Document 6wKLwZQ9Ooz4oYxZYGMj3nDOR

From www.bloodjournal.org at HOUSTON ACADEMY OF MEDICINE on November 18, 2009. For personal use only. 1981 58: 45-51 Factors predicting long-term survival in diffuse mixed, histiocytic, or undifferentiated lymphoma RI Fisher, SM Hubbard, VT DeVita, CW Berard, R Wesley, J Cossman and RC Young Information about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/misc/rights.dtl#repub_requests Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/misc/rights.dtl#reprints Information about subscriptions and ASH membership may be found online at: http://bloodjournal.hematologylibrary.org/subscriptions/index.dtl Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published semimonthly by the American Society of Hematology, 1900 M St, NW, Suite 200, Washington DC 20036. Copyright 2007 by The American Society of Hematology; all rights reserved. From www.bloodjournal.org at HOUSTON ACADEMY OF MEDICINE on November 18, 2009. For personal use only. Factors Predicting Histiocytic, Long-Term Survival or Undifferentiated in Diffuse Lymphoma Mixed, By Richard I. Fisher, Susan M. Hubbard, Vincent T. DeVita, Costan Jeffrey Cossman, and Robert C. Young W. Berard, Robert Wesley, Clinical diffuse and histopathologic material from 1 51 cases of mixed, diffuse histiocytic. and diffuse undifferen- tiated non-Burkitt's lymphomas have been reviewed to determine the factors that predict long-term survival. Median survival of all patients was 34 mo with 43% alive at 70 mo. Factors associated with a poor prognosis include: male sex, constitutional symptoms. advanced stage. bone marrow involvement, huge (>10 cm) abdominal masses with gastrointestinal involvement, hepatic involvement, hemoglobin prediction <12 g/dl. or serum LDH >250 U. The best of a given patient's survival was defined by a set of four variables, which includes marrow status, and the presence sex, symptoms, bone or absence of a huge D URING THE LAST I 5 yr, the results obtained from the treatment of the aggressive forms of diffuse lymphomas have improved significantly. Diffuse histiocytic lymphoma has classically been selected as the prototype of these aggressive diffuse lymphomas since it is the most common type. During the I 960s, I 0%-20% of all patients with diffuse histio- cytic lymphoma were alive at 5 yr.' Radiation therapy did lead to 30%-50% survival at 5 yr when clinical stage I patients were treated.2 With the advent of pathologic staging and improved radiotherapeutic techniques, 70%-80% of stage I patients are now alive and disease free at 5 yr.3'4 Patients with more advanced stages of diffuse histiocytic lymphoma rarely achieved long-term survival with either radiation therapy or single agent chemotherapy. The first report that demonstrated that long-term disease-free survival could be obtained with combination chemotherapy was published in l975. Subsequently, numerous other authors have demon- strated that a subset of patients with advanced stages of diffuse histiocytic lymphoma can achieve long-term disease-free survival after combination chemothera- py.'#{176} In 1977, we analyzed 56 cases of advanced stage diffuse histiocytic lymphoma to determine what prognostic factors predicted the success or failure of combination chemotherapy." That study demon- strated that the determination of the sites of tumor involvement and extent of tumor mass during the initial evaluation allow one to accurately predict a patient's prognosis. This study, however, provided no information about patients with a Rappaport diagnosis of diffuse mixed or diffuse undifferentiated lymphoma (neither of these groups is rare). There is considerable histopathologic overlap between these three diagnoses and, indeed, abdominal mass with gastrointestinal involvement. In contrast, classification of these patients according to the histopathologic categories of Rappaport or Strauchen did not define patient groups with significant differences in survival, nor did these categories correlate with the previously described clinical factors. Knowledge of the distribution of these prognostic factors in any clinical trial is needed before therapeutic results can be compared. In addition, such data may define subsets of patients for whom current therapy is inadequate and conversely those patients for whom current therapy yields excellent long- term survival. disagreement among expert pathologists is not uncom- mon. Often the subgroups are treated identically. Recently, several authors have also suggested that subclassification of these aggressive forms of diffuse lymphoma on histopathologic criteria may provide significant prognostic information. 