|Year : 2017 | Volume
| Issue : 2 | Page : 291-296
Evaluation of clinical process in osteosarcoma patients treated with chemotherapy including cisplatin, adriamycin, ifosfamide, and etoposide and determination of the treatment sequels in a long-term 11-year follow-up
Mozaffar Aznab1, Maryam Hematti2
1 Department of Internal Medicine, Talaghani Hospital, Kermanshah University of Medical Sciences, Kermanshah 6714415333, Iran
2 Department of Obstetrics, Shahid Beheshti BLND, Kermanshah 6714415333, Iran
|Date of Web Publication||23-Jun-2017|
Department of Internal Medicine, Talaghani Hospital, Kermanshah University of Medical Sciences, Shahid Beheshti BLND, Kermanshah 6714415333
Source of Support: None, Conflict of Interest: None
Aim: The aim of this study was to evaluate the effect of adding etoposide and ifosfamide chemotherapy drugs to treatment regimen of patients affected with osteosarcoma and to determine the clinical process and response to treatment during a follow-up period of 11 years.
Materials and Methods: Forty patients with osteosarcoma participated in this study from July 2005 to 2016. Treatments were started based on the following schema and after initial examinations including biochemical profile, checking for lung metastasis by simple radiography, chest computed tomography scan, and bones scan. The initial chemotherapy which consisted of four cycles of cisplatin and adriamycin alternative with ifosfamide and etoposide was provided. Afterward, resection of the primary tumor and also the metastatic lesions was performed in patients with lung metastasis in case they had radiological evidence of response to the treatment.
Results: The mean of follow-up duration in this study was 50 months. Thirty-four patients did not have metastasis and six were metastatic. Of 34 patients, 18 had relapse and 16 patients never had relapse. Five patients experienced only local relapse, nine had only systemic relapse, and two patients had simultaneous systemic and local relapses. Thirteen patients had died. The mean of overall survival in patients was 81 months. The mean of survival in patients with and without primary metastasis was 30 and 90 months, respectively.
Conclusion: Favorable response to the treatment was obtained with an appropriate multiple disciplinary works in the osteosarcomas of extremities, and there were no considerable side effects and sequels in the long-term follow-up of these treatments.
Keywords: Adjuvant chemotherapy, neoadjuvant, osteosarcoma, tumor necrosis
|How to cite this article:|
Aznab M, Hematti M. Evaluation of clinical process in osteosarcoma patients treated with chemotherapy including cisplatin, adriamycin, ifosfamide, and etoposide and determination of the treatment sequels in a long-term 11-year follow-up. J Can Res Ther 2017;13:291-6
|How to cite this URL:|
Aznab M, Hematti M. Evaluation of clinical process in osteosarcoma patients treated with chemotherapy including cisplatin, adriamycin, ifosfamide, and etoposide and determination of the treatment sequels in a long-term 11-year follow-up. J Can Res Ther [serial online] 2017 [cited 2019 Nov 22];13:291-6. Available from: http://www.cancerjournal.net/text.asp?2017/13/2/291/199447
| > Introduction|| |
Osteosarcoma is one of the primary and common tumors of bones which originate from osteoid productive cells next to growth plate. Most of the osteosarcoma cases are sporadic. Osteosarcoma accounts for 5% of cancers in children and forms about 36% of bone cancers., It has been estimated that in the United States, there are 4.4 new cases of osteosarcoma out of one million people yearly which usually affects metaphysis of long bones. This tumor has two age-related peaks: Puberty period and older ages. The most commonly affected regions are distal of femur, and proximal of tibia and humerus,, respectively. From the pathologic point of view, osteosarcoma is divided into three subgroups of intramedullary, superficial, and extraskeletal., Conventional or classic, telangiectatic, and small cell could be named from medullary subgroup. Well-differentiated parosteal and periosteal osteosarcomas could also be mentioned in the superficial subgroup. The average age for disease diagnosis is 20 years. The most prevalent type of osteosarcoma is the conventional or classic type that constitutes 80% of osteosarcoma cases. Pain, swelling, and limitation in moving the affected limb are the most common clinical presentations of these patients, and there are diagnostic features in simple radiographs. Osteosarcoma treatment is a multiple disciplinary treatment which includes chemotherapy and surgery. These tumors should be treated in reference centers. Chemotherapy has been used both before (neoadjuvant) and after surgery (adjuvant therapy)., Chemotherapy causes the tumor size to decrease, thereby the limb salvage, and prevents us from amputation in the surgery. Besides, it can reduce disease relapse through affecting micrometastasis. The patients' survival in recent years has increased from 40 to 70% in people younger than 15 years and from 56 to 66% in people aged 19–20 years. Despite ameliorated survival, disease relapse is still an important problem. The purpose of the current study is to add 21-day courses of ifosfamide and etoposide to treatment regimen of cisplatin and adriamycin as the alternative regimen, and to evaluate the primary response and effects on reducing the amputation and limb salvage and also on decreasing the relapse and increasing survival. Furthermore, the long-term side effects of this compound aggressive chemotherapy have been studied.
