Obesity and outcomes in patients treated with chemoradiotherapy for esophageal carcinoma.

Body mass index (BMI) is a risk factor for comorbid illnesses and cancer development. It was hypothesized that obesity status affects disease outcomes and treatment-related toxicities in esophageal cancer patients treated with chemoradiotherapy (CRT). From March 2002 to April 2010, 405 patients with non-metastatic esophageal carcinoma at MD Anderson Cancer Center treated with either definitive or neoadjuvant CRT were retrospectively analyzed. Patients were categorized as either obese (BMI ≥ 25 kg/m(2) ) or nonobese (BMI < 25 kg/m(2) ). Progression-free survival and overall survival times were examined using the Kaplan-Meier method and Cox proportional hazards regression analysis. One hundred fifteen (28.4%) patients were classified as nonobese and 290 (71.6%) as obese. Obese patients were more likely than others to have several comorbid diseases (P < 0.001), adenocarcinoma located distally (P < 0.001), and have undergone surgery (P = 0.004). Obesity was not associated with either worse operative morbidity/mortality (P > 0.05) or worse positron emission tomography tumor response (P = 0.46) on univariate analysis, nor with worse pathologic complete response (P = 0.98) on multivariate analysis. There was also no difference in overall survival, locoregional control, or metastasis-free survival between obese and nonobese patients (P = 0.86). However, higher BMI was associated with reduced risk of chemoradiation-induced high-grade esophagitis (P = 0.021), esophageal stricture (P < 0.001), and high-grade hematologic toxicity (P < 0.001). In esophageal cancer patients treated with CRT, obesity is not predictive of poorer disease outcomes or operative morbidities; instead, data suggest it may be associated with decreased risk of acute chemotherapy- and radiotherapy-related treatment toxicities.

Risk factors for local and regional recurrence in patients with resected N0-N1 non-small-cell lung cancer, with implications for patient selection for adjuvant radiation therapy.

BACKGROUND: The purpose of this study was to evaluate the actuarial risk of local and regional failure in patients with completely resected non-small-cell lung cancer (NSCLC), and to assess surgical and pathological factors affecting this risk. PATIENTS AND METHODS: Between January 1998 and December 2009, 1402 consecutive stage I-III (N0-N1) NSCLC patients underwent complete resection without adjuvant radiation therapy. The median follow-up was 42 months. RESULTS: Local-regional recurrence was identified in 9% of patients, with local failure alone in 3% of patients, regional failure alone in 4% of patients, and both local and regional failure simultaneously in 2% of patients. Patients who had local failure were found to be at increased risk of mortality. By multivariate analyses, three variables were shown to be independently significant risk factors for local [surgical procedure (single/multiple wedges+segmentectomy versus lobectomy+bilobectomy+pneumonectomy), tumor size>2.7 cm, and visceral pleural invasion] and regional (pathologic N1 stage, visceral pleural invasion, and lymphovascular space invasion, LVI) recurrence, respectively. CONCLUSION: Patients with N0-N1 disease have low rates of locoregional recurrence after surgical resection. However, several prognostic factors can be identified that increase this risk and identify patients who may benefit from adjuvant treatment.

Switching in polaritonic-photonic crystal nanofibers doped with quantum dots.

We have studied the acousto-optic effect in polaritonic nanofibers made by embedding a cylindrical polaritonic nanowire within a photonic crystal. Here the nanowire consists of either a phonon-polaritonic or an exciton-polaritonic material. The nanowire is doped with ensemble of noninteracting quantum dots. Quantum dots interact with the nanofiber via the exciton-polariton interaction. It is found that for the certain acoustic strain intensity the nanofiber has a localized-to-delocalized polariton transition similar to the metal-to-insulator transitions in doped semiconductors. It is also found that nanofiber has a transparent state due to the exciton-bound polariton coupling. The transparent state can be switched ON or OFF by the external acoustic strain intensity. These are very useful discoveries that can be used to fabricate new types of polaritonic nanoswitches and nanosensors.

c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations.