2.13 Therefore, we have reviewed the clinical history and pathologic material from 151 patients with all stages of mixed, histiocytic, and undifferentiated lymphomas treated at the National Cancer Institute in order to determine the important prognostic factors influenc- ing long-term survival. This information should also enable clinical investigators to determine the adequacy of current treatment programs for various subgroups of patients with diffuse lymphoma and should permit more accurate comparisons of the results obtained in different clinical trials. MATERIALS AND METHODS All patients with diffuse mixed, histiocytic, and undifferentiated non-Burkitt's lymphoma treated at the National Cancer Institute between I 964 and I 977 were evaluated for entry into this study. The medical records were completely reviewed and interpreted by two of the authors (R.I.F. and S.M.H.). All pathologic material was reviewed by the two experienced pathologists (C.W.B. and iC.) and a consensus interpretation reached. In order to be included in this study, the initial pathologic material had to include at least one biopsy site that contained one of the previously mentioned forms of diffuse lymphoma. Any biopsy containing areas of nodular lympho- From the Medicine Branch. Laboratort' of Pathology. and Bio- metric Research Branch, National Cancer Institute, National Insti- tutes ofHealth, Bethesda, Md. Submitted November 25, 1980; accepted March 4. /98!. Address reprint requests to Richard I. Fisher, M.D., Building /0, Room 12N226, National Cancer Institute. Bethesda, Md. 20205. (( 1981 by Grune & Stratton, Inc. 0006-497l/8l/580!-0007$Ol.00/0 Blood, Vol. 58, No. 1 (July). 1981 45 From www.bloodjournal.org at HOUSTON ACADEMY OF MEDICINE on November 18, 2009. For personal use only. 46 ma, in addition to diffuse lymphoma, was considered a nodular lymphoma and, therefore, not included in this analysis. One- hundred and fifty-one patients met the above criteria. The clinical and histologic characteristics of these 1 5 1 patients are shown in Table I . Sixty-two percent of the patients were male. The median age was 49 yr with a range from 8 to 74 yr. Only 9% of all patients were less than 20 yr old. Constitutional symptoms (fever, night sweats, or loss of 10% of total body weight) were present in 45%. The initial pathologic diagnoses according to the Rappaport classification'4 were diffuse mixed, 20%; diffuse histiocytic, 60%; diffuse undifferentiated non-Burkitt's, 1 3%; and unclassifiable lymphoma, 7%. Staging procedures were defined in prior reports.5'7"5 performed at the time of admission, For this analysis, all staging data as were reinterpreted according to our current criteria for pathologic staging that have been defined by Chabner et al.'6 Ifan adequate evaluation of a given organ site had not been performed, then that organ was considered not evaluable. As outlined by the Ann Arbor Confer- ence,'7 13% of patients were stage I, 23% stage II, 14% stage III, and 50% stage IV. Initial therapy following referral to the National Cancer Institute consisted of radiation alone in 37 patients (25%). Involved field or extended field radiation was given to 29 of the 37 radiation patients, while the remainder received more extensive fields. Combination chemotherapy 93 patients, was initial treatment for 93 patients (61%). Of these 1 4 received cyclophosphamide, vincristine, and predni- sone (CVP);'8 37 received cyclophosphamide vincristine, procarbazine, and prednisone or mechlorethamine, (C-MOPP or MOPP);5 and 40 received cyclophosphamide, doxorubicin, mycin, and prednisone (BACOP).7 For patients disease, 30/54 (56%) received radiation alone vincristine, with stage and 1 1 /54 bleoI or II (20%) Table 1 . Clinical and Histologic Characteri With Diffuse Lymphomas sties of Patients Characteristic Number Total Patients Sex Males Females Age (yr) Less than 20 20-40 40-60 Greaterthan6O Constitutional symptoms A B Histologic diagnosist Diffuse mixed Diffuse histiocytic Diffuse undifferentiated non-Burkitt's Unclassifiable Stage I II Ill IV Initial therapy Radiation Combination chemotherapy Combined modality Other 15 1 93 58 13 40 70 28 83 68 31 91 19 10 20 34 21 76 37 93 16 5 Fever, night sweats, or loss of 10% of total body weight. tAccording to Rappaport classification. Percent 100 62 38 9 26 46 19 55 45 20 60 13 7 13 23 14 50 25 61 11 3 FISHER ET AL. radiation plus C-MOPP. For the 97 patients with stage III or IV disease, 83 (86%) received