Can cure in patients with osteosarcoma be achieved exclusively with chemotherapy and abrogation of surgery?

Authors


Abstract

BACKGROUND

Contemporary therapy for osteosarcoma is comprised of initial treatment with chemotherapy and surgical extirpation of the primary tumor in the affected bone. In view of the major advances forged by chemotherapy in the treatment of the primary tumor, an attempt was made to destroy the tumor exclusively with this therapeutic modality and abrogate surgery.

METHODS

Thirty-one consecutive patients were treated. All had localized disease (absence of metastases) at the time of diagnosis. Initial treatment with chemotherapy was comprised of high-dose methotrexate and leucovorin rescue (MTX-LF) in 3 patients and intraarterial cisplatin in 28 patients. Clinical, radiologic, angiographic, radionuclide, and histologic investigations were utilized to assess the efficacy of treatment. After a response at 3 months, entry into the study was permitted and treatment was maintained for a total of 18–21 months with a combination of agents comprised of MTX-LF, intraarterial cisplatin, and doxorubicin. Patients were monitored closely for disease recurrence with the investigations outlined earlier. Two informed consents were required: one at the time of diagnosis and another at 3 months after the initial response had been attained.

RESULTS

Only 3 of 31 patients were cured with the administration of chemotherapy alone. Local recurrence and pulmonary metastases were not reported to develop in these 3 patients during a follow-up period of 204+ to 225+ months. Four other patients also possibly were cured with chemotherapy alone. At their request, several months after the cessation of chemotherapy, they underwent surgical extirpation of the tumor. No evidence of viable tumor was found. These patients remained free of disease for 192+ to 216+ months. Thus, only seven patients did not develop local recurrence and/or pulmonary metastases. Among the remaining 24 patients, 9 developed local recurrences without pulmonary metastases 14–74 months (median, 30 months) after the initial response. Eight of the nine patients were rendered tumor free by extirpation of the local recurrence. Two of these eight patients subsequently died, one of the acquired immunodeficiency syndrome (AIDS) and the other of varicella septicemia. The ninth patient refused amputation and died of metabolic complications. Three other patients developed local recurrences 20–69 months and pulmonary metastases 10–98 months after achievement of the initial response. These patients were rendered tumor free by extirpation of the local recurrence and metastasectomy. One of these patients also later died of AIDS. In the remaining 12 patients, local recurrences developed 5–29 months (median, 14 months) after the initial response was achieved. The patients also developed pulmonary metastases 11–60 months after the initial response. In eight patients the local recurrences were extirpated and metastasectomy was performed; however, these patients later died of recurrent pulmonary metastases. The remaining four patients refused to undergo extirpation of the local recurrence. The pulmonary metastases were not resected. They failed to respond to alternate therapy. Thus, the tumor-free survival rate was 23% (7 of 31 patients): 3 patients who were treated with chemotherapy only and 4 patients who were treated with chemotherapy plus surgery. The overall survival rate (patients who remained free of disease and those who underwent resection for local recurrence and metastasectomy) was 48% (15 of 31 patients). Prior to the deaths from AIDS and varicella septicemia, the overall survival was 58% (18 of 31 patients).

CONCLUSIONS

Utilizing the regimen employed in the current study, only 3 of 31 patients with osteosarcoma (10%) were cured exclusively with chemotherapy. Four additional patients who underwent extirpation of the primary tumor without disease recurrence and in whom no viable tumor was found in the resected specimens possibly could increase the number of patients who potentially were cured with chemotherapy to 7 (23%). With an overall expected cure rate of 50–65% with “conventional” strategies, the results of the current study do not justify the adoption of current forms of chemotherapy as exclusive treatments for osteosarcoma. Cancer 2002;95:2202–10. © 2002 American Cancer Society.

DOI 10.1002/cncr.10944

The current treatment of osteosarcoma involves an integrated strategy incorporating chemotherapy and surgery. Treatment generally commences with preoperative chemotherapy (“neoadjuvant” or “primary” chemotherapy) for a defined period.1 The tumor then is extirpated by means of an amputation or a limb salvage procedure. This is followed by postoperative “adjuvant” chemotherapy. In most instances, the results obtained with preoperative chemotherapy are utilized to design the postoperative adjuvant regimen. Thus, if preoperative chemotherapy appears to be ineffective, additional or other agents are introduced. Alternatively, if an adequate initial response is obtained, the preoperative regimen generally is retained. Utilizing these tactics and strategies, the majority of treatment centers have reported cure rates of 50–65%.2–5 This may be compared with historic and concurrent controls in which the cure rate rarely exceeded 20%.5–7

