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© 1999 American Society for Clinical Oncology Combined Modality Treatment for Osteosarcoma Occurring as a Second Malignant DiseaseFrom the Abteilung für pädiatrische Hämatologie und Onkologie, Kinderklinik, Universitäts-Krankenhaus Hamburg-Eppendorf; Klinik und Poliklinik für Kinderheilkunde, Pädiatrische Hämatologie/Onkologie, Westfälische-Wilhelms-Universität Münster; and Orthopädische Gemeinschaftspraxis Poststraße Hamburg, Germany. Address reprint requests to Stefan Bielack, MD, Cooperative Osteosarkomstudiengruppe, Westfälische-Wilhelms-Universität Münster, Klinik und Poliklinik für Kinderheilkunde, Pädiatrische Hämatologie/Onkologie, Albert-Schweitzer-Str. 33, D-48149 Münster, Germany; email coss{at}uni-muenster.de
PURPOSE: The prognosis of osteosarcoma occurring as a second malignant disease (OS-SMD) is thought to be poor. We attempted to evaluate whether this holds true when OS-SMD is treated with combined modality therapy as developed for primary osteosarcoma and if factors that influence survival might be identified. PATIENTS AND METHODS: All patients with OS-SMD registered at the Cooperative German-Austrian-Swiss Osteosarcoma Study Group (COSS) study center between 1980 and June 1996 were evaluated for patient- and treatment-related factors, local and systemic outcome, and survival. Therapy was to be given according to contemporary COSS protocols for primary extremity osteosarcoma, including surgery and multiagent chemotherapy. RESULTS: Thirty patients with OS-SMD were registered (median latency period, 9 years 2 months). The first malignancies had been retinoblastoma (10 patients), sarcoma (10 patients), lymphoma (five patients), carcinoma (four patients), and medulloblastoma (one patient). Treatment for these malignancies had included radiotherapy in 24 patients, surgery in 20, and chemotherapy in 14. Twelve osteosarcomas were located axially and 18 were located in an extremity; 17 were radiation-related. Twenty-seven patients presented with localized disease; three presented with primary metastases (two skip, one lung). All 30 patients received chemotherapy, 29 with multiple drugs. Twenty-eight patients underwent operation. At 7 years, actuarial overall survival, survival free from osteosarcoma progression, and survival free from progression of any cancer were 50%, 34%, and 30%, respectively. In 24 patients with local tumor control, the corresponding values were 63%, 46%, and 38%. All seven local failures occurred in patients with axial osteosarcomas who did not undergo operation with wide surgical margins. CONCLUSION: Provided that local tumor control is achieved, OS-SMD treated with combined modality therapy may have a prognosis that approaches that of otherwise comparable primary osteosarcoma.
BONE SARCOMAS, particularly osteosarcomas, are among the secondary malignancies that occur most frequently after childhood cancer.1-4 The hereditary form of retinoblastoma5 and Li-Fraumeni's cancer syndrome6 are examples of genetic disorders that are associated with the development of secondary osteosarcomas. Prior irradiation of bone is another well-defined risk factor for secondary sarcomas, especially osteosarcomas7,8; the risk is apparently related to radiation dose.9 Previous chemotherapy (with alkylating agents but also with anthracyclines) has also been implicated as a contributing factor in the development of secondary bone sarcomas.3,10,11 Traditionally, secondary bone sarcomas have been associated with an especially grave prognosis.12 The introduction of chemotherapy into interdisciplinary treatment has led to dramatic improvements for patients with primary extremity osteosarcoma,13-15 but only small series of secondary osteosarcomas treated in a similar fashion have been reported. So far, no definitive statement regarding the efficacy of chemotherapy for this disease entity can be made. It has been suggested that chemotherapy does not seem to display as much promise in secondary as in classical osteosarcoma.16,17 Such statements, however, were based on patients who were often treated with less intensive chemotherapy than might nowadays be considered appropriate. To determine how patients with osteosarcoma as a second malignancy might fare when treated on modern intensive polychemotherapy protocols, we searched the database of the Cooperative German-Austrian-Swiss Osteosarcoma Study Group (COSS) for all patients with osteosarcoma whose bone tumor occurred after at least one previous cancer. We attempted to evaluate whether factors that predict prognosis in primary osteosarcoma, like resectability and response to neoadjuvant chemotherapy, might also apply to secondary osteosarcoma.
