective chart review was performed on 141 consecutive patients who received neoadjuvant chemoradiation (5-fluorouracil +/- cisplatin and 4,500-5,040 cGy) for biopsy-proven locally advanced adenocarcinoma of the rectum. Surgery was performed 4 to 8 weeks after completion of chemoradiation. Standard statistical methods were used to analyze recurrence and survival. RESULTS: Median follow-up was 27 months, and mean age was 59 years (range 28-81). Mean tumor distance from the anal verge was 6 cm (range 1-15). Of those staged before surgery with endorectal ultrasound or magnetic resonance imaging, 57% of stage II patients and 82% of stage III patients were downstaged. The chemotherapeutic regimens were well tolerated, and resections were performed on 140 patients. The percentage of sphincter-sparing procedures increased from 20% before 1996 to 76% after 1996. On pathologic analysis, 24% of specimens were T0. However, postoperative pathologic T stage had no effect on either recurrence or survival. Positive lymph node status predicted increased local recurrence and decreased survival. CONCLUSIONS: Neoadjuvant chemoradiation is safe, effective, and well tolerated. Postoperative lymph node status is the only independent predictor of recurrence and survival.

Adjuvant radiotherapy following radical prostatectomy is more effective and less toxic than salvage radiotherapy for a rising prostate specific antigen.

Despite the trend toward earlier diagnosis of adenocarcinoma of the prostate, approximately 25% of men undergoing radical prostatectomy will have pathologic evidence of cancer extending outside of the prostate. These patients are at high risk for subsequent recurrence. Such relapses are almost always manifested initially as a rise in the Prostate Specific Antigen (PSA). Currently utilized PSA assays, however, will not detect a recurrence smaller than 10(7) to 10(8) cells, nor does PSA identify the site of recurrence. In contrast, the pathologic findings at the time of surgery can be used to reliably distinguish patients at risk for local recurrence from those more likely to fail distantly. Furthermore, adjuvant pelvic radiotherapy after prostatectomy, given to patients with an undetectable PSA who are at high risk for local recurrence, results in a higher disease free survival and fewer side effects than if radiotherapy is delayed until the PSA begins to rise. Thus, patients at high risk for local failure following radical prostatectomy, but at low risk for distant metastases (i.e., those with positive surgical margins and an undetectable PSA) should be offered immediate adjuvant radiotherapy.

73.6 Gy and beyond: hyperfractionated, accelerated radiotherapy for non-small-cell lung cancer.

PURPOSE: To assess results with twice-daily high-dose radiotherapy (RT) for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between 1991 and 1998, 94 patients with unresectable NSCLC were prescribed > or = 73.6 Gy via accelerated fractionation. Fifty were on a phase II protocol (P group); 44 were similarly treated off-protocol (NP group). The clinical target volume received 45 Gy at 1.25 Gy bid (6-hour interval). The gross target volume received 1.6 Gy bid to 73.6 to 80 Gy over 4.5 to 5 weeks using a concurrent boost technique. Overall survival (OS) and local progression-free survival (LPFS) were calculated by the Kaplan-Meier method. Median follow-up durations for surviving P and NP patients were 67 and 16 months, respectively. RESULTS: Total doses received were > or = 72 Gy in 97% of patients. The median OS by stage was 34, 13, and 12 months for stages I/II, IIIa, and IIIb, respectively. LPFS was significantly longer for patients with T1 lesions (median, 43 months) versus T2-4 (median, 7 to 10 months; P =.01). Results were similar in the P and NP groups. Acute grade > or = 3 toxicity included esophagus (14 patients; 15%), lung (three patients; 3% [one grade 5]), and skin (four patients; 4%). Grade > or = 3 late toxicity in 86 assessable patients included esophagus (three patients; 3%), lung (15 patients; 17% [three grade 5]), skin (five patients; 6%), heart (two patients; 2%), and nerve (one patient; 1%). CONCLUSION: This regimen yielded favorable survival results, particularly for T1 lesions. Acute grade > or = 3 toxicity seems greater than for conventional RT, though most patients recovered. Late grade > or = 3 pulmonary toxicity occurred in 17%. Because of continued locoregional recurrences, we are currently using doses > or = 86 Gy.