Treatment with chemotherapy usually results in the complete disappearance of symptoms (i.e., pain and discomfort) and functional restoration of the affected limb. In many instances, pathologic examination of the resected specimen reveals approximately 95–100% chemotherapy-induced tumor necrosis.2, 8, 9 These observations induced us to consider an investigative procedure to determine whether cure in osteosarcoma could be achieved exclusively with chemotherapy and the elimination of surgery. The stimulus to undertake the investigation was prompted by three factors: 1) chemotherapy appeared highly successful in the treatment of the primary tumor; 2) improved cure rates attested to the efficacy of chemotherapy in destroying (pulmonary) micrometastases, which are considered to be present in > 80% of patients at the time of presentation;5–7 and 3) after attaining initial dramatic responses in the treatment of the primary tumor, several parents requested that surgical treatment be deferred or supplanted by maintenance chemotherapy.

The current study describes the results in 31 consecutive pediatric patients who initially underwent definitive treatment with chemotherapy as opposed to surgery. Three of these patients were treated initially with high-dose methotrexate and leucovorin rescue (MTX-LF) and were the subject of a preliminary report.10 The remaining 28 patients were treated initially with intraarterial cisplatin. The study was initiated in 1978 for the patients treated with MTX-LF and in 1982 for the patients treated with intraarterial cisplatin.

MATERIALS AND METHODS

Chemotherapy

Details relating to the prerequisites and administration of MTX-LF and intraarterial cisplatin have been published previously.2, 10–12 Briefly, prerequisites included normal hemogram values, cardiac and liver function studies, serum electrolytes, and a creatinine clearance. Several initial MTX-LF courses were administered by the intraarterial route.11 After achieving a complete response (vide infra), patients were treated with maintenance chemotherapy comprised of MTX-LF, doxorubicin, and intraarterial cisplatin (Fig. 1).

Figure 1.

Chemotherapy regimen. I/A CDP: intraarterial cisplatin (150 mg/m2); MTX: high-dose methotrexate (12.5 g/m2) and leucovorin rescue (15 mg every 3 hours intravenously × 2 followed by 15 mg every 6 hours orally for ± 72 hours); ADR: doxorubicin, 25 mg/m2/day × 3.

Primary Evaluation and Follow-Up Studies

Prior to treatment, the primary tumor was evaluated by conventional radiographic studies, angiography, radionuclide bone scans, and computed tomography (CT) scans. The absence of pulmonary metastases was confirmed by chest radiographs and CT scans. Chest radiographs were obtained at monthly intervals and CT scans of the chest and radionuclide bone scans were obtained at 6-month intervals for 3.5 years. The interval between the chest radiographs then was extended and eventually the examination was obtained at annual intervals after the fifth year from diagnosis. Radiographs of the primary lesion were obtained prior to each course of treatment and angiographic studies were obtained with each course of intraarterial cisplatin. The primary tumor was monitored initially by these means every 2–3 weeks for 20 months. It then was monitored by radiographic studies and occasional CT and radionuclide scans at 3–6-month intervals until the 5th year and annually thereafter by conventional radiographs.

Clinically, responses manifested by a reduction in the size of the tumor and the disappearance of pain, discomfort, and localized tenderness and the resumption of normal ambulation. The clinical findings were confirmed by concurrent radiographic studies demonstrating a reduction or disappearance of the soft tissue component of the tumor, repair of lytic components, and reconstitution of the cortex. The angiogram required for intraarterial chemotherapy demonstrated reduction and/or the disappearance of tumor neovascularity and stain.12

Responses were confirmed by histologic examination of the tumor in situ after 12 weeks by random percutaneous core needle biopsy. Complete response was defined as total tumor necrosis and fibrovascular regeneration. This result was considered to be consistent with 90–100% tumor necrosis as observed in surgical specimens.13 Clinical, radiographic, and histologic responses were specific requirements for entry into the study.

Patients were monitored at weekly or biweekly intervals during the administration of chemotherapy. After the cessation of chemotherapy, clinical and radiologic monitoring was implemented according to the schedule outlined previously. Any evidence of tumor escape called for the immediate termination of treatment and a surgical procedure, generally amputation. A similar strategy was adopted for tumor escape after the completion of therapy.

Informed consent was obtained according to Institutional Review Board requirements.