combination chemotherapy, 7 (7%) received extensive radiation therapy, 5 (5%) received radiation plus combination chemotherapy, and 2 (2%) received single agents. Only those patients with no evidence of residual tumor at restag- ing have been called complete responders. Those in whom there was a 50% decrease in tumor size and those attaining a complete clinical remission with microscopic disease present ered partial responders. All other patients at restaging were considwere classified as nonre- sponders. Survival was calculated from the start of therapy and plotted by the life table method. Survival curves were analyzed by the general- ized Wilcoxon test of Gehan'9 or the generalized Kruskal-Wallis test of Breslow.2#{176}Response rates were compared statistically by the Fisher exact test.2' All p values are of the two-sided type. To assess the relative effect of different prognostic factors on survival, the proportional hazards model of Cox22 was used. A modified forward stepwise regression method was applied to find the most important set of factors for predicting survival. Of the prognostic factors found to be individually important, all subsets of size two are analyzed to find the best pair, then a stepwise procedure was used to continue. A backward stepwise regression method was also used to check the results and gave the same final subset of prognostic factors. RESULTS The median follow-up for all patients on the study now exceeds 6 yr. The actuarial survival for all 151 patients is shown in Fig. 1 . Median survival is 34 mo with 43% of patients alive greater than 70 mo. As noted in previous studies,"23 only those patients achieving a complete remission had prolonged disease-free survival. Fifty-four percent of all patients achieved a complete remission, and their median survival has not been reached, with 76% of the complete responders alive at 70 mo. The median survival of the 37% of patients who achieved a partial response and the 9% who had no response are 6 and 7 mo, respectively. Complete response rates according to .0 3.9 0.S :- Q.5 0.5 - TOTAL DEilO 151 80 [7 -0.2 0.1 0 .0 0 --j------ 0 36 -_----i t_ I 54 70 90 108 126 144 MON I HO I. 162 180 Fig. 1 . Actuarial survival curve for all patients with aggressive forms of diffuse lymphoma. From www.bloodjournal.org at HOUSTON ACADEMY OF MEDICINE on November 18, 2009. For personal use only. PROGNOSTIC FACTORS FOR DIFFUSE LYMPHOMAS 47 stage were as follows: stage I, 100%; stage II, 56%; stage III, 66%; and stage IV, 38%, Eight clinical factors, easily determined prior to the initiation of therapy, can be utilized to predict the survival of patients with these diffuse lymphomas. The relationship of the patients' sex to his survival is shown in Fig. 2. Survival of female patients exceeded that of male patients (p = 0.05). Of interest, sex is the only clinical factor that significantly affected patient survival without affecting the complete remission rate. Furthermore, there was no significant association of females with any particular stage of disease, site of tumor involvement, or histology. The presence of fever, night sweats, or weight loss greater than 10% of the total body weight was asso- ciated with both a lower complete response rate and survival. The complete response rate for patients with constitutional symptoms was 38% compared to 67% for asymptomatic patients (p < 0.002). Likewise, median survival for patients with constitutional symp- toms is 10 mo, while the median for asymptomatic patients has not been reached (p = 0.002) (data not shown). A patient's initial stage was inversely correlated with the complete response rate and also survival, as shown in Fig. 3 (p < 0.002). The only exception is the fact that patients with stage II disease had a lower complete response rate and survival than those patients with stage III lymphoma. This fact is partially explained by the inclusion of 5 patients with huge abdominal masses involving the gastrointestinal tract in the stage II category. These patients had a poor prognosis and will be discussed later. Although only I 5% of all evaluable patients had bone marrow infiltration with malignant lymphoma, C .0 H 3.5 0.53.4 3.3 - 0.2 - -,--`--. `0i0. DEHO 20 [7 507E 3' [6 [7 58GE 21 9 #{163} STHOE 48 X SOOE II ::: P<0.002 . ..O-.