Stephen R. Smalley

Updated Analysis of SWOG-Directed Intergroup Study 0116: A Phase III Trial of Adjuvant Radiochemotherapy Versus Observation After Curative Gastric Cancer Resection

PURPOSE Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up. This update, with a more than 10-year median follow-up, presents data on failure patterns and second malignancies and explores selected subset analyses. PATIENTS AND METHODS In all, 559 patients with primaries ≥ T3 and/or node-positive gastric cancer were randomly assigned to observation versus radiochemotherapy after R0 resection. Fluorouracil and leucovorin were administered before, during, and after radiotherapy. Radiotherapy was given to all LRF sites to a dose of 45 Gy. RESULTS Overall survival (OS) and relapse-free survival (RFS) data demonstrate continued strong benefit from postoperative radiochemotherapy. The hazard ratio (HR) for OS is 1.32 (95% CI, 1.10 to 1.60; P = .0046). The HR for RFS is 1.51 (95% CI, 1.25 to 1.83; P < .001). Adjuvant radiochemotherapy produced substantial reduction in both overall relapse and locoregional relapse. Second malignancies were observed in 21 patients with radiotherapy versus eight with observation (P = .21). Subset analyses show robust treatment benefit in most subsets, with the exception of patients with diffuse histology who exhibited minimal nonsignificant treatment effect. CONCLUSION Intergroup 0116 (INT-0116) demonstrates strong persistent benefit from adjuvant radiochemotherapy. Toxicities, including second malignancies, appear acceptable, given the magnitude of RFS and OS improvement. LRF reduction may account for the majority of overall relapse reduction. Adjuvant radiochemotherapy remains a rational standard therapy for curatively resected gastric cancer with primaries T3 or greater and/or positive nodes.

Prostate Cancer Clinical Guidelines Panel Summary Report on the Management of Clinically Localized Prostate Cancer

PURPOSE The American Urological Association convened the Prostate Cancer Clinical Guidelines Panel to analyze the literature regarding available methods for treating locally confined prostate cancer, and to make practice policy recommendations based on the treatment outcomes data insofar as the data permit. MATERIALS AND METHODS The panel searched the MEDLINE data base for all articles from 1966 to 1993 on stage T2 (B) prostate cancer and systematically analyzed outcomes data for radical prostatectomy, radiation therapy and surveillance as treatment alternatives. Outcomes considered most important were survival at 5, 10 and 15 years, progression at 5, 10 and 15 years, and treatment complications. RESULTS The panel found the outcomes data inadequate for valid comparisons of treatments. Differences were too great among treatment series with regard to such significant characteristics as age, tumor grade and pelvic lymph node status. The panel elected to display, in tabular form and graphically, the ranges in outcomes data reported for each treatment alternative. CONCLUSIONS In making its recommendations, the panel presented treatment alternatives as options, identifying the advantages and disadvantages of each, and recommended as a standard that patients with newly diagnosed, clinically localized prostate cancer should be informed of all commonly accepted treatment options.

Adjuvant radiation therapy after surgical resection of solitary brain metastasis: Association with pattern of failure and survival

We reviewed patients treated by resection of solitary cerebral metastasis at the Mayo Clinic from January 1, 1972, to December 1, 1982. Eighty-five patients rendered clinically disease-free and who received intramural follow-up after craniotomy were studied. Adjuvant whole-brain radiation therapy (WBRT) was delivered to 34, and 51 were observed after craniotomy. Pattern-of-failure analysis showed a much smaller incidence of subsequent brain relapse in the adjuvant WBRT group than in the observation group (21% versus 85%, respectively). Multivariate analysis utilizing 17 patient, tumor, and treatment characteristics showed adjuvant WBRT to have the strongest association with brain control (p less than 0.0001). The only other variable which was significant (p less than 0.01) was multilobe involvement of the metastatic lesion, which was associated with a greater likelihood of brain failure. Systemic failures were more frequent (61% versus 37%), and the proportion of patients remaining disease-free (29% versus 4%) was higher in the adjuvant group. Those patients who received adjuvant WBRT to a dose of 39 Gy or greater manifested an 11% rate of subsequent brain failure versus a 31% rate when less than 39 Gy was delivered. The median survival was longer for the adjuvant WBRT group (21 months versus 11.5 months). Multivariate analysis indicated that adjuvant WBRT was one of several variables (including female gender, long disease-free survival, and good neurologic function prior to craniotomy) significantly associated with improved survival. This study suggests that adjuvant cranial irradiation may help prevent clinical recurrence of resected metastatic intracranial disease and that improved control of intracranial disease may be associated with an improved survival in patients without clinical evidence of systemic disease at the time of craniotomy.

