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Intra-arterial induction chemotherapy for soft tissue sarcomas
Annals of Oncology 3 (Suppl. 2): S67-S70, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Intra-arterial induction chemotherapy for soft tissue sarcomas A. Azzarelli,1 V. Quagliuolo,1 S. Fissi,1 P. Casali,2 A. Garbuglia,1 P. Bignami,1 A. Santoro,2 S. Andreola3 & L. Gennari1 1
Division of Oncologia Chirurgica 'A'; 2Division of Oncologia Medica A'; 3 Division of Anatomia e Istologia Patologica, Istituto Nazionale Tumori, Milano
response was highly predictive of survival: 63% versus 36% (p = 0.01) 5-year survival in the group of responders and non-responders, respectively, whereas the pathological parameter of response was not so predictive. The improved effect of delivering the drug intra-arterially is theoretically expected but not proved in our experience. The major practical effect of this induction chemotherapy is the selection of patients with better prognosis and the possiblity of perform, in some cases, easier limb salvage procedures. The last regimen combining i.a. ADR + i.v. Ifosfamide seems to provide little better but not yet significant results.
Introduction
Patient selection
It was about 1980 when some experiences suggested that preoperative intra-arterial chemotherapy could improve the management of soft tissue sarcomas [1-8]. The 'neoadjuvant' treatment was expected to facilitate the removal of the primary tumor, to evaluate in vivo the chemo-responsivity, and to provide an early protection against the development of distant metastases. In addition the regional drug delivery through a catheter placed into a selective artery was expected to improve the local response, reducing systemic toxicity. Despite these hopeful intents and some encouraging reports, ours included, results remain up to now controversial and nonconvincing [9, 10]. The main cause is the limited number of cases which, combined with the several clinical and pathological situations, leads to inconsistent statistical analyses. Since 1981 in our Institute preoperative regional chemotherapy has been delivered to a highly selected group of patients with non-metastatic soft tissue sarcomas [8, 10]. The study is not randomized and was designed with the purpose of confining the several clinico-pathological variables, the frequent cause of unremarkable results. This selected series collected in a single institution is numerically relevant, and some incontrovertible points have been identified and cannot be forgotten when designing future protocols.
All the evaluable patients, with ages ranging from 15 to 70 years and general conditions fit for the treatment, had a histologically confirmed primary soft tissue sarcoma, located in the extremities and potentially operable with adequate margins, even if the operation would require exarticulation, excluding hemipelvectomy [patients candidated to hemipelvectomy have been included in different protocols designed for advanced stages]. Recurrent lesions were eligible provided they were not pretreated with chemo or radiation therapy. All the lesions were clinically evaluable and larger than 8 cm in the lower or 5 cm in the upper extremity. Since the third protocol (1983) eligible hystotypes were restricted to the typical grade III spindle cell sarcomas, and cases formerly included but not fullfilling this new rationale are reported separately in the present review.
Treatment schedules
Four similar regimens were employed in consecutive periods, all including adriamycin given intra-arterially (i.a. ADR) at a dose of 100 mg/m2 when alone or 80 mg/m2 when in combination, for 1 or 2 preoperative cycles. The first schedule with i.a. ADR alone for one cycle (19 cases) gave some encouraging results so that the second schedule associated i.a. ADR with i.a. cisdiaminoplatinum (CDP) for two preoperative cycles, followed by three postoperative cycles (9 cases). Due to
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on September 4, 2015
Summary. One hundred-one patients were treated in our institution with intra-arterial preoperative adriamycin (i.a. ADR) for large soft tissue sarcomas of the extremities, 45% recurrent at entry. Of the 78 high grade evaluable patients 38% had clinical and 45% had pathological responses to chemotherapy. Limb conservative surgery was performed in 80% of cases, with about 10% improvement made possible by the preoperative treatment. The local recurrence rate was 29%, and 50% five-year actuarial survival with a median follow-up of 68 months. These poor results are related to the severe selection of high risk cases. The clinical parameter of
68
complications, toxicity and not evident improvement in results, CDP was removed, and the third schema (Jan. 1983-April 1988) scheduled i.a. ADR alone for two preoperative cycles and three postoperative (38 cases). In May 1988 a cooperative study was begun scheduling i.a. ADR combined with intravenous Ifosfamide (6Gr/ mVcylce) (35 cases) [11]. This regimen also scheduled intravenous ADR for lesion of the upper limbs and of the trunk, but these cases are not reported here. The last regimens provided better results than previous, but differences are still not significant and, for simplicity, results of this report take into account the entire series as a whole without stratification by chemotherapy regimens. All these treatment schedules have been submitted and approved by the internal scientific and ethical committee.