--- o.o a 18 6 i 54 `? MO9THO SC 108 26 [44 162 HO Fig. 3. Survival of all patients according to their stage. the prognosis of these patients was extremely poor. The complete response rate was only 9% for patients with bone marrow infiltration versus 62% for all other patients without marrow lymphoma (p < 0.002). As shown in Fig. 4, median survival drops from 5 1 mo for all other patients without marrow involvement to 6 mo for patients with it (p < 0.002). This detrimental effect of bone marrow involvement was also present in the subset of patients with diffuse histiocytic lympho- ma. No other histologic category had sufficient numbers of patients with marrow involvement to be analyzed independently. The prognosis of patients with huge abdominal mass and gastrointestinal involvement is shown in Fig. 5. For this analysis we have again defined a huge abdom- inal mass as one greater than 10 cm in diameter," .3 3.9 3;H3L. 3EP3 MPLE 3.8 58 24 [7 EEMHLE 0.5 T34L 3 i: 0.8 L3 ..O' 3 55P,[4'i35TVi P <0 002 S -555j, [[50V4 3.4 3.3 0.? 0. - 0 .0 0 0 35 -- I 54 90 1(19 126 -. 44 52 80 Fig. 2. Survival of all patients according to their sex. [).5 L . .=. ::: t13- o.oF 0.1 0.0 0 .0. 18 35 54 72 90 MONT IS I1 08 125 [44 162 i 80 Fig. 4. Effect of bone marrow involvement on survival. From www.bloodjournal.org at HOUSTON ACADEMY OF MEDICINE on November 18, 2009. For personal use only. 48 1.0 0.9 0.8 TOTAL OERO 136 tO 0 NEGATIVE) 0.7 15 14 0 POSITIVE1 P.30.002 > 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 18 36 54 72 90 108 126 144 162 lAO MONTHS Fig. 5. involvement Effect of huge abdominal on survival. mass with gastrointestinal Although only 10% of all evaluable patients actually had a huge abdominal mass with gastrointestinal involvement, their complete response rate of 7% and median survival of 6 mo were significantly less than that of all other patients (60% and 5 1 mo, respectively, p = 0.002). We have previously reported that both gastrointestinal involvement and huge masses appear to adversely affect the survival of patients treated with combination chemotherapy." In the present study with a larger number of patients, we found that only a huge abdominal mass with gastrointestinal involve- ment adversely affects prognosis. We cannot demon- strate that gastrointestinal involvement without a huge abdominal mass or huge masses in other sites are important prognostic factors. The poor prognosis of these patients with huge abdominal masses and gastro- intestinal involvement could also be demonstrated in the subset of patients with diffuse histiocytic lympho- ma. There were insufficient numbers of these patients in other histologic categories to analyze them indepen- dently. Involvement of the liver by these forms of diffuse lymphoma also adversely affects the prognosis. Twelve percent of evaluable patients had documented hepatic parenchymal involvement. Of these patients, 25% had a complete response, and median survival was 6 mo. This is significantly worse than the results from all other patients without liver invovement, i.e., 59% and 51 mo, respectively (p = 0.01). In this analysis, we were unable to demonstrate that other common sites of extranodal involvement with diffuse lymphomas, such as the skin, lung, bone, spleen, or central nervous system, resulted in a signifi- cantly lower survival. The patient's initial hemoglobin level predicted FISHER ET AL. response to therapy and survival. Patients whose hemoglobin was less than 12 g/dl had a 41% complete response rate and 10 mo median survival compared to 63% and 7 1 mo for patients whose hemoglobin was greater than or equal to 1 2 g/dl (p <0.002). Finally, patients' initial serum LDH (lactic dehy- drogenase) values provided useful prognostic informa- tion. Patients with an LDH greater than 250 U had a 39% complete response rate and a median survival of 1 3 mo. In contrast, patients with a normal LDH, i.e., less than 250 U, had a 74% complete response rate and a median survival that was not reached with 57% of the patients alive at 70 mo (p = 0.003). The patients could also be analyzed to determine whether these seven clinical factors were as important in patients with localized disease (stage I or II) or advanced disease (stage III or IV). When comparisons were made among stage III and IV patients only, sex, symptoms, marrow involvement, huge abdominal masses with gastrointestinal involvement, LDH, and hemoglobin all significantly affected survival. Liver involvement was also associated with a lower survival, although this difference did not reach statistical signif- icance (p = 0.10). Obviously, bone marrow or liver involvement caused the patients to be classified as stage IV and thus were not found in stages I or II patients. Of the remaining factors, only symptoms and huge abdominal masses with gastrointestinal