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An alternating chemotherapy and radiotherapy combination for non-Hodgkin's lymphomas of unfavourable histologies: Feasibility and preliminary results
Radiotherapy and Oncology, 3 (1985) 133 138 Elsevier
133
RTO00090
An alternating chemotherapy and radiotherapy combination for non-Hodgkin's lymphomas of unfavourable histologies: Feasibility and preliminary results J. M. Cosset, F. O z a n n e , M. H e n r y - A m a r , P. C a r d e , J. L. Amiel, M. H a y a t , J. L. H a b r a n d a n d M. T u b i a n a lnstitut Gustave-Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France
(Received 28 March 1984, revision received 5 July 1984, accepted 10 August 1984)
Key words." Non-Hodgkin's lymphomas; Alternating therapies; Combination radiotherapy/chemotherapy
Summary In 1980, on the basis of fundamental and clinical data, a protocol was developed at the Institut GustaveRoussy, alternating eight monthly courses of chemotherapy (CHVP) and two or three radiotherapy sequences (15 Gy in 6 fractions of 10 days, each), to treat non-Hodgkin's lymphomas o f unfavourable histologies, mainly stage II, presenting bulky tumours. Systemic, haematological and digestive tolerances were satisfactory. For 19 previously untreated stage II patients, overall survival and relapse-free survival after 30 months were 85 and 65%, respectively. Three of the relapses were observed in patients who did not receive the alternating schedule in an optimal way; this suggests that these results can be further improved.
Introduction Combinations of drug therapy and radiation have been extensively used for over two decades. Usually, a complete course of irradiation is given, either before or after chemotherapy, with an interval of 3 or 4 weeks between the two treatment modalities. When radiation therapy is given first, chemotherapy must be delayed for at least 5 or 6 weeks. During this time, tumoural microfoci may grow and reach a significant size. When chemotherapy is given first, it may be unable, in some instances, to effect a rapid shrinking of a bulky tumour. Moreover, in the case of massive
tumours, the probability of development of a resistant tumour cell line may increase significantly (Goldie and Coldman model) [13]. Thus, a delay in the administration of irradiation - a non cross-resistant treatment modality - should be avoided. In order to overcome these problems, several protocols attempted to give drugs and radiation concomitantly. However, concomitant administration may enhance toxic effects on normal tissues without significantly improving tumour control. Interaction between the two modalities frequently added to the complications and analysis of published data showed that the therapeutic gain of such a scheme, if any, was very small: in most instances,
0167-8140/85/$03.30 9 1985 Elsevier Science Publishers B.V. (BiomedicalDivision)
134 it appears more detrimental than beneficial [6,7,9,11,12,16,24,27-30,32]. Only one paper reports an improvement in survival [25]. In 1980, a new protocol was developed at the Institut Gustave-Roussy, in order to overcome both the delay of each treatment modality, in the "conventional" sequential schedule, and the usual toxicity of the concomitant administration, by means of an alternating sequential regimen. This consists of eight monthly courses of chemotherapy, alternating with two or three radiotherapy courses respecting the optimal scheduling of chemotherapy. Experimental and clinical data suggest that the toxic effects of drugs and radiation on normal tissues are decreased, or even avoided, when a gap of 8-10 days is introduced between the completion of chemotherapy and the initiation of radiotherapy, or conversely [1,10,23,27-29,32]. This alternating protocol was tested at the Institut Gustave-Roussy on several types of tumours: carcinomas of the lung [2,3] and stage III carcinoma of the uterine cervix. This combination also appeared relevant for non-Hodgkin's lymphomas (NHL) of unfavourable histologies, and the aim of this paper is to report the feasibility of such a protocol and the preliminary results that were obtained on patients with stage II NHL.
TABLE I Distribution of patients according to histology: EORTC - Kid classification. No. of patients Diffuse immunoblastic Diffuse centrocyticand centroblastic Diffuse centroblastic Nodular and diffusecentrocyticand centroblastic Lymphoblastic, convoluted cell type Lymphoblastic (non-Burkitt, non-convoluted) Diffuse, large-cellNHL (not specified) Total
7 5 4 3 1 1 3 24
piratory tract ( U R D T ) (seven patients had at least one localization superior to 5 cm). One patient presented an orbital localization. Five patients presented infradiaphragmatic disease (four of them with bulky tumour masses, superior to 5 cm). (2) Five additional patients were treated for a relapse occurring after treatment by chemotherapy alone. The alternating combination was then utilized as a "salvage" treatment. Of these, one patient was initially classified as clinical stage II, two patients as clinical stage III and two others as stage IV.