Prior to the initiation of treatment, the informed consent advised patients and parents of the prevailing forms of treatment and the experimental nature of the investigation. Three options for therapy were presented: 1) immediate amputation followed by postoperative chemotherapy; 2) preoperative chemotherapy followed by amputation or limb salvage in eligible patients followed by postoperative adjuvant chemotherapy; and 3) preoperative chemotherapy for 3 months to determine whether an adequate response by specific criteria (as outlined previously) could be attained. This would be followed by a defined course of chemotherapy. Surgery would be eliminated but would, however, be introduced when there was evidence of disease recurrence. It was clearly stated that this third tactic was highly experimental.

In view of the highly investigational nature of the current study, a repeat informed consent at 3 months again was requested. This again emphasized that definitive treatment with chemotherapy was a radical departure from conventional therapy in that surgical extirpation of the tumor was the accepted mode of treatment.

At the termination of the study, periodic written communication of the results was provided to all patients whose disease remained in continuous remission. The participants were informed of the number of patients who had developed a disease recurrence and the number of patients whose disease was in sustained remission. All patients whose disease was in remission were offered an opportunity to (re) consider surgical intervention. Such intervention could comprise amputation or limb salvage in eligible patients.

Patients

Thirty-one newly diagnosed, consecutive patients with high-grade osteosarcoma whose disease was nonmetastatic and who were age < 16 years were treated (Table 1). Thirty patients had tumor localized to an extremity and in 1 patient it was localized to an innominate bone. All patients with the exception of one (Patient 26) satisfied the criteria for entry into the study. The tumor in the latter patient still exhibited isolated viable cells in the core needle biopsy specimen. She refused amputation and “maintenance” therapy was implemented. Repeat core needle biopsy 3 months later demonstrated a complete response.

Table 1. Patients, Tumor Characteristics, Treatment, and Outcome
Patient no.Age (yrs)SitePathology subtypeLocal recurrence (mos)Pulmonary metastases (mos)Amputation (mos)Limb salvage (mos)Survival (mos)Comment
  • AIDS: acquired immunodeficiency syndrome.

  • a

    Initial response to high-dose methotrexate with leucovorin rescue; all other initial responses were to cisplatin.

  • b

    Patient died without evidence of osteosarcoma.

Cure with chemotherapy (3 patients)
1a13TibiaChondroblastic    225+ 
213TibiaTelangiectactic    216+ 
35FemurTelangiectactic    204+ 
Request for limb salvage (no viable tumor) (4 patients)
411TibiaChondroblastic   38216+ 
515FemurUnspecified   37216+ 
613FibulaOsteoblastic   10204+ 
714FemurOsteoblastic   13192+ 
Local recurrence (no pulmonary metastases) (9 patients)
812FemurTelangiectactic40  40216+ 
917FemurChondroblastic16 16 216+ 
1012TibiaChondroblastic32 32 216+ 
1114TibiaChondroblastic30 30 210+ 
1212TibiaOsteoblastic26 26 36bDeath of yaricella Septicemia
1315FemurOsteoblastic36  36202+ 
1417TibiaOsteoblastic63  63216+ 
1517TibiaUnspecified14 14 28bDied of AIDS
1613FemurTelangiectactic15   18Refused amputation. Died of metabolic complications
Local recurrence and pulmonary metastases (3 patients)
1715FemurUnspecified69109369216+ 
189FemurTelangiectactic6198 91204+ 
1912TibiaChondroblastic201320 68bDied of AIDS
Local recurrence. Death from pulmonary metastases (12 patients)
20a12FemurOsteoblastic244523 47 
21a11IliumChondroblastic244239 48 
2214FemurOsteoblastic141814 20 
2311TibiaFibroblastic182418 30 
2412FemurOsteoblastic141414 30 
2513FemurUnspecified9119 18 
Local recurrence. Death from pulmonary metastases (12 patients)
2614FibulaChondroblastic266026 72Viable tumor at study entry
2711TibiaTelangiectactic989 20 
2815FibulaUnspecified2944  74Refused amputation
2915FemurOsteoblastic1925  39Refused amputation
3014FemurTelangiectactic57  11Refused amputation
3113TibiaChondroblastic911  24Refused amputation

Statistical Analysis

The actuarial disease-free and overall survival rates were calculated according to the method of Kaplan and Meier from the date of diagnosis.14 Disease-free survival (“first events”) reflects the development of pulmonary metastasis or local recurrence (whichever was detected first) (Table 1). Overall survival reflects patients who died of osteosarcoma and other causes (acquired immunodeficiency syndrome [AIDS], varicella septicemia, and a metabolic derangement). The results were updated to September 2000.

RESULTS

Of the 31 patients, 3 achieved a complete response with MTX-LF and 28 with intraarterial cisplatin. However, at the time of last follow-up, only 3 patients remained continuously disease-free from 204+ to 225+ months (Table 1; Fig. 2).

Figure 2.

