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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 145-151

Life and limb after limb salvage surgery for osteosarcoma in an Indian tertiary cancer center


1 Department of General Surgery, S Nijalingappa Medical College, Bagalkot, Karnataka, India
2 Department of Surgical Oncology, Malabar Cancer Center, Thalassery, Kerala, India
3 Department of Biostatistics and Cancer Registry, Malabar Cancer Center, Thalassery, Kerala, India
4 Department of Physiotherapy, Malabar Cancer Center, Thalassery, Kerala, India

Date of Web Publication20-Dec-2019

Correspondence Address:
Nizamudheen Mangalasseri Pareekutty
Department of Surgical Oncology, Malabar Cancer Center, Thalassery - 670 103, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_44_19

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  Abstract 


Background: Limb salvage surgery (LSS) is the current surgical standard for malignant bone tumors. The advancements in imaging, surgical techniques, chemotherapy, and biomedical engineering have made LSS oncologically safe and with improved functional outcome. In this retrospective study, we report our experience with LSS and perioperative chemotherapy for osteosarcoma in a tertiary cancer center in India.
Materials and Methods: A total of 41 LSS were performed from January 2009 to January 2015. Perioperative chemotherapy was administered to all patients after histopathological confirmation of osteosarcoma. The functional outcome of the patients was evaluated using the musculoskeletal tumor society (MSTS) scoring system at regular intervals. Statistical analysis involved the use of descriptive and inferential statistics for data analysis. Kaplan–Meier method was used for calculating the recurrence free and overall survival (OS) and log-rank test for comparing survival functions. Spearman and Karl Pearson's methods were used for correlation analysis.
Results: The mean age was 19.3 years (range, 8–49 years). Twenty-five (61%) patients were males. Thirty-six (88%) patients had conventional high-grade osteosarcoma. Five-year relapse-free survival and OS were 56.1% ± 7.8% (95% confidence interval [CI], 53.7–58.5) and 58.5% ± 7.7% (95% CI, 56.1–60.9), respectively. The mean MSTS scores at 1 year for tumors of the upper tibia and distal femur were 64 and 75.9, respectively. Patients with high rate of chemotherapy-induced tumor necrosis (>99%) had significantly better median OS (85.70 ± 8.22 months) compared to those with less (<99%) tumor necrosis (58.15 ± 11.77 months), P = 0.030.
Conclusion: The oncological and functional outcomes in osteosarcoma patients in the present study are comparable to those from the world literature. Chemotherapy-induced tumor necrosis is a favorable prognostic factor for patients treated for osteosarcoma with curative intent.

Keywords: Custom made prosthesis, limb salvage surgery, osteogenic sarcoma, osteosarcoma, sarcoma


How to cite this article:
Ankalkoti B, Pareekutty NM, Kattepur AK, Kumbakara R, Vazhayil R, Balasubramanian S. Life and limb after limb salvage surgery for osteosarcoma in an Indian tertiary cancer center. Cancer Res Stat Treat 2019;2:145-51

How to cite this URL:
Ankalkoti B, Pareekutty NM, Kattepur AK, Kumbakara R, Vazhayil R, Balasubramanian S. Life and limb after limb salvage surgery for osteosarcoma in an Indian tertiary cancer center. Cancer Res Stat Treat [serial online] 2019 [cited 2020 Feb 28];2:145-51. Available from: http://www.crstonline.com/text.asp?2019/2/2/145/273673




  Introduction Top


Osteosarcoma is the most common primary malignant tumor of the bone in adults[1],[2],[3] and children.[4],[5] The age distribution of osteosarcoma is bimodal, with peaks in early adolescence and adults over the age of 65 years.[6],[7],[8] Patients with osteosarcoma generally present with localized pain and swelling, typically of several months' duration. The most important finding on physical examination is a bony swelling with a soft tissue mass, which is frequently large and tender on palpation. 10%–20% of patients have demonstrable metastatic disease at presentation, most often involving the lung.[9] The histologic diagnosis of osteosarcoma is based on the presence of a malignant sarcomatous stroma, associated with the production of tumor osteoid and bone. Conventional (intramedullary high grade) osteosarcoma accounts for approximately 90% of all osteosarcomas.[10] Other less common histologic variants include small cell, telangiectatic, surface (juxtacortical) extraosseous osteosarcomas, and undifferentiated high-grade pleomorphic sarcoma of bone (previously known as malignant fibrous histiocytoma of the bone).[11]

