Molecular basis of cancer and clinical applications.

This article attempts to show the vertiginous advances that exist today in the concept of what cancer is. The authors chose some multiple biologic concepts that have enabled the progress in the knowledge of this disease to occur at a speed no one could imagine until recently. Although the areas and biologic problems that remain to be solved are more numerous and complex than they expected, the basic fundamentals already partially understood and the multidisciplinary integration of the various medical specialties with biomolecular research enable physicians to face the next millennium with great optimism about the possibilities of therapeutic success, prevention, and effective early diagnosis.

Apoptosis and the Bcl-2 gene family -- patterns of expression and prognostic value in stage I and II follicular center lymphoma.

PURPOSE: The prognostic significance of spontaneous levels of apoptosis and Bcl-2, Bax, and Bcl-x protein expression in follicular center lymphoma (FCL) is unknown. The objectives of this retrospective study were (1) to investigate the relationship between pretreatment apoptosis levels and long-term treatment outcome in patients with Stage I and II FCL; (2) to define the incidence and patterns of Bax and Bcl-x protein expression in human FC; and (3) to determine the relationship of Bcl-2, Bax, and Bcl-x expression with spontaneous apoptosis levels and clinical outcome in localized FCL. METHODS AND MATERIALS: Between 1974 and 1988, 144 patients with Stage I or II FCL were treated. Hematoxylin and eosin (H & E) stained tissue sections of pretreatment specimens were retrieved for 96 patients. Treatment consisted of regional radiation therapy (XRT) for 25 patients, combined modality therapy (CMT) consisting of combination chemotherapy and XRT for 57 patients, and other treatments for 14 patients. Median follow-up for living patients was nearly 12 years. The apoptotic index (AI) was calculated by dividing the number of apoptotic cells by the total number of cells counted and multiplying by 100. Expression of Bcl-2, Bax, and Bcl-x proteins was assessed using immunohistochemistry. RESULTS: The mean and median AI values for the entire group were 0.53 and 0.4, respectively (range: 0-5.2). The AI strongly correlated with cytologic grade, with mean AI values of 0.25 for grade 1, 0.56 for grade 2, and 0.84 for grade 3 (p < 0.0005; Kendall correlation). A positive correlation was present between grouped AI and grouped mitotic index (MI) (p = 0.014). For patients treated with CMT, an AI < 0.4 correlated with improved freedom from relapse (FFR) p = 0.0145) and overall survival (OS) (p = 0.0081). An AI < 0.4 did not correlate with clinical outcome for the entire cohort or for patients receiving XRT only. Staining of tumor follicles for the Bcl-2 protein was positive, variable, and negative in 73%, 15%, and 12% of cases, respectively. Positive staining of tumor follicles was observed in 96% of cases for both the Bax and Bcl-x proteins. Expression of Bcl-2, Bax, or Bcl-x did not correlate with AI or clinical outcome. CONCLUSION: The level of spontaneous apoptosis in pretreatment specimens correlates with cytologic grade of FCL and is a significant predictor of FFR and OS for patients with localized FCL receiving CMT.

Long-term outcome of treatment for Ann Arbor stage 1 Hodgkin's disease: patterns of failure, late toxicity and second malignancies.