COSS is an international, multi-institutional group that has conducted prospective studies on the treatment of osteosarcoma since 1977. Preoperative, neoadjuvant chemotherapy was introduced into the group's protocols in 1980. All studies were accepted by the local ethics committee. Before initiation of treatment, informed consent was obtained from all patients and/or their legal guardians, depending on the patient's age. Between 1980 and June 1996, when the group's most recent completed study, COSS-86C, was closed for patient entry, 1,733 patients were enrolled. Among these, we searched for all patients in whom osteosarcoma had developed as a secondary or further cancer. For these, the patient charts maintained at the COSS data center were analyzed. Additional information not available from these records was obtained by direct contact with the individual institutions. Age at diagnosis of the first cancer, as well as its type, site, and treatment history (surgery, radiation, chemotherapy), were extracted from the database. The diagnosis of osteosarcoma was established by clinical and x-ray findings and confirmed by open biopsy in all cases. The minimum requirements for exclusion of primary metastases were a negative chest x-ray and a negative technetium-99m–methylene diphosphonate bone scan. Pre- and postoperative chemotherapy for secondary osteosarcoma was to be given to all patients according to the COSS protocol active at the time of enrollment. No specific guidelines for secondary osteosarcoma were given; rather, protocol modifications were to be made on an individual basis, taking into account an individual's previous treatment. The use of cumulative anthracycline doses in excess of 450 mg/m2 was not encouraged. All neoadjuvant COSS protocols included high-dose methotrexate at 12 g/m2 per course with leucovorin rescue, in varying combinations with doxorubicin 60 to 90 mg/m2 per course ± cisplatin 90 to 150 mg/m2 per course ± ifosfamide 6 to 10 g/m2 per course ± bleomycin, cyclophosphamide, and dactinomycin, with doses as published previously.14,18 Guidelines for hydration routines and other supportive measures were given in all protocols. Minimum required blood counts and other laboratory parameters were specified for each treatment cycle. Definitive surgery was scheduled to take place between weeks 9 and 18 for patients treated according to protocol COSS-8014 and between weeks 9 and 11 for patients treated on all other protocols.18-20 Surgical checklists, surgical reports, and pathology reports were reviewed in order to define the surgical margins, which were graded as radical, wide, marginal, or intralesional according to standard definitions.21 Response to preoperative chemotherapy was assessed histologically in the resected osteosarcoma specimens according to the criteria of Salzer-Kuntschik et al.22 A good response was defined as less than 10% viable tumor.
Overall survival was calculated from the day of diagnosis of osteosarcoma until death from any cause, survival free from progression of osteosarcoma until progression of a preexisting osteosarcoma lesion, new osteosarcoma metastases, local relapse of osteosarcoma, or death from any cause, whichever occurred first. Recurrence of the primary cancer and development of a third or further malignancy was added to these for the calculation of survival free from cancer progression. Fisher's exact test and
Thirty patients (18 male and 12 female) with osteosarcoma occurring as a second or further malignancy were identified. In 29 patients, osteosarcoma was the second cancer, whereas it was the third cancer in one patient. Detailed patient and tumor characteristics are listed in Table 1.
The median age at diagnosis of the first cancer was 4 years 5 months (range, 1 month to 39 years) for 28 of 30 patients with available information. The most frequent first malignancies were retinoblastoma (eight bilateral, two unilateral) and sarcoma (five rhabdomyosarcomas, four Ewing's tumors, one fibrosarcoma) with 10 cases each, followed by lymphoma with five cases (four Hodgkin's disease, one non–Hodgkin's-lymphoma), carcinoma with four cases (two gynecologic, one breast, one gastric), and medulloblastoma with one case (Table 1). Among 28 patients who had only one region of involvement for the first malignancy, the region of involvement was an extremity in only five patients, whereas the head and neck were involved in 14 patients and the trunk in nine patients. Multiple axial sites had been involved in two patients suffering from Hodgkin's lymphoma (Table 1, Fig 1).
