Neoadjuvant Chemotherapy: Osaka University Osteosarcoma (OOS) Regimen

Fig 8.1

OOS-D regimen

Complete blood count (CBC) and renal and hepatic functions were monitored before and after each chemotherapy administration. Granulocyte colony-stimulating factor was given to patients with grade 3 or 4 leukopenia. Chemotherapy was delayed or dose reduction (80 %) was allowed if granulocyte count was less than 1,000/mL, or platelet count was less than 100,000/mL, or there was renal or hepatic disorder. Normal renal function was required before each chemotherapy administration.

Surgical resection of tumor was scheduled after four courses of chemotherapy. All patients received limb salvage surgery. In principle, en bloc wide margin resection of the tumor was performed. Reconstruction was performed with either prosthetic replacement or intraoperative radiated autologous bone graft (IORBG) [15]. Postoperative chemotherapy was to start 3 weeks after surgery.

Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 4.0. Histological response to chemotherapy was evaluated in resected tumor specimens. Good response was defined as total or more than 90 % necrosis of the tumor. Poor response was defined as lesser than 90 % necrosis of tumor [16].

8.2.1 Statistics

The event-free survival (EFS) was calculated from the date of start of chemotherapy until the date of first event including recurrence (local or distant) or chemotherapy-related death or the date of last follow-up examination. The overall survival (OS) was calculated from the date of start of chemotherapy until the date of death or the date of last follow-up examination. Survival curves were estimated using the Kaplan-Meier method and were compared by means of the log-rank test. Statistical analyses were performed using JMP ver. 10.0 software (SAS institute, North Carolina).

8.3 Results

From 1997 to 2012, out of 271 patients treated for osteosarcoma at our institute, 82 patients were eligible for this study. The patient characteristics are listed in Table 8.1. The median follow-up period for surviving patients was 113 months (range 29–193 months).

Table 8.1

Patient characteristics

	No.	%
Age (years)
Median	16
Mean	17.2
Range	7–37
Gender
Male	54	66
Female	28	34
Surgical stage
IIA	7	9
IIB	75	91
Site
Femur	43	52
Tibia	22	27
Humerus	11	13
Fibula	6	7
Histological subtype
Osteoblastic	51	62
Chondroblastic	9	11
Fibroblastic	6	7
Telangiectatic	5	6
Small round cell	1	1
Not specified	10	12

8.3.1 Chemotherapy Compliance and Toxicity

Of the 82 patients, 59 (72 %) completed all ten courses of chemotherapy. Of the courses uncompleted, HD-MTX was skipped the most at eight times. This was due to delayed excretion of MTX in the first week of HD-MTX, and the second week was skipped. HD-IFM was skipped four times due to severe prolonged hematological toxicity from the previous course. Other causes for discontinuation were renal disorder, wound infection, and patient’s request.

One patient died as a result of chemotherapy-related toxicity. A 15-year-old boy died from acute heart failure 2 months after completion of therapy. There were no other patients who reported with cardiomyopathy. All patient experienced grade 4 hematologic toxicity.

8.3.2 Histological Response

During the preoperative chemotherapy, no clinical or radiological progression of disease was confirmed. Histological response to chemotherapy was good in 39 patients (56 %) and poor in 31 patients. The histological response of 12 patients could not be obtained because histological examination of the whole tumor was not available.

8.3.3 Patient Outcome

At the last follow-up, 61 (74 %) patients were continuously disease-free, 11 (13 %) patients were alive with no evidence of disease, 3 (4 %) patients were alive with disease, 6 (7 %) patients died of disease, and 1 (2 %) patient died of treatment-related toxicity. The 5-year and 10-year EFS rates were 77 % (95 % CI, 67–84 %) and 73 % (95 % CI, 62–82 %), respectively (Fig. 8.2). The 5-year and 10-year OS rates were 95 % (95 % CI, 87–97 %) and 90 % (95 % CI, 81–95 %), respectively (Fig. 8.3).

Fig 8.2

Event-free survival of all patients

Fig 8.3

Overall survival of all patients

Two patients (2 %) had local recurrence 23 and 24 months after the start of treatment. Both patients had amputation of the affected limb. Seventeen patients (21 %) had lung metastasis and one patient (1 %) had bone metastasis. Median time to metastasis was 23.5 months (range 9–91 months). All patients underwent metastasectomy. The 3-year and 5-year post-relapse survival rates were 84 % and 67 %, respectively.

For good responders, the 5-year and 10-year EFS rates were both 82 % and were significantly better than poor responders at 65 % and 55 % (p = 0.025), respectively (Fig. 8.4). The 5-year and 10-year OS rates for good responders were 100 % and 94 % and were better than those for poor responders at 87 and 82 % though not statistically significant (p = 0.11) (Fig. 8.5).

Fig 8.4

Event-free survival: good responder (red); poor responder (blue): p = 0.025

Fig 8.5

Overall survival: good responder (red); poor responder (blue): p = 0.11

8.4 Discussion

The prognosis for patients with osteosarcoma has greatly improved with the introduction of multidrug chemotherapy. At our institution, since the introduction of chemotherapy, the 5-year OS has improved from 13 % to 49 % (OOS-A) to 72 % (OOS-B) to 78 % (OOS-C) [12]. The current OOS-D regimen has improved the 5-year OS to 95 % (Table 8.2). In planning for the OOS-D regimen, there were discussions on whether MTX should be included in preoperative chemotherapy. Previously at our institute, we had two cases of severe MTX excretion delay which led to the delay of chemotherapy and progression of disease. Because of this experience, we decided to omit HD-MTX from the preoperative regimen and include it only in the postoperative regimen. The histological response rate of this study was 56 % which was about equal to other studies even without MTX [14, 17].

Table 8.2

Overall survival of OOS regimens [12]

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