The current management strategy for curative treatment of newly diagnosed osteosarcoma includes cytotoxic chemotherapy and surgical resection.[12] Chemotherapy is administered perioperatively.

The present study was conducted with the aim of analyzing the oncological and functional outcome of osteosarcoma patients undergoing limb salvage surgery (LSS) at a rural tertiary cancer center in India.


  Materials and Methods Top


The study protocol was approved by the Institutional Review Board (IRB) [Supplementary Appendix 1: Study Protocol]. This was a retrospective cohort analysis. Requirement of individual patient consent was waived by the IRB. Patients who underwent treatment between January 2009 and January 2015 were included in the study. Patient numbers were obtained from the surgical database. Patient files, surgical register, histopathology reports (HPRs), treatment charts, and follow-up data were reviewed for data collection. The information collected included the demographic profile, clinical features, histopathological features, treatment provided, functional outcome, and survival.

Jamshidi needle (J needle) biopsy was used to confirm histopathological diagnosis. In cases where J needle biopsy was inconclusive or there was a discrepancy between the radiological and histological findings after two attempts at needle biopsy, open biopsy with a carefully placed longitudinal incision was performed.

Initial workup included digital X-ray and magnetic resonance imaging (MRI) of the local part, computed tomography (CT) scan of the chest, and bone scan. Enneking system was used for staging.[13] The system classifies malignant bone tumors into three stages based on grade, tumor extent, and the presence of distant metastasis. Stage I tumors are low-grade and Stage II are high-grade non-metastatic cancers. Stage I and II are further subclassified into A and B categories based on the local extent. Metastatic cancers are Stage III.

All cases were discussed in the multidisciplinary tumor board. All patients received three cycles of neoadjuvant chemotherapy (NACT) with injection ifosfamide (1.3 g/m2, days 1–3), injection adriamycin (50 mg/m2, on day 1), and injection cisplatin (100 mg/m2, divided over 3 days) at once-every-3-weekly intervals.[14] In four patients, there was a delay in the arrival of the prosthesis, and a fourth cycle was administered. Response assessment was done with MRI, and the patient was taken up for surgery after 3 weeks from the last day of chemotherapy.

All patients underwent LSS by surgical oncologists trained in orthopedic oncology. We used custom-made prosthesis for reconstruction. Measurements for custom made prosthesis were made using the plain X-ray scanogram. Order for the prosthesis was placed before initiation of NACT in all patients. Adjuvant chemotherapy with the same regimen and dose as preoperative therapy was administered to complete a total of six cycles (including the NACT) once the sutures were removed. If there was an associated surgical morbidity, adjuvant treatment was delayed till wound healing.

Morbidity was assessed based on the Clavien–Dindo grading system.[15] The grading is based on the type of therapy required to correct the specific complications that may arise after the surgery. Grades I or II morbidity indicate minor complications not requiring surgical intervention. Grade IIIA morbidity requires intervention under local anesthesia and IIIB requires surgical intervention under general/regional anesthesia. Grade IV is life-threatening complication with single (IVA) or multiple (IVB) organ failure whereas Grade V denotes death of the patient.

Patients were followed up at three-monthly intervals for the initial 2 years, six-monthly intervals till 5 years, and yearly thereafter. At each follow-up visit, physical examination was performed, and X-ray of the local part and chest were obtained. CT scan of the chest was done yearly and when suspicious findings was noted on chest X-rays. Local or systemic relapse of disease was labeled as an event.