Information on treatment of the first malignancy was available for 28 of 30 patients. Radiation therapy was used in 24 of 28 patients; the median dose in 20 patients with available data was 40 Gy (range, 22 to 80 Gy). Surgery for the primary malignancy was reported for 20 patients and chemotherapy for 14. Chemotherapy included alkylating agents in all of these patients and an anthracycline in eight (Table 1). The median age at diagnosis of osteosarcoma was 14 years 9 months (range, 4 years 5 months to 66 years 1 month). All 30 patients were in complete remission of their previous malignancies when the diagnosis of osteosarcoma was made. Among 28 patients with available data, the median latency period between the diagnosis of the first cancer and the diagnosis of osteosarcoma was 9 years 2 months (range, 10 months to 19 years 1 month). Seventeen of the 30 osteosarcomas arose within (16 cases) or adjacent to (one case) a former field of irradiation (Fig 1). Among these 17 cases of postirradiation sarcomas, four cases occurred after retinoblastoma, six occurred after sarcoma, and seven occurred after another cancer (Table 1). All 30 secondary osteosarcomas were high-grade malignancies; 29 were classical "central" osteosarcomas of bone and one was an extraskeletal osteosarcoma. In contrast to the first malignancies, secondary osteosarcomas showed a predilection for the extremities (18 of 30 patients). The head or neck were involved in five patients and the rest of the trunk was involved in seven patients (Fig 1). At diagnosis of osteosarcoma, distant metastases to the lung were present in only one of 30 patients, skip metastases were found in another two patients, and the remaining 27 patients presented with localized disease. All 30 patients received chemotherapy that was adapted to the COSS protocol active at the time of enrollment; 26 patients were given neoadjuvant chemotherapy before surgery. However, only eight of 30 patients received a complete COSS regimen; chemotherapy was terminated early in 11 patients, and modified regimens were used in the remaining 11 patients. Chemotherapy included high-dose methotrexate in 29 patients, doxorubicin and cisplatin in 25 patients each, and ifosfamide in 21 patients. Twenty-five of 30 patients (83%) received three or even all four of these drugs. Additional agents were used to treat 10 patients (Table 1). Definitive surgery was performed for 28 of 30 secondary osteosarcomas. Resections were used for 19 tumors; ablative procedures were used for nine tumors. One tumor was treated with 10-Gy neutron irradiation preoperatively. Reported surgical margins according to Enneking et al21 were designated as at least wide in 20 cases. Wide margins were not achieved in eight cases, including one patient with marginal surgery, five with intralesional surgery, and two without any surgery. Margins were not reported for two of 28 operated osteosarcomas. Postirradiation osteosarcomas showed a predilection for the axial skeleton: 11 of 17 postirradiation osteosarcomas were located in the head, neck, or trunk, compared with only one of the other 13 osteosarcomas (P < .01; Fisher's exact test) (Fig 1). Axial osteosarcomas, in turn, were far less likely to be removed completely by surgery than were appendicular tumors: wide or radical margins were reported for 16 of 17 extremity tumors but only for four of 11 axial osteosarcomas with available information (P < .01). Information on histologic response of the osteosarcoma to preoperative chemotherapy was available for 14 patients and unavailable for 16 (no surgery for two patients, no preoperative chemotherapy for four patients, and no data for 10 patients). Among those tumors with available data, nine responded well (> 90% tumor necrosis) and five responded poorly. With a median follow-up period of 7 years (range, 1 year 8 months to 17 years 4 months) for surviving patients, 16 of 30 patients were still alive, for an actuarial overall survival probability of 50%. The corresponding values for survival without osteosarcoma progression and for survival without progression of any cancer were 34% and 30%, respectively (Fig 2).