Although the process of mammary tumorigenesis requires multiple genetic events, it is unclear to what extent carcinogenesis proceeds through preferred secondary pathways following a specific initiating oncogenic event. Similarly, the extent to which established mammary tumors remain dependent on individual mutations for maintenance of the transformed state is unknown. Here we use the tetracycline regulatory system to conditionally express the human c-MYC oncogene in the mammary epithelium of transgenic mice. MYC encodes a transcription factor implicated in multiple human cancers. In particular, amplification and overexpression of c-MYC in human breast cancers is associated with poor prognosis, although the genetic mechanisms by which c-MYC promotes tumor progression are poorly understood. We show that deregulated c-MYC expression in this inducible system results in the formation of invasive mammary adenocarcinomas, many of which fully regress following c-MYC deinduction. Approximately half of these tumors harbor spontaneous activating point mutations in the ras family of proto-oncogenes with a strong preference for Kras2 compared with Hras1. Nearly all tumors lacking activating ras mutations fully regressed following c-MYC deinduction, whereas tumors bearing ras mutations did not, suggesting that secondary mutations in ras contribute to tumor progression. These findings demonstrate that c-MYC-induced mammary tumorigenesis proceeds through a preferred secondary oncogenic pathway involving Kras2.

Randomized dose-searching phase ILE/II trials of fractionation in radiation therapy for cancer.

This article describes a new design, phase ILE/II dose searching, used in four prospective, randomized, multicenter clinical trials of escalating total doses of hyperfractionated radiation. This design combines an experimental protocol with a statistical application of ranking and selection theory. Its purpose was to identify (within a certain margin of error) a dose that achieved the highest rate of clinical response from a set of doses that were tolerable in terms of both acute (within 90 days) and late (more than 90 days) toxic effects (LE). We calculated the number of patients required to reliably test toxicity under various assumptions. To determine the maximum tolerated total dose for hyperfractionated radiation, we randomly assigned patients with tumors that responded to radiation therapy in a dose-dependent manner from four body sites (lung, upper respiratory and digestive tract, bladder, and brain) to one of three regimens receiving total doses (D1, D2, or D3) differing by increments of 4.8 Gy. All patients received two fractions of 1.2 Gy each (separated by 4-6 hours) daily 5 days a week. The lowest total dose was set at the level considered tolerable with standard once-a-day radiation therapy. We tested tumor responses and late toxic effects of higher doses by assigning patients to these three regimens until acute effects and early estimates of late effects were found to be acceptable for the highest dose D3; thereafter, regimen D1 was closed, and additional patients were assigned to D2, D3, and D4 (an escalated total dose greater than D3 by an increment of 4.8 Gy). The assignment of patients was performed in a weighted manner (1:1:2), so that greater numbers were assigned to the highest dose regimen (whether D3 or D4) to allow rapid evaluation of the feasibility of the highest dose.

Comparison of prognostic factors and survival among black patients and white patients treated with irradiation for non-small-cell lung cancer.

BACKGROUND: Many studies have reported differences in cancer incidence and survival between populations of Blacks and Whites. A 45% higher death rate from lung cancer for Black men and a survival duration for Black patients with lung cancer that is generally shorter than that for White patients have also been reported. PURPOSE: The purpose of this study was to evaluate whether race affects known prognostic factors for non-small-cell lung cancer in Black versus White patients. This analysis attempts to determine which prognostic factors may contribute to the reported differences in disease outcome. METHODS: We used data from 1565 patients with non-small-cell lung cancer treated in four randomized prospective trials conducted by the Radiation Therapy Oncology Group (RTOG). The data were pooled for a retrospective analysis of survival and prognostic factors by race. RESULTS: Univariate analysis showed significant differences between Blacks and Whites with regard to sex, weight loss, histology, and RTOG T stage (P < .05), but the only clinically significant difference (P < or = .01) was weight loss. Despite these findings, overall survival for Blacks and Whites did not differ significantly (P = .67). Median survival for Blacks and Whites with a Karnofsky performance status (KPS) of 90 or more was 12.1 and 11.3 months, respectively (P = .45). Survival for Blacks and Whites with a KPS of less than 90 was 7.8 and 6.8 months, respectively. Cause of death did not differ between the two races. For both races, KPS, age, sex, weight loss, and RTOG T and N stages were significant prognostic factors for survival (P < .01), but race was not a significant prognostic factor. CONCLUSION: Further studies of the differential in cancer survival for Blacks and Whites may be indicated, but greater impact may be achieved by addressing socioeconomic factors, lifestyle and occupational risk factors, health education, and access to adequate health care.

p53 status and prognosis of locally advanced prostatic adenocarcinoma: a study based on RTOG 8610.

