Anthony H. Russell

Recursive partitioning analysis of 1999 radiation therapy oncology group (RTOG) patients with locally-advanced non–small-cell lung cancer (LA-NSCLC): Identification of five groups with different survival

PURPOSE Survival of patients with locally-advanced non-small-cell lung cancer (LA-NSCLC) is predicted by the stage of the disease and other characteristics. This analysis was undertaken to identify these characteristics in a large cooperative group patient population, as well as to define subgroups of the population with differing outcomes. PATIENTS AND METHODS Analysis included 1,999 patients treated in 9 RTOG trials between 1983 and 1994 with thoracic irradiation (RT) with (n = 355) or without chemotherapy (CT). RESULTS In univariate analysis, the following characteristics were significantly associated with an improved survival: use of CT, CT delivered without major deviation, abnormal pulmonary function tests, normal hemoglobin, protein, LDH and BUN, presence of dyspnea, hemoptysis, cough or hoarseness, uninvolved lymph nodes, T1 or T2 stage, no malignant pleural effusion (PE), weight loss of < 8%, Karnofsky performance status (KPS) of at least 90, adenocarcinoma histology, female gender, and age less than 70 years. Recursive partitioning analysis (RPA) was subsequently applied to identify 5 patient subgroups with significantly different median survival times (MST): Group I, KPS of > or = 90, who received chemotherapy (MST 16.2 months); Group II, KPS of > or = 90, who received no CT, but had no PE (MST 11.9 months); Group III, KPS < 90, younger than 70 years, with non-large cell histology (MST 9.6 months); Group IV, KPS > or = 90, but with PE, or KPS < 90, younger than 70 years, and with large cell histology, or older than 70 years, but without PE (MST 5.6-6.4 months); Group V, older than 70, with PE (MST 2.9 months). CONCLUSION Cisplatinum-based CT improves survival, for excellent prognosis of LA-NSCLC patients, over RT alone. The presence of a malignant pleural effusion is a major negative prognostic factor for survival. The identification of RPA prognostic groups among patients with LA-NSCLC provides prognostic information and may serve as a basis of stratification in future trials.

Anal sphincter conservation for patients with adenocarcinoma of the distal rectum: long-term results of radiation therapy oncology group protocol 89-02

PURPOSE To assess the outcome of a multi-institutional, national cooperative group study attempting functional preservation of the anorectum for patients with limited, distal rectal cancer. METHODS AND MATERIALS Between September 21, 1989 and November 1, 1992, a Phase II trial of sphincter-sparing therapy was conducted for patients with clinically mobile rectal cancers located below the pelvic peritoneal reflection. Protocol treatment was designed for patients who were, in the judgement of their attending surgeon, unsuitable for anal sphincter conservation in the context of anterior resection, and would have required abdominoperineal resection (APR) as conventional surgical therapy. Primary cancers were estimated to be 4 cm or less in largest clinical diameter, and occupied 40% or less of the rectal circumference. Chest radiography and computerized axial tomography (CT) of the abdomen and pelvis excluded patients with overt lymphatic or hematogenous metastases. Protocol surgery was intended to remove the primary cancer by en-bloc, transmural excision of an ellipse of rectal wall by transanal, transcoccygeal, or trans-sacral technique, while conserving the anal sphincter. Based on tumor size, T classification, grade, and adequacy of surgical margins, patients were allocated to one of three treatment assignments: observation, or adjuvant treatment with 5-fluorouracil (5-FU) and one of two different dose levels of local-regional radiation. After completion of protocol therapy, patients were observed with follow-up that included periodic general physical and rectal examination, determinations of CEA, abdominopelvic CT, chest radiography, and surveillance endoscopy. Sixty-five eligible and analyzable patients were registered. RESULTS With minimum follow-up of 5 years and median follow-up of 6.1 years, 11 patients have failed: 3 patients recurred local-regionally only, 3 patients had distant failure alone, and 5 patients manifested local-regional and distant failure. Eight patients died of intercurrent illness. Local-regional failure correlated with T-category revealed: T1 1/27 (4%), T2 4/25 (16%), and T3 3/13 (23%). Local-regional failure escalated with percentage involvement of the rectal circumference: 2/31 (6%) among patients with cancers involving 20% or less of the rectal circumference, and 6/34 (18%) among patients with cancers involving 21-40% of the circumference. Distant dissemination rose with T-category with 1/27 (4%) T1, 3/25 (12%) T2, and 4/13 (31%) T3 patients manifesting hematogenous spread. Eight patients (12%) required temporary or permanent colostomy. Five of 8 patients with local-regional recurrence achieved local-regional control with management including surgery, although 4 of these patients subsequently developed distant dissemination. Three patients (5%) had persistent, uncontrolled, local disease. Actuarial freedom from pelvic relapse at 5 years is 88% based on the entire study population, and 86% for the less favorable patients treated with adjuvant radiation and 5-FU. CONCLUSION Conservative, sphincter-sparing therapy is a feasible alternative treatment for selected patients with limited cancer involving the middle and lower rectum. Risk of both local and distant failure appears to escalate with increasing T-category (depth of invasion). Results achieved in the multi-institutional, cooperative group setting approximate results reported from single institutions.