Twelve of the 14 deceased patients succumbed to progressive osteosarcoma. The only patient in whom the osteosarcoma had developed as a third malignancy died of a fourth cancer, malignant fibrous histiocytoma of the pelvis, while still in first complete remission of osteosarcoma. The cause of the one remaining death in remission was not specified. Twelve of 16 surviving patients were in first complete remission of osteosarcoma, and four were alive at 2 months to 8 years 5 months after metastatic relapse (three patients were in second complete remission and one patient was in third complete remission). One patient (no. 11), always in first complete remission of osteosarcoma, developed histologically verified pulmonary metastases of his primary malignancy (Ewing's sarcoma) on two separate occasions, but was nevertheless alive without evidence of either malignancy at 10 years 3 months after last treatment for Ewing's sarcoma (Table 1). Overall, 13 patients had distant osteosarcoma metastases, almost always involving the lungs. Of these, one patient had primary metastases with consecutive progression and 12 had metachronous metastases. Ten of the 13 patients experienced treatment failure at distant sites only, whereas three patients suffered combined local and systemic failures. Local tumor control was reported for 24 osteosarcomas; local failure was reported for six (three with local failure only, three with combined failure). All local failures occurred in axial sites, with four of five osteosarcomas of the head and neck and two of seven osteosarcomas of the trunk failing locally, whereas local control was achieved in all 18 extremity osteosarcomas (Tables 1 and 2). Local control was a prerequisite for survival, with no patient surviving for 2 years post–local failure (Table 1). In contrast, the probabilities for overall survival, survival without osteosarcoma progression, and survival without progression of any cancer were 63%, 46%, and 38% for 24 patients with local tumor control (Fig 3).
Six of eight tumors for which wide surgical margins were not achieved relapsed or progressed locally, whereas no local relapse or progression occurred in any of the 20 tumors with wide or radical resection margins. Consequently, survival probabilities were significantly inferior for patients whose tumors could not be removed with wide margins (Table 2). Reflecting this fact, survival without osteosarcoma progression was also less likely for patients with axial tumors compared with patients with limb tumors. Although local failure occurred more frequently in patients with postirradiation osteosarcoma than it did in others, owing to the predominance of axial sites and, hence, reduced operability (six of 18 v 0 of 13 patients), survival probabilities did not differ significantly between both groups. Only one relapse occurred among nine patients with postirradiation osteosarcomas who underwent operation with wide or radical surgical margins (two patients died of other causes) (Table 2). All five patients with osteosarcomas that had documented poor response to preoperative chemotherapy experienced progression or recurrence of their disease. Two of these patients did not undergo operation with wide margins: one patient experienced local failure and one developed metastases, as did the remaining three patients. The reported surgical margins were wide in eight of nine tumors that responded well to chemotherapy; margins were unspecified for one tumor. Two of the nine patients with osteosarcomas that responded well relapsed, both with distant metastases. One of these patients was alive in second complete remission; the other died of progressive disease. Another patient died of unrelated causes after experiencing a good tumor response. Actuarial overall survival in case of good response was 73% (SE = 15%); the corresponding value for both survival without osteosarcoma progression and without progression of any cancer was 60% (SE = 17%). When analyzed according to the type of the first malignancy, the 10 patients with osteosarcomas that developed secondary to another sarcoma had the best prognosis, followed by osteosarcoma after retinoblastoma. Outcome was extremely poor for patients with other primary diagnoses (Table 2).
Although osteosarcoma is among the secondary cancers that occur most frequently after childhood malignancy1-4 and ranks foremost among cancers that develop secondary to radiation therapy,8 surprisingly little information regarding the role of chemotherapy in such tumors is available. This article reports our multicentric group's experience with 30 osteosarcomas that developed secondary to a previous malignancy. The affected patients were treated according to our group's guidelines for the treatment of primary high-grade central-extremity osteosarcoma. These guidelines prescribe complete surgery of all detectable osteosarcoma foci, plus intensive multiagent chemotherapy. The results achieved in this cohort demonstrate that a significant number of patients with secondary osteosarcoma may enjoy long-term survival if such an approach is used. We chose to restrict our analysis to osteosarcomas