PURPOSE: Radiation therapy results in excellent short-term survival in patients with early-stage Hodgkin's disease. However, the optimal therapeutic scheme that achieves the highest disease-free survival with the minimum long-term toxicity is yet to be determined. An analysis of the patterns of failure and late complications after radiation therapy was conducted to address this question. METHODS AND MATERIALS: A retrospective study was conducted of 145 patients with Stage I Hodgkin's disease treated at M. D. Anderson Cancer Center from 1967 through 1987. Follow-up extended from a minimum of 30 to 339 months, with a median period of observation of 16.5 years. All the patients were treated with radiation therapy and, and 16 received combination MOPP-based chemotherapy as part of their initial treatment. The radiotherapy technique, was involved/regional in 71 (49%), extended in 62 (43%), and subtotal nodal irradiation in 12 patients. The median total dose was 40 Gy. RESULTS: The actuarial freedom from progression at 10 and 20 years was 76% and 69%, respectively. Forty of 145 patients relapsed (27.6%). The site of primary disease was cervical adenopathy in 30 (75%), axillary in 7 (17.5%), mediastinal in 2 patients and subdiaphragmatic in one patient. Twenty-two patients were treated with involved/regional technique (55%), 17 with extended (42.5%), and 1 with subtotal nodal irradiation technique. There were three in field and four marginal recurrences. Six relapses occurred in non-irradiated nodal regions at the same side of the diaphragm and 17 in non-irradiated transdiaphragmatic lymph nodes (57.5%). Nine patients (22.5%) relapsed with visceral disease. Nineteen patients (47.5%) relapsed within the first 2 years, 15 (37.5%) 3 to 10 years after diagnosis and the remaining 6 (15%) after 10 years. Eleven of 40 patients died of disease after the first or subsequent relapses (27.5%). Three of six patients with late relapses had progression in viscera but only two died with disease. Thirty-eight of 145 patients developed late toxicity from the treatment (26.2%). Twenty-three patients experienced ischemic heart disease (15.9%), only 13 of whom received mediastinal irradiation (9%). Fifteen patients developed secondary malignant solid tumors (10.3%). Nine of those (6.2%) occurred within the irradiation field (two were also treated with chemotherapy). Two additional patients, one of whom received chemotherapy as part of the initial treatment, died of acute myelogenous leukemia. Non-Hodgkin's lymphoma and lung cancer were the most common second malignancies. CONCLUSIONS: Limited field radiotherapy results in a significant number of relapses in non-irradiated, especially transdiaphragmatic lymph nodes. Subtotal nodal irradiation can prevent some relapses and therefore improve freedom from progression. Careful design of the treatment fields may decrease the risk of morbidity and mortality from coronary artery disease and second malignancies in early-stage Hodgkin's disease. Careful long-term surveillance may permit early detection and management of late relapses and treatment complications.

Long-term outcome of treatment for Ann Arbor Stage I Hodgkin's disease: prognostic factors for survival and freedom from progression.

PURPOSE: The earliest stages of Hodgkin's disease are associated with excellent short-term survival with radiation therapy. This has led to controversies regarding pretreatment evaluation, the extent of irradiation, the role of chemotherapy, and the relative importance of prognostic factors. Long-term results were sought to address these controversies. METHODS AND MATERIALS: A retrospective study was conducted of patients with Stage I Hodgkin's disease treated at the M. D. Anderson Cancer Center from 1967 through 1987. The median age at presentation of 145 patients was 31 years, and the male-to-female ratio was 1.8. Pretreatment evaluation included lymphangiography and bone marrow aspiration and biopsy in all patients. Laparotomy was performed in 101 of the 145 patients (70%). There were 133 patients with supradiaphragmatic presentations; 12 patients had infradiaphragmatic adenopathy. Only five patients had B symptoms (3.5%). Histologic subtypes of the disease included lymphocyte predominance 17.9%, nodular sclerosis 40.7%, mixed cellularity 40.7%, and one unclassified Hodgkin's disease with primary splenic involvement. All patients were treated with radiotherapy, and 16 (11%) also received combination chemotherapy as part of their initial treatment. Radiotherapy techniques included involved/regional field in 49%, extended field in 42.7% (mantle or inverted Y), and subtotal nodal irradiation in 8.3%. Follow-up extended from a minimum of 30-339 months, with a median period of observation of 16.5 years. RESULTS: The median survival was 13.7 years. The 10- and 20-year survival rates were 83% and 66%, respectively. The only factor important for decreased survival was age >40 years at diagnosis (p < 0.0001). Out of 43 deaths, 11 were the result of Hodgkin's disease and the remaining 32 resulted from intercurrent disease, including treatment-related causes. Median freedom from progression was 10.5 years, and the 10- and 20-year freedom from progression were 76% and 69%, respectively. Out of 39 relapses, 5 (13%) occurred beyond 10 years. Women had higher freedom from progression (p = 0.0534) than men. Age, histology, bulk of disease, site of involvement including the mediastinal presentations, and the addition of chemotherapy did not influence the freedom of progression. Although very few patients (12 of 145) received subtotal nodal irradiation, the freedom from progression at 10 years was 91.7% for this group versus 64.7% for the group of patients who were treated with more limited techniques. CONCLUSION: Treatment with radiation therapy for patients with Stage I Hodgkin's disease leads to an excellent outcome, but patients require long-term surveillance as late relapses are not rare. Age is the only factor that affects survival, and gender marginally affects freedom from progression. Subtotal nodal irradiation may improve freedom from progression; further investigation of this treatment is justified.