Treatment protocol Methods and material
Selection of patients Twenty-four patients with "unfavourable" N H L were treated. The unfavourable group was defined as in the E O R T C protocols, on the basis of Kiel classification. Histological types are given in Table I. Two types of patients were entered in the study: (1) Nineteen clinical stage II patients (according to Ann Arbor classification), previously untreated. There were 11 males and 8 females. The mean age was 43 years (range 18-71). Fourteen patients presented supradiaphragmatic disease. Of these, 1 l showed an involvement of upper digestive and res-
Chemotherapy consisted of eight monthly courses of CHVP, according to previous E O R T C LR2 trial: Adriamycin 50 mg/m 2 VM 26 60 mg/m 2 Cyclophosphamide 300 mg/m 2 Prednisone 40 mg
day day day day
1 1 3 and 4 3 to 7
At least two radiotherapy courses were alternated with chemotherapy courses: between chemotherapy courses 2 and 3, and 3 and 4. Each radiotherapy course delivered 15 Gy in 6 fractions of 10 days. The irradiated volumes were usually the initiallyinvolved areas and the adjacent lymph node groups (Table II). A third irradiation course was optional, and only given in case of residual disease after one
135 TABLE II
Results
Distribution of the 19 previously-untreated stage II patients according to the irradiated volumes (first two radiotherapy courses).
Tolerance
No. of cases
Supradiaphragmatic: Waldeyer's ring + Mantle field (without mediastinum) Waldeyer's ring + cervical areas Waldeyer's ring + mantle field Waldeyer's ring Mediastinum Mantle field without mediastinum Orbit
7
Infradiaphragmatic: Iliac and inguinal nodes Inverted Y Whole abdomen Total
3 1 1
19
or two radiotherapy courses (between chemotherapy courses 4 and 5). The third irradiation sequence delivered 15 Gy, with the same fractionation, in as reduced a volume as possible. Nineteen patients received two radiotherapy courses; five received three alternating courses. The time intervals between chemotherapy and radiotherapy or vice versa were to be no shorter than 8 days and no longer than 10. Statistical methods Estimations of relapse-free survival (RFS) and overall survival were calculated from the first day of treatment according to the Kaplan and Meier method [15]. Time at risk for RFS or overall survival ended at relapse, death, or last known status on April, 15, 1984. Only the patients who achieved a complete remission (18 patients out of 19) were taken into account for RFS. Confidence limits were calculated using the binomial distribution. Data were stored and analysed in the Institut GustaveRoussy Medical Statistics Department, using a general database management system [33].
During the treatment time systemic tolerance was usually good. Haematological tolerance was scored from 0 (no change) to 4 (severe bone marrow toxicity), according to the W H O grading; among the 19 previously-untreated patients, grades 3-4 were reached in eight patients at least once during the entire treatment. Among the five previously-treated patients, grades 3-4 were reached in two cases. No complication was caused by bone marrow hypoplasia, which was transitory in most instances. In only three patients (out of 24) the total duration of treatment was increased to more than 10 months due to bone marrow toxicity. Digestive side effects were minor: U R D T tolerance was markedly better with this type of splitcourse radiotherapy schedule than with the conventional irradiation course. Since the follow-up is still short, the data concerning late tolerance are limited; however, they did not reveal any untoward side effects. Survival The overall survival curve for the 19 stage II patients is shown in Fig. 1. The survival rate at 30 months was 85%. With respect to the five "salvage treatments": three patients died, 11, 21 and 26 months, respec1.00
I
i
I k_
.75
0.85 I | SURVIVAL (n=19)
1
RFS
0.65
.50
.25
~ (n=181
NHL STAGES II UNFAVOURABLE HISTOLOGIES ;
~
~ .....
Fig. 1. Overall survival and relapse-free survival curves for the previously untreated stage II, unfavourable histology. Error bar: 95% confidence limits.
136 tively, after the initial treatment. Two patients are alive with no evidence of disease and with a follow-up of 21 and 37 months, respectively.