arising secondary to other malignancies and not to include those that developed after seemingly benign conditions, because we wanted to avoid the inclusion of tumors that might have been erroneously misclassified as benign lesions at first presentation but were really classical primary osteosarcomas to begin with. Such diagnostic dilemmas can, for example, occur with presumed aneurysmal bone cysts or even fibrous dysplasia. Among the 30 consecutive patients with secondary osteosarcoma who were entered onto COSS studies, we found the same preponderance of males over females known for primary osteosarcoma.12 The median latency interval of approximately 9 years between first cancer and osteosarcoma in our series was very similar to that of other recent reports on postirradiation and other secondary osteosarcomas.3,8,25-29 It is well known that secondary osteosarcomas are far more likely to involve the trunk, head, or neck than are primary osteosarcomas.12,30 In our cohort, this was only true for irradiation-related tumors, whereas those that developed outside of irradiated fields showed the same predilection for the metaphyses of long bones that is so characteristic of primary osteosarcoma. Nonetheless, axial osteosarcomas accounted for approximately two fifths of the secondary osteosarcomas in our study. A variety of different cancers preceded the secondary osteosarcomas in our series, retinoblastoma being the most frequent and accounting for approximately one third of cases, followed by Ewing's and soft tissue sarcomas. The association between these tumors and secondary osteosarcoma is well defined.5,29,31 The high prevalence of typical malignancies of children and adolescents in our cohort is best explained by the dominantly pediatric constituency of our cooperative group. Therefore, although osteosarcomas in older persons are far more likely to be secondary than are those occurring in younger patients,32 the median age at diagnosis of secondary osteosarcoma in our cohort was just below 15 years, which is similar to that reported for patients with primary osteosarcoma12 and younger than one would expect for patients with secondary osteosarcoma in general. This fact must be kept in mind when interpreting the results detailed in the present study. Nevertheless, the reported cohort also includes typical primary cancers of adult postirradiation sarcoma, such as Hodgkin's disease, which is thought by some to be the most common first tumor among radiation-induced sarcomas in previously normal bone,33 as well as breast cancer and gynecologic carcinoma, which are also among the most frequent predecessors to postirradiation bone sarcoma.34 Some of the secondary osteosarcomas probably developed as a result of individual predisposition alone, for example, cases of extremity osteosarcoma after bilateral retinoblastoma or breast cancer; these associations have been linked to germline abnormalities of the RB35 and p53 genes,36 respectively. Induction by previous radiotherapy or chemotherapy will have contributed to oncogenesis in others; for many of these, a combination of induction and individual predisposition will have been causative.37 Patients with secondary osteosarcomas have been reported to have a bleak prognosis. In addition to osteosarcoma progression, these patients are at risk to develop a late relapse of the first cancer and may also be at an increased risk to suffer third or even further malignancies. All factors would contribute to poor survival chances. Many of the reports describing poor outcomes for patients with secondary osteosarcomas have exclusively focused on postirradiation sarcomas, often with comparatively older patients.7,8 In a review of the English language literature on postirradiation sarcomas published in 1988, Robinson et al8 identified 95 patients with postirradiation osteosarcomas and reported 2- and 5-year survival rates of only 12% and 6.2%, respectively. Smith and Donaldson38 reviewed the literature on secondary malignancies (which were most commonly sarcomas of bone) after retinoblastoma and Ewing's sarcoma in 1991 and concluded that the prognosis for patients with a secondary sarcoma had been poor, with few cures reported until then. Even some very recent studies from pediatric institutions arrived at similar results. Bechler et al,25 from the Children's Hospital of Philadelphia (where only one of nine children with osteosarcoma that developed as a second malignant neoplasm in a previously irradiated site survived free of disease), concluded that this complication was usually fatal. In a report from St. Jude Children's Research Hospital by Pratt et al,17 only three of 18 patients with secondary osteosarcomas of any site were survivors, including one patient with locally recurrent disease. Those poor results, as well as the overall survival probability of 50% and the osteosarcoma progression-free survival probability of 34% for our 30 patients (which are clearly inferior to those contemporarily achieved by our group in primary localized-extremity osteosarcoma18,19,39), are partly explained by the high proportion of axial lesions among the secondary