involve- ment were predictive of lower survival for stage I or II patients. Sex and level of LDH or Hgb did not statisti- cally predict survival for stage I or II patients. In addition to the clinical factors discussed previously, we have attempted to determine whether histopathologic subclassification of these diffuse lymphomas provides additional useful prognostic information. Survival of all patients, according to the Rappaport classification, is shown in Fig. 6. Although the prognosis worsens from diffuse mixed to diffuse histiocytic to diffuse undifferentiated lymphoma, there is no significant difference among the categories (p = 0.27). In 1978, Strauchen et al. proposed a new histo- pathologic system of classifying patients with these types of diffuse lymphoma.'2 The authors retrospec- tively reviewed a series of 66 cases and divided the patients into the five categories: large cleaved, large noncleaved, mixed follicular center cell, blastic, and pleomorphic pyroninophilic. In the initial report, this classification appeared to delineate good, interme- diate, and poor prognostic groups. The pathologic material from this initial report has been re-reviewed by one of the original authors (C.W.B.). In only 67% of the cases were the original interpretations reproduc- ible. This classification was then applied to the larger series of I 5 I cases. The results are demonstrated in From www.bloodjournal.org at HOUSTON ACADEMY OF MEDICINE on November 18, 2009. For personal use only. PROGNOSTIC FACTORS FOR DIFFUSE LYMPHOMAS 49 0_H : 0.4 (4.3 0. . ,-0.1 0.9 ` ` ` I 0 18 36 54 77 MONTHS TOTALAT SE4A8T [7 OHL1 34 14 [7 OML PO27 9 12 8 GUI5 -I l I I 90 108 126 144 16, I lAO Fig. 6. Survival of the aggressive forms of diffuse lymphomas according to the classification of Rappaport. Fig. 7. Although the curves appear in the same order as described in the initial report, Strauchen's catego- ries do not separate these patients into significantly different prognostic groups (p = 0.16). In addition, none of Strauchen's categories correlated with the previously described clinical prognostic factors. A multifactor Cox regression analysis was performed to delineate the relative strength of any of these eight clinical prognostic factors while taking into account the contribution of all the other factors listed above. Because each of the eight variables was individ- ually highly predictive of survival, it was not possible to unequivocally define the exact order of importance of each of these factors. Moreover, the model may give equal weight to a factor that is strongly predictive for poor survival but present in relatively few patients and a factor that is associated with a moderate decrement in survival but is present in a larger proportion of the population. However, the best prediction of the patient's course was achieved using a set of four prognostic variables that defined the patient's status in regard to bone marrow, huge abdominal masses with gastrointestinal involvement, symptoms, and sex. include: (1 ) male sex; (2) constitutional symptoms; (3) advanced stage; (4) bone marrow involvement; (5) huge abdominal masses with gastrointestinal involve- ment; (6) liver involvement; (7) hemoglobin less than 12 g/dl; and (8) serum LDH greater than 250 U. These clinical factors, with the exception of sex, all affected the survival of patients because fewer complete remissions were achieved. Indeed, there was no evidence that the survival of patients with poor prognostic factors who achieved a complete remission was less than that of other complete responders. This once agains emphasizes the concept that improved survival of patients with diffuse lymphoma will result when larger numbers of complete remissions are obtained. In contrast to these clinical factors, histopathologic subclassification of these patients according to the systems proposed by Rappaport'4 or Strauchen'2 did not add significant additional prognostic information. In fact, the interpretations established by the Strauchen system were not satisfactorily reproducible. Armitage et al. used a similar classification scheme and applied it to patients with a Rappaport diagnosis of diffuse histiocytic lymphoma.13 They reported an 86% concurrence rate between two pathologists read- ing the slides independently but did not determine the reproducibility of a given pathologists' reading. The survival of patients with four of the subcategories was identical but inferior to the group with large noncleaved cells. Whether other histopathologic clas- Si fications can