Normal tissue radiobiology: from the laboratory to the clinic.

This manuscript is in four parts, presenting the four talks given in a symposium on normal tissue radiobiology. The first part addresses the general concept of the role of parenchymal cell radiosensitivity vs. other factors, highlighting research over the last decade that has altered our understanding of factors underlying normal tissue response. The other three parts expand on specific themes raised in the first part dealing in particular with (1) modifications of fibroblast response to irradiation in relation to the induction of tissue fibrosis, (2) the use of the linear-quadratic equation to model the potential benefits of using different means (both physical and biologic) of modifying normal tissue response, and (3) the specific role of the growth factor TFG-beta1 in normal tissue response to irradiation. The symposium highlights the complexities of the radiobiology of late normal tissue responses, yet provides evidence and ideas about how the clinical problem of such responses may be modified or alleviated.

Can we predict radiation-induced changes in pulmonary function based on the sum of predicted regional dysfunction?

PURPOSE: To determine whether changes in whole-lung pulmonary function test (PFT) values are related to the sum of predicted radiation therapy (RT)-induced changes in regional lung perfusion. PATIENTS AND METHODS: Between 1991 and 1998, 96 patients (61% with lung cancer) who were receiving incidental partial lung irradiation were studied prospectively. The patients were assessed with pre- and post-RT PFTs (forced expiratory volume in one second [FEV1] and diffusion capacity for carbon monoxide [DLCO]) for at least a 6-month follow-up period, and patients were excluded if it was determined that intrathoracic recurrence had an impact on lung function. The maximal declines in PFT values were noted. A dose-response model based on RT-induced reduction in regional perfusion (function) was used to predict regional dysfunction. The predicted decline in pulmonary function was calculated as the weighted sum of the predicted regional injuries: equation [see text] where Vd is the volume of lung irradiated to dose d, and Rd is the reduction in regional perfusion anticipated at dose d. RESULTS: The relationship between the predicted and measured reduction in PFT values was significant for uncorrected DLCO (P = .005) and borderline significant for DLCO (P = .06) and FEV1 (P = .08). However, the correlation coefficients were small (range,.18 to.30). In patients with lung cancer, the correlation coefficients improved as the number of follow-up evaluations increased (range,.43 to.60), especially when patients with hypoperfusion in the lung adjacent to a central mediastinal/hilar thoracic mass were excluded (range,.59 to.91). CONCLUSION: The sum of predicted RT-induced changes in regional perfusion is related to RT-induced changes in pulmonary function. In many patients, however, the percentage of variation explained is small, which renders accurate predictions difficult.

Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor (M6P/IGF2R) locus predisposes patients to radiation-induced lung injury.

PURPOSE: To investigate the relationship between loss of heterozygosity (LOH) at the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) gene locus and the development of radiation-induced lung injury. MATERIAL AND METHODS: Thirty-five lung cancer patients with both stored plasma for Transforming Growth Factor beta1 (TGFbeta1) analysis and sufficient quantities of archival pathology tissue to screen for LOH were studied. All patients had been treated with thoracic radiotherapy for their malignancy and had radiographically detectable tumor present before beginning radiotherapy. Tumor and normal cells were microdissected from archival lung cancer pathology specimens. Two polymorphisms in the 3' untranslated region of the M6P/IGF2R were used to screen for LOH. Plasma TGFbeta1 levels were measured using acid-ethanol extraction and an ELISA. TGFbeta1 and M6P/IGF2R protein expression was estimated by immunofluorescence and immunohistochemical staining. Symptomatic radiation pneumonitis was scored according to National Cancer Institute Common Toxicity Criteria without knowledge of the results of TGFbeta or LOH analyses. RESULTS: Of the 35 patients, 10 were homozygous for this polymorphism (noninformative) and were excluded. Of the 25 informative patients, 13 had LOH. Twelve of 13 patients with LOH had increased pretreatment plasma TGFbeta1 levels, vs. 3/12 patients without LOH (p < 0.01). A decrease or loss of M6P/IGF2R protein in the malignant cell accompanied by increased latent TGFbeta1 protein in extracellular matrix and tumor stroma was found in tumors with LOH, suggesting that this mutation resulted in loss of function of the receptor. Seven of 13 (54%) LOH patients developed symptomatic radiation-induced lung injury vs. 1/12 (8%) of patients without LOH (p = 0.05). CONCLUSION: Loss of the M6P/IGF2R gene strongly correlates with the development of radiation pneumonitis after thoracic radiotherapy (RT). Furthermore, patients with LOH (in the setting of measurable tumor) are much more likely to have elevated plasma TGFbeta, suggesting an inability to normally process this cytokine. Thus, loss of the M6P/IGF2R gene may predispose patients to the development of radiation-induced lung injury.

Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas.

BACKGROUND: The use of neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors. This article reports our experience with neoadjuvant CRT for localized pancreatic cancer. METHODS: Since 1995, 111 patients with radiographically localized, pathologically confirmed pancreatic adenocarcinoma have received neoadjuvant external beam radiation therapy (EBRT; median, 4500 cGy) with 5-flourouracil-based chemotherapy. Tumors were defined as potentially resectable (PR, n = 53) in the absence of arterial involvement and venous occlusion and locally advanced (LA, n = 58) with arterial involvement or venous occlusion by CT. RESULTS: Five patients (4.5%) were not restaged due to death (n = 3) or intolerance of therapy (n = 2). Twenty-one patients (19%) manifested distant metastatic disease on restaging CT. Twenty-eight patients with initially PR tumors (53%) and 11 patients with initially LA tumors (19%) were resected after CRT. Histologic examination revealed significant fibrosis in all resected specimens and two complete responses. Surgical margins were negative in 72%, and lymph nodes were negative in 70% of resected patients. Median survival in resected patients has not been reached at a median follow-up of 16 months. CONCLUSIONS: Neoadjuvant CRT provided an opportunity for patients with occult metastatic disease to avoid the morbidity of resection and resulted in tumor downstaging in a minority of patients with LA tumors. Survival after neoadjuvant CRT and resection appears to be at least comparable to survival after resection and adjuvant (postoperative) CRT.

Complete response to neoadjuvant chemoradiation for rectal cancer does not influence survival.

BACKGROUND: Up to 30% of patients with locally advanced rectal cancer have a complete clinical or pathologic response to neoadjuvant chemoradiation. This study analyzes complete clinical and pathologic responders among a large group of rectal cancer patients treated with neoadjuvant chemoradiation. METHODS: From 1987 to 2000, 141 consecutive patients with biopsy-proven, locally advanced rectal cancer were treated with preoperative 5-fluorouracil-based chemotherapy and radiation. Clinical restaging after treatment consisted of proctoscopic examination and often computed tomography scan. One hundred forty patients then underwent operative resection, with results tracked in a database. Standard statistical methods were used to examine the outcomes of those patients with complete clinical or pathologic responses. RESULTS: No demographic differences were detected between either clinical complete and clinical partial responders or pathologic complete and pathologic partial responders. The positive predictive value of clinical restaging was 60%, and accuracy was 82%. By use of the Kaplan-Meier life table analysis, clinical complete responders had no advantage in local recurrence, disease-free survival, or overall survival rates when compared with clinical partial responders. Pathologic complete responders also had no recurrence or survival advantage when compared with pathologic partial responders. Of the 34 pathologic T0 tumors, 4 (13%) had lymph node metastases. CONCLUSIONS: Clinical assessment of complete response to neoadjuvant chemoradiation is unreliable. Micrometastatic disease persists in a proportion of patients despite pathologic complete response. Observation or local excision for patients thought to be complete responders should be undertaken with caution.

The physical parameters and molecular events associated with radiation-induced lung toxicity.

Radiation therapy (RT) is frequently used to treat patients with tumors in and around the thorax. Clinical radiation pneumonitis is a common side effect, occurring in 5% to 20% of patients. Efforts to identify patients at risk for pneumonitis have focused on physical factors, such as dose and volume. Recently, the underlying molecular biological mechanisms behind RT-induced lung injury have come under study. Improved knowledge of the molecular events associated with RT-induced lung injury may translate into a better ability to individualized therapy. This review discusses our current understanding of the physical and molecular factors contributing to RT-induced pulmonary injury.