Treatment outcomes of patients treated at LSMU KK ORT for chondrosarcomas and osteosarcomas. A treatment analysis.

(1)

Treatment outcomes of patients treated at LSMU KK ORT for chondrosarcomas and osteosarcomas. A treatment analysis.

LSMU KK ORT

Author: Algimantas Jonas Puteris LSMU Medical Faculty

Supervisor: M.D. Mindaugas Stravinskas

Kaunas, Lithuania May 1

^st

2018

(2)

1. SUMMARY

Kremzlinės, kaulinės ir Ewingo sarkomos yra didžiausiai pasitaikantys piktybiniai navikai kauluose (1, 2). Paplitimas siekia 0.2% populiacijos 100,000 gyventojų per metus (3). Pastaruosius 30 metų taikyti gydymo metodai ir naudojami chemoterapiniai vaistai neturėjo reikšmingo poveikio siekiant gerinti pacientų, kuriems buvo diagnozuotas vėlyvos stadijos kaulų ar kremzlių navikas, išgyvenamumą (3-7). Dažniausiai pasitaikantis navikas yra osteosarkoma, kuris plinta ilguosiuose kauluose. Antras pagal dažnumą - chondrosarkoma (1, 2). Pagrindinė gydymo metodika yra chirurginis naviko šalinimas, atliekant plačią rezekciją. Osteosarkomų ir chondrosarkomų gydymas yra sudetingas dėl jų atsparumo chemoterapijai, radioterapijai, galimo lokalaus išplitimo ar metastazių į plaučius (2, 3, 8). Mūsų tyrimo tikslas buvo išanalizuoti pacientus, sergančius šiomis onkologinėmis ligomis, gydytus LSMU KK ORT 2006-2018. Įvertinti navikų dažnumą, paplitimą, gydymą, pasiskirstymo pobūdį, metastazes ir bendrą išgyvenamumą. Iš 72 pacientų, kuriems buvo diagnozuotas pirminis kaulų auglys, buvo tiriami 63 pacientai, kurių navikai buvo tik kietuosiuose audiniuose. Remiantis literatūros šaltiniais, tirtų atvejų chondrosarkomų lokalizacija buvo statistiškai reikšminga. Pastebėta, kad išgyvenamumas priklauso nuo stadijos sunkumo. Kuo vėlesnė chondrosarkomos stadija, tuo mažesnė tikimybė išgyventi. Mirties rizika padidėja 5 kartus, nepriklausomai nuo lyties ar amžiaus.

Osteosarchomųų ir chodrosarkomų MSTS balas priklauso nuo stadijos, kuo navikų stadija vėlesnė, tuo MSTS balas žemesnis ir išgyvenamumas mažesnis.

Osteosarcomas, chondrosarcomas, along with Ewing’s sarcomas comprise the majority of primary malignant bone cancers in the population (1, 2). Despite advances in treatment strategies, use of chemotherapy, and development of new surgical techniques, high grade osteosarcoma and chondrosarcoma outcomes and overall long-term survival remain poor for those diagnosed with higher grade disease (3-7). More advanced disease or distribution in inoperable areas of the body have demonstrated high rates of mortality and severe morbidity following treatment, despite having significant advances in imaging techniques and the development of beneficial chemotherapy regiments (3-7). Despite the low rates of incidence of these cancers <0.2% of the general public, osteosarcomas remain one of the leading causes of solid tumours in adolescents and account for >10% of all solid neoplastic lesions in this population (3). Chondrosarcomas most frequently are present in the form of benign lesions however, in both low and high grade malignant disease, chemo and radiotherapy proves to be ineffective due to high resistance making these lesions notoriously difficult to treat (2, 3, 8). Our aim was to assess the incidence, treatment, distribution patterns, local recurrence, metastatic progression and overall survival of patients who were diagnosed with either osteosarcomas or chondrosarcomas and treated at LSMU KK ORT (Lithuanian university of health sciences Kaunas clinics orthopaedics and trauma) between 2006 and 2018. Of the 72 cases of primary bone cancers, 63 met our inclusion criteria

(4)

which, excluded soft tissue bone tumours. Localization of the cancers when compared to histological type was also found to be significant once the exclusion criteria were applied. There were consistencies with literature regarding decreased rates of overall survival of patients, when compared to the grade of diagnosed chondrosarcoma during their diagnosis. Higher grade chondrosarcomas were found to have an important impact on the overall 10-year survival of patients. Those with higher grade chondrosarcomas were found to have a 5-fold increase in mortality, irrespective of gender, or age. MSTS (Musculoskeletal tumour society) scoring as well as metastatic progression of both malignancies was also compared to overall 10-year survival of patients and found, that in patients diagnosed with disseminated disease, remission and prognosis significantly diminished, consistent with much of the published literature.

2. CONFLICTS OF INTEREST

There were no conflicts of interest during the study.

3. ETHICS COMMITTEE APPROVAL

Ethics approval will be added when all supporting documents are presented.