| > Materials and Methods|| |
Forty patients with osteosarcoma from July 2005 to May 2016 were included in this study. Biochemical profile including alkaline phosphatase and lactic dehydrogenase and kidney and liver evaluation were performed before starting the treatment. Cardiac evaluation and simple radiograph of thorax were also performed. Lung computed tomography (CT) scan and nuclear scan of bones were carried out to examine metastasis, and patients with metastasis were determined. Similar treatment regimen was begun for both metastatic and nonmetastatic patients (neoadjuvant patient). The chemotherapy treatment included intravenous infusion of cisplatin 30 mg/m 2 in 1.5 h for 1st and 2nd days and adriamycin 25 mg/m 2 in an infusion of 10 min for 1st and 2nd days. Each 21-day alternative with etoposide 100 mg/m 2 for 3 days and ifosfamide 2 g/m 2 in an infusion of 6 h simultaneous with mesna 2 g/m 2 for 6 days was also prescribed. Granulocyte colony-stimulating factor (G-CSF) was injected every other days since 24 h after chemotherapy ending. Cellular count was performed weekly while using ifosfamide and etoposide regimen. In the case of reduction in cellular count, G-CSF was administered again. If fever occurred, the patient was hospitalized, and fever and neutropenia were evaluated. Cellular count was done before starting each of the treatments, and if the platelet count was lower than 100,000/μL or white blood cells were lower than 3000/μL, the chemotherapy drug was not administered until the cellular count reached the reference limit, and the drug dose was also reduced. Electrolytes were checked between the treatments, and liver evaluation was performed after each two treatments. Clinical and radiological examination of primary tumor was performed after 4 course of treatment, and surgery for the primary tumor was carried out. After the primary tumor surgery, if necrosis of over 50% was observed in pathology, the same treatment as initial one was repeated two more times, and if a <50% necrosis was seen, the high-dose methotrexate was replaced. In those cases that had lung metastasis at the time of referral, the patient was candidate for lung metastasis surgery in addition to the primary tumor surgical treatment if the lung metastasis had shown the desired response to therapy. The decisions for primary tumor surgery (limb salvage or amputation) and the type of repair (allograft or prosthesis) were made based on the location of primary tumor and its spread and the patients' age and their lifestyle. After completion of the treatment in patients with primary neoadjuvant therapy, the patients were examined and asked to take simple thoracic radiograph every 3 months for a year. Afterward, they were examined every 6 months for 5 years and simple thorax radiograph was taken every 4 months, and thus the patient was evaluated for metastasis. If the simple radiograph was suspicious, CT scan was performed. The patients' data were all evaluated and recorded. In the case of local relapse, the patient was candidate for surgery, and if systemic relapse was found out, they were candidate for chemotherapy and surgery together. During both therapy procedure and follow-up, all the patients were monitored for the treatment sequels. The most important sequels which had to be considered are as follows: Fever and neutropenia, bone marrow myelosuppression, cardiomyopathy, hemorrhagic cystitis, decrease in hearing level, renal function disorder, secondary malignancies, severe nausea and vomiting, remarkable pinkish color change of skin, diarrhea, electrolytes disorders, and hepatic function disorder, all of which were recorded if occurred. Multimodal therapy in osteosarcoma might have been accompanied by the permanent changes in kidneys, heart, hearing, reproduction, and permanent orthopedic problems and the second cancer. Considering the reports of delayed metastasis after 10 years of therapy, long-term follow-up was required; therefore, the controls were continued yearly.
| > Results|| |
Forty patients were studied in the current study, of which 13 (32.5%) were females and 27 (67.5%) were males. The mean and median of follow-up period in this study were 49.78 (standard deviation [SD] ±36.047 months) and 46 months, respectively. The shortest follow-up was 5 months and the longest was 116 months, with a follow-up range of 111 months. Patients' age range was 13–58 years with the mean of 26 years in this study. The most prevalent bone locations were distal femur and proximal tibia, which were affected in 18 (45%) and 9 (22.5%) patients, respectively, and other affected regions are orderly shown in [Table 1]. Pathologic type categorization is shown in [Table 2].