BACKGROUND: The p53 tumor suppressor gene (also known as TP53) is one of the most frequently mutated genes in human cancer. Several studies have shown that p53 mutations are infrequent in prostate cancer and are associated with advanced disease. PURPOSE: We assessed the prognostic value of identifying abnormal p53 protein expression in the tumors of patients with locally advanced prostate cancer who were treated with either external-beam radiation therapy alone or total androgen blockade before and during the radiation therapy. METHODS: The study population consisted of a subset of patients entered in Radiation Therapy Oncology Group protocol 8610 ("a phase III trial of Zoladex and flutamide used as cytoreductive agents in locally advanced carcinoma of the prostate treated with definitive radiotherapy"). Immunohistochemical detection of abnormal p53 protein in pretreatment specimens (i.e., needle biopsies or transurethral resections) was achieved by use of the monoclonal anti-p53 antibody DO7; specimens in which 20% or more of the tumor cell nuclei showed positive immunoreactivity were considered to have abnormal p53 protein expression. Associations between p53 protein expression status and the time to local progression, the incidence of distant metastases, progression-free survival, and overall survival were evaluated in univariate (logrank test) and multivariate (Cox proportional hazards model) analyses. Reported P values are two-sided. RESULTS: One hundred twenty-nine (27%) of the 471 patients entered in the trial had sufficient tumor material for analysis. Abnormal p53 protein expression was detected in the tumors of 23 (18%) of these 129 patients. Statistically significant associations were found between the presence of abnormal p53 protein expression and increased incidence of distant metastases (P = .04), decreased progression-free survival (P = .03), and decreased overall survival (P = .02); no association was found between abnormal p53 protein expression and the time to local progression (P = .58). These results were independent of the Gleason score and clinical stage. A significant treatment interaction was detected with respect to the development of distant metastases: Among patients receiving both radiation therapy and hormone therapy, those with tumors exhibiting abnormal p53 protein expression experienced a reduced time to the development of distant metastases (P = .001); for patients treated with radiation therapy alone, the time to distant metastases was unrelated to p53 protein expression status (P = .91). CONCLUSIONS: Determination of p53 protein expression status yield significant, independent prognostic information concerning the development of distant metastases, progression-free survival, and overall survival for patients with locally advanced prostate cancer who are treated primarily with radiation therapy. IMPLICATIONS: The interaction of radiation therapy plus hormone therapy and abnormal p53 protein expression may provide a clinical link to experimental evidence that radiation therapy and/or hormone therapy act, at least in part, by the induction of apoptosis (a cell death program) and suggests that this mechanism may be blocked in patients whose tumors have p53 mutations.

A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11.

A phase Ilate/II trial of hyperfractionated (HFX) radiation therapy for non-small-cell carcinoma of the lung (NSCCL) was conducted by the Radiation Therapy Oncology Group (RTOG) between 1983 and 1987. Fractions of 1.2 Gy were administered twice daily with greater than or equal to 4 hours between fractions. Patients were randomized to receive minimum total doses of 60.0, 64.8, and 69.6 Gy. After acceptable risks of acute and late effects were found, 74.4 Gy and 79.2 Gy arms were added, and the lowest total dose arms were closed. No significant differences in the risks of acute or late effects in normal tissues were found among the 848 patients analyzed in the five arms; risks of severe or life-threatening pneumonitis were 2.6% for 60.0 to 64.8 Gy, 5.7% for 69.6 to 74.4 Gy, and 8.1% for 79.2 Gy. Among 350 patients who had the same criteria as Cancer and Leukemia Group B (CALGB) protocol 84-33 (American Joint Committee on Cancer Staging [AJCCS], 1984, stage III; Karnofsky performance status [KPS] 70 to 100; less than 6% weight loss), there was a dose response for survival: survival with 69.6 Gy (median, 13.0 months; 2 years, 29%) was significantly (P = .02) better than the lower total doses. There were no differences in survival among the three highest total-dose arms. Comparisons with results in similar patients treated with 60 Gy in 30 fractions of 2.0 Gy 5 days per week for 6 weeks suggest benefit from HFX radiation therapy with 69.6 Gy. Improvement in survival with HFX radiation therapy at 69.6 Gy total dose without increase in normal tissue effects, justifies phase III comparison with standard fractionation alone and combined with systemic chemotherapy in this common presentation of NSCCL.