Localized primary malignant lymphoma of bone.

PURPOSE: A single institution's experience with the treatment of localized primary malignant lymphoma of bone (PLB) was analyzed to identify major prognostic factors, toxicity, and optimal treatment for this rare malignancy. METHODS AND MATERIALS: A retrospective analysis of 45 previously untreated patients with Ann Arbor stage IE and IIE PLB from 1967 to 1992 was undertaken. All histopathologic material was reviewed. Irradiated patients received at least 40 Gy. Systemic chemotherapy was generally doxorubicin based. Overall survival (OS), progression free survival (PFS), and disease-specific survival (DSS) were calculated actuarially. RESULTS: Histologically, there were 41 diffuse large cell, 2 diffuse mixed cell, 1 lymphocytic, and 1 lymphoblastic lymphomas. International Index scores were assessed on 43 patients. Thirty-six patients were treated with chemotherapy and radiation (CMT), five patients were treated with radiation only, and four patients were treated with chemotherapy only. Univariate analysis revealed significantly improved 5-year OS for those patients who had International Index scores of 0 vs. scores of 1 or 2 (85 vs. 53%, respectively, p = 0.004). Analysis failed to demonstrate a difference in OS, PFS, or DSS when comparing radiotherapy alone versus CMT, stage IE vs. stage IIE, or axial skeleton involvement vs. extremities. CONCLUSION: The outcome of patients with PLB is relatively favorable in the era of CMT. Doses of radiation in the range of 46 Gy provide optimal local control with an acceptable rate of complications. The International Index is a valid prognostic tool for PLB.

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.

Long term assessment of patterns of treatment failure and survival in patients with stage I or II follicular lymphoma.

BACKGROUND: Follicular lymphoma is a clearly defined type of malignant lymphoma. The many treatment approaches reported in the literature attest to the lack of agreement on its best management. The treatment experiences of patients with Stage I or II follicular lymphoma who were at risk for at least 5 years were reviewed to assess their survival, disease free survival, and patterns of failure. METHODS: Between 1974 and 1988, 144 patients with Stage I or II follicular lymphoma were treated at The University of Texas M. D. Anderson Cancer Center. Initial staging studies included lymphangiography in 87% of the patients, computerized tomography of the abdomen and pelvis in 60%, bone marrow biopsy in 98%, and diagnostic or staging laparotomy in 33%. Forty-five patients were treated with regional radiotherapy, 84 patients with combined chemotherapy and radiotherapy, and 15 patients were treated with chemotherapy alone. RESULTS: With a median follow-up of 8.7 years (range, 48-182 months) the actuarial survival rates at 5, 10, and 15 years were 81, 69, and 63%, respectively. The freedom from relapse (FFR) rates were 66, 56, and 46%, respectively. The FFR rate was better for patients treated with chemotherapy-radiotherapy than for patients treated with radiotherapy alone (63 vs. 35% at 15 years). In addition, there were no relapses after 7.5 years in patients treated with chemotherapy-radiotherapy, but relapses continued even beyond 15 years in patients treated with radiotherapy alone. Univariate analysis for each of the treatment groups revealed age to be the only significant prognostic factor. There was no significant difference in survival or disease free survival rates for the three histologic subtypes of follicular lymphoma. CONCLUSION: The addition of chemotherapy to radiotherapy may have increased the probability of cure for patients with Stages I or II follicular lymphoma.