Relapse The RFS curve is given in Fig. 1 for the 18 previously-untreated stage II patients achieving complete remission. The RFS at 30 months was 65%. Complete remission was observed after the two first courses of chemotherapy (therefore before irradiation) in 13 patients. In the five other patients, complete remission was achieved only after the radiotherapy courses. Among the 18 patients in whom complete remission was obtained, five relapses were noted. Two occurred in non-irradiated lymph node areas, and viscera (skin, liver) 8 and 12 months after completion of the treatment. Three occurred within the irradiated volumes. One in-field recurrence was observed concomitantly with a systemic evolution of the disease, 2 months after completion of the protocol. This patient had not received adriamycin for the last four chemotherapy courses because he was in North Africa at a time when this drug was not available there. The two other in-field recurrences were observed just after and 4 months after the end of the treatment; these two patients only received two irradiation courses (15 Gy + 15 Gy in 47 days). Among the five patients on whom the alternating protocol was used as a salvage treatment, three complete, and two partial, remissions were observed. Out of the three complete remissions, one patient subsequently relapsed outside the irradiated areas and died (at 26 months).
Discussion
For stage II unfavourable NHL, chemotherapy is now generally considered mandatory [8,17,18, 21,22]. Some authors even argue that chemotherapy could be used alone, and question the role of radiotherapy in those patients [5,19,20]. Chemotherapy alone, without radiation therapy, might be considered for patients with small, non
life-threatening lesions. At the Institut GustaveRoussy, most patients present large tumoural masses. These bulky tumours are often located in the upper respiratory and digestive tract (especially Waldeyer's ring). One should recall that the incidence of Waldeyer's ring involvement is higher in Europe (30-50% of NHL cases) than in the U.S.A. (about 10%) - references in [14]. In those patients with bulky masses, especially those involving Waldeyer's ring, the use of complementary irradiation appears warranted for two reasons: most recurrences occur at the site of initial bulky tumours [4,18,31], and these large lesions, when not shrinking rapidly under chemotherapy, cause compression of the URDT and severe discomfort to the patient. Even the groups who advocate chemotherapy alone have used an "adjuvant radiotherapy" in a significant number of instances (in 12 patients out of 31 in the last series of Miller and Jones [20]). Where chemotherapy and radiotherapy are associated, one can discuss the treatment schedule. Both the delay of irradiation (until the completion of eight chemotherapy courses) or chemotherapy and concomitant administration, have noticeable drawbacks [6,7,9,11-13,16,24,27-30,32]. The alternating schedule appears to be a promising regimen based on both experimental and clinical data [2,3,10,23,29,32]. However, this complex protocol deserves further discussion. (1) Is this sophisticated schedule 'feasible"? At the onset of this study, we experienced minor problems due to the difficulty of organizing appointments for the various sequences. Thus, the intervals between chemotherapy and irradiation were sometimes a little longer than prescribed in the protocol. Nevertheless, the complete alternating treatment was given in less than 10 months to all patients but three, whose bone marrow toxicity caused significant delays. However, these patients were kept in the study and analyzed for this paper. Now, a better organisation allows the precise monitoring of the alternating schedule's timing. (2) Is this protocol well-tolerated? Haematological tolerance appeared acceptable: 10 patients (out of 24) reached grades 3-4 (WHO), but no patient
137
experienced complications and treatment was significantly delayed in only three cases. Systemic and digestive tolerance were good. No increase in late toxicity was detected but the follow-up is still short. As expected, these observations suggest that the 8 to 10-day gap between drug and radiation help to avoid the normal tissues' enhanced toxicity of the concomitant schedules. (3) What are the clinical results? The overall survival and relapse-free survival at 30 months are equal to 85 and 65%, respectively. They compare favourably with the best published data [4,17,1822]. Analysis of the data suggests that these results can possibly be improved. Among the six relapses observed in the previously untreated stage II patients, three failed after a complete alternating treatment (one partial remission, and two systemic relapses). Concerning the three other patients: one presented an early diffuse recurrence and a relapse in an irradiated area (two courses of 15 Gy) but had not received adriamycin for the last four chemotherapy courses. The two others relapsed only in an irradiated area, which only received two irradiation courses (15 Gy each). These three in-field relapses (out of 19 patients receiving two 15 Gy courses) can suggest that the dose is insufficient for bulky tumours, even if a complete regression has been obtained after two chemotherapy courses and is consistent with previous data showing that in this case doses over 45 Gy are required [4,31]. Thus, we can assume that these last three relapses may have been avoided by the use of an "optimal" protocol, with eight complete CHVP courses (of adequate doses) and a systematic delivery of three irradiation courses. The results observed in this first study confirm the promising data published by the group of Houston [18] which used another type of alternating programme. Long-term results are needed to confirm these encouraging preliminary data.