Outcome of patients after achievement of complete response. Aids: acquired immunodeficiency syndrome.

At their request, four other patients whose disease was in continuous complete remission underwent limb salvage procedures when apprised of the disease recurrence reported in several patients. Histologic examination of the resected specimens failed to reveal any evidence of viable tumor. At the time of last follow-up, these patients had remained free of disease for 192+ to 216+ months. Thus, at the time of last follow-up, only seven patients had not been reported to develop local recurrence and/or pulmonary metastases.

Of the remaining 24 patients, 9 developed local recurrences without pulmonary metastases at 14–74 months (median, 30 months) after the initial response. In eight patients the primary tumors were extirpated and each patient was rendered free of disease. Two of these patients subsequently died, one of AIDS and the other of overwhelming varicella septicemia. The ninth patient refused amputation and died of metabolic complications. Three other patients developed local recurrences at 20–69 months and pulmonary metastases 10–98 months after the initial response. These patients also were rendered tumor-free by extirpation of the local recurrence and metastasectomy. One of these patients also later died of AIDS.

The remaining 12 patients developed local recurrences 5–29 months (median, 14 months) and pulmonary metastases 11–60 months after the initial response. In eight patients the local recurrences and pulmonary metastases were extirpated surgically; however, these patients later died of recurrent pulmonary metastases. The remaining four patients refused amputation and the pulmonary metastases were not resected. These patients failed to respond to alternate chemotherapy and radiation delivered to the local recurrences.

Therefore, the tumor-free survival rate was 23% (7 of 31 patients). In three patients tumor-free survival was achieved with chemotherapy only and in four patients it was achieved with chemotherapy and surgery (no viable tumor was present in the resected specimens). The overall survival rate (patients who remained free of disease and those who underwent resection for local recurrence and metastasectomy) was 48% (15 of 31 patients). Prior to the cases of death from AIDS and varicella septicemia, the overall survival rate was 58% (18 of 31 patients) (Fig. 3).

Figure 3.

Actuarial survival in 31 patients. Initial failure event was indicated by local recurrence in 21 patients and pulmonary metastasis in 3 patients. Twenty-four patients eventually developed local recurrence and 15 pulmonary metastasis.

Imaging studies demonstrating response were described earlier. Patients who presented with or developed fractures during treatment achieved healing of the fractures. Bone scans usually demonstrated moderate improvement but the findings never reverted to normal. Selected radiographic response studies are presented in Figures 4–6. (Other radiographic responses are depicted in a prior publication.10)

Figure 4.

Telangiectatic osteosarcoma of proximal tibia (Patient 3, cure with chemotherapy only). (A) Osteolytic lesion of the tibial metaphysis (long arrow). The lesion (most likely) crossed the cartilaginous growth plate to involve the epiphysis (short arrows). (B) Twenty months after therapy there was concentric healing and an attempt in reconstituting the cortex (arrows). (C) Three years later, the osteolytic area had been replaced by reactive bone and there was reconstitution of the cortex (arrowheads). Note the concentric healing of the epiphyseal component (arrows).

Figure 5.

(Patient 10). Osteosarcoma of the tibia with healing and posttherapy bone marrow infarction. (A) A metadiaphyseal lesion with destruction of both cortical (closed arrows) and medullary (open arrow) bone. Notice ossification center for tibial tuberosity (arrowhead). (B) Two months after therapy there was reconstitution of the cortex (arrows). (C) Two years later, the lesion was no longer appreciated except for a residual endosteal scalloping. Diffuse bone marrow infarction had developed as evidenced by numerous nodular and serpiginous sclerotic densities (arrows).

Figure 6.

(Patient 11). Periosteal osteosarcoma of the proximal tibial diaphysis with local recurrence. Subtle destruction of the cortical bone and aggressive periosteal reaction (Codman triangle) are indicated by arrows. (A) Two years after intraarterial chemotherapy there was almost complete healing and focal thickening of the cortex (arrows). (B) Seven months later, the tumor recurred. (C) There was now a soft tissue mass (curved arrows) and periosteal reaction (arrowheads) at the site of the healed cortex.