Gastric surgical adjuvant radiotherapy consensus report: rationale and treatment implementation

PURPOSE Radiation therapy has recently emerged as a pivotal modality in the management of completely resected, high-risk gastric cancer. The recently published results of the Intergroup 0116 Gastric Surgical Adjuvant Trial randomized high-risk (T3,4 and/or node positive), completely resected gastric or gastroesophageal adenocarcinomas to receive either observation alone or radiochemotherapy after complete resection. Radiochemotherapy produced significant improvements in relapse-free (p < 0.0001) and overall survival (p = 0.01). Radiation oncologists must now clearly comprehend the principles governing the rationale supporting this therapy to apply it to those afflicted with this disease. This paper represents a consensus report reviewing data supporting radiotherapy, important clinical and anatomic issues related to radiotherapy, and details of the practical application of radiation therapy to commonly occurring clinical presentations. Supportive therapy during and after radiochemotherapy is also discussed.

Phase III Trial of Fluorouracil-Based Chemotherapy Regimens Plus Radiotherapy in Postoperative Adjuvant Rectal Cancer: GI INT 0144

PURPOSE Adjuvant chemoradiotherapy after or before resection of high-risk rectal cancer improves overall survival (OS) and pelvic control. We studied three postoperative fluorouracil (FU) radiochemotherapy regimens. PATIENTS AND METHODS After resection of T3-4, N0, M0 or T1-4, N1, 2M0 rectal adenocarcinoma, 1,917 patients were randomly assigned to arm 1, with bolus FU in two 5-day cycles every 28 days before and after radiotherapy (XRT) plus FU via protracted venous infusion (PVI) 225 mg/m2/d during XRT; arm 2 (PVI-only arm), with PVI 42 days before and 56 days after XRT + PVI; or arm 3 (bolus-only arm), with bolus FU + leucovorin (LV) in two 5-day cycles before and after XRT, plus bolus FU + LV (levamisole was administered each cycle before and after XRT). Patients were stratified by operation type, T and N stage, and time from surgery. RESULTS Median follow-up was 5.7 years. Lethal toxicity was less than 1%, with grade 3 to 4 hematologic toxicity in 49% to 55% of the bolus arms versus 4% in the PVI arm. No disease-free survival (DFS) or OS difference was detected (3-year DFS, 67% to 69% and 3-year OS, 81% to 83% in all arms). Locoregional failure (LRF) at first relapse was 8% in arm 1, 4.6% in arm 2, and 7% in arm 3. LRF in T1-2, N1-2, and T3, N0-2 primaries who received low anterior resection (those most suitable for primary resection) was 5% in arm 1, 3% in arm 2, and 5% in arm 3. CONCLUSION All arms provide similar relapse-free survival and OS, with different toxicity profiles and central catheter requirements. LRF with postoperative therapy is low, justifying initial resection for T1-2, N0-2 and T3, and N0-2 anterior resection candidates.

Hepatoma in the noncirrhotic liver.