Consensus statements on radiation therapy of prostate cancer: guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. American Society for Therapeutic Radiology and Oncology Consensus Panel.

PURPOSE: To develop evidence-based guidelines for (1) prostate re-biopsy after radiation and (2) radiation therapy with rising prostate-specific antigen (PSA) levels after radical prostatectomy in the management of patients with localized prostatic cancer. DESIGN: The American Society of Therapeutic Radiology and Oncology (ASTRO) challenged a multidisciplinary consensus panel to address consensus on specific issues in each of the two topics. Four well-analyzed patient data sets were presented for review and questioning by the panel. The panel sought criteria that would be valid for patients in standard clinical practice as well as for patients enrolled in clinical trials. Subsequent to an executive session that followed these presentations, the panel presented its consensus guidelines. RESULTS AND CONCLUSIONS: Based on the data presented, the prostate re-biopsy negative rates ranged from 62% to 80% for patients with stage T1-2 tumors. The panel judged that prostate re-biopsy is not necessary as standard follow-up care and that the absence of a rising PSA level after radiation therapy is the most rigorous end point of total tumor eradication. Further, the panel judged that re-biopsy may be an important research tool. Based on the data presented, the long-term (5 years or more) PSA remission rate after salvage radiation therapy ranges from 27% to 45%. The panel requested results from prospective randomized trials to evaluate optimally this information. The panel judged that the total dose of radiation should be 64 Gy or slightly higher and that, in patients with or without radiation therapy, there is no standard role for androgen suppressant therapy for rising PSA values after prostatectomy.

Central lymphatic irradiation for stage III nodular malignant lymphoma: long-term results.

PURPOSE: To report the long-term results of central lymphatic irradiation for stage III nodular malignant lymphoma. PATIENTS AND METHODS: Between 1969 and 1985, 34 patients (26 with nodular poorly differentiated lymphoma, four with nodular mixed lymphocytic/histiocytic lymphoma, and four with nodular histiocytic lymphoma) were treated with central lymphatic irradiation. Median age of the group was 51 years (range, 30 to 73). There were 15 men and 19 women. Staging work-up included a physical examination and bone marrow biopsy in all patients. Seventy-four percent had a lymphangiogram (LAG) and 44% a laparotomy (LAP). Eighty-two percent had either a LAP or a LAG. Thirty-two patients were Ann Arbor stage IIIA and two were stage IIIB. All patients received lymphatic irradiation that encompassed cervical, supraclavicular, axillary, mediastinal, paraaortic, mesenteric, pelvic, and femoral lymphatics to total doses ranging from 20 to 30 Gy in 1.0- to 1.8-Gy fractions. Waldeyer's ring was initially treated in 17 patients. Follow-up information is available on all 34 patients. Median follow-up is 9 years, 8 months (range, 15 to 244 months). RESULTS: Life-table actuarial overall, disease-free, and cause-specific survival rates at 15 years are 28%, 40%, and 46%, respectively. Only one relapse was observed after 9 years. Disease-free survival was significantly improved in patients with five or fewer sites of involvement (P = .02). Age, sex, B symptoms, histology, and technique of irradiation were not prognostically significant. Salvage therapy, including further irradiation and/or chemotherapy, was delivered to 20 patients. Ten percent of these patients remain alive without evidence of disease. Toxicity data were available for the patients treated at the Medical College of Wisconsin (MCW). Radiation Therapy Oncology Group (RTOG) acute hematologic, gastrointestinal, and salivary toxicity scores were < or = 2 in 83% of patients. Late toxicity scores were < or = 2 in 96%. Persistent xerostomia was noted in 23% of patients who received initial treatment to Waldeyer's ring. CONCLUSION: These results suggest that initial comprehensive central lymphatic irradiation may be the preferred approach to achieve a durable relapse-free interval for this group of patients.

Serial determination of the bcl-2 gene in the bone marrow and peripheral blood after central lymphatic irradiation for stages I-III follicular lymphoma: a preliminary report.