References 1 Aristizabal, S. A., Miller, R. C., Schtichtemeier, A. L., Jones, S. E. and Boone, M. L . M . Adriamycin-irradiation cuta-
neous complications. Int. J. Radiat. Oncol. Biol. Phys. 2:
325 331, 1977. 2 Arriagada, R., Le Chevalier, T. and Sillet Bach, I. Association de radioth6rapie et de chimioth6rapie s6quentielle dans le traitement des carcinomes 6pidermoides bronchiques inoperables. Bull. Cancer (Paris) 68:163 165, 1981. 3 Arriagada, R., Le Chevalier, T., Pico, J. L., Rouesse, J., Hayat, M., Duroux, P., Baldeyroux, P. and Homasson, J. P. Chimioth6rapie et radioth6rapie s6quentielles dans les carcinomes anaplasiques ~. petites cellules. R6sultats pr61iminaires. Bull. Cancer (Paris) 69:98 101, 1982. 4 Bush, R. S. and Gospodarowicz, M. The place of radiation therapy in the management of patients with localized nonHodgkin's lymphoma. In: Malignant Lymphomas, pp. 485 502. Editors: S. A. Rosenberg and H. S. Kaplan. Academic Press, London, 1982. 5 Cabanillas, F., Bodey, G. R. and Freireich, E. J. Chemotherapy alone for management of stage I or II malignant lymphoma of unfavorable histology. Proc. Am. Assoc. Cancer Res. 20: 19, 1979. 6 Cachin, Y. and Eschwege, F. Association radioth6rapiechimioth6rapie dans les carcinomes des voies a6ro-digestives sup6rieures. Bull. Cancer (Paris) 68:158 162, 1981. 7 Cachin, Y., Jortay, A., Sancho, H., Eschwege, F., Madelain, H., Desaulty, A. and Gerard, P. Preliminary results of a randomized EORTC study comparing radiotherapy and concomitant Bleomycine to radiotherapy alone in epidermold carcinomas of the oropharynx. Eur. J. Cancer 13: 1389 1395, 1977. 8 Cosset, J. M., Carde, P. and Tubiana, M. Lymphomes non Hodgkiniens de l'adulte; le point sur les essais r6cents. J. Eur. Radiother. 2:71 84, 1981. 9 Dalley, V. M. Radiotherapy and chemotherapy in the treatment of head and neck cancers. Int. J. Radiat. Oncol. Biol. Phys. 4:173 179, 1978. 10 Dethlefsen, L. A. and Riley, R . M . The effects of Adriamycin and X-irradiation on murine duodenal crypt cell proliferation. Int. J. Radiat. Oncol. Biol. Phys. 5:501 506, 1979. 11 Fazekas, J. T., Sommer, C. and Kramer, S. Adjuvant intravenous methotrexate or definitive radiotherapy alone for advanced squamous cancers of the oral cavity, oropharynx, supraglottic larynx or hypopharynx. Int. J. Radiat. Onco]. Biol. Phys. 6: 533-541, 1980. 12 Fu, K. K., Silverberg, I. J., Phillips, T. L. and Friedman, M. A. Combined radiotherapy and multidrug chemotherapy for advanced head and neck cancer: results of radiation therapy oncology group pilot study. Cancer Treat. Rep. 63: 351 357, 1979. 13 Goldie, J. H. and Coldman, A.J. A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat. Rep. 63:1727 1733, 1979. 14 Hoppe, R. T. Burke, J. S. Glastein, E. and Kaplan, H. S. Non-Hodgkin's Lymphoma. Involvement of Waldeyer's ring. Cancer 42: 1096-1104, 1978.