The pathologic features, clinical presentation and natural history of hepatocellular carcinoma (HCC) developing in the noncirrhotic liver were studied in 61 patients against a background of 63 patients seen concurrently with HCC complicating cirrhosis. Noncirrhotic HCC had a bimodal age distribution, with females predominating the first age‐clustering (10–50 years) and males predominating the second age‐clustering (50–90 years). Cirrhotic HCC had a unimodal age distribution (40–90 years) with male dominance throughout. Estrogen exposure was noted in 57% of the noncirrhotic HCC women overall and in 80% of those in the younger age‐clustering. The majority of noncirrhotic HCC presented with a single hepatic mass or a dominant primary with satellite lesions in contrast to the usual multinodular or diffuse disease seen with cirrhosis. Twenty‐nine noncirrhotic patients survived complete resection of disease limited to the liver and exhibited a median survival of 2.7 years with a 5‐year survival of 25%. Low histologic grade, minimal necrosis, and the absence of hemoperitoneum, hepatomegaly, and adjacent organ involvement were all favorable prognostic variables. Patients with metastatic or locally unresectable noncirrhotic HCC had a median survival of 9 months, and 24% survived in excess of 2 years. This survival experience is significantly more favorable than cirrhotic HCC patients, who had only a 1.2‐month median and a 3% 2‐year survival. Low histologic grade, mild mitotic activity and the presence of some fibrosis within the specimen were associated with a favorable outcome in advanced noncirrhotic HCC. The favorable prognosis and heterogeneous composition of the noncirrhotic, when compared to the cirrhotic HCC cohort, may be important considerations in the design and evaluation of future clinical trials.

Impact of postoperative radiation therapy and other perioperative factors on outcome after orthopedic stabilization of impending or pathologic fractures due to metastatic disease.

PURPOSE AND METHODS We reviewed 64 orthopedic stabilization procedures in 60 consecutive patients diagnosed with metastatic disease to previously unirradiated femurs, acetabula, and humeri with pathologic or impending pathologic fracture. Thirty-five patients who received adjuvant postoperative radiation therapy were compared with 29 patients who were treated with surgery alone. Many potential perioperative and tumor prognostic variables were evaluated. RESULTS On univariate analysis, surgery plus radiation therapy and prefracture functional status were the only significant predictors of patients who achieved normal use of the extremity (with or without pain) after surgery; on Cox multivariate analysis, only postoperative radiation therapy was significant (P = .02). Surgery-related factors such as use of methylmethacrylate, location of fracture, and type of surgery were not associated with improved functional status. The estimated probability of achieving normal use of the extremity (with or without pain) any time was 53% for postoperative radiation therapy versus 11.5% for surgery alone (P < .01). Second orthopedic procedures to the same site were more frequent in the group that received surgery alone. The actuarial median survival duration of the surgery-alone group was 3.3 months, compared with 12.4 months for the postoperative radiation therapy group (P = .02). CONCLUSION While this study is limited by possible unaccountable selection biases, only postoperative radiation therapy was associated with patients regaining normal use of their extremity (with or without pain) and undergoing fewer reoperations to the same site. The improved overall survival associated with postoperative radiation therapy may represent selection bias.

Radiotherapeutic considerations in the treatment of hemangioblastomas of the central nervous system