Two-thirds of patients with follicular lymphoma have rearrangement of bcl-2 major breakpoint region (MBR) through t(14;18) (q32;q21). This rearrangement can serve as a sensitive marker for follicular lymphoma cells. This study was undertaken to assess the molecular complete response rate of stages I-III follicular lymphoma to central lymphatic irradiation (CLI) by detection of PCR-amplifiable bcl-2 MBR rearrangement in the bone marrow and peripheral blood before and after CLI. Twenty patients with stages I-III follicular lymphoma were treated with CLI. Twelve of them were part of a prospective randomization trial comparing CLI with multi-agent chemotherapy. Bone marrow and peripheral blood samples were obtained from the patients before the initiation of treatment. By using the PCR technique, the DNA sequences from the bone marrow and peripheral blood samples that flank the bcl-2 MBR involved in t(14;18) (q32;q21) were amplified. In PCR-positive patients, bone marrow and blood samples were followed at regular intervals during and after CLI. The results of the PCR amplification were correlated with clinical findings. All 20 patients achieved clinical complete response after CLI. Median follow-up was 22 months (range, 12-37 months), and no patient has relapsed. Pretreatment PCR results were available in all patients (19 patients for peripheral blood samples and 16 patients for bone marrow samples). Nine of 19 peripheral blood samples and 9 of 16 bone marrow samples were PCR-positive for bcl-2 MBR rearrangement. Eight PCR-positive patients converted to negative (8 of 9 blood samples and 2 of 3 bone marrow samples) 2-20 months from the first day of CLI. Bone marrow and peripheral blood with PCR-amplifiable bcl-2 MBR rearrangement can be converted from positive to negative after chemotherapy in patients with follicular lymphoma. Early results from our study show for the first time that peripheral blood and bone marrow can be converted from positive to negative after CLI. The prognostic significance of the observed conversions requires longer follow-up.

Radiation palliation of cervical cancer.

Radiation is a useful modality for palliation of local-regional disease in patients with cervical cancer who require palliation because of distant metastases, extensive local-regional disease, medical consideration, or patient concerns. Two radiation schedules have been reported on for the treatment of advanced pelvic disease including cervical cancer. The large single-dose schedule consisted of 10-Gy fractions repeated at monthly intervals to a maximum of 30 Gy. This schedule has produced good palliative results with symptomatic improvement in approximately 50% of patients and objective response in 35%-80%. However, severe late toxicity was shown to be as high as 42% (actuarial). The second schedule tested by the Radiation Therapy Oncology Group consisted of 3.7-Gy fractions given twice a day for 2 days (14.8 Gy) repeated after 2-4 weeks for a maximum of 44.4 Gy. There were 284 patients accrued, and the subgroup of 61 cervical cancer patients is analyzed in this article. The subjective response (50%-100% complete response) and objective response (53%) were similar to those observed with the large single-fraction schedule. The late toxicity was significantly lower (7%-actuarial). For patients who may survive 6 months or longer, this second schedule is preferable.

Randomized phase III study of chemoradiation with or without amifostine for patients with favorable performance status inoperable stage II-III non-small cell lung cancer: preliminary results.

A prospective randomized study was conducted to determine whether amifostine (Ethyol) reduces the rate of severe esophagitis and hematologic and pulmonary toxicity associated with chemoradiation or improves control of non-small cell lung cancer (NSCLC). Sixty patients with inoperable stage II or III NSCLC were treated with concurrent chemoradiotherapy. Both groups received thoracic radiation therapy (TRT) with 1.2 Gy/fraction, 2 fraction per day, 5 days per week for a total dose 69.6 Gy. All patients received oral etoposide (VP-16), 50 mg Bid, 30 minutes before TRT beginning day 1 for 10 days, repeated on day 29, and cisplatin 50 mg/m(2) intravenously on days 1, 8, 29, and 36. Patients in the study group received amifostine, 500 mg intravenously, twice weekly before chemoradiation (arm 1); patients in the control group received chemoradiation without amifostine (arm 2). Patient and tumor characteristics were distributed equally in both groups. Of the 60 patients enrolled, 53 were evaluable (27 in arm 1, 26 in arm 2) with a median follow-up of 6 months. Median survival times were 26 months for arm 1 and 15 months for arm 2, not statistically significantly different. Morphine intake to reduce severe esophagitis was significantly lower in arm 1 (2 of 27, 7.4%) than arm 2 (8 of 26, 31%; P =.03). Acute pneumonitis was significantly lower in arm 1 (1 of 27, 3.7%) than in arm 2 (6 of 26, 23%; P =.037). Hypotension (20 mm Hg decrease from baseline blood pressure) was significantly more frequent in arm 1 (19 of 27, 70%) than arm 2 (1 of 26, 3.8%; P =.0001). Only 1 patient discontinued treatment because of hypotension. These preliminary results showed that amifostine significantly reduced acute severe esophagitis and pneumonitis. Further observation is required to assess long-term efficacy.