Two kinds of results are identified in this report: short term and long term results and possible relationship. Parameters for short terms results are the feasibility and toxicity of the preoperative chemotherapy, clinical improvement of the primary lesion, pathologic chemoinduced necrosis. Long term results evaluate the local recurrence rate, disease-free interval and survival. Clinical response. The clinical response was rated on four parameters of the primary lesion, all evaluated by physical and radiological examinations: size, consistency, demarcation of margins, mobility or split over deeper structure. A score table, always compiled by the same physician before and after the infusion chemotherapy, was then resumed in four conclusive judgements of response: (1) progression of the lesion; (2) stable disease or minor response; (3) objective response; (4) complete disappearance of any evaluable parameter. A simplified score classified as responders points 3 and 4, and nonresponders points 1 and 2. Pathologic response The pathologic response was a synthesis of macro and microscopic evaluations of the chemoinduced necrosis. The accepted definition of necrosis is the 'total absence of identifiable nuclei' [12]. The percentage of necrosis is the mean value of many single specimens evaluated macroscopically on the surgical piece cut along its major diameter and microscopically on at least six samples taken from the tumor edge where the lesion is usually more viable, and others taken at random within the mass, avoiding areas where the tissue is evidently necrotic or haemorrhagic. A standard method of pathologic evaluation of response is still controversial and not easy: minor cellular damages such as hyperchromatism, pycnosis, cytoplasmatic vacuolization are
Long term results Long term results evaluate the local recurrence rate, the free of disease interval and survival. These values, properly stratified, will be reported in five-year actuarial figures. Statistical analysis The study is not randomized and the series is analyzed after stratification by criteria which could affect the outcome - like site of the primary lesion, adequacy of surgery, lesions recurrent at entry, responsivity to chemotherapy. Recurrence-free and survival curves are rated by life tables and differences verified with log rank test. The limited number of cases did not allow a reliable multivariate analysis. Some patients with an atypical sarcoma formerly included in the protocol, are here reported in Table 1 but not evaluated in survival figure.
Results Up to now 1.01 patients have entered the study: male/ female ratio = 1.0, median age 48 years, (male 44; female 51). Fourteen patients treated in the first two years belong to further excluded histotypes (eight low grade liposarcomas, four clear cell sarcomas, one small cell sarcoma and one extraskeletal chondrosarcoma); for different reasons 11 patients, two of them belonging to excluded histotypes, are not evaluable; the remaining 78 cases constitute the core of this report: 45% were already recurrent at entry in the study. The pretreatment judgment of operability considered 65% of cases surely operable with conservative surgical procedures, 10% dubious and 25% candidated to amputations; the final limb salvage rate was 80%, meaning that a percentage ranging from 5% to 15% underwent limb salvage in force of the treatment. Short term results Clinical response was documented in 38% of cases and pathological in 45% but clinical and pathological response did not coincide in all cases: clinical response
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on September 4, 2015
Evaluation of results
frequent and cannot be considered necrosis but have an influence on the pathologic impression of responsivity. However, the main bias is the presence of spontaneous areas of necrosis existing before chemotherapy which cannot be easily distinguished from the induced necrosis, especially in the central portion of the lesion. Different from the chemoinduced cellular damages, areas of spontaneous necrosis have a worsening prognostic effect. For these reasons and despite the attempt to standardize the methodology, the final pathologic report cannot be dissociated from a trained but still subjective impression.