Twenty-seven hemangioblastomas of the central nervous system were treated at the Mayo Clinic with radiation therapy from January 1963 to August 1983. Six patients had von-Hippel Lindau syndrome, and four presented with polycythemia. The median age among the 15 males and 12 females was 48 years (range 20-68). Two clinical groups were apparent: those that received postoperative radiation therapy for clinically suspect, or microscopically positive margins (6 patients) and those who underwent therapy for gross residual disease (20 patients). One patient did not fall into either group because his initially unresectable tumor was treated with planned pre-operative radiotherapy to 40 Gy and was subsequently successfully cured by surgery. Because the combined modality approach did not allow assessment of local control with radiation alone, he was excluded from the gross residual cohort in terms of time-dose relationship analysis. The cohort with gross residual disease was particularly unfavorable as 12 of these patients had developed 17 local recurrences prior to radiation. Three had multiple lesions, and four had the von-Hippel Lindau syndrome. In-field disease control appeared to be improved when patients were treated more aggressively. Patients treated to a dose of 50 Gy manifested local control in 4/7 (57%) vs 4/12 (33%) in patients treated to less than 50 Gy. In-field local control was also better if patients received a TDF greater than 75 (local control in 66%) vs a TDF of 65-75 (local control in 22%). Actuarial analysis of in-field disease control showed more aggressive treatment improved control whether analyzed by dose level (greater than or equal to 50 Gy vs less than 50 Gy, or TDF greater than 75 vs less than 75). Four of the six patients who received radiation therapy for microscopically positive or clinically suspect margins achieved local control. Both patients manifesting in-field relapse were successfully surgically salvaged. Overall survival for the entire group of 27 patients was 85%, 58%, 58%, and 46% at 5, 10, 15, and 20 years, respectively. Recurrence-free survival was 76%, 52%, and 42% at 5, 10, and 15 years, respectively. Half of all in-field recurrences had occurred by 2 years, but the remaining half recurred from 5.6 to 14.4 years. Patients who developed in-field failure usually died from disease with a median survival of only 1.5 years, but surgical salvage was accomplished in 4/12. Hydro-myelia developed in two patients and required operation. Surveillance for systemic tumors also was important and revealed seven benign and four malignant tumors.(ABSTRACT TRUNCATED AT 400 WORDS)

HAVE COMPLICATION RATES DECREASED AFTER TREATMENT FOR LOCALIZED PROSTATE CANCER

PURPOSE The American Urological Association Prostate Cancer Clinical Guidelines Panel reviewed 12,501 publications on prostate cancer from 1955 to 1992 to determine whether the complication rates of external beam radiation therapy, interstitial radiotherapy and radical prostatectomy have decreased. MATERIALS AND METHODS Complications reported in at least 6 series, study duration and sample sizes were extracted. Year specific study weighted mean patient ages and complication rates were computed. Regression analysis was performed of the study year on weighted mean patient age and complication rate. RESULTS Study year had a significant effect on mean patient age and rate of the majority of complications examined. Data indicated a gradual increase in study patient age and a simultaneous decrease in complications from 1960 to 1990. CONCLUSIONS Complication rates in the treatment of localized prostate cancer have decreased during the last 20 to 40 years. This decrease occurred despite evidence that the average age of treated patients had increased during the same period.

Radiotherapy as initial treatment for bulky stage II testicular seminomas.

Sixteen consecutive patients with bulky stage II seminoma were treated with primary radiotherapy from 1971 to 1982. Bulky stage II seminoma was defined as either Union Internationale Contre le Cancer (UICC) stage IIC (retroperitoneal metastases greater than 5 cm) or IID (palpable retroperitoneal metastases) with no evidence of visceral or supradiaphragmatic disease. The median age was 38 years (range, 26 to 52) and the median size of retroperitoneal disease was 11.5 cm (range, 5 to 25 cm). Patients were treated with generous radiation ports (such as wide hockey-stick or whole abdomen) often followed by boosts to the sites of bulky disease. Median tumor dose was 3,235 cGy (range, 2,700 to 5,668 cGy). Mediastinal (with or without supraclavicular) prophylactic radiation was administered to 15 of the 16 patients with a median dose of 2,590 cGy (range, 1,200 to 3,700 cGy). Treatment toxicity was mild. All 16 patients achieved a complete remission (CR) with radiotherapy. Median follow-up from the time of diagnosis was 60 months, and all patients are currently disease-free. Two patients recurred after therapy but were rendered disease-free with further radiation. These two relapsing patients have remained disease-free, following initial recurrence, for 8 years. The excellent results obtained with modern imaging and radiotherapeutic techniques justify radiotherapy as the initial treatment of choice for bulky stage II seminomas.