Treatment was well tolerated with the exception of nausea and emesis, which invariably were associated with the use of cisplatin. The majority of patients received 18–21 courses of intraarterial cisplatin. In several instances, the creatinine clearance values deteriorated to borderline toward the end of therapy.15 There were a few episodes of myelosuppression (leukocyte count of ≤ 2000/mL, hemoglobin of 8 g%, and a platelet count of ≤ 75,000/mL). Some decreases were associated with fever and/or infection. Platelet and blood transfusions were required to combat thrombocytopenia and anemia in approximately 33% of the courses. There were no reported episodes of cardiac failure or changes in the echocardiogram. All patients developed deterioration in the audiogram, but only three patients required hearing aids.16

DISCUSSION

Major advances have been forged in the treatment of osteosarcoma during the past 30 years. These advances derive principally from the application of chemotherapy. With the impressive demonstration that this therapeutic modality could produce destruction of the primary tumor and an increase in the cure rate, an attempt to eradicate the disease exclusively with chemotherapy appeared logical. However, in the current study, only 3 of 31 patients (10%) were cured by this means. The majority of patients developed local disease recurrence and nearly 50% of these patients developed pulmonary metastases.

Four patients who requested limb salvage possibly also may have attained cure exclusively with chemotherapy. There was no evidence of viable tumor in the resected specimens, suggesting complete eradication of disease. If this premise is accepted, the overall disease-free survival rate could be increased to 23% (7 of 31 patients). However, the small number of patients potentially cured in these circumstances does not justify the adoption of this strategy as a standard of treatment.

A number of patients who developed local recurrence and/or pulmonary metastases again were rendered disease free by resection of the local recurrence and metastasectomy. The metastases, which developed after treatment with aggressive chemotherapy, usually were limited in number and delayed in appearance. This phenomenon, attributed to chemotherapy, has been described previously.17 This pattern of recurrence permitted resection of the metastases, thereby rendering additional patients free of disease. Therefore, the overall long-term survival rate (prior to the death of patients with AIDS and varicella septicemia) was 58% (18 of 31 patients). This result is similar to the survival rate of 50–65% generally attained with conventional modes of therapy.2–5 However, the result was associated with increased morbidity and a necessity to extirpate the local tumor recurrence and metastasectomy.

The parameters to establish response comprised clinical, imaging, and histologic studies.12 The definitive arbiter was the core needle biopsy. However, although this demonstrated nonviable tumor, it was not a reliable or truly representative sample in that 24 of the patients with an apparent complete response subsequently developed a disease recurrence. Therefore, core needle biopsy, although useful in establishing a diagnosis in a patient with an untreated tumor, should not be utilized to authenticate effects of therapy.

An assiduous attempt was made to maintain (or induce) response with aggressive therapy. A major component was cisplatin. This is superior to MTX and was administered by the intraarterial route.18 This tactic produces high local tumoricidal concentrations and effective systemic levels to destroy pulmonary micrometastases.11 However, despite the aggressive treatment and diligent monitoring, it was not possible to sustain a permanent local response in the majority of patients. To our knowledge, whether the addition of ifosfamide, which also is reported to be active in osteosarcoma, would achieve the objective is unknown.19

It is interesting to note that the study was initiated at a time when the utility of chemotherapy in patients with osteosarcoma, particularly MTX, was being assailed.20–24 Three patients achieved initial responses with MTX. This included what to our knowledge is the longest long-term survivor.

The current study also demonstrated the contribution of parents and patients to the conduct of therapeutic research. The attempt at cure exclusively with chemotherapy was highly unusual and could be initiated only at the request of the patient and/or parent. Because of the unorthodox nature of the therapeutic approach, two informed consents were requested. It also was considered important to keep participants continually apprised of results. Indeed, four patients burdened with the threat of local recurrence, as reported in periodic updated communications, later requested surgical intervention. In contrast, several parents, after initially signing two informed consents, refused surgical intervention when local disease recurrence was detected.

To our knowledge, only one other attempt at exclusive treatment with chemotherapy has been reported to date.25 This involved an osteosarcoma of the vertebra. Intraarterial doxorubicin and systemic treatment with cyclophosphamide, vincristine, MTX, phenylalanine mustard, and doxorubicin were utilized (COMPADRI-III).26 Six years later, the patient was well without any apparent neurologic deficits.

Utilizing the therapeutic agents described in the current study, only 10% of patients (3 of 31 patients) with osteosarcoma were cured exclusively with chemotherapy. The absence of viable tumor in 4 resected specimens possibly could escalate the number of potentially cured patients to 23% (7 of 31 patients). However, this assumption also acknowledges the fact that total tumor necrosis does not necessarily imply cure. Some of the latter patients also could have developed a disease recurrence later. This phenomenon has been observed in patients who undergo conventional therapy with 100% tumor necrosis.

Periodic requests to abrogate surgery and resort to chemotherapy continue to be raised. With an expected cure rate of 50–65% with “conventional”multimodal strategies, the results of the current study do not appear to justify the adoption of current forms of chemotherapy as exclusive treatment of osteosarcoma.

Ancillary