Treatment planning for colorectal cancer: radiation and surgical techniques and value of small-bowel films

For colorectal cancer, the adjuvant radiation dose levels required to achieve a high incidence of local control closely parallel the radiation tolerance of small bowel (4500-5000 rad), and for patients with partially resected or unresected disease, the dose levels exceed tolerance (6000-7000 rad). Therefore, both the surgeon and the radiation oncologist should use techniques that localize tumor volumes and decrease the amount of small intestine within the irradiation field. Surgical options include pelvic reconstruction (reperitonealization, omental flaps, retroversion of uterus, etc.) and clip placement. Radiation options include the use of radiographs to define small bowel location and mobility combined with treatment techniques using multiple fields, bladder distention, shrinking or boost fields, and/or patient position changes (prone, decubitus, etc.). When both specialties interact in optimum fashion, local control can be increased with minimal risks to achieve a suitable therapeutic ratio.

ACCELERATED HYPERFRACTIONATED HEPATIC IRRADIATION IN THE MANAGEMENT OF PATIENTS WITH LIVER METASTASES: RESULTS OF THE RTOG DOSE ESCALATING PROTOCOL

PURPOSE This study was prepared to address two objectives: (a) to determine whether progressively higher total doses of hepatic irradiation can prolong survival in a selected population of patients with liver metastases; (b) to refine existing concepts of liver tolerance for fractionated external radiation employing a fraction size which might be appropriate in clinical protocols evaluating elective or adjuvant radiation of the liver. METHODS AND MATERIALS One hundred seventy-three analyzable patients with computed tomography measurable liver metastases from primary cancers of the gastrointestinal tract were entered on a dose escalating protocol of twice daily hepatic irradiation employing fractions of 1.5 Gy separated by 4 hr or longer. Sequential groups of patients received 27 Gy, 30 Gy, and 33 Gy to the entire liver and were monitored for acute and late toxicities, survival, and cause of death. Dose escalation was implemented following survival of 10 patients at each dose level for a period of 6 months or longer without clinical or biochemical evidence of radiation hepatitis. RESULTS The use of progressively larger total doses of radiation did not prolong median survival or decrease the frequency with which liver metastases were the cause of death. None of 122 patients entered at the 27 Gy and 30 Gy dose levels revealed clinical or biochemical evidence of radiation induced liver injury. Five of 51 patients entered at the 33 Gy level revealed clinical or biochemical evidence of late liver injury with an actuarial risk of severe (Grade 3) radiation hepatitis of 10.0% (+/- 7.3% S.E.) at 6 months, resulting in closure of the study to patient entry. CONCLUSION The study design could not credibly establish a safe dose for hepatic irradiation, however, it did succeed in determining that 33 Gy in fractions of 1.5 Gy is unsafe, carrying a substantial risk of delayed radiation injury. The absence of apparent late liver injury at the 27 Gy and 30 Gy dose levels suggests that a prior clinical trial of adjuvant hepatic irradiation in patients with resected colon cancer may have employed an insufficient radiation dose (21 Gy) to fully test the question.