69 alone: 18%; pathological response alone: 25%; clinical+path. response: 20%; no response of any kind: 37%. For reasons which will be discussed later only clinical response will be taken into account in this analysis. In Table 1 the clinical response is reported, stratified by major histotypes: despite the great differences in response rate these values are only suggestive and do not reach statistical significance. Long term results
Discussion Examining results of this non-randomized study, we can only describe the natural history of our series and analyze some logical possible conclusions. Considering local response to induction chemotherapy, some points on the evaluation parameters must be outlined. Clinical and pathological response Table 1. Clinical response by histology. Histotype
Clinical response
Mai. Fibrous Histiocytoma High Grade Liposarcoma Synovialsarcoma Mai. Schwannoma Low Grade Liposarcoma Leiomyosarcoma Unclassified Sarcoma Clear Cell Sarcoma Others Total
26% 69% 40% 44% 62% 29% 71%
No. cases responders/total 6/23 9/13 4/10 4/9 5/8 2/7 5/7 4/4
100%
3/11 42/92
27% 46%
Survival by Clinical Response
p = 0.01
20-
0 Fig. I.
-*- Responders 31 —~ No Responders 46 6
12
18
24
30 36 Months
42
48
54
60
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on September 4, 2015
Conservative operations resulted in 29% of local recurrences (22% when surgery was considered adequate and 40% when surgery was marginal and followed by radiation therapy). Up to now the median exposure to follow-up is 68 months. In Fig. 1 the five-year actuarial survival is stratified by clinical response. The five-year overall survival is 54%. Sixteen and four patients are still living free of disease at five and ten years, respectively.
were coincident only in the 34% of cases who revealed some kind of response; the other 'responders' had only pathologic or only clinical response. The explanation is probably that the clinical shrinkage of the lesion can be combined with a pathological report of poor necrosis; in fact, the residual lump is mostly constituted by viable cells. On the contrary, a clinically stable lesion can appear microscopically highly necrotic. On the other hand, necrosis could be a spontaneous expression of the tumor itself, and this eventuality has a negative prognostic value. This consideration can explain why the clinical parameter is more accurate than the pathological in predicting survival. Our conservative operations had a high incidence of local recurrences; survival rate is also poor and this data also seems to be in part correlated to local recurrence rate. In fact, the group of adequately operated patients have a 5-year survival of 56%, versus 40% where surgery was marginal. The severe long term results with high local recurrence rate and poor free of disease survival was in part due to the fact that the patient selection rationale tended toward advanced lesions (median diameter 14 cm ranging 6 to 34). Many of these tumors (hard, fixid, large in size, recurrent at entry) might therefore be compared to other experiences with regimens designed for locally advanced stages, where expectancies are less optimistic. Once again we feel the necessity to confide in a reliable commonly accepted staging sytem which is still missing, and this is one major bias when matching experiences. The most extensive experience in this matter is reported by Eilber and coworkers [2, 3, 10], who employed preoperative intra-arterial ADR for years without proving the real improved effect of the intra-arterial procedure. We do not think that the Eilber regimens, however randomized, could ever verify the difference between intravenous versus intra-arterial delivery of adriamycin, particularly if the main expected result is local control of disease, mainly because intra-arterial chemotherapy is associated with radiation therapy, and because ADR is delivered at a very low dose for a short time of infusion. Comparing ours to Eilber's protocol, we scheduled higher dose of ADR (100 mg/mVcycle, vs. 90 mg total dose in the Eilber's protocol) for a longer time of infusion (about 200, vs. 72h) employing chemotherapy alone, not combined with radiation therapy. Nevertheless we do not emphasize now the necessity of the intra-arterial delivery of adriamycin: this is only a different access for a systemic chemotherapy. In fact, the drug leakage from an extremity is almost total and the better theoretical effect is the larger amount of drug which can be delivered to the primary lesion with lower myelo and cardio-toxicity made possible by the very slow continuous infusion. The ongoing regimen combining i.a. ADR+i.v. Ifosfamide suggests a little better effect, but the small number of cases do not allow conclusions of significance. After several stratifications of our series an important significant data was constantly valid through the
70
6. 7. 8.