4. ABBREVIATIONS LIST

LSMU KK ORT – Lithuanian university of health sciences Kaunas clinics orthopaedics and traumatology department

MSTS – Musculoskeletal tumour society JBJS – Journal of bone and joint surgery

5. TERMS

EXT – Exotosin

MAP – Methotrexate, Doxorubicin, and Cisplatin STATA – StataCorp

CI- Confidence Interval

(5)

6. AIM AND OBJECTIVES

Our aim was to assess the incidence, treatment, distribution patterns, local recurrence, metastatic progression and overall survivability of patients who were diagnosed with either osteosarcomas or chondrosarcomas and treated at LSMU KK between 2006 and 2018. Patient case histories meeting inclusion criteria would be retrieved and analyzed to quantify the results and assess statistical significance.

1. Evaluate the overall survival of patients comparing it to the grade of tumour, tumour type, MSTS scoring outcomes as well as metastatic progression.

2. Evaluate the presence of local recurrence in patients who had undergone treatment and see if it correlated to the volume of the tumour.

3. Assess if there are correlations between age, gender, and outcomes.

4. Compare the type of tumour based on histological results, and evaluate if it had a specific distribution pattern consistent with published literature.

7. LITERATURE REVIEW

Osteosarcomas, chondrosarcomas along with Ewing’s sarcomas comprise the majority of primary malignant bone cancers in the population (1, 2). Despite advances in treatment strategies, use of chemotherapy, and development of new surgical techniques, high grade osteosarcoma outcomes and overall long-term survivability remain poor for those diagnosed.

Osteosarcomas are osteogenic, malignant, mesenchymal tumours, accounting for around one fifth of primary bone cancers. Various differentiation methods can be applied based on characteristics of growth such as the site affected, involvement within the structures of bone itself (cortical or medullary), the degree of differentiation or lack thereof within the cells of the cancer, the degree of spread, penetration into surrounding soft tissues and other histological features (1). The most common osteosarcoma is an intramedullary, osteogenic, primary solitary tumour (1, 9). It is locally aggressive with rapid microscopic penetration into surrounding tissue, and has a high tendency to metastasize early to pulmonary tissue (10). Its classification is based upon the histological presentation and composition of respective tissue cells types, such as conventional, teleangiectatic, parosteal, periosteal, low-grade central, small-cell, and not otherwise specified (1, 10). The conventional type of osteosarcoma comprises 80% to 90% of all instances involving high grade tumours and will be the focus of this article.

(6)

Their incidence is biphasic affecting young adults within the first two decades of age with incidence peaking again in the elderly population above the age of 60 (1, 9). There is a slight tendency for these cancers to affect the male population. It is thought to be associated with rapid bone growth during adolescence, and may have a genetic component predisposing people, with specific diseases, such as bone dysplasias and others including Paget’s disease, though the etiology remains largely unknown (9, 10).

These tumours may arise in any portion of the musculoskeletal system, though osteosarcomas have a greater tendency to affect long bones in younger populations (1, 9). The metaphyseal portions of long bones have the highest propensity to develop neoplastic changes, especially those in the extremities such as the knee ~80%, with 42% affecting the distal femur and 19% as the proximal tibia (1, 9). Pelvic areas are especially prone to developing larger tumours that are of a higher grade at the time of diagnosis because of the room available for growth. Although pelvic lesions account for 10% of osteosarcomas, 5-year overall survivability with those affected ranges from 27% to 47% (11). Osteosarcomas commonly destroy cortical structures producing necrotic lesions with variable histological appearances, though they are definitively diagnosed if there is production of mineralized or un-mineralized osteoid bone.

Macroscopically disseminated presentations of these cancers occur in approximately 15-20%

of those initially diagnosed, of which 80-85% are present as lung metastases (10). Due to this spread it is assumed that 80-90% of diagnosed patients suffer from micro-metastatic disease which, may be radiologically undiagnosed and subclinical (5, 9, 12, 13).

Local and distant rates of recurrence are between 30-40% in patients, with the majority developing them within the first 24-36 months and most commonly in the lungs (14, 15). A predictably poorer prognosis and overall survival is associated earlier rates of recurrence (14, 16). Overall long- term over 5-years survival in these patients has been reported to range between 23-29% in those diagnosed with local recurrence, and 28-33% for limited pulmonary metastases (17). In younger populations under the age of 20, the 5-year survival is around 60% (18, 19).

Historically, surgical excision of tumours without the use of chemotherapy, was associated with long term survival rates ranging between 10% to 20% however, advances imaging and diagnostic procedures along with concomitant use of chemotherapeutic agents, have allowed for survival rates to rise over 60% (3, 20). Due to the hematogenous spread, and high rates of metastases, in patients diagnosed with osteosarcomas, consideration of local micro-metastases must be taken into consideration and amputation or wide excisional margins are often sought after during surgical treatment in conjunction with chemotherapy (1, 5).