Adenocarcinoma of the proximal colon sites of initial dissemination and patterns of recurrence following surgery alone

Seven hundred ninety‐five patients were adenocarcinomas of the proximal colon were reviewed. Two hundred forty‐five patients presented with disseminated disease at the time of diagnosis, and were analyzed to identify mechanisms and sites of disease spread. Five hundred fifty patients underwent radical resection, and were followed for a minimum of 48 months or until time of documented relapse. One hundred eightysix patients (34%) manifested recurrent carcinoma, 64 (34.5%) of whom underwent second laparotomy at the time of initial recurrence. In 139 patients (74.5%), the distribution of clinical recurrence was confined to the abdomen, retroperitoneum, and liver. Prognostic influence of initial stage and tumor grade are analyzed, and possible implications for surgical staging and adjuvant therapy are discussed.

Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: Results of a prospective randomized trial conducted by the radiation therapy oncology group

Beginning in February 1984, 187 evaluable patients with adenocarcinoma or large cell carcinoma of the lung clinically confined to the chest were randomized to receive either conventionally fractionated thoracic irradiation alone or thoracic irradiation with concurrent, prophylactic cranial irradiation. The study population included 161 patients treated for medically or surgically inoperable primary cancers, and 26 patients undergoing adjuvant postoperative mediastinal irradiation following attempted curative resection of primary cancers found to have metastasized to hilar or mediastinal lymph nodes. Elective brain irradiation was not effective in preventing the clinical appearance of brain metastases, although the time to develop brain metastases appears to have been delayed. Eighteen of 94 patients (19%) randomized to chest irradiation alone have developed brain metastases as opposed to 8/93 patients (9%) randomized to receive prophylactic cranial irradiation (p = .10). No survival difference was observed between the treatment arms. Among the 26 patients undergoing prior resection of all gross intrathoracic disease, brain metastases were observed in 3/12 patients (25%) receiving adjuvant chest irradiation alone, compared to none of 14 receiving prophylactic cranial irradiation (p = .06). In the absence of fully reliable therapy for the primary disease, and without effective systemic therapy preventing dissemination to other, extrathoracic sites, prophylactic cranial irradiation for inoperable non-small cell lung cancer cannot be justified in routine clinical practice. Further investigation in the adjuvant, postoperative setting may be warranted.

Late injury of cancer therapy on the female reproductive tract

The purpose of this article is to review the late effects of cancer therapy on the female reproductive tract. The anatomic sites detailed are the vulva, vagina, cervix, uterus, fallopian tubes, and ovaries. The available pathophysiology is discussed. Clinical syndromes are presented. Tolerance doses of irradiation for late effects are rarely presented in the literature and are reviewed where available. Management strategies for surgical, radiotherapeutic, and chemotherapeutic late effects are discussed. Endpoints for evaluation of therapeutic late effects have been formulated utilizing the symptoms, objective, management, and analytic (SOMA) format. Late effects on the female reproductive tract from cancer therapy should be recognized and managed appropriately. A grading system for these effects is presented. Endpoints for late effects and tolls for the evaluation need to be further developed.

Subset analysis of RTOG 85-31 and 86-10 indicates an advantage for long-term vs. short-term adjuvant hormones for patients with locally advanced nonmetastatic prostate cancer treated with radiation therapy.