Treatment of patients with lymphomas of the uterus or cervix with combination chemotherapy and radiation therapy.

BACKGROUND: Primary lymphomas of the uterus or cervix are so rare that treatment series of single institutions consist of very small numbers of patients, making standard treatment difficult to define. The outcome of patients treated with a combination of chemotherapy and radiation therapy was analyzed for all but patients with the most advanced disease. METHODS: From 1976 to 1992, 16 patients received definitive treatment. Thirteen patients had intact uteri (group 1) and 3 presented with paracolpal lymphomas after previous hysterectomies (group 2). Twelve of the patients received chemotherapy and external irradiation. The remaining four underwent only chemotherapy. The overall survival and freedom from disease progression were analyzed according to Kaplan-Meier methods. Prognoses were related to the International Index, Ann Arbor stage, and International Federation of Gynecology and Obstetrics stage. RESULTS: Five-year survival and freedom from disease progression were 77% and 67%, respectively, for group 1, and all patients in group 2 were cured. A statistically significant correlation of survival with scores of the International Index was found in group 1. For patients with scores in the low or low-intermediate range (n = 10), 5-year survival was 90%. All patients who scored in the high-intermediate or high range (n = 3) died by 66 months after their diagnosis (P = 0.0153). The Ann Arbor stage had less predictive value, with 5-year survival of 89% for Stage I and II patients (n = 9), compared with 50% survival for the four Stage III and IV patients (P = 0.0701). International Federation of Gynecology and Obstetrics staging did not predict outcome. CONCLUSIONS: The combination of chemotherapy and irradiation is the most effective treatment regimen for all uterine and cervical lymphomas. The International Index is most predictive of outcome.

Radiobiology of total body radiation.

The first bone marrow transplants (BMTs) in human patients were performed after conditioning with total body irradiation (TBI). TBI remains an important part of BMT protocols. The morbidity and mortality of BMT remains significant, but can be decreased by the introduction of optimized TBI regimens. This requires dosimetric control and a detailed analysis and description of the physics of the TBI procedure in every BMT center that utilizes TBI. Recommendations for such procedures are given. Radiobiological models are of help in developing less toxic TBI procedures, but can only be effective after dosimetric control has been obtained and if the influence of other variables on the outcome of BMT are taken into account. Fractionated TBI (fraction size over 3.0 Gy or higher) appears to be more effective and better tolerated than single fraction TBI. Lung shielding is possible during TBI. Smaller organs or organs that cannot be imaged easily are not recommended for shielding. Radiolabeled immunoglobulins are but low molecular weight bone seeking radioisotopes and are not expected to improve the therapeutic ratio of TBI. Other variables in BMT are more difficult to quantify and model than TBI (e.g. high-dose chemotherapy, graft-versus-host disease) and will be more difficult to optimize.

Improvement in radiotherapy for a murine sarcoma by indomethacin plus WR-2721.

The study was designed to determine whether the improvement in the therapeutic ratio of radiotherapy by indomethacin, a potentiator of tumor radioresponse through immunostimulation, can be improved further by combining it with WR-2721, a potent radioprotector of normal tissue. Mice bearing the syngeneic sarcoma FSA (8 mm) in the leg were treated with single graded doses of gamma rays to the tumor or with gamma rays plus indomethacin, WR-2721, or both. The effect of these compounds was assessed on local tumor control, radiation-caused hair loss, and radiation-induced leg contracture. Indomethacin increased local tumor control by a factor of 1.7, a value that was not influenced significantly by the addition of WR-2721. Indomethacin did not affect radiation-induced hair loss or radiation-induced leg contracture, whereas WR-2721 protected against them by factors of 1.4 and 1.5, respectively. These protection factors were not influenced by the addition of indomethacin. Thus the combination of indomethacin and WR-2721 can increase the therapeutic ratio of radiotherapy more than either drug given alone.