9.
10.
11.
References 1. Didolkar MS, Kanter PM, Baffi RR et al. Comparison of regional versus systemic chemotherapy with adriamycin. Ann Surg 1978; 187: 332-6. 2. Eilber FR, Mirra JJ, Grant TT et al. Is amputation necessary for sarcomas? A seven-year experience with limb salvage. Ann Surg 1980; 192: 431-8. 3. Eilber FR, Morton DL, Eckardt J et al. Limb salvage for skeletal and soft tissue sarcomas. Multidisciplinary preoperative therapy. Cancer 1984; 53: 2579-84. 4. Karakousis CP, Lopez R, Catane R et al. Intraarterial adriamycin in the treatment of soft tissue sarcomas. J Surg Oncol 1980; 13: 21-7. 5. Karakousis CP, Emrich LJ, Rao U, Khalil M. Limb salvage in
12.
13.
soft tissue sarcomas with selective combination of modalities. EurJ Surg Oncol 1991; 17:71-80. Krabyll WM, Harrison M, Sasaki T et al. Regional intra-arterial infusion of adriamycin in the treatment of cancer. Surg Gynecol Obstet 1977; 144: 335-8. Mantravadi RVP, Trippon MJ, Patel MK et al. Limb salvage in extremity soft tissue sarcoma: combined modality therapy. Radiology 1984; 152: 523-6. Azzarelli A, Quagliuolo V, Audisio RA, Bonfanti G, Andreola S, Gennari L. Intraarterial adriamycin followed by surgery for limb sarcomas. Preliminary report. Eur J Cancer Clin Oncol 1983; 19:885-90. Azzarelli A, Gennari L, Vaglini M et al. Intra-arterial infusion and perfusion chemotherapy for soft tissue sarcomas of the extremities. In Pinedo HM, Verweij J (eds): Clinical management of soft tissue sarcomas. Martinus Nijhoff: Boston, 1986, pp. 103-29. Eilber FR, Giuliano AE, Huth JF et al. A randomized prospective trial using postoperative adjuvant chemotherapy (Adriamycin) in high-grade extremity soft-tissue sarcoma. Am J Clin Oncol 1988; 11:39. Azzarelli A, Casali P, Collella G et al. Intra-arterial adriamycin and systemic ifosfamide for operable soft tissue sarcoma: pilot experience and prospective polycentric trial. Reg Cancer Treat 1989; 2: 184. Morton DL, Eilber FR, Townsend CM Jr et al. Limb salvage from a multidisciplinary treatment approach for skeletal and soft tissue sarcomas of the extremities. Ann Surg 1980; 184: 268-78. Pezzi CM, Pollock RE, Evans HL et al. Preoperative chemotherapy for soft tissue sarcomas of the extremities. Ann Surg 1990; 211:476-81.
Correspondence to: Dr. A. Azzarelli Istituto Nazionale Tumori Via Venezian 1 20133 Milano, Italy
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on September 4, 2015
years and recently reported also by others [13]. This was the correlation between clinical response rate and free of disease survival [pathological response was not so predictive]. The 5-year actuarial survival of the 31 clinically responsive patients is 63% vs. 36% of the 46 non-responders (p = 0.01). It is not clear in our experience that this is a cause-effect relationship; may only indicate a selection of cases which would have had in any case a favourable outcome. This is important information on prognosis and probable modulation of adjuvant postoperative treatment. Finally, we are convinced that about 10% of our patients underwent limb salvage operations in force of this medical induction therapy, and we are still reluctant to abandon this multimodal treatment procedure, even if it is difficult to prove without randomization, not feasible in a single center.