Evolution and accomplishments of the Radiation Therapy Oncology Group.

PURPOSE: The Radiation Therapy Oncology Group (RTOG) recently completed its first quarter century as a cooperative clinical cancer research organization. It is timely and appropriate to document its origins, evolution, and accomplishments. METHODS AND MATERIALS: The historical review of the RTOG called upon written and oral documentation. RESULTS: The RTOG is the most enduring product of the Committee for Radiation Therapy Studies (CRTS). Although not one of the original 17 clinical trials groups developed by the National Cancer Institute in 1956, the RTOG has pursued trials suggested by laboratory findings including the oxygen effect, intrinsic radiosensitivity, proliferation kinetics of normal and tumor cells, and interactions with other cytotoxic agents. Improvements in survival have been demonstrated for patients with carcinoma of the esophagus and cervix, and nonsmall cell carcinomas of the lung. The national and international radiation oncology communities have benefitted from standards and quality control/assurance guidelines for established and new modalities. A growing number of institutions in North America participate in RTOG trials. CONCLUSION: The RTOG is an important clinical research resource, which has contributed to improved outcome for patients with many forms of cancer. It has become increasingly productive and widely adopted and endorsed by oncologists throughout North America.

Radiotherapy for lung cancer.

The role of radiation therapy in the management of lung cancer was reviewed at a workshop held in Cambridge, England, in June 1984. It was concluded that there was a continuing role for radiation therapy in the primary management of small cell lung cancer, including the loco-regional treatment for patients with limited disease. Radical radiotherapy for patients with non-small cell carcinoma could be curative for a proportion of patients with limited disease. Careful planning and quality control was essential. Palliative radiotherapy provided useful treatment for many other patients. Other related aspects of treatment are also presented.

Do prostatic biopsies 12 months or more after external irradiation for adenocarcinoma, Stage III, predict long-term survival?

Serial biopsies of the prostate after high dose external irradiation for adenocarcinoma show a gradual disappearance of the neoplastic cells. With such treatment, results of the biopsies do not have any short term prognostic significance. However, positive biopsies 12 months or more after treatment are reputed to be an unfavorable sign for long-term survival. From August, 1970 through February, 1974, 46 consecutive patients with locally advanced (Stage III, C, or T3 and T4) adenocarcinoma of the prostate underwent external irradiation with 2 MV X rays or cobalt-60 teletherapy. The technique included parallel, opposed, 14 X 14 cm anterior and posterior fields, and a 10 X 14 cm perineal field. The center of the prostate received a total dose of 70 Gy in 30-37 fractions in 43 to 56 days. Details of the dosimetry reveal inhomogeneity of the dose of +/- 7% within an enlarged prostate. With a median follow-up of 8 years, the actuarial survival rates, uncorrected for death from intercurrent disease, are 69% at 5 years and 49% at 10 years. Biopsies of the prostate 12 months or more after treatment were available from 31 patients: 19 had one or more positive biopsies and 12 had consistently negative biopsies; the survival curves are identical for those with and those without positive biopsies. Prostatic biopsies obtained 24 months or more after treatment were available from 21 patients: 10 had positive and 11 had negative biopsies; the survival curves are identical for those with and without residual cancer cells. Following adequate irradiation of patients with locally advanced adenocarcinoma of the prostate, the results of biopsies obtained one or two years after treatment do not predict long-term survival.

International Clinical Trials in Radiation Oncology. Lung sites.

The lung studies of the RTOG have been among the most productive of any in the group. The development of studies has been predicated upon failure pattern analyses from previous trials. Multiple approaches to attacking these diseases have been taken, including dose/fraction studies and high LET irradiations to improve local-regional control, prophylactic irradiation of sites of frequent, distant metastases, systemic chemotherapy and radioimmunoglobulins to control distant metastases, and biologic response modifiers to restore or enhance host defense mechanisms. All studies have been predicated upon making incremental advances in improving treatment outcome in these common disease, based on the philosophy that small improvements in survival will save thousands of lives.

Frequency of brain metastasis in adenocarcinoma and large cell carcinoma of the lung: correlation with survival.