Even with localized lesions, adjuvant chemotherapy in conjunction with surgery provides the most beneficial outcomes for overall survival and prevention of relapse whilst maintaining limb-salvage techniques (21). Since their development, the three primary agents used in combination with one another

(7)

for chemotherapy during osteosarcoma treatment have been methotrexate, doxorubicin, and cisplatin, otherwise referred to as the MAP treatment which, may also utilize ifosfamide as an additional agent (21). The use of this regimen has been at the foundation of chemotherapeutic treatment tactics, and has improved long term survival of patients to 65% with localized disease (22). Overall survival, as well as a disease-free status following treatment can also be predicted by analyzing the degree of necrosis following chemotherapeutic procedures in patients; with larger areas of necrotic zones in lesions being considered better responders to therapy (21). In 2003, Bacci et al. were also able to demonstrate that by increasing the quantity of various pre-surgical chemotherapeutic agents, larger necrotic zones were attained in patients which, were associated with better overall survival (23). The mainstay of neoadjuvant chemotherapy 8 to 10 weeks prior to planned surgery is the standard for high grade osteosarcoma treatment (5). During this time frame that planning of surgical approaches, and reconstructive techniques can be done alongside radiological monitoring of the tumour progression. The use of the aforementioned chemotherapeutic agents has improved the survival of patients however, radiologically detectable effectiveness during neoadjuvant treatment is still being hindered primarily due to the bone matrix deposition caused by the tumour growth (21). This was demonstrated in a study conducted by (24) (goorin), which concluded there were no beneficial results in delaying surgery with the administration of standard neoadjuvant chemotherapy.

Due to the high rates of recurrence associated with osteosarcomas, complete surgical excision is fundamental for complete elimination of the disease even when other treatment modalities are used (25). Limb salvage which, has only been possible in recent decades is always sought after during treatment, alongside the greatest preservation of biological function, and minimal destruction of healthy tissue (5, 25). There are still some discrepancies between the exact surgical approach to take. When comparing results of wide resection margins to narrower ones, two studies which assessed outcomes following narrow resections of <5mm with neoadjuvant chemotherapy and compared them to results of wide en-bloc resections with the same chemotherapeutic treatment and concluded that there was no difference in the rate of local recurrence, between the two approaches in patients who achieved complete remission of their tumours (7, 26).

These tumours are the second most common primary malignancy affecting the musculoskeletal system (2). They are often the result of malignant transformations from benign precursor lesions of hyaline cartilage in bones that undergo endochondral ossification, and their outcomes are strongly correlated to their histological grading (27). In contrast to osteosarcomas, growth of low grade tumours is slow, they rarely metastasize, and have excellent results following surgical treatment which is postulated to be due to the low vascularization and division of cells in cartilaginous tissue (2). This however is paradoxical, because it makes treatment of these tumours difficult as they are often both chemo and radiotherapy resistant. With higher grade chondrosarcomas however, the presence of

(8)

increased cellularity, vascularization, and mitosis are apparent resulting in the theory that resistance is inherited and maintained through anti-apoptotic pathways (28)

Chondrosarcomas have an average annual incidence of 3 cases per 100000 with a higher frequency prevalent in the older population above the age of 50 (2).

85% of all chondrosarcomas are considered to be conventional and are further classified based on their location in bone with the majority being primary medullary or central chondrosarcomas (2).

Both central and peripheral chondrosarcomas share many similarities and have similar grading systems correlating to their behaviour. Differentiation between these chondrosarcoma subtypes can be done with the use of genetic screening for the presence of EXT (exostosin) genes which, are related to the production of heparin sulphate (2, 29). These genes are commonly associated most with the peripheral type, and are not present in the more common central chondrosarcoma (2). Difficulty arises however, when trying to differentiate benign precursor enchondromas and malignant, grade 1 chondrosarcomas and is subjective in nature during histological examination (2). Since 2013, low grade 1 chondrosarcomas, have been reclassified as atypical cartilaginous tumours (6).

Even using methods such as dynamic MRI scanning, unequivocal distinction between benign and precursor lesions is not possible; although the size of the lesion especially if it is present in the axial skeleton can be an indicator of malignancy especially if it is greater than 5 cm in size (30). Low grade 1 tumours show decreased cellularity, are not associated with metastatic progression and are typically restricted to a locally aggressive course (6). This is contrasted to higher grade 2-3 tumours which, histologically have higher cellularity with the presence of mitoses, have reduced cartilaginous matrix which can undergo metastatic progression associated with the high mortality rates of these lesions (6).

The most frequent, conventional type chondrosarcomas, are found in many of the flat bones within the body, though they are frequently found in adults within the pelvic girdle and femur (8).

Primary central chondrosarcomas and secondary peripheral type chondrosarcomas which constitute 85%

of all lesions are not limited to these two sites and may affect any bone in the body.

Many chondrosarcomas are present as benign masses or the aforementioned atypical cartilaginous tumour (Grade 1) and are restricted to locally aggressive invasion of surrounding tissues with little to no presence of metastatic progression (3, 8). In higher grade chondrosarcomas, the increased cellularity of the tumours, combined with the diminished cartilaginous matrix allow for metastatic progression of the tumour with as many as 20-30% of patients developing metastases following treatment (3, 7, 8). Patients with low grade tumours or non-axial presentation of malignancies have demonstrated better prognosis, overall survivability, less recurrence and less metastases when compared to higher grade lesions which, is likely attributable to adequate resection margins during treatment (4).

As with osteosarcomas, radical treatment can only be achieved through the use of surgical procedures such as wide en-bloc excisions especially for higher grade chondrosarcomas (2). These

(9)

operations however, are demanding due to the use of extensive reconstructive procedures and the inherent characteristics of malignant chondrosarcomas leading to the high morbidity seen in patients (2, 6). Intralesional and marginal excision of tumours may be done in low grade chondrosarcomas followed by local adjuvant therapy without the significant impact that is associated with wide en-bloc excisions while maintaining local control (31). Local adjuvant therapy such as the use of phenol or cryosurgery techniques is however, limited to low grade chondrosarcomas confined solely within the bone (31).