Original article Intra-arterial induction chemotherapy for soft tissue sarcomas A. Azzarelli,1 V. Quagliuolo,1 S. Fissi,1 P. Casali,2 A. Garbuglia,1 P. Bignami,1 A. Santoro,2 S. Andreola3 & L. Gennari1 1
Division of Oncologia Chirurgica 'A'; 2Division of Oncologia Medica A'; 3 Division of Anatomia e Istologia Patologica, Istituto Nazionale Tumori, Milano
response was highly predictive of survival: 63% versus 36% (p = 0.01) 5-year survival in the group of responders and non-responders, respectively, whereas the pathological parameter of response was not so predictive. The improved effect of delivering the drug intra-arterially is theoretically expected but not proved in our experience. The major practical effect of this induction chemotherapy is the selection of patients with better prognosis and the possiblity of perform, in some cases, easier limb salvage procedures. The last regimen combining i.a. ADR + i.v. Ifosfamide seems to provide little better but not yet significant results.
Introduction
Patient selection
It was about 1980 when some experiences suggested that preoperative intra-arterial chemotherapy could improve the management of soft tissue sarcomas [1-8]. The 'neoadjuvant' treatment was expected to facilitate the removal of the primary tumor, to evaluate in vivo the chemo-responsivity, and to provide an early protection against the development of distant metastases. In addition the regional drug delivery through a catheter placed into a selective artery was expected to improve the local response, reducing systemic toxicity. Despite these hopeful intents and some encouraging reports, ours included, results remain up to now controversial and nonconvincing [9, 10]. The main cause is the limited number of cases which, combined with the several clinical and pathological situations, leads to inconsistent statistical analyses. Since 1981 in our Institute preoperative regional chemotherapy has been delivered to a highly selected group of patients with non-metastatic soft tissue sarcomas [8, 10]. The study is not randomized and was designed with the purpose of confining the several clinico-pathological variables, the frequent cause of unremarkable results. This selected series collected in a single institution is numerically relevant, and some incontrovertible points have been identified and cannot be forgotten when designing future protocols.
All the evaluable patients, with ages ranging from 15 to 70 years and general conditions fit for the treatment, had a histologically confirmed primary soft tissue sarcoma, located in the extremities and potentially operable with adequate margins, even if the operation would require exarticulation, excluding hemipelvectomy [patients candidated to hemipelvectomy have been included in different protocols designed for advanced stages]. Recurrent lesions were eligible provided they were not pretreated with chemo or radiation therapy. All the lesions were clinically evaluable and larger than 8 cm in the lower or 5 cm in the upper extremity. Since the third protocol (1983) eligible hystotypes were restricted to the typical grade III spindle cell sarcomas, and cases formerly included but not fullfilling this new rationale are reported separately in the present review.
Treatment schedules
Four similar regimens were employed in consecutive periods, all including adriamycin given intra-arterially (i.a. ADR) at a dose of 100 mg/m2 when alone or 80 mg/m2 when in combination, for 1 or 2 preoperative cycles. The first schedule with i.a. ADR alone for one cycle (19 cases) gave some encouraging results so that the second schedule associated i.a. ADR with i.a. cisdiaminoplatinum (CDP) for two preoperative cycles, followed by three postoperative cycles (9 cases). Due to
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on September 4, 2015
Summary. One hundred-one patients were treated in our institution with intra-arterial preoperative adriamycin (i.a. ADR) for large soft tissue sarcomas of the extremities, 45% recurrent at entry. Of the 78 high grade evaluable patients 38% had clinical and 45% had pathological responses to chemotherapy. Limb conservative surgery was performed in 80% of cases, with about 10% improvement made possible by the preoperative treatment. The local recurrence rate was 29%, and 50% five-year actuarial survival with a median follow-up of 68 months. These poor results are related to the severe selection of high risk cases. The clinical parameter of
68
complications, toxicity and not evident improvement in results, CDP was removed, and the third schema (Jan. 1983-April 1988) scheduled i.a. ADR alone for two preoperative cycles and three postoperative (38 cases). In May 1988 a cooperative study was begun scheduling i.a. ADR combined with intravenous Ifosfamide (6Gr/ mVcylce) (35 cases) [11]. This regimen also scheduled intravenous ADR for lesion of the upper limbs and of the trunk, but these cases are not reported here. The last regimens provided better results than previous, but differences are still not significant and, for simplicity, results of this report take into account the entire series as a whole without stratification by chemotherapy regimens. All these treatment schedules have been submitted and approved by the internal scientific and ethical committee.