138 15 Kaplan, E. S. and Meier, P. Non-parametric estimation from incomplete observation. Am. Stat. Assoc. J. 53: 457480, 1958. 16 Kramer, S. Methotrexate and radiation therapy in the treatment of advanced squamous cell carcinoma of the oral cavity, oropharynx, supraglottic larynx and hypopharynx. Can. J. Otolaryngol. 4: 213-218, 1975. 17 Landberg, T. G., Hakansson, L. G., Moiler, T. R., Mattson, W. K. I., Landys, K. E., Johansson, B. G., Killander, D. C. F., Molin, B. F., Wastling, P. F., Lenner, P. H. and Dahl, O . G . CVP-remission-maintenance in stage I or II nonHodgkin's lymphomas. Cancer 44:831 838, 1979. 18 Lester, J. N., Fuller, L. M., Conrad, F. G., Sullivan, J. A., Velasquez, W. S., Butler, J. J. and Shullenberger, C.C. The roles of staging laparotomy, chemotherapy and radiotherapy in the management of localized diffuse large cell lymphoma: a study of 75 patients. Cancer 49: 1746-1753, 1982. 19 Miller, T. P. and Jones, S. E. Is there a role for radiotherapy in localized diffuse lymphomas? Cancer Chemother. Pharmacol. 4:67 70, 1980. 20 Miller, T. P. and Jones, S.E. The management of localized diffuse non-Hodgkin's lymphomas. Curr. Concepts Oncol. 3: 6-9, 1981. 21 Monfardini, S., Banff, A., Bonadonna, G., Rilke, F., Milani, F., Valagussa, P. and Lattuada, A. Improved five years survival after combined radiotherapy-chemotherapy for stage I II non-Hodgkin's lymphoma. Int. J. Radiat.Oncol. Biol. Phys. 6:125 134, 1980. 22 Nissen, N. I., Ersboll, J., Hansen, H. S., Walbom-Jorgensen, S., Pedersen-Bjergaard, J., Hansen, M. M. and Rygard, J. A randomized study of radiotherapy versus radiotherapy plus chemotherapy in stage I-II non-Hodgkin's lymphomas. Cancer 52:1 7, 1983. 23 Pearson, A. E. and Steel, G . G . Chemotherapy in combination with pelvic irradiation; a time-dependence study in mice. Radiother. Oncol. 2:49 55, 1984. 24 Peckham, M. J. and Collis, C. H. Clinical objectives and
25
26
27 28 29
30
31
32
33
normal tissue responses in combined chemotherapy and radiotherapy. Bull. Cancer (Paris) 68: 132-141, 1981. Shanta, V. and Krishnamurthi, S. Combined bleomycin and radiotherapy in oral cancer. Clin. Radiol. 31: 617-620, 1980. Schenken, L. L., Burholt, D. R. and Kovacs, C. J. Adriamycin-radiation combinations: drug induced delayed gastrointestinal radiosensitivity. Int. J. Radiat. Oncol. Biol. Phys. 5: 1265-1269, 1979. Tubiana, M. Les associations radioth6rapie-chimioth6rapie. Bull. Cancer (Paris) 68:109 115, 1981. Tubiana, M. Les associations radioth6rapie-chimioth~rapie. J. Eur. Radiother. 1:107 114, 1980. Tubiana, M., Arriagada, R. and Cosset, J . M . New types of fractionation for optimization of combination of radiotherapy and chemotherapy. In: Progress in Radio-Oncology II, pp. 387 391. Editors: K. H. K/ircher, H. D. Kogelnik and G. Reinarty. Raven Press, New York, 1982. Tubiana, M., Frindel, E. and Vassort, F. Critical survey of experimental data on in vivo synchronisation by hydroxyurea, In: Recent results in Cancer Research, Vol. 52, pp. 187-205. Editors: E. Grudmann and R. Gross. Springer-Vetlag, Berlin and New York, 1975. Tubiana, M., Pouillart, P., Hayat, M., Schlienger, M., Gerard-Marchant, R., Schlumberger, J., Brugere, J., Amid, J. L. and Mathe, G. R6sultats de la radioth6rapie dans les stades I et II des lymphosarcomes et r6ticulosarcomes. Bull. Cancer (Paris) 61: 93-110, 1974. Vaeth, J . M . Combined Effects of Chemotherapy and Radiotherapy on Normal Tissue Tolerance. Frontiers of Radiation Therapy and Oncology, Vol. 13. Karger, Basel and New York, 1979. Wartelle, M., Kramar, A., Jan, P. and Kruger, D. "Pigas": an interactive statistical database management system. In: Proceedings of the Second International Workshop on Statistical Database Management, Sept. 2729, pp. 124-132. Los Altos, California, U.S.A., 1983.