When tumours are present in non resectable portions of the body such as the base of the skull or within the pelvis, only palliative treatment is available as an option (2, 3).

8. RESEARCH METHODOLOGY AND RESULTS

Our aim was to analyse the incidence and treatment outcomes of primary bone cancers which were diagnosed and treated at LSMU KK ORT department between 2006 and 2018. Those patients, including some from the paediatrics department diagnosed and treated with primary osteosarcomas and chondrosarcomas were included in the study. We excluded soft tissue tumours which affected the bone such as Ewing’s sarcoma. A total of 72 patients were included in the study of which 63 fit our criteria.

Records were collected from the department of pathological histology as well as from the orthopaedic and traumatology centre database from those 11 years, and categorized based on various factors such as age, gender, grade of tumour, site of the tumour, metastatic presence, MSTS scoring as well as local recurrence. STATA was used for statistical analysis of all data collected during the study.

9. RESULTS AND THEIR DISCUSSION

9.1 Gender and age distribution of tumours based on type

In our study results, the mean age of those affected by any primary bone cancers was 48.73 with a total of 72 cases reported. The gender distribution between those affected was approximately equal, between the two sexes with 56% of patients being male and 44% female. A T-test was performed to assess the relation between tumour type and sex which, found there was no statistically significant difference in our population (p>0.05).

(10)

9.2 Histologically classified distribution of tumours based on site

Fig. 1 Distribution of histological tumour types based on site

Fig. 1 above describes the histological subtypes of primary bone cancers, and the incidence in our population based on the site affected, prior to the exclusion of cancers affecting soft tissues. It can be noted that the majority of the population was affected by chondosarcomas, which accounted for approximately 50% of the entire population. The primary distribution of tumours affected the distal femur, tibia, fibula and or foot as well as the pelvic bones and spine. Osteosarcomas on the other hand accounted for around 32% of our population with the majority of incidences occurring in the distal femur and tibia, fibula, and foot. There was no statistically significant distribution (Fisher’s Exact p>0.05) of histological subtypes based on site prior to imposing the exclusion criteria. After exclusion of soft tissue tumours, our sample was comprised of 63 patients of which 63% (40 cases) were diagnosed with chondrosarcomas and the remaining 37% (23 cases) with osteosarcomas.

1 6 7

1 1

3

2 4 2 1

10

1 2

5

8 2

2 1

20

2 1

10 7 2

20

1

8 1

13

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 PAROSTEAL OSTEOSARCOMA (2.78%)

GIANT CELL TUMOUR (2.78%) FIBROBLASTIC OSTEOSARCOMA (4.17%) OSTEOBLASTIC OSTEOSARCOMA (26.39%) ANGIOSARCOMA (1.39%) CHONDROSARCOMA (47.22%) DEDIFFERENTIATED CHONDROSARCOMA (5.56%) EWING'S SARCOMA (5.56%) EXTRAOSEAL OSTEOSARCOMA (2.78%) EXTRAOSEAL CHONDROSARCOMA (1.39%) TOTAL CASES: 72 (100%)

Scapula and Humerus Ulna, Radius and Hand Proximal Femur

Tibia, Fibula and Foot Distal Femur Pelvic Bones and Sacrum/Spine

(11)

9.3 Prevalence of tumours based on site

Fig.. 2 Distribution of selected tumours based on site

Using the remaining sample of 63 patients, we calculated distribution of osteosarcomas and chondrosarcomas based on site and found a statistically significant (Fisher’s Exact p>0.05) distribution pattern amongst the data which can be seen in Fig 2. Osteosarcomas have a tendency to grow around the knee and of the 23 patients that had osteosarcomas, more than 70% originated in this location, consistent with published literature (14, 32). Chondrosarcomas can affect any bone in the body, but have a tendency to grow in the femur and pelvic girdle as well as other flat bones in the body in the adult population (8). In our sample, 40% of patients (17) had this distribution pattern.

9.4 Surgical resection types and frequency

Fig. 3 Surgical resection type and frequency

0 1

3 7

11 1

23

6 1

6 10 7

10

40

0 5 10 15 20 25 30 35 40 45

SCAPULA AND HUMERUS ULNA, RADIUS AND HAND PROXIMAL FEMUR TIBIA, FIBULA AND FOOT DISTAL FEMUR PELVIC BONES AND

SACRUM/SPINE TOTAL

Chondrosarcoma Osteosarcoma

0 10 20 30 40 50 60 70 80

WIDE EN-BLOC EXCISION (68.08%) AMPUTATION (15.28%) INTRALESIONAL EXCISION (4.17%) MARGINAL EXCISION (9.72%) FIXATION OF PATHOLOGICAL FRACTURES (2.78%) TOTAL:

49 11

3 7 2

72

(12)