Two kinds of results are identified in this report: short term and long term results and possible relationship. Parameters for short terms results are the feasibility and toxicity of the preoperative chemotherapy, clinical improvement of the primary lesion, pathologic chemoinduced necrosis. Long term results evaluate the local recurrence rate, disease-free interval and survival. Clinical response. The clinical response was rated on four parameters of the primary lesion, all evaluated by physical and radiological examinations: size, consistency, demarcation of margins, mobility or split over deeper structure. A score table, always compiled by the same physician before and after the infusion chemotherapy, was then resumed in four conclusive judgements of response: (1) progression of the lesion; (2) stable disease or minor response; (3) objective response; (4) complete disappearance of any evaluable parameter. A simplified score classified as responders points 3 and 4, and nonresponders points 1 and 2. Pathologic response The pathologic response was a synthesis of macro and microscopic evaluations of the chemoinduced necrosis. The accepted definition of necrosis is the 'total absence of identifiable nuclei' [12]. The percentage of necrosis is the mean value of many single specimens evaluated macroscopically on the surgical piece cut along its major diameter and microscopically on at least six samples taken from the tumor edge where the lesion is usually more viable, and others taken at random within the mass, avoiding areas where the tissue is evidently necrotic or haemorrhagic. A standard method of pathologic evaluation of response is still controversial and not easy: minor cellular damages such as hyperchromatism, pycnosis, cytoplasmatic vacuolization are
Long term results Long term results evaluate the local recurrence rate, the free of disease interval and survival. These values, properly stratified, will be reported in five-year actuarial figures. Statistical analysis The study is not randomized and the series is analyzed after stratification by criteria which could affect the outcome - like site of the primary lesion, adequacy of surgery, lesions recurrent at entry, responsivity to chemotherapy. Recurrence-free and survival curves are rated by life tables and differences verified with log rank test. The limited number of cases did not allow a reliable multivariate analysis. Some patients with an atypical sarcoma formerly included in the protocol, are here reported in Table 1 but not evaluated in survival figure.
Results Up to now 1.01 patients have entered the study: male/ female ratio = 1.0, median age 48 years, (male 44; female 51). Fourteen patients treated in the first two years belong to further excluded histotypes (eight low grade liposarcomas, four clear cell sarcomas, one small cell sarcoma and one extraskeletal chondrosarcoma); for different reasons 11 patients, two of them belonging to excluded histotypes, are not evaluable; the remaining 78 cases constitute the core of this report: 45% were already recurrent at entry in the study. The pretreatment judgment of operability considered 65% of cases surely operable with conservative surgical procedures, 10% dubious and 25% candidated to amputations; the final limb salvage rate was 80%, meaning that a percentage ranging from 5% to 15% underwent limb salvage in force of the treatment. Short term results Clinical response was documented in 38% of cases and pathological in 45% but clinical and pathological response did not coincide in all cases: clinical response
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on September 4, 2015
Evaluation of results
frequent and cannot be considered necrosis but have an influence on the pathologic impression of responsivity. However, the main bias is the presence of spontaneous areas of necrosis existing before chemotherapy which cannot be easily distinguished from the induced necrosis, especially in the central portion of the lesion. Different from the chemoinduced cellular damages, areas of spontaneous necrosis have a worsening prognostic effect. For these reasons and despite the attempt to standardize the methodology, the final pathologic report cannot be dissociated from a trained but still subjective impression.