The median follow-up was calculated using the reverse Kaplan–Meier method. The oncological outcomes were calculated, and the results were analyzed for correlation with age, sex, stage at presentation, site of the primary lesion, histological subtype, and post-chemotherapy tumor necrosis.

Functional assessment was done using the musculoskeletal tumor society (MSTS) scoring system.[16] The scoring system contains seven parameters for assessment, namely pain, range of motion, strength, joint stability, joint deformity, emotional acceptance, and overall function. Each item is scored from 0 to 5 with a maximum possible score of 35. Higher score indicates improved functional outcome. The score was calculated by the physiotherapist regularly at 3 months, 6 months, and 1 year in all patients, and the data were prospectively collected and maintained in the register.

Statistical analysis

The database was locked and data were analyzed on June 26, 2019. The software used for analysis was IBM SPSS (Statistical Package for the Social Sciences) for Windows, version 20.0. (Armonk, NY, USA: IBM Corp.). Descriptive and inferential statistics were used for data analysis. Kaplan–Meier method,[17] was used for calculating the recurrence-free survival (RFS) and overall survival (OS) and log-rank test for comparing survival functions. Spearman and Karl Pearson's methods were used for correlation analysis. Five percent level of significance was used for statistical test. Cox regression was used to assess the influence of the various factors on survival.[18],[19]

OS was defined as the interval from disease diagnosis till the date of death or the date of last follow-up. RFS was defined as the time interval from the date of completion of treatment till the date of disease relapse, death, or last follow-up, whichever was earlier. Endoprosthetic survival (prosthesis in situ survival) was defined as the percentage of patients alive with prosthesis inside their limb at the time of assessment.


  Results Top


Forty-one patients underwent perioperative chemotherapy and LSS. The mean age was 19.34 years (range, 8-49 years). There were 25 males (60.98%). The most common site of tumor was distal femur (n = 18, 43.9%) followed by proximal tibia in 16 patients (39%). According to Enneking staging for malignant musculoskeletal tumors, nine patients (21.9%) presented in Stage I, 24 (58.5%) in Stage II, and 8 (19.5%) in Stage III disease.

Thirty-seven patients received three cycles and four received four cycles of NACT. Details regarding chemotherapy toxicity were not available. All patients underwent LSS: in 38 patients (92.7%), non-biological reconstruction (custom made titanium mega prosthesis) was used, and in 3 patients (7.3%), biological reconstruction (free fibular graft) was performed. Eight patients with concomitant lung metastases underwent lung metastasectomy. Mean time to surgery was 22.8 days (range, 13–38 days).

Adjuvant chemotherapy was started in thirty-eight patients within 1 month after the surgery. Mean time to start adjuvant chemotherapy after surgery was 23.4 days (range, 16–46 days). Thirty-nine patients (95%) completed total prescribed chemotherapy of six cycles. Two could not complete adjuvant chemotherapy due to late wound morbidity. Three patients had delay in starting adjuvant chemotherapy due to wound morbidity but received all cycles prescribed.

Postoperative morbidity (Clavien–Dindo score of IIIB or more) was encountered in 5 (12.19%) patients. The early postoperative complications are listed in [Table 1]. Reoperation within 30 days was performed in 5 (12.19%) patients. Wound closure with flap cover was done in 3 (7.31%) patients and prosthesis removal was done in 2 (4.88%) patients. Two patients required prosthesis removal due to infection. The mean MSTS score with time of assessment is mentioned in [Table 2].
Table 1: Early postoperative complications following neoadjuvant chemotherapy and limb salvage surgery with Clavien-Dindo grading

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Table 2: Mean musculoskeletal tumor society scores with duration of assessment from the date of completion of the treatment

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Final histopathology report (HPR) showed conventional osteosarcoma in 36 patients (87.8%), fibroblastic osteosarcoma in 4 (9.76%), and chondroblastic osteosarcoma in 1 (2.44%). Twenty-three patients (56.09%) had more than 99% tumor necrosis in the final HPR.