In our population, we also analysed the surgical resection types and found that wide, en-bloc excisions were the most common accounting for more than 2/3 of operations. This is consistent with much of the literature regarding the treatment of osteosarcomas and chondrosarcomas, with a common tendency towards limb salvaging surgeries and adjuvant therapy versus limb amputation occurring over the last few decades (2, 3). Wide resections may be the only beneficial method of treatment however, when tumours are large, and or confined within the pelvic bones, which were present in 11 of our patients (17%) (2). When considering treatment strategies for osteosarcomas, one must consider that the rate of local penetration and metastasis to pulmonary tissues is high, and local control of tumours is not adequate with systemic treatment or surgery alone (2, 3). In high grade chondrosarcomas, wide en-bloc resection remains at the foundation of surgical treatment especially in higher grade tumours (2, 3, 6, 8, 27). When rates of local recurrence in patients were compared to the various types of surgical treatment, much of the literature states, that rates of local recurrence are higher in those that received intralesional or marginal excisions, compared to wide en-bloc resections (2, 3). In our group, we found no association between the surgical treatment modality and the rate of local recurrence seen in patients (Log-test p>0.05).

9.5 MSTS vs Surgical approach

Fig. 4 MSTS scoring outcomes related to the surgical approach

The Fig. 4 describes patient outcomes based on the MSTS scoring system, comparing them to various surgical interventions. Radical surgery, which encompasses amputations, had the highest morbidity scores amongst the sample; while intralesional, marginal, and en-bloc excisions had better outcomes amongst the patients in the study. Most of our sample received wide en-bloc excisions to treat their

0 5 10 15 20 25 30 35 40

Amputations Palliative external

fixation

Intralesional

excision Marginal

excision Wide en-bloc resection

13 12

30 31

29

(13)

various cancers. In high grade chondrosarcomas, wide en-bloc resection remains at the foundation of surgical treatment, especially in higher grade tumours, providing clear resection margins, maintaining limb salvage while correcting the neoplastic disease (2, 3, 6, 8, 27).

9.6 JBJS Henderson classification of endoprosthetic complications

Fig 5 2011 JBJS endoprosthetic complications related to oncological treatment

Fig 5. above shows the associated complications of surgery in oncological patients. Type 1 to type 3 are associated with mechanical endoprosthetic failure, while the remaining type 4 and 5 fall into groups of non-mechanical and oncological complication categories. In our group, the most frequent complication was local recurrence, following intervention; with a total of 16 local recurrences occurring amongst the 63 participants (25%). One patient had an infection following surgery (1.5%). The majority, of local recurrences were present in patients with chondrosarcomas, and although they comprised the majority of our patients, local recurrence has been associated with larger tumours or those present in places such as the pelvic bones, where wide en-bloc excisions are difficult and resection margins are not clear (2). It is also important to note that many of the patients had high grade chondrosarcomas which, likely impacted the volume of excised tumours seen in our study.

(14)

9.7 The rate of local recurrence based on the type of tumour

Fig. 6 Demonstrates the rate of local recurrence based on the type of tumour

Fig 6. depicts rates of local recurrence based on cancer type in our sample study. We found that nearly 75% of our patients did not have presence of local recurrence which, may be attributed to the high rate of wide en-bloc excisions that were performed in our group, though this was not statistically significant (Pearson chi p>0.05).

9.8 Local recurrence based on the volume of the tumour

Fig 7 Volume of specific tumours vs tumour volume with and without local recurrence

4

12 19 16

28

47

OSTEOSARCOMAS CHONDROSARCOMAS TOTAL

Local Recurrence No Local Recurrence

367

566

497

419

718

0 100 200 300 400 500 600 700 800 900

Osteosarcomas Chondrosarcomas Total No Local

Recurrence Local Recurrence

(15)

The following Fig. 7 demonstrates the volumes of osteochondromas and chondrosarcomas compared to rates of local recurrence. Volume was not found to be an important indicator of disease in our group study (Log test p>0.05). Volume of neoplastic growths also had no association with tumour grade, nor did it have a direct association with the surgical approach performed. These findings contradict the published literature; however, they may be misrepresented due to the small sample size and wide CI (Confidence Interval). In our study, we found that tumours with local recurrence had an average volume of 420 cm³ (CI 95% ± 546 cm³), whereas those with local recurrence had an average volume of 714 cm³ (CI 95% ± 1144 cm³). During the study, the volume of tumours was assessed and compared to the rates of local recurrence. The average volume of excised tumours was 497 cm³ irrespective of type. Between the two groups we found no statistically significant difference in tumour volume, and the tumour type, with osteosarcomas constituting an average volume of 367 cm³(CI 95% ± 297cm³) and chondrosarcomas 566 cm³(CI 95% ± 899 cm³). It was then assessed whether or not the rate of local recurrence was associated with tumour volume in our sample group, irrespective of the type of tumour, and it was found to not be not statistically significant; although this may have been attributed to the small number of patients that were present in our sample. In general, larger tumours, irrespective of grade or type have been associated with a higher rate of local recurrence.

9.9 Amputation rates compared to the volume of the tumour

The rate of amputation amongst patients receiving treatment was around 15%. Amputation in the past has been the go to solution when treating higher grade chondrosarcomas, and osteosarcomas, as it provides radical excision of the tumour with clear resection margins (2, 3, 7, 8, 10, 27). Amongst our participants, the decision to amputate, was dictated to some degree by the institution where people were first treated. More than 80% of our patients receiving radical amputation procedures were treated at local/regional hospitals prior to their arrival to LSMU KK ORT. This tendency demonstrates the adequacy and importance of early diagnosis, and treatment in patients diagnosed with osteosarcomas and chondrosarcomas.

9.10 Overall Survival

The combined overall survival of patients in our group, irrespective of tumour type for 5 years was over 80% and was 72% after 10 years. We also compared the overall survival of patients suffering from each cancer type over 10 years and found no statistically significant difference between the two groups (Log rank test p>0.05). Despite published results presented in current literature, the rates of local

(16)

recurrence in our sample had no role in the development of future neoplastic disorders. This factor was not influenced by tumour grade, nor the surgical approach taken on by surgeons in the field. When considering treatment strategies for osteosarcomas, one must consider that the rate of local dissemination and metastasis to pulmonary tissues is high, and local control of tumours is not adequate with systemic treatment or surgery alone (2, 3). In high grade chondrosarcomas, wide en-bloc resection remains at the foundation of surgical treatment, especially in higher grade tumours where resistance to chemotherapeutic agents as well as radiotherapy is prevalent (2, 3, 6, 8, 27).

Fig. 8 Comparison of the overall survival between chondrosarcomas and osteosarcomas In fig. 8 depicted above, chondrosarcomas had a higher 10-year overall survival (0.74) when compared to osteosarcomas (0.68), (Log-rank test p>0.05). These survival rates coincide with the current treatment modalities that have been implemented over the last few decades, with the advent of chemotherapy, prior to which, overall survival rates of osteosarcomas were around 20% following initial diagnosis (33). This was largely attributed to local dissemination of the disease, and rapid development of lung metastases.

(17)

9.11 Overall survival based on the grade of the tumour

Fig. 9 Comparison of overall survival of patients diagnosed with G1+G2 vs G3 Chondrosarcomas Our group was divided based on their cancer type, and then further divided based on the grade of tumours with respect to overall survival. While we found no statistically significant trend within the osteosarcoma group (Log-rank test p>0.05), the overall survival at 10 years within patients diagnosed with chondrosarcomas was found to be statistically significant based on grade (Log rank test p<0.05).

In our study, we grouped G1+G2 grade chondrosarcomas together, and found that overall survival was 85% at 10 years compared to 53% with those patients diagnosed with higher grade G3 stage chondrosarcomas. After analysing the hazard ratio using a cox regression, patients diagnosed with high grade chondrosarcomas were 5 times more likely to die when compared to G1+G2-grade chondrosarcomas, irrespective of age, or gender (p<0.05). Many of our patients were diagnosed with higher grade chondrosarcomas which, impacted the overall survival after 10 years even after they received adequate treatment. More aggressive chondrosarcomas have been shown to be resistant to chemo and radio therapies, postulated to be caused by the activation of anti-apoptotic pathways as means of survival and spread (28). Further analysis was done in our group encompassing volume of the tumour as well as grade, while subdividing them into their respective categories, and found that there was no significant difference amongst the groups (p>0.05). The fact that there was such a small group incorporated in the study may have influenced the results, and further examinations with larger groups must be done for accurate representation of data.

(18)

9.12 Overall survival between cancer types without the presence of local recurrence

Fig. 10 Comparison of overall survival in patients between types of cancer who did not have local recurrence

Overall survival in patients was compared to the absence of any local recurrences as the primary oncological complication. It was approximately found to be 85% in both groups 5 years after diagnosis, and just under 80% after 10 years (Log-rank test p>0.05). Local recurrence, and metastatic disease has been demonstrated in other literature, to have a significant impact on the overall survival of patients (8, 34). Local recurrence in higher grade chondrosarcomas can be attributed to areas associated with difficult operation such as pelvic bones, where clear resection margins are difficult to achieve, or the increased cellularity, mitotic activity and decreased hyaline matrix associated with these tumours, lead to greater metastatic potential (2, 8, 34). Osteosarcomas on the other hand, have been known to have rapid systemic dissemination due to their ability to spread haematogenously, and have been associated with elevated rates of local micro-metastases in which, clear resection margins are difficult to attain (1, 5).

(19)

9.13 Cumulative risk of developing local recurrence over 5-years

Fig 11 Cumulative risk of developing local recurrence over 5-years related to the type of cancer In our study, the cumulative risk of developing local recurrence of cancer was approximately 20% in those diagnosed with osteosarcomas, and 30% with chondrosarcomas irrespective of grade after 5 years. The results were found to not be statistically significant in our group (Log-rank test p>0.05) which, may have been due to the size of the sample. Similar studies have concluded that in those diagnosed with an osteosarcoma, the risk of progression to a metastatic disease course, or the presence of a complication such as a local recurrence is between 30-40% (14). The primary causes of recurrent osteosarcomas are however, lung metastases, which develop within the first 2-3 years following treatment, and are generally associated with a poorer prognosis, as well as patient survival (10, 15, 25).