69 alone: 18%; pathological response alone: 25%; clinical+path. response: 20%; no response of any kind: 37%. For reasons which will be discussed later only clinical response will be taken into account in this analysis. In Table 1 the clinical response is reported, stratified by major histotypes: despite the great differences in response rate these values are only suggestive and do not reach statistical significance. Long term results
Discussion Examining results of this non-randomized study, we can only describe the natural history of our series and analyze some logical possible conclusions. Considering local response to induction chemotherapy, some points on the evaluation parameters must be outlined. Clinical and pathological response Table 1. Clinical response by histology. Histotype
Clinical response
Mai. Fibrous Histiocytoma High Grade Liposarcoma Synovialsarcoma Mai. Schwannoma Low Grade Liposarcoma Leiomyosarcoma Unclassified Sarcoma Clear Cell Sarcoma Others Total
26% 69% 40% 44% 62% 29% 71%
No. cases responders/total 6/23 9/13 4/10 4/9 5/8 2/7 5/7 4/4
100%
3/11 42/92
27% 46%
Survival by Clinical Response
p = 0.01
20-
0 Fig. I.
-*- Responders 31 —~ No Responders 46 6
12
18
24
30 36 Months
42
48
54
60
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on September 4, 2015
Conservative operations resulted in 29% of local recurrences (22% when surgery was considered adequate and 40% when surgery was marginal and followed by radiation therapy). Up to now the median exposure to follow-up is 68 months. In Fig. 1 the five-year actuarial survival is stratified by clinical response. The five-year overall survival is 54%. Sixteen and four patients are still living free of disease at five and ten years, respectively.
were coincident only in the 34% of cases who revealed some kind of response; the other 'responders' had only pathologic or only clinical response. The explanation is probably that the clinical shrinkage of the lesion can be combined with a pathological report of poor necrosis; in fact, the residual lump is mostly constituted by viable cells. On the contrary, a clinically stable lesion can appear microscopically highly necrotic. On the other hand, necrosis could be a spontaneous expression of the tumor itself, and this eventuality has a negative prognostic value. This consideration can explain why the clinical parameter is more accurate than the pathological in predicting survival. Our conservative operations had a high incidence of local recurrences; survival rate is also poor and this data also seems to be in part correlated to local recurrence rate. In fact, the group of adequately operated patients have a 5-year survival of 56%, versus 40% where surgery was marginal. The severe long term results with high local recurrence rate and poor free of disease survival was in part due to the fact that the patient selection rationale tended toward advanced lesions (median diameter 14 cm ranging 6 to 34). Many of these tumors (hard, fixid, large in size, recurrent at entry) might therefore be compared to other experiences with regimens designed for locally advanced stages, where expectancies are less optimistic. Once again we feel the necessity to confide in a reliable commonly accepted staging sytem which is still missing, and this is one major bias when matching experiences. The most extensive experience in this matter is reported by Eilber and coworkers [2, 3, 10], who employed preoperative intra-arterial ADR for years without proving the real improved effect of the intra-arterial procedure. We do not think that the Eilber regimens, however randomized, could ever verify the difference between intravenous versus intra-arterial delivery of adriamycin, particularly if the main expected result is local control of disease, mainly because intra-arterial chemotherapy is associated with radiation therapy, and because ADR is delivered at a very low dose for a short time of infusion. Comparing ours to Eilber's protocol, we scheduled higher dose of ADR (100 mg/mVcycle, vs. 90 mg total dose in the Eilber's protocol) for a longer time of infusion (about 200, vs. 72h) employing chemotherapy alone, not combined with radiation therapy. Nevertheless we do not emphasize now the necessity of the intra-arterial delivery of adriamycin: this is only a different access for a systemic chemotherapy. In fact, the drug leakage from an extremity is almost total and the better theoretical effect is the larger amount of drug which can be delivered to the primary lesion with lower myelo and cardio-toxicity made possible by the very slow continuous infusion. The ongoing regimen combining i.a. ADR+i.v. Ifosfamide suggests a little better effect, but the small number of cases do not allow conclusions of significance. After several stratifications of our series an important significant data was constantly valid through the
70
6. 7. 8.