Oncological outcomes

Twenty patients were alive at the time of assessment. Fourteen have died, and seven were lost to follow-up. The median follow-up duration was 84.4 ± 11.01 months (95% confidence interval [CI], 72.8–116). The 5-year OS was 58.5% ± 7.7% (95% CI, 56.1–60.9), and 5-year RFS was 56.1% ± 7.8% (95% CI, 53.7–58.5). The mean OS was 77.2 ± 7.7 months (95% CI, 62–92.3). Median OS and RFS were not reached. The Kaplan–Meir curves for OS and RFS are depicted in [Figure 1] and [Figure 2] respectively.
Figure 1: Kaplan–Meir curve for overall survival of the patients who received neoadjuvant chemotherapy and limb salvage surgery. The estimated 5-year overall survival was 58.5% (n = 41)

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Figure 2: Kaplan–Meir curve for relapse-free survival of the patients who received neoadjuvant chemotherapy and limb salvage surgery. The estimated 5-year relapse-free survival was 56.1% (number at risk = 41)

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Eighteen patients (26.82%) developed recurrence or disease progression. The pattern of recurrences is shown in [Table 3]. Three patients with local recurrences were treated with amputation and three patients with lung metastases underwent lung metastasectomy. All other patients with recurrent disease were offered best supportive care. No patient was treated with second-line chemotherapy.
Table 3: The pattern of recurrence after curative treatment of osteosarcoma with chemotherapy and limb salvage surgery

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Factors affecting the survival

The influence of various tumor- and patient-related factors on OS is shown in [Table 4]. Survival was significantly affected by stage and percentage of tumor necrosis (≥99%) in the surgical specimen [Figure 3] and [Figure 4]. Patients with primary in the femur had a worse survival compared to those with primary in the tibia. The survival was not affected by age or sex.
Table 4: Influence of variables on overall survival and the P values from log-rank test

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Figure 3: Stage-wise overall survival with staging based on the Enneking system. Numbers at risk for Stage I (low-grade localized disease) = 9, Stage II (high-grade localized disease) = 24, and Stage III (metastatic disease) = 8. Five-year overall survival for Stage I, II, and III were 77.8%, 62.5%, and 25%, respectively

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Figure 4: Chemotherapy-induced tumor necrosis and overall survival. Curve 1 represents those with ≥99% tumor necrosis and had significantly better survival among the two groups. Five-year overall survival for those with ≥99% necrosis was 73.9%, and for those with <99% necrosis, it was 38.9%. Numbers at risk – tumor necrosis ≥ 99% = 23, tumor necrosis <99% = 18

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Endoprosthetic survival

Two patients underwent prosthesis removal in the early postoperative period due to infection. Three patients required amputation for local recurrence. The estimated endoprosthetic survival at 5 years was 55.6%.


  Discussion Top


In our experience in 41 patients with osteosarcoma who underwent limb salvage surgery (LSS) at a rural tertiary cancer center in India, the mean age at presentation was 19.34 years, ranging from 8 to 49 years. Twenty-five were males (61%). The most common site of tumor was distal femur (43.9%) followed by proximal tibia (39%). Thirty-three patients had non-metastatic disease, and eight presented with lung metastasis. Forty-one patients received perioperative chemotherapy with ifosfamide, adriamycin, and cisplatin and underwent LSS. Eight patients underwent lung metastasectomy along with LSS. Twenty-three patients (56.1%) had more than 99% tumor necrosis in the final HPR. Thirty-nine completed total six cycles of perioperative chemotherapy prescribed. Eighteen patients had disease relapse and fourteen died. The estimated 5-year OS was 58.5%, and estimated 5-year RFS was 56.1%.