provide prognostic information compa- rable to or greater than that provided by the clinical factors remains to be determined. Although we initially had hoped that we could place the prognostic factors in sequential order of impor- TOTAL 23 0080 TO TI I RRGI CI EHVEO 33 7 03 1 ARGO .P4ONCI I HAT 3T 4 A 8,010 FOIl CUIHK CINIII9 CUt POTS TA 2x 84 TST It 35 24 0 PLTOMORPHIC I'TKO$INOPHII IC Ii .6 CONCLUSIONS We have studied the factors that predict long-term survival in patients with diffuse mixed, histiocytic, or undifferentiated non-Burkitt's lymphoma in a retro- spective review of 1 5 1 patients who have been followed for a median time in excess of 6 yr. Indeed, improved results have been obtained during the last I S yr. since 43% of all patients are alive at 70 mo. Eight clinical factors that can be determined prior to the initiation of therapy adversely affected the prognosis. They 1 .. 0.3 0.? 0.I 0.11 0 I I I I I I *I I IA 36 [4 7? 90 108 126 144 MONTHS , 62 I 80 Fig. 7. Survival of the aggressive forms of diffuse lymphomas according to the classification of Strauchen. From www.bloodjournal.org at HOUSTON ACADEMY OF MEDICINE on November 18, 2009. For personal use only. 50 FISHER ET AL. tance by use of a Cox regression model, this goal was not possible. Part of the difficulty could be attributed to the fact that the regression model may give equal importance to two types of factors-one that is present in very few patients but has devastating impact, and a second one that may be present in about half of the patients but has only moderate negative impact. Nevertheless, when a patient's status was defined in regard to sex, symptoms, bone marrow involvement, and huge abdominal masses with gastrointestinal involvement, no other clinical variable provided signif- icant additional prognostic information. No truly comparable analysis of the factors predict- ing long-term survival in these diffuse lymphomas has been published. Our previous analysis dealt only with advanced stages of diffuse histiocytic lymphoma treated with intensive combination chemotherapy." Stage IV disease, bone marrow involvement, gastroin- testinal involvement, and a tumor mass greater than 10 cm in diameter in a single location were found to be poor prognostic factors. These factors are also impor- tant in the current study, although we can now demon- strate that it is a huge abdominal mass with gastroin- testinal involvement that is important, not a huge mass in another site or a gastrointestinal involvement with- out a huge abdominal mass. Cabanillas et al. studied the factors that influenced response and survival in patients with advanced stages of non-Hodgkin's lymphoma (approximately half nodular and half diffuse) treated with the less inten- sive combi nation chemotherapy, cyclophosphamide, vincristine, and prednisone.24 Factors that influenced prognosis included tumor bulkiness, prior therapy, nodular or diffuse pattern of growth, hemoglobin level, and presence or absence of constitutional symptoms. These results certainly are consistent with our findings when one notes that patients with prior treatment and those with nodular lymphoma were not part of our anlaysis. In addition, in the M.D. Anderson study, bone marrow biopsy and liver biopsy were not routinely performed, and serum LDH levels were not analyzed. Ferraris et al. have reported that an elevated serum LDH was a poor prognostic factor in all types of non-Hodgkin's lymphomas25 and Arseneau reported similar results in Burkitts' lymphoma,26 but otherwise there has been limited investigation of prognostic factors. Numerous clinical trials are currently in progress throughout the world in an attempt to improve the therapy of diffuse lymphomas. In order to compare these regimens, it is important to know the distribution of clinical prognostic factors present in a given trial and the complete response rate for each category of patients. This is especially important since one can easily predict that differences in the prognosis of patients entering a given study could be of the same order of magnitude as the differences observed between two therapeutic modalities. Finally, it may now be appropriate to attempt to develop new treat- ment strategies for some patients with diffuse lympho- mas-specifically those patients in whom we can prospectively predict poor therapeutic results. REFERENCES 1. Zuks Z, Bull M, Kadin ME, Dorfman HS, Rosenberg SA, Kim H: Lymphoma. IV. Clinicopathologic correlations. Cancer 31:806-823, 1973 2. Peckham Mi: Radiation therapy of the non-Hodgkin's