9.
10.
11.
References 1. Didolkar MS, Kanter PM, Baffi RR et al. Comparison of regional versus systemic chemotherapy with adriamycin. Ann Surg 1978; 187: 332-6. 2. Eilber FR, Mirra JJ, Grant TT et al. Is amputation necessary for sarcomas? A seven-year experience with limb salvage. Ann Surg 1980; 192: 431-8. 3. Eilber FR, Morton DL, Eckardt J et al. Limb salvage for skeletal and soft tissue sarcomas. Multidisciplinary preoperative therapy. Cancer 1984; 53: 2579-84. 4. Karakousis CP, Lopez R, Catane R et al. Intraarterial adriamycin in the treatment of soft tissue sarcomas. J Surg Oncol 1980; 13: 21-7. 5. Karakousis CP, Emrich LJ, Rao U, Khalil M. Limb salvage in
12.
13.
soft tissue sarcomas with selective combination of modalities. EurJ Surg Oncol 1991; 17:71-80. Krabyll WM, Harrison M, Sasaki T et al. Regional intra-arterial infusion of adriamycin in the treatment of cancer. Surg Gynecol Obstet 1977; 144: 335-8. Mantravadi RVP, Trippon MJ, Patel MK et al. Limb salvage in extremity soft tissue sarcoma: combined modality therapy. Radiology 1984; 152: 523-6. Azzarelli A, Quagliuolo V, Audisio RA, Bonfanti G, Andreola S, Gennari L. Intraarterial adriamycin followed by surgery for limb sarcomas. Preliminary report. Eur J Cancer Clin Oncol 1983; 19:885-90. Azzarelli A, Gennari L, Vaglini M et al. Intra-arterial infusion and perfusion chemotherapy for soft tissue sarcomas of the extremities. In Pinedo HM, Verweij J (eds): Clinical management of soft tissue sarcomas. Martinus Nijhoff: Boston, 1986, pp. 103-29. Eilber FR, Giuliano AE, Huth JF et al. A randomized prospective trial using postoperative adjuvant chemotherapy (Adriamycin) in high-grade extremity soft-tissue sarcoma. Am J Clin Oncol 1988; 11:39. Azzarelli A, Casali P, Collella G et al. Intra-arterial adriamycin and systemic ifosfamide for operable soft tissue sarcoma: pilot experience and prospective polycentric trial. Reg Cancer Treat 1989; 2: 184. Morton DL, Eilber FR, Townsend CM Jr et al. Limb salvage from a multidisciplinary treatment approach for skeletal and soft tissue sarcomas of the extremities. Ann Surg 1980; 184: 268-78. Pezzi CM, Pollock RE, Evans HL et al. Preoperative chemotherapy for soft tissue sarcomas of the extremities. Ann Surg 1990; 211:476-81.
Correspondence to: Dr. A. Azzarelli Istituto Nazionale Tumori Via Venezian 1 20133 Milano, Italy
Downloaded from http://annonc.oxfordjournals.org/ at University of Manitoba on September 4, 2015
years and recently reported also by others [13]. This was the correlation between clinical response rate and free of disease survival [pathological response was not so predictive]. The 5-year actuarial survival of the 31 clinically responsive patients is 63% vs. 36% of the 46 non-responders (p = 0.01). It is not clear in our experience that this is a cause-effect relationship; may only indicate a selection of cases which would have had in any case a favourable outcome. This is important information on prognosis and probable modulation of adjuvant postoperative treatment. Finally, we are convinced that about 10% of our patients underwent limb salvage operations in force of this medical induction therapy, and we are still reluctant to abandon this multimodal treatment procedure, even if it is difficult to prove without randomization, not feasible in a single center.