133
RTO00090
An alternating chemotherapy and radiotherapy combination for non-Hodgkin's lymphomas of unfavourable histologies: Feasibility and preliminary results J. M. Cosset, F. O z a n n e , M. H e n r y - A m a r , P. C a r d e , J. L. Amiel, M. H a y a t , J. L. H a b r a n d a n d M. T u b i a n a lnstitut Gustave-Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France
(Received 28 March 1984, revision received 5 July 1984, accepted 10 August 1984)
Key words." Non-Hodgkin's lymphomas; Alternating therapies; Combination radiotherapy/chemotherapy
Summary In 1980, on the basis of fundamental and clinical data, a protocol was developed at the Institut GustaveRoussy, alternating eight monthly courses of chemotherapy (CHVP) and two or three radiotherapy sequences (15 Gy in 6 fractions of 10 days, each), to treat non-Hodgkin's lymphomas o f unfavourable histologies, mainly stage II, presenting bulky tumours. Systemic, haematological and digestive tolerances were satisfactory. For 19 previously untreated stage II patients, overall survival and relapse-free survival after 30 months were 85 and 65%, respectively. Three of the relapses were observed in patients who did not receive the alternating schedule in an optimal way; this suggests that these results can be further improved.
Introduction Combinations of drug therapy and radiation have been extensively used for over two decades. Usually, a complete course of irradiation is given, either before or after chemotherapy, with an interval of 3 or 4 weeks between the two treatment modalities. When radiation therapy is given first, chemotherapy must be delayed for at least 5 or 6 weeks. During this time, tumoural microfoci may grow and reach a significant size. When chemotherapy is given first, it may be unable, in some instances, to effect a rapid shrinking of a bulky tumour. Moreover, in the case of massive
tumours, the probability of development of a resistant tumour cell line may increase significantly (Goldie and Coldman model) [13]. Thus, a delay in the administration of irradiation - a non cross-resistant treatment modality - should be avoided. In order to overcome these problems, several protocols attempted to give drugs and radiation concomitantly. However, concomitant administration may enhance toxic effects on normal tissues without significantly improving tumour control. Interaction between the two modalities frequently added to the complications and analysis of published data showed that the therapeutic gain of such a scheme, if any, was very small: in most instances,
0167-8140/85/$03.30 9 1985 Elsevier Science Publishers B.V. (BiomedicalDivision)
134 it appears more detrimental than beneficial [6,7,9,11,12,16,24,27-30,32]. Only one paper reports an improvement in survival [25]. In 1980, a new protocol was developed at the Institut Gustave-Roussy, in order to overcome both the delay of each treatment modality, in the "conventional" sequential schedule, and the usual toxicity of the concomitant administration, by means of an alternating sequential regimen. This consists of eight monthly courses of chemotherapy, alternating with two or three radiotherapy courses respecting the optimal scheduling of chemotherapy. Experimental and clinical data suggest that the toxic effects of drugs and radiation on normal tissues are decreased, or even avoided, when a gap of 8-10 days is introduced between the completion of chemotherapy and the initiation of radiotherapy, or conversely [1,10,23,27-29,32]. This alternating protocol was tested at the Institut Gustave-Roussy on several types of tumours: carcinomas of the lung [2,3] and stage III carcinoma of the uterine cervix. This combination also appeared relevant for non-Hodgkin's lymphomas (NHL) of unfavourable histologies, and the aim of this paper is to report the feasibility of such a protocol and the preliminary results that were obtained on patients with stage II NHL.
TABLE I Distribution of patients according to histology: EORTC - Kid classification. No. of patients Diffuse immunoblastic Diffuse centrocyticand centroblastic Diffuse centroblastic Nodular and diffusecentrocyticand centroblastic Lymphoblastic, convoluted cell type Lymphoblastic (non-Burkitt, non-convoluted) Diffuse, large-cellNHL (not specified) Total
7 5 4 3 1 1 3 24
piratory tract ( U R D T ) (seven patients had at least one localization superior to 5 cm). One patient presented an orbital localization. Five patients presented infradiaphragmatic disease (four of them with bulky tumour masses, superior to 5 cm). (2) Five additional patients were treated for a relapse occurring after treatment by chemotherapy alone. The alternating combination was then utilized as a "salvage" treatment. Of these, one patient was initially classified as clinical stage II, two patients as clinical stage III and two others as stage IV.