Thirty-four of forty patients underwent chemotherapy in neoadjuvant state and six patients underwent chemotherapy in metastatic setting. Of 6 patients, 5 had referred with metastasis to lung and one case had referred with simultaneous bone marrow and lung metastasis. Three of the six patients who had primary metastasis (one case with only lung metastasis, one with multifocal bone involvement and lung metastasis, and one case with simultaneous lung and bone marrow metastasis) had drug resistance, and they finally died during the follow-up. The remaining three metastatic patients experienced repeated relapse after considerable remission. All the six patients with primary metastasis died finally. Only in four cases among those who had been neoadjuvant treated, the surgeon had to amputate the organ. Thirteen patients had allograft and 11 had prostheses surgery. Two patients had fibula osteosarcoma and underwent complete surgery without repair, and one case had disease in index and had complete surgery. Repair surgery was not performed in cases of maxilla, mandible, sacrum, ilium, and craniofacial bone involvement. Of 34 patients, 16 (47%) never had relapse. Systemic relapse in lung happened in 11 (32.5%) patients, two of which also had simultaneous local relapse. Of 11 patients, 7 died at last, and the other 4 are still alive. Those with systemic relapse of less than two nodules, which were actually two cases had nodule surgery and systemic chemotherapy, and they are both in remission. One case who had one nodule relapse in lung is in remission after surgery [Figure 1]. One case with three nodules has also passed surgery and chemotherapy and is in remission. Seven patients had more than three nodules in lung, one of which had also bone and bone marrow simultaneous relapse. Six of these seven patients had died; one of them died after 18 months. Local relapse occurred in seven patients, two of which had simultaneous systemic relapse in addition to local form. Amputation of the affected limb was performed in six of these seven patients with local relapse. Any kind of systemic or local relapse did not happen within average of 5 years from treatment ending. The cutoff point has been considered as over 50% necrosis. Twelve patients had necrosis of <50% and 25 patients had necrosis more than 50%. If necrosis cutoff is considered as more than 60%, 18 patients are <60% and 19 are more than 60%. Thirty-four patients did not show metastasis in simple radiograph and CT scan of the chest. Lung metastasis was discovered with simple thoracic radiograph in five of six patients who had primary metastatic lesions in lungs and all the six lung metastasis were diagnosed by CT scan, which means simple radiograph missed one case of metastasis. None of the craniofacial patients survived and all died. Fever, neutropenia, and cardiomyopathy were among the important sequels observed in the follow-up of some of the patients, but none of them resulted in death [Table 3].
|Figure 1: Overall survival in patients with lung relapsed with two nodules (green) versus patients with ≥ pulmonary nodules (blue)|
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The mean of overall survival in patients was 81 months [Figure 2]. The survival mean in patients with metastasis was 29.33 months (SD ± 14.078 months). The survival mean was 90.34 months [Figure 3] (SD ± 74.95 months) in those without metastasis, with a follow-up range of 111 months. The mean survival of patients who had systematic relapse was equal to 42 months in this study, and it was 86 months for those who only had local relapse. Besides, survival mean in patients who had both types of relapse was 24 months. The mean of survival for the cases of more than 50% necrosis was 107.58 months (SD ± 12.175 months), with a follow-up range of 111 months and the obtained survival for necrosis of <50% was 40.074 months (SD ± 5.6 months), with a follow-up range of 99 months. The mean of survival in those with necrosis of <60% was calculated as 54.37 months (SD ± 11.11 months), with a follow up range of 99 months and as 111 months (SD ± 4.73 months) in cases with more than 60% necrosis, with a follow-up range of 107 months. Two patients among the female participants of this study became pregnant after 6 and 7 years of follow-up and delivered healthy babies.