PURPOSE The benefit of adjuvant hormones in prostate cancer patients receiving definitive radiation therapy (RT) in RTOG 85-31 and 86-10 has previously been reported. This analysis excludes those patients with positive lymph nodes or postprostatectomy to determine the benefit of adjuvant hormones in men with locally advanced nonmetastatic prostate cancer receiving definitive RT. METHODS AND MATERIALS Nine hundred ninety-three eligible patients from RTOG 85-31 and 86-10 treated between 1987-1992 were included in this study. Five hundred seventy-five patients with T3N0M0 disease were included from RTOG 85-31 and 418 patients with T2b-T4N0M0 disease from RTOG 86-10. Patients randomized to receive long-term hormones (LTH) on 85-31 received goserelin starting the last week of RT and continued indefinitely. Patients treated with short-term hormones (STH) on 86-10 received goserelin and flutamide 2 months prior to and during RT. The median follow-up for all patients in this analysis was 71 months (range, 0.6-129 months). RESULTS Combining both studies, statistically significant improvements in outcome were observed between the RT and hormones (I) and RT alone (II) groups for biochemical disease-free survival (bNED control) and distant metastases failure (DMF). Statistically significant improvements in bNED control, DMF and cause-specific failure (CSF) were observed for patients receiving LTH compared with STH. In those patients receiving LTH, the benefit in bNED control (p = 0.0002), DMF (p = 0.05), and CSF (p = 0.02) was limited to centrally reviewed Gleason score of 7 and 8-10 tumors. For all patients treated on 85-31, statistically significant improvements for bNED control, DMF, and CSF were observed between Group I and II. Multivariate analysis demonstrated Gleason score and the use of LTH to be independent predictors for bNED control (p < 0.0001), DMF (p < 0.0001), and CSF (p < 0.002). CONCLUSIONS Based on this analysis, adjuvant long-term hormones compared to short-term hormones resulted in statistically significant improvements in bNED control, DMF, and CSF rates for patients with locally advanced nonmetastatic prostate cancer.

Adenocarcinoma of the stomach: Autopsy observations with therapeutic implications for the radiation oncologist

Autopsy and clinical records of 85 patients dying of stomach cancer were reviewed in order to study patterns of recurrence and dissemination. Loco-regional recurrence was observed in 15 of 16 patients who had undergone potentially curative surgical resection, and was the most common form of treatment failure. Peritoneal seeding, seen in 29% of the patients who died without treatment, was the most common manifestation of cancer dissemination (47%), and was associated with shorter average duration of survival. Among patients undergoing potentially curative resection, initial serosal involvement was predictive of subsequent peritoneal recurrence (7/10), whereas only 1 of 6 patients with initially uninvolved serosa developed this pattern of failure. Patients with primary cancers involving the gastro-esophageal junction were more likely to have extra-abdominal spread (9/13, 69%) than patients whose cancers involved more distal portions of the stomach (35/72, 49%). Potential implications for surgical staging, choice of radiation treatment volume, and design of clinical trials are discussed.

Addition of chemotherapy to radiation therapy alters failure patterns by cell type within non-small cell carcinoma of lung (NSCCL): Analysis of radiation therapy oncology group (RTOG) trials

Abstract Purpose: To evaluate the influence of cell type within non-small cell carcinoma of lung (NSCCL) on failure patterns when chemotherapy (CT) is combined with radiation therapy (RT). Methods and Materials: Data from 4 RTOG studies including 1415 patients treated with RT alone, and 5 RTOG studies including 350 patients also treated with chemotherapy (RT + CT) were analyzed. Patterns of progression were evaluated for squamous cell carcinoma (SQ) ( n = 946), adenocarcinoma (AD) ( n = 532) and large cell carcinoma (LC) ( n = 287). Results: When treated with RT alone, SQ was more likely to progress at the primary site than LC (26% vs. 20%, p = 0.05). AD and LC were more likely to progress in the brain than SQ (20% and 18% vs. 11%, p = 0.0001 and 0.011, respectively). No differences were found in intrathoracic and distant metastasis by cell type. When treated with RT + CT, AD was less likely to progress at the primary than either SQ or LC (23% vs. 34% and 40%, respectively; p = 0.057 and 0.035). AD was more likely than SQ to metastasize to the brain (16% vs. 8%, p = 0.03), and other distant sites (26% vs. 14%, p = 0.019). No differences were found in intrathoracic metastasis. LC progressed at the primary site more often with RT + CT than with RT alone (40% vs. 20%, p = 0.036). Death with no clinical progression was more likely with SQ than AD or LC for RT alone and RT + CT ( p p Conclusion: CT, although effective in reducing distant metastasis in all types of NSCCL, has different effects on the primary tumor by cell type, and has no effect on brain metastasis or death with no progression. Different treatment strategies should be considered for the different cell types to advance progress with RT + CT in NSCCL.