Treatment protocol Methods and material
Selection of patients Twenty-four patients with "unfavourable" N H L were treated. The unfavourable group was defined as in the E O R T C protocols, on the basis of Kiel classification. Histological types are given in Table I. Two types of patients were entered in the study: (1) Nineteen clinical stage II patients (according to Ann Arbor classification), previously untreated. There were 11 males and 8 females. The mean age was 43 years (range 18-71). Fourteen patients presented supradiaphragmatic disease. Of these, 1 l showed an involvement of upper digestive and res-
Chemotherapy consisted of eight monthly courses of CHVP, according to previous E O R T C LR2 trial: Adriamycin 50 mg/m 2 VM 26 60 mg/m 2 Cyclophosphamide 300 mg/m 2 Prednisone 40 mg
day day day day
1 1 3 and 4 3 to 7
At least two radiotherapy courses were alternated with chemotherapy courses: between chemotherapy courses 2 and 3, and 3 and 4. Each radiotherapy course delivered 15 Gy in 6 fractions of 10 days. The irradiated volumes were usually the initiallyinvolved areas and the adjacent lymph node groups (Table II). A third irradiation course was optional, and only given in case of residual disease after one
135 TABLE II
Results
Distribution of the 19 previously-untreated stage II patients according to the irradiated volumes (first two radiotherapy courses).
Tolerance
No. of cases
Supradiaphragmatic: Waldeyer's ring + Mantle field (without mediastinum) Waldeyer's ring + cervical areas Waldeyer's ring + mantle field Waldeyer's ring Mediastinum Mantle field without mediastinum Orbit
7
Infradiaphragmatic: Iliac and inguinal nodes Inverted Y Whole abdomen Total
3 1 1
19
or two radiotherapy courses (between chemotherapy courses 4 and 5). The third irradiation sequence delivered 15 Gy, with the same fractionation, in as reduced a volume as possible. Nineteen patients received two radiotherapy courses; five received three alternating courses. The time intervals between chemotherapy and radiotherapy or vice versa were to be no shorter than 8 days and no longer than 10. Statistical methods Estimations of relapse-free survival (RFS) and overall survival were calculated from the first day of treatment according to the Kaplan and Meier method [15]. Time at risk for RFS or overall survival ended at relapse, death, or last known status on April, 15, 1984. Only the patients who achieved a complete remission (18 patients out of 19) were taken into account for RFS. Confidence limits were calculated using the binomial distribution. Data were stored and analysed in the Institut GustaveRoussy Medical Statistics Department, using a general database management system [33].
During the treatment time systemic tolerance was usually good. Haematological tolerance was scored from 0 (no change) to 4 (severe bone marrow toxicity), according to the W H O grading; among the 19 previously-untreated patients, grades 3-4 were reached in eight patients at least once during the entire treatment. Among the five previously-treated patients, grades 3-4 were reached in two cases. No complication was caused by bone marrow hypoplasia, which was transitory in most instances. In only three patients (out of 24) the total duration of treatment was increased to more than 10 months due to bone marrow toxicity. Digestive side effects were minor: U R D T tolerance was markedly better with this type of splitcourse radiotherapy schedule than with the conventional irradiation course. Since the follow-up is still short, the data concerning late tolerance are limited; however, they did not reveal any untoward side effects. Survival The overall survival curve for the 19 stage II patients is shown in Fig. 1. The survival rate at 30 months was 85%. With respect to the five "salvage treatments": three patients died, 11, 21 and 26 months, respec1.00
I
i
I k_
.75
0.85 I | SURVIVAL (n=19)
1
RFS
0.65
.50
.25
~ (n=181
NHL STAGES II UNFAVOURABLE HISTOLOGIES ;
~
~ .....
Fig. 1. Overall survival and relapse-free survival curves for the previously untreated stage II, unfavourable histology. Error bar: 95% confidence limits.
136 tively, after the initial treatment. Two patients are alive with no evidence of disease and with a follow-up of 21 and 37 months, respectively.