|Figure 3: Overall survival in patients with localized disease (green) versus metastatic disease (blue)|
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| > Discussion|| |
Therapy from the curative point of view for osteosarcoma includes combination of an effective chemotherapy regimen in addition to local control through surgery and removal of the whole tumor which is observed macroscopically and clinically., There is no universal agreement on a standard chemotherapy regimen yet. One of the commonly used chemotherapy regimens includes cisplatin, adriamycin, and high-dose methotrexate.,, Chemotherapy regimen without methotrexate resulted in survival results similar to those of cisplatin, adriamycin, and high-dose methotrexate combination. The addition of newer chemotherapy agents has been evaluated in many studies. Ifosfamide is considered as one of the most effective treatments in osteosarcoma, with significant response rates. Ferrari et al. reported an appropriate response with ifosfamide in the recurrent and primary osteosarcomas. Ifosfamide is used in combination with other drugs in treating metastatic osteosarcoma. Thus, it may also be useful in cases of primary disease. Several studies have showed that ifosfamide response rates could be comparable to doxorubicin and methotrexate. The addition of ifosfamide in the current Mayo Clinic protocol appears to have improved the overall survival in patients with extremity osteosarcoma. Combinations of ifosfamide and etoposide have been evaluated in pediatric sarcomas. Other phase II studies confirm its efficacy both as a single agent and as combination schedules. Etoposide has been used in a number of phase II trials in children with recurrent malignant solid tumors and has shown a high proportion of complete and partial responses. Support for its efficacy in combination with ifosfamide is provided by the results of the Rizzoli Orthopaedic Institute second neoadjuvant study, in which it was used as salvage therapy, and the results of the Children's Oncology Group. The tolerability of this combination is confirmed by the fact that their nonhematopoietic toxicities do not overlap. We report the clinical process and response rate and overall survival and prognosis of forty patients with osteosarcoma, treated by a regimen of 21-day cisplatin and adriamycin courses to which we added ifosfamide and etoposide alternatively. Our study has been conducted in two hospitals and within a follow-up period of 11 years. The overall survival is 81 months that is longer than other studies. In the current study, surgery has been used in the cases of local relapse, and aggressive surgical treatment is required for local relapses to make the survival longer. Five out of seven patients with localized relapse underwent salvage therapy with surgery and are in remission. Necrosis has also been used as a criterion in evaluating the response of patients to this therapy regimen in addition to the percentage of patients who did not need amputation, so that the more the necrosis has been, the better the prognosis. In the cases of more than 60% necrosis compared to 50% necrosis, the patients survived more and the patients with less necrosis had more relapse. The results of this study which has been conducted from October 2005 to 2016 during an average of 50 months have demonstrated that this therapy regimen has caused 16 of 34 patients to be without relapse in long-term follow-up. The most prevalent metastasis region in our study has been lungs which was similar to other studies. One case of difference in lung metastasis diagnosis by simple radiograph and CT scan was seen in this study, and if only simple chest radiograph had been taken, one patient's diagnosis was missed. Therefore, we recommend lung CT scan for discovering the metastasis. There are also long-term treatment sequels, so certainly long-term follow-up is required. Side effects during treatment or within short intervals after treatment and also sequels after a long time from the treatment are among the most important sequels which could be expected with this therapy regimen. Cardiomyopathy is an important side effect which only occurred at the last treatment course of one patient and it did not result in death. Secondary malignancy was one of the other sequels which was expected but did not happen in any patient. Of course, lack of these two mentioned problems might be because of the low number of patients, so no special conclusion could be made, and a larger study is needed to prove these claims. Fever and neutropenia could also be mentioned as side effects which caused the patients to get hospitalized but did not have any special effect on the patients' progress other than a short delay in therapy. The male patients did not accept to perform the infertility status experiments, but one of the women became pregnant 6 and 7 years after therapy ending and has two healthy children now. This treatment regimen led to reduction in amputation cases and caused a remarkable percentage of patients to be candidate for limb salvage. The possibility of limb salvage was 85% in our study which seems more interesting than the 80% rate reported in other studies. Those cases with one metastasis in lungs demonstrated a good prognosis in our study [Figure 1] which is similar to other studies, and all the patients are in remission after surgery, but only one of the two patients with more than two nodules was alive in follow-up. Using the therapy regimens of ifosfamide-adriamycin and etoposide-cisplatin results in a considerable recovery and cure. Fifty-five percent of the patients were totally without metastasis at the end of follow-up. As similar to the other studies, prognosis of those patients with osteosarcoma of the limbs was proved to be better compared to other regions. None of the osteosarcoma cases of pelvis and jaw got cured. None of the patients with craniofacial lesions survived and they all died, the reason of which might be unfortunately inappropriate surgery and having residue after the surgery.
| > Conclusion|| |
The osteosarcoma treatment is multiple disciplinary, and surgery along with chemotherapy seems essential to achieve a considerable survival in patients. The results of therapy in patients with limb osteosarcoma who had lung metastasis were desirable when there were less than two metastatic nodules in lungs. Drug toxicity has not been significant and therapy-related death did not happen.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]