osteosarcomas: surgical margins that are designated as at least wide according to Enneking's criteria21 are necessary for the safe local control of any osteosarcoma.40 Wide margins are often not achievable outside of the limbs, so that both osteosarcomas of the trunk30 and craniofacial osteosarcomas41 are far less likely to be controlled locally than are extremity osteosarcomas. Patients with local failure after treatment for osteosarcoma, however, have a dismal prognosis, both in our group's42 as well as other's40,43 experiences. In the present series of 30 secondary osteosarcomas, local progression or relapse occurred in six of eight patients who did not undergo operation of their osteosarcoma with wide margins. All of these were located in the axial skeleton, and all were within previously irradiated fields. All six patients died from their disease. In contrast, no local failures occurred in 20 patients who underwent operation with wide or radical margins, and 13 of these patients survived, 10 in first remission. A realistic chance for survival in case of complete surgery has previously been observed for patients with postirradiation osteosarcoma at the Memorial Sloan-Kettering Cancer Center,16 where six of 18 patients whose surgical margins were designated as least wide (but only one of 16 patients with closer margins) remained disease-free. Similarly, in an abstract presented at the International Society of Pediatric Oncology meeting in Vienna, Austria, the French Society of Pediatric Oncology reported that six of seven patients with radiation-associated osteosarcoma occurring after other childhood solid tumors (excluding retinoblastoma) who had not achieved complete remissions had died, whereas 13 of 17 patients who had reached a complete remission were alive after 5 months to 10 years of follow-up.28 Authors from the M.D. Anderson Cancer Center noted that among 162 patients seen at their institution between 1951 and 1991 who had developed a second malignancy after treatment for childhood cancer, all eight patients with periorbital osteosarcoma had unresectable tumors and died, and eight of nine patients with osteosarcomas of the pelvis or chest wall died, whereas both of the two patients with mandibular osteosarcomas had resectable tumors and were still alive, as was the case for nine of 13 patients with extremity osteosarcomas.44 They concluded that salvageability, in large part, was dependent on the location and resectability of the tumor. Data from the Mayo Clinic, where survival was 30% for extremity postirradiation osteosarcomas compared with only 4% for axial postirradiation osteosarcomas, further enhance this point.45 If, as evidence has it, local surgical control is a prerequisite for cure, what is the role of chemotherapy in osteosarcoma that develops as a second malignancy? So far, the published evidence suggesting that chemotherapy might enhance the cure rate for secondary osteosarcoma has remained largely anecdotal, with most reports based on very few patients. Our results clearly demonstrate that (young) patients with such tumors can often tolerate aggressive cytotoxic treatment, even when the first round of cancer treatment already included chemotherapy. Although the regimen given to treat the secondary osteosarcoma often had to be modified compared with that scheduled by the contemporary COSS protocol, most patients did go on to receive multiagent chemotherapy with at least three or even more agents, without a single toxic death in the whole cohort. This is in contrast to the report by Pratt et al17 in which three of 18 patients with secondary osteosarcoma died of chemotherapy-related side effects. The results achieved in our patients, in accordance with evidence presented by others, clearly point out that chemotherapy cannot outweigh the deleterious effects of insufficient surgery. Our results do, however, suggest that intensive polychemotherapy can help to prevent metastatic disease in patients with local tumor control. The 24 of our 30 patients who did not develop local progression or relapse had an overall survival probability of 63% and a probability of 46% to survive without recurrent osteosarcoma. These results do not seem to be dramatically inferior to those achieved in primary localized osteosarcoma of the limbs, both in contemporary COSS trials18,19,39 and in contemporary trials by other multi-institutional groups.15,46-48 They suggest that aggressive chemotherapy given in an adjuvant or neoadjuvant setting may be able to achieve similar efficacy in secondary osteosarcoma as is achieved in primary osteosarcoma, at least in young patients. This is in contrast to some earlier and even some more recent publications, in which chemotherapy for secondary osteosarcoma was not associated with either high response or high cure rates. For example, chemotherapy with single drugs or combinations of agents rarely yielded responses in the group of 18 patients from St. Jude Children's Research Hospital already mentioned above.17 At the Memorial Sloan-Kettering Cancer Center, adjuvant chemotherapy was not identified as a variable of prognostic significance