Relapse The RFS curve is given in Fig. 1 for the 18 previously-untreated stage II patients achieving complete remission. The RFS at 30 months was 65%. Complete remission was observed after the two first courses of chemotherapy (therefore before irradiation) in 13 patients. In the five other patients, complete remission was achieved only after the radiotherapy courses. Among the 18 patients in whom complete remission was obtained, five relapses were noted. Two occurred in non-irradiated lymph node areas, and viscera (skin, liver) 8 and 12 months after completion of the treatment. Three occurred within the irradiated volumes. One in-field recurrence was observed concomitantly with a systemic evolution of the disease, 2 months after completion of the protocol. This patient had not received adriamycin for the last four chemotherapy courses because he was in North Africa at a time when this drug was not available there. The two other in-field recurrences were observed just after and 4 months after the end of the treatment; these two patients only received two irradiation courses (15 Gy + 15 Gy in 47 days). Among the five patients on whom the alternating protocol was used as a salvage treatment, three complete, and two partial, remissions were observed. Out of the three complete remissions, one patient subsequently relapsed outside the irradiated areas and died (at 26 months).
Discussion
For stage II unfavourable NHL, chemotherapy is now generally considered mandatory [8,17,18, 21,22]. Some authors even argue that chemotherapy could be used alone, and question the role of radiotherapy in those patients [5,19,20]. Chemotherapy alone, without radiation therapy, might be considered for patients with small, non
life-threatening lesions. At the Institut GustaveRoussy, most patients present large tumoural masses. These bulky tumours are often located in the upper respiratory and digestive tract (especially Waldeyer's ring). One should recall that the incidence of Waldeyer's ring involvement is higher in Europe (30-50% of NHL cases) than in the U.S.A. (about 10%) - references in [14]. In those patients with bulky masses, especially those involving Waldeyer's ring, the use of complementary irradiation appears warranted for two reasons: most recurrences occur at the site of initial bulky tumours [4,18,31], and these large lesions, when not shrinking rapidly under chemotherapy, cause compression of the URDT and severe discomfort to the patient. Even the groups who advocate chemotherapy alone have used an "adjuvant radiotherapy" in a significant number of instances (in 12 patients out of 31 in the last series of Miller and Jones [20]). Where chemotherapy and radiotherapy are associated, one can discuss the treatment schedule. Both the delay of irradiation (until the completion of eight chemotherapy courses) or chemotherapy and concomitant administration, have noticeable drawbacks [6,7,9,11-13,16,24,27-30,32]. The alternating schedule appears to be a promising regimen based on both experimental and clinical data [2,3,10,23,29,32]. However, this complex protocol deserves further discussion. (1) Is this sophisticated schedule 'feasible"? At the onset of this study, we experienced minor problems due to the difficulty of organizing appointments for the various sequences. Thus, the intervals between chemotherapy and irradiation were sometimes a little longer than prescribed in the protocol. Nevertheless, the complete alternating treatment was given in less than 10 months to all patients but three, whose bone marrow toxicity caused significant delays. However, these patients were kept in the study and analyzed for this paper. Now, a better organisation allows the precise monitoring of the alternating schedule's timing. (2) Is this protocol well-tolerated? Haematological tolerance appeared acceptable: 10 patients (out of 24) reached grades 3-4 (WHO), but no patient
137
experienced complications and treatment was significantly delayed in only three cases. Systemic and digestive tolerance were good. No increase in late toxicity was detected but the follow-up is still short. As expected, these observations suggest that the 8 to 10-day gap between drug and radiation help to avoid the normal tissues' enhanced toxicity of the concomitant schedules. (3) What are the clinical results? The overall survival and relapse-free survival at 30 months are equal to 85 and 65%, respectively. They compare favourably with the best published data [4,17,1822]. Analysis of the data suggests that these results can possibly be improved. Among the six relapses observed in the previously untreated stage II patients, three failed after a complete alternating treatment (one partial remission, and two systemic relapses). Concerning the three other patients: one presented an early diffuse recurrence and a relapse in an irradiated area (two courses of 15 Gy) but had not received adriamycin for the last four chemotherapy courses. The two others relapsed only in an irradiated area, which only received two irradiation courses (15 Gy each). These three in-field relapses (out of 19 patients receiving two 15 Gy courses) can suggest that the dose is insufficient for bulky tumours, even if a complete regression has been obtained after two chemotherapy courses and is consistent with previous data showing that in this case doses over 45 Gy are required [4,31]. Thus, we can assume that these last three relapses may have been avoided by the use of an "optimal" protocol, with eight complete CHVP courses (of adequate doses) and a systematic delivery of three irradiation courses. The results observed in this first study confirm the promising data published by the group of Houston [18] which used another type of alternating programme. Long-term results are needed to confirm these encouraging preliminary data.
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