In a study of 1702 patients enrolled in the neoadjuvant studies by the Cooperative Osteosarcoma Study Group in Germany before July 1998, the 5-year OS was 63.3% and RFS was 52.8%.[20] A study from the Rizzoli Institute showed that patients with localized disease at initial presentation had a 10-year OS and RFS of 70% and 59%, respectively.[21] Our results showed OS and RFS rates comparable to other studies from abroad[22],[23],[24],[25],[26] and from India [Table 5].[20],[21],[22],[23],[24],[25],[26],[27],[28],[29]
Table 5: Survival outcome of osteosarcoma in previous studies from India and abroad along with oncological outcomes from the current study

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The various important factors affecting the outcome in osteosarcoma described in the literature include age, sex, site of cancer, stage at the time of presentation, tumor histology, and response to chemotherapy. Age have been identified as a prognostic factor for osteosarcoma. Poorer survival rates in patients under the age of 10[30] or 12 years[31] have been reported in some reports, which suggest aggressive behavior of this disease in smaller children. Other studies have failed to confirm this.[32],[33] We could not assess the influence of age below 10 years in our study as only two patients were younger than 10 years. A comparative analysis keeping the age cutoff as 20 years did not show any significant differences in survival. Gender did not show significant correlation with survival in our study, and there seems to be no unanimous answer regarding the relationship of gender on survival in the available literature.[20],[34]

The present study was not powerful enough to identify differences in oncological outcome based on variation in histopathology. Histological response has been more favorable in fibroblastic and telangiectatic groups and less favorable in the chondroblastic group.[35],[6] The study by Hudson et al. reported that the chondroblastic subtype could be the one with the best prognosis.[37] Patients with tumor in the proximal tibia had favorable survival compared to those with a primary in the femur. The more proximal the site of the lesion, the more likely for it to grow larger and hence affect survival. Literature shows inferior survival for patients with tumor in the femur or humerus compared to those with tumor in the tibia or fibula.[20] Patients with Enneking Stage III had significantly worse survival compared with those with Stage I and II.

Degree of tumor necrosis as histological response to NACT is considered the most important prognostic factor in high-grade osteosarcoma.[38],[39] The percentage of patients who have a favorable response (≥90% tumor necrosis) ranges from 50% to 60% in the literature.[38],[39] In our study, 56.1% had ≥ 99% tumor necrosis. Bacci et al. showed 5-year RFS of 66.9% in good responders and 49% in poor responders.[24] McTiernan et al. showed that strong correlation exists between histological response and oncological outcome (5-year OS was 71% for good responders vs. 47% for poor responders).[40] In our study as well, we found that tumor necrosis ≥99% in the pathological specimen following NACT was a powerful prognostic marker.

Following surgery, postoperative morbidity with a Clavien–Dindo score of IIIB and above occurred in 5 (12.19%) patients, and all were wound-related issues. Reoperation within 30 days was required in 5 (12.19%) patients, of which 2 (4.88%) required prosthesis removal. Studies have reported that LSS is associated with a significant rate of major complications varying from 20% to 40%.[41],[42] Rate of infection reported in most series of LSS with endoprosthesis ranges from 10% to 15%.[43],[44] Tumor endoprosthetic survival rates in most studies are about 60%–80% at 5 years and 40%–70% at 10 years;[25],[45],[46],[47] our endoprosthetic survival at a median follow-up of 94.4 months was 55.6%.

The MSTS score provides standardized evaluation and comparison of the functional long-term outcome of patients with primary bone tumors who were treated by means of an endoprosthesis. The mean MSTS score was 69.95 in our study which concurs with world literature.[48],[49],[50]

Strengths and limitations of the study

About 95.1% of our patients completed the prescribed treatment and we have 82.9% follow-up. We have long-term follow-up, and data have been well maintained. The MSTS scores were regularly calculated at every patient visit, and register is maintained by the physiotherapist. We have found only three other publications from India on this topic so far.[51] Our study is however limited by small number of patients and the retrospective design.