(20)

9.14 Overall Survival of patients with or without pulmonary metastases diagnosed with either chondrosarcomas or osteosarcomas

Fig. 12 Overall survival of patients with chondrosarcomas who have the presence or absence of pulmonary metastases

Fig. 13 Overall survival of patients with osteosarcomas who have the presence or absence of pulmonary metastases

(21)

Overall survival after 10 years, was assessed in patients with both osteosarcomas and chondrosarcomas, and compared to those with and without pulmonary metastases. It was observed that in patients who were diagnosed with chondrosarcomas and pulmonary metastases, the 10-year survival was approximately 22% whereas, in those with osteosarcomas and metastases on the lungs, it was 20%

during the same time frame, with statistically significant results in both groups (Log-rank test p<0.05).

When compared to the overall survival of those without pulmonary metastases, those with chondrosarcomas had an overall 10-year survival of 90% and those with osteosarcomas 100%. At the time of diagnosis, literature states that approximately 10-20% of patients have radiologically visible evidence of metastases resulting from osteosarcomas however, subclinical local penetration of tissues is assumed to be as high as 80-90% (13). With respect to chondrosarcomas, many of them recur in the form of metastases, primarily to the lungs and bone, similar to osteosarcomas, and occur within the first five years following treatment (35). The data presented that those with advanced disease, in the form of pulmonary metastases in both groups, had a higher mortality rate, and poorer overall survival at 10 years as reported by much of the current literature.

10. Conclusions

While the annual incidence of both osteosarcomas and chondrosarcomas remains low, mortality rates in both of these cancer groups is high, despite advances in radiological detection, and treatment methodologies. The site distribution, affected by both of these cancer groups coincided with current literature, however there were no statistically significant outcomes with respect to sex, age, or volume in our sample group. Presence of pulmonary metastases in both groups proved to be a worse prognostic factor when determining overall survival. Volume of tumours, or their type did not coincide with local recurrence though this may have been due to the fact that the sample size was small. The cumulative risk of oncological complications such as local recurrence, based on the cancer type was consistent with published literature, but proved to be insignificant in our study. While en-bloc wide resections remain the mainstay for surgical approaches in higher grade osteosarcomas, and chondrosarcomas, the results attained from our study were inconclusive on the matter. It is important to note that the majority of surgical procedures were en-bloc resections, and the majority of cancers encountered were chondrosarcomas, despite the lack of a significant association between the two. It is important to develop new novel strategies for treating chondrosarcomas which are associated with high rates of resistance to both chemo and radiotherapy; and early diagnosis, and treatment of osteosarcomas is imperative to prevent local recurrence, or metastatic disease. The results attained in this study coincide with much of the published literature, and can shed light onto effective means of diagnosis, and treatment strategies in the future.

(22)

11. References

1. Kumar V, Abbas AK, Aster JC, Robbins SL. Robbins basic pathology. 9th ed. Philadelphia, PA: Elsevier/Saunders; 2013. viii, 909 p. p.

2. Gelderblom H, Hogendoorn PC, Dijkstra SD, Van Rijswijk CS, Krol AD, Taminiau AH, et al.

The clinical approach towards chondrosarcoma. The oncologist. 2008;13(3):320-9.

3. The EESNWG. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Annals of Oncology. 2014;25(suppl_3):iii113-iii23.

4. Nakamura T, Matsumine A, Yamada S, Tsukushi S, Kawanami K, Ohno T, et al. Oncological outcome after lung metastasis in patients presenting with localized chondrosarcoma at extremities:

Tokai Musculoskeletal Oncology Consortium study. OncoTargets and therapy. 2016;9:4747-51.

5. Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment – Where do we stand? A state of the art review. Cancer Treatment Reviews. 2014;40(4):523-32.

6. Hogendoorn P, Bovee J, Nielsen GP. Chondrosarcoma (grades I-III), including primary and secondary variants and periosteal chondrosarcoma2013. 264-8 p.

7. Andreou D, Bielack SS, Carrle D, Kevric M, Kotz R, Winkelmann W, et al. The influence of tumor- and treatment-related factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. Annals of Oncology. 2011;22(5):1228-35.

8. Angelini A, Guerra G, Mavrogenis AF, Pala E, Picci P, Ruggieri P. Clinical outcome of central conventional chondrosarcoma. Journal of Surgical Oncology. 2012;106(8):929-37.

9. Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004. Cancer. 2009;115(7):1531-43.

10. Bacci G, Longhi A, Bertoni F, Briccoli A, Versari M, Pignotti E, et al. Bone metastases in osteosarcoma patients treated with neoadjuvant or adjuvant chemotherapy The Rizzoli experience in 52 patients. Acta Orthopaedica. 2006;77(6):938-43.

11. Ozaki T, Flege S, Kevric M, Lindner N, Maas R, Delling G, et al. Osteosarcoma of the Pelvis:

Experience of the Cooperative Osteosarcoma Study Group. Journal of Clinical Oncology.

2003;21(2):334-41.

12. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. Prognostic Factors in High-Grade Osteosarcoma of the Extremities or Trunk: An Analysis of 1,702 Patients Treated on Neoadjuvant Cooperative Osteosarcoma Study Group Protocols. Journal of Clinical Oncology. 2002;20(3):776-90.

13. Geller DS, Gorlick R. Osteosarcoma: A review of diagnosis, management, and treatment strategies. Clinical Advances in Hematology and Oncology. 2010;8(10):705-18.