in 160 patients with radiation-associated sarcoma, of which 21% were osteogenic. Response rates were not reported.34 At the Mayo Clinic, the prognosis for patients with postirradiation osteosarcoma treated between 1980 and 1989, when chemotherapy would have been available, did not improve in comparison to earlier years,49 but no information regarding whether the latter patients had actually received chemotherapy was given. More favorable results with aggressive combined modality therapy that incorporates chemotherapy have previously been reported for several patients with osteosarcoma occurring after hereditary retinoblastoma.50,51 Also, three of five patients with secondary radiation-associated osteosarcoma from the Memorial Sloan-Kettering Cancer Center who were younger than 24 years and had both a resection of the osteosarcoma and adjuvant chemotherapy were alive with no evidence of disease after more than 3 years of follow-up.34 A comparatively large group of postirradiation osteosarcomas occurring after childhood solid tumors that were treated by a multimodal approach has been reported in abstract form by the French Society of Pediatric Oncology.28 In that study, after a median follow-up of 5 years, 13 of 17 patients who had achieved surgical remissions (of whom 14 had received additional chemotherapy) survived. Patients in whom retinoblastoma had been the first cancer, however, were excluded from the study. Such tumors may represent a subgroup that have reduced susceptibility to chemotherapy. After all, absence of the retinoblastoma protein has been shown to mediate resistance to antimetabolites such as methotrexate in human sarcoma cell lines,52 and clinical studies have suggested an unfavorable outcome for osteosarcomas with loss of heterozygosity at the RB locus.53 Only 10 patients with osteosarcoma occurring after retinoblastoma were entered onto our studies; this is too few to draw definitive conclusions about the relative efficacy of therapy in comparison with other secondary osteosarcomas. The prognosis for these 10 patients, however, was not obviously worse than was that of the other patients. Two of four patients with postretinoblastoma tumors with available data responded well to neoadjuvant chemotherapy. Among the seven postretinoblastoma patients who did not experience local failure, there were five survivors (three in first remission). The fact that nine of 14 assessable secondary osteosarcomas in our cohort responded well to preoperative chemotherapy further strengthens the opinion that chemotherapy can be effective against secondary osteosarcomas. Tumor response to preoperative chemotherapy is a powerful prognostic factor in primary, localized, resectable osteosarcoma, possibly the most powerful of all.54 Although, due to limited numbers, our results can in no way be conclusive, they do not contradict the interpretation that a good tumor response can also be used as a positive prognostic indicator in secondary osteosarcoma. In summary, our results support the conclusion that the same principles that are applied to the treatment of primary osteosarcoma should also be used for osteosarcoma presenting as a second malignancy. The prognosis for patients with secondary osteosarcoma who achieve local tumor control within a setting of aggressive combined modality therapy is not dismal.
The following institutions and collaborators from Germany, Austria, and Switzerland contributed to the study: Universitätsklinik für Orthopädie Vienna (R. Kotz, R. Windhager, T. Zettl), the Pediatric Hospitals Kinderklinik Stenglinstrasse, Augsburg (A. Gnekow, P. Heidemann), Kinderspital LK Salzburg (N. Jones, W. Sperl), St. Anna-Kinderspital Vienna (H. Gadner, A. Zoubek), and Kinderklinik Eleonorenstiftung Zürich (E. Frey, F. Niggli); the Medical University Hospitals Hannover (A. Ganser, P. Schöffski), Kiel (M. Helweg, H. Löffler), and Münster (W.E. Berdel, T. Birkfellner); the St. Elisabeth-Hospital Hamm (H. Reineken), the Medizinische Klinik Karlsruhe (J.Th. Fischer, G. Isele), the Medizinische Klinik Klagenfurth (D. Geissler, J Klocker); and the Pediatric University Hospitals Cologne (F. Berthold, D. Schwamborn), Düsseldorf (U. Göbel, D. Körholz), Erlangen (J. Beck, H. Schirmer), Freiburg (M. Brandis, C. Niemeyer), Hamburg (S. Bielack, B. Kempf-Bielack, K. Winkler), Hannover (P. Weinel, K. Welte), Heidelberg (B. Selle, L. Winkel), Münster (H. Jürgens, J. Ritter), Magdeburg (U. Kluba, U. Mittler), Tübingen (D. Niethammer, H. Scheel-Walter), and Ulm (W. Behnisch, K.-M. Debatin, M. Ziegler).
Supported by Deutsche Krebshilfe and Fördergemeinschaft Kinderkrebszentrum Hamburg. We acknowledge the physicians, nurses, data managers, and support staff of the collaborating centers for their active participation. We thank Henning Astheimer, Doris Epler, Klaus Rath, and Beate Wulff for their assistance with data management and study coordination.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 analysis were used to compare unrelated probabilities, whichever appropriate. All survival analyses were performed using the Kaplan-Meier-Method.
), those not associated with radiation fields.