From January 1970 through December 1981, 469 patients with histologically or cytologically proven adenocarcinoma (AC) (349) and large cell carcinoma (LC) (120) of the lung were seen at the Department of Radiation Oncology, Medical College of Wisconsin Affiliated Hospitals. One quarter (126/469) of these patients had brain metastasis: 48 patients presented with brain metastasis (AC 35/349 = 10% and LC 13/120 = 11%) and 78 patients subsequently developed brain metastasis (AC 61/314 = 19%, LC 17/107 = 16%). Those patients who received prophylactic cranial irradiation were excluded from this study. Brain was the dominant site of metastasis in 82 patients who received only cranial + thoracic irradiation; 37 patients (17 simultaneous, 20 metachronous) also required irradiation of other sites of metastasis. All 17 patients with LC, and 47/61 (77%) with AC who developed metachronous brain metastasis did so within one year. The cumulative probability of brain metastasis increased with survival to the levels predicted by autopsy studies. Therapeutic brain irradiation may result in long-term survival in patients with single organ brain metastasis. Three of 119 patients who underwent whole brain irradiation for metastasis, are alive at 60 (LC), 48 (AC) and 48 months (AC) after treatment. Since patients with AC and LC so frequently develop brain metastasis and the brain may be the only site of metastasis, prophylactic cranial irradiation may significantly reduce morbidity and mortality from these diseases.

Total dose, fraction size, and tumor volume in the local control of Hodgkin's disease.

There are important uncertainties in the radiation therapy of Hodgkin's disease. These uncertainties are related to dose-fractionation and total dose necessary to control subclinical disease (prophylactic irradiation), small-size tumors, and especially bulky tumors such as those frequently encountered in the mediastinum. Data are lacking on total dose and tumor control as a function of tumor volume. A retrospective study was undertaken of patients with Hodgkin's disease Stages I-III treated with radiation therapy alone at the Medical College of Wisconsin Affiliated Hospitals between 1970 and 1982. Detailed dose calculations of off-axis points were made to assign precise minimum doses to 1,304 separate lymph node regions. Treatment volumes received individual fractions of 150 cGy to 300 cGy and total doses of 30 Gy to 42 Gy. Tumor control was correlated with tumor size at presentation, fractionation schedule, and total dose. The results confirm the absence of a dose-response relationship for tumor control, between 30 Gy and 42 Gy total dose. In addition, there is no apparent difference in total dose required for larger tumors relative to that required for small tumors.

Phase I-II study of prophylactic hepatic irradiation with local irradiation and systemic chemotherapy for adenocarcinoma of the pancreas.

Although the addition of 5-FU to radiation therapy for locally advanced adenocarcinoma of the pancreas improved short-term survival (GITSG), there were no differences in patterns of failure. Hepatic metastases were equally common in both groups. Therefore, a pilot study of prophylactic hepatic irradiation was developed. Between March 1983 and May 1985, 16 patients were entered in a Phase I/II study of prophylactic hepatic irradiation with local irradiation and systemic chemotherapy for adenocarcinoma of the pancreas at the Medical College of Wisconsin Affiliated Hospitals. Megavoltage radiation (1.8 Gy/fraction) was given to the pancreas with a minimal margin (2 cm) around the tumor, localized by surgical clips or CT scan with a total dose of 61.2 Gy over 7 weeks. Prophylactic hepatic irradiation was added to the fourth week of irradiation to a total dose of 23.4 Gy over 21/2 weeks. 5-Fluorouracil, 500 mg/M2/day was given at Day 1, 2, 3, 29, 30, and 31 of radiotherapy, then a weekly maintenance for 1 year. Fifteen patients were evaluable: One patient refused chemotherapy. The follow-up period was 14 to 50 months (median 26 months). The most common side effect was nausea. Maintenance 5-FU was discontinued in one patient because of GI bleeding. Three-quarters of the patients developed temporary elevations of hepatic enzymes. No severe or life-threatening complications were observed. One, 2-, 3-, and 4-year disease-free survivals are 66.7%, 46.7%, 20% and 13.3%, respectively. Patterns of failure revealed that only two patients had hepatic metastasis as the first site of failure, five patients died of abdominal carcinomatosis, and three patients failed in the pancreas. Two patients died without evidence of cancer. Two patients are alive and well beyond 4 years after the diagnosis. This study confirms that such aggressive combined modality treatment is well tolerated and suggests that the frequency of hepatic metastasis can be reduced.