(23)

14. Kempf-Bielack B, Bielack SS, Jürgens H, Branscheid D, Berdel WE, Exner GU, et al.

Osteosarcoma Relapse After Combined Modality Therapy: An Analysis of Unselected Patients in the Cooperative Osteosarcoma Study Group (COSS). Journal of Clinical Oncology. 2005;23(3):559-68.

15. Ta HT, Dass CR, Choong PFM, Dunstan DE. Osteosarcoma treatment: state of the art. Cancer and Metastasis Reviews. 2009;28(1):247-63.

16. Franke M, Hardes J, Helmke K, Jundt G, Jürgens H, Kempf-Bielack B, et al. Solitary skeletal osteosarcoma recurrence. Findings from the Cooperative Osteosarcoma Study Group. Pediatric Blood

& Cancer. 2011;56(5):771-6.

17. Carrle D, Bielack S. Osteosarcoma Lung Metastases Detection and Principles of Multimodal Therapy. In: Jaffe N, Bruland OS, Bielack S, editors. Pediatric and Adolescent Osteosarcoma. Boston, MA: Springer US; 2010. p. 165-84.

18. Ries LAG, SEER Program (National Cancer Institute (U.S.)). Cancer incidence and survival among children and adolescents : United States SEER program 1975-1995 /[edited by Lynn A.

Gloecker Ries ... et al.]. Bethesda, MD: National Cancer Institute, SEER Program; 1999. vi, 182 p. p.

19. Pizzo PA, Poplack DG, Adamson PC, Blaney SM, Helman LJ. Principles and Practice of Pediatric Oncology. 2015.

20. Cosker T, Gibbons CLMH. Surgical management of primary bone sarcomas. Orthopaedics and Trauma. 2017;31(3):173-9.

21. Gill J, Ahluwalia MK, Geller D, Gorlick R. New targets and approaches in osteosarcoma.

Pharmacology & Therapeutics. 2013;137(1):89-99.

22. Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, et al.

Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. Journal of Clinical Oncology.

2005;23(9):2004-11.

23. Bacci G, Forni C, Ferrari S, Longhi A, Bertoni F, Mercuri M, et al. Neoadjuvant

Chemotherapy for Osteosarcoma of the Extremity: Intensification of Preoperative Treatment Does Not Increase the Rate of Good Histologic Response to the Primary Tumor or Improve the Final Outcome.

Journal of Pediatric Hematology/Oncology. 2003;25(11):845-53.

24. Goorin AM, Schwartzentruber DJ, Devidas M, Gebhardt MC, Ayala AG, Harris MB, et al.

Presurgical Chemotherapy Compared With Immediate Surgery and Adjuvant Chemotherapy for Nonmetastatic Osteosarcoma: Pediatric Oncology Group Study POG-8651. Journal of Clinical Oncology. 2003;21(8):1574-80.

25. Errani C, Longhi A, Rossi G, Rimondi E, Biazzo A, Toscano A, et al. Palliative therapy for osteosarcoma. Expert Review of Anticancer Therapy. 2011;11(2):217-27.

(24)

26. Li X, Moretti VM, Ashana AO, Lackman RD. Impact of close surgical margin on local recurrence and survival in osteosarcoma. International Orthopaedics. 2012;36(1):131-7.

27. van Oosterwijk JG, Anninga JK, Gelderblom H, Cleton-Jansen A-M, Bovée JVMG. Update on targets and novel treatment options for high-grade osteosarcoma and chondrosarcoma. Hematol Oncol Clin North Am. 2013;27(5):1021-48.

28. Bovée JVMG, Hogendoorn PCW, Wunder JS, Alman BA. Cartilage tumours and bone development: molecular pathology and possible therapeutic targets. Nature Reviews Cancer.

2010;10:481.

29. McCormick C, Leduc Y, Martindale D, Mattison K, Esford L, Dyer A, et al. The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nature genetics.

1998;19(2):158.

30. Geirnaerdt MJ, Hermans J, Bloem JL, Kroon HM, Pope TL, Taminiau AH, et al. Usefulness of radiography in differentiating enchondroma from central grade 1 chondrosarcoma. American Journal of Roentgenology. 1997;169(4):1097-104.

31. Leerapun T, Hugate RR, Inwards CY, Scully SP, Sim FH. Surgical Management of

Conventional Grade I Chondrosarcoma of Long Bones. Clinical Orthopaedics and Related Research®.

2007;463:166-72.

32. Isakoff MS, Bielack SS, Meltzer P, Gorlick R. Osteosarcoma: Current Treatment and a Collaborative Pathway to Success. Journal of Clinical Oncology. 2015;33(27):3029-35.

33. Klein M, Siegal G. Osteosarcoma Anatomic and Histologic Variants2006. 555-81 p.

34. Tang C-H. Molecular mechanisms of chondrosarcoma metastasis. BioMedicine. 2012;2(3):92- 8.

35. Mottard S, Sumathi VP, Jeys L. (ii) Chondrosarcomas. Orthopaedics and Trauma.24(5):332- 41.

(25)

Treatment outcomes of patients treated at LSMU KK ORT for chondrosarcomas and osteosarcomas. A treatment analysis.