lymphomas. Semin Hematol I 1:41-58, 1974 3. Bitran JD, Kinzie J, Sweet DL, Variakajis D, Grien ML, Golomb HM, Miller JB, Oetzel N, Ultmann JE: Survival of patients with localized histiocytic lymphoma. Cancer 39:342-348, 1977 4. Toonkel LM, Fuller LM, Gamble iF, Butler ii, Martin RG, Shullenberger CC: Laparotomy staged I and II non-Hodgkin's lymphomas: Preliminary results of radiotherapy and adjunctive chemotherapy. Cancer 45:249-260, 1980 5. DeVita VT, Canellos GP, Chabner BA, Schein P, Hubbard SP, Young RC: Advanced diffuse histiocytic lymphoma, a poten- tially curable disease. Lancet 1 :248-250, 1975 6. Berd D, Cornog J, DeConti R, Levitt M, Bertino JR: Long term remission in diffuse histiocytic lymphoma treated with combi- nation sequential chemotherapy. Cancer 35:1050-1054, 1975 7. Schein PS, DeVita VT, Hubbard SP, Chabner BA, Berard cw, Young RC: Bleomycin, adriamycin, cyclophosphamide, vincristine and prednisone (BACOP) combination chemotherapy in the treatment of advanced diffuse histiocytic lymphomas. Ann Intern Med 85:417-422, 1976 8. Skarin AT, Rosenthal DS, Maloney WC, Frei E: Combination chemotherapy of advanced non-Hodgkin's lymphoma with bleomy- cm, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP). Blood 49:759-769, 1977 9. Jones SE, Grozea PN, Metz EN, Haut A, Stephens RL, Morrison FS, Butler JJ, Byrne GE, Moon TE, Fisher R, Haskins CL, Coltman CA: Superiority of adriamycin containing combina- tion chemotherapy in the treatment of diffuse lymphoma. Cancer 43:417-425, 1979 10. Sweet DL, Golomb HM, Ultmann JE, Miller JB, Stein RS, Lester EP, Mintz U, Bitran JD, Streuli RA, Daly K, Roth NO: Cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (COMLA) combination sequential chemo- therapy for advanced diffuse histiocytic lymphoma. Ann Intern Med 92:785-790, 1980 1 1 . Fisher RI, DeVita, VT, Johnson BL, Simon R, Young RC: Prognostic factors for advanced diffuse histiocytic lymphoma following treatment with combination chemotherapy. Am J Med 63:177-182, 1977 I 2. Strauchen JA, Young RC, DeVita VT, Anderson T, Fantone JC, Berard CW: Clinical relevance of the histopathological subclas- sification of diffuse histiocytic lymphoma. N EngI J Med 299:1382- 1387, 1978 I 3. Armitage JO, Dick FR, Platz CE, Corder MP, Lennert JT: Clinical usefulness and reproducibility of histologic subclassifica- tion of advanced diffuse histiocytic lymphoma. Am J Med 67:929- 934, 1979 From www.bloodjournal.org at HOUSTON ACADEMY OF MEDICINE on November 18, 2009. For personal use only. PROGNOSTIC FACTORS FOR DIFFUSE LYMPHOMAS I 4. Rappaport H: Tumors of the hematopoietic system, in: Atlas of Tumor Pathology, Section 3, Fascicle 8. Washington DC, Armed Forces Institute of Pathology, 1966 I 5. Lowenbraun 5, DeVita VT, Serpick AA: Combination chemotherapy with nitrogen mustard, procarbazine, and prednisone in lymphosarcoma and reticulum cell sarcoma. Cancer 25:1018- 1025, 1970 16. Chabner BA, Johnson RE, Young RC, Canellos GP, Hubbard SP, Johnson staging of non-Hodgkin's SK, DeVita lymphoma. VT: Sequential non-surgical Ann Intern Med 85:149-154, I 976 I 7. Carbone PP. Kaplan HS, Musshoff K, Smithers DW, Tubiana M: Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31:1860-1861, 1971 18. Bagley CM, DeVita VT, Berard CW, Canellos GP: Advanced lymphosarcoma: Intensive cyclical combination chemo- therapy with cyclophosphamide, vincristine, and prednisone. Ann Intern Med 76:227-234, 1972 I 9. Gehan E: A generalized Wilcoxon test for comparing arbi- trarily singly-censored samples. Biometrika 52:203-223, 1965 20. Breslow N: A generalized Kruskal-Wallis test for comparing 51 K samples subject to unequeal 57:579-594, 1970 patterns of censorship. Biometrika 21. Armitage P: Statistical York, Wiley, I 971 Methods in Medical Research. New 22. Cox D: Regression 34:187-200, 1972 models and life-tables. J R Stat Soc B 23. Anderson T, Bender RA, Fisher RI, DeVita VT, Chabner BA, Berard CW, Norton L, Young RC: Combination chemotherapy for non-Hodgkin's lymphoma: Results of long-term follow-up. CancerTreat Rep6l:l057-1066, 1977 24. Cabanillas, F, Burke JS, Rodriquez V: Factors predicting with advanced non-Hodgkin's 138:413-418, 1978 Smith TL, for response lymphoma. Moon TE, Butler JJ, and survival in adults Arch Intern Mcd 25. Ferraris AM, Guintini P. Gaetani GF: Serum lactic dehydro- genase as a prognostic tool for non-Hodgkin's lymphomas. Blood 54:928-932, 1979 26. Arseneau JC, Canellos GP, Banks PM, Berard CW, Gral- nick HP, DeVita VT: American Burkitt's lymphoma: A clinico- pathologic study of 30 cases. Am J Med 3 1 4-32 1 , I 975