Lessons learned

Custom-made prosthesis is a cheaper but comparable option for reconstruction in LSS, especially in low-volume centers. The systemic treatment options for recurrent osteosarcoma are not well defined and may be less effective. Our future research should be directed to the development of new molecules for this purpose, repurposing the available molecules and evaluating their efficacy in relapsed osteosarcoma. Curative treatment is still possible in a proportion of patients with metastatic disease. Hence, it is important to maintain an aggressive approach in selected patients with metastatic cancer.


  Conclusion Top


The functional and oncological outcomes in Indian patients with osteosarcoma are comparable to those in the world literature. Custom-made prosthesis is a cheaper method of reconstruction with comparable functional outcome in LSS. Stage at presentation and chemotherapy-induced tumor necrosis (>99%) are favorable prognostic factors in osteosarcoma.


  Supplementary Appendix 1: Study Protocol Top



  Introduction Top


Osteosarcoma is the most common primary malignant tumor of the bone in adults[1],[2],[3]/sup> and children.[4],[5] The age distribution of osteosarcoma is bimodal, with peaks in early adolescence and adults over the age of 65.[6],[7],[8] Patients with osteosarcoma generally present with localized pain and swelling, typically of several months' duration. The most important finding on physical examination is a bony swelling with a soft tissue mass, which is frequently large and tender on palpation. Ten percent to 20% of patients have demonstrable metastatic disease at presentation, most often involving the lung.[9] The histologic diagnosis of osteosarcoma is based on the presence of a malignant sarcomatous stroma, associated with the production of tumor osteoid and bone. Conventional (intramedullary high grade) osteosarcoma accounts for approximately 90% of all osteosarcoma.[10] Other less common histologic variants include small cell, telangiectatic, surface (juxtacortical) extraosseous osteosarcomas, and undifferentiated high-grade pleomorphic sarcoma of bone (previously known as malignant fibrous histiocytoma of the bone).[11]

The current management strategy for newly diagnosed osteosarcoma includes neoadjuvant chemotherapy (NACT) followed by surgical removal of the primary tumor along with all clinically evident resectable lung metastases, plus the addition of adjuvant chemotherapy.[12]

The present study was conducted with the aim of analyzing the oncological and functional outcome of osteosarcoma patients undergoing limb salvage surgery (LSS) at a rural tertiary cancer center in India.

Research question and aim - what is the oncological and the functional outcome of the patients with osteosarcoma of the extremity who underwent perioperative chemotherapy followed by limb salvage surgery in Malabar Cancer Center?

Objectives

Aim

  1. To determine the overall survival and disease-free survival of the treated patients
  2. To ascertain the functional outcome of the treated patients using musculoskeletal tumor society scoring system.


Secondary objectives

  1. To find the epidemiological profile and disease profile of the patients undergoing treatment for osteosarcoma
  2. To determine the morbidity and mortality of the treated patients using Clavien–Dindo scoring
  3. To ascertain the variables of the histopathology report including the pathological type of osteosarcoma and the response to NACT in the form of Huvos scoring system
  4. To find out the factors affecting survival.



  Materials and Methods Top


This is a retrospective study. Patients who underwent treatment with NACT and LSS from January 2009 to January 2015 will be included in the study. Patient numbers will be obtained from the surgical database. Patient files, surgical register, histopathology reports, treatment charts, and follow-up data will be reviewed for demographic profile, clinical features, histopathological features, treatment provided, functional outcome, and survival. Morbidity will be assessed based on the Clavien–Dindo grading system.

Study setting

Malabar Cancer Centre (MCC), the study site, is a 200-bedded Tertiary Cancer Centre with a referral base from northern part of Kerala and neighboring state of Karnataka and Mahe (Puduchery).

Study design – Retrospective study

Study period

The patients diagnosed of osteosarcoma of the extremity who underwent limb salvage surgery in MCC, Thalassery from January 2009 to January 2015 will be included.

Study population

Patients diagnosed of osteosarcoma of the extremity who underwent limb salvage surgery from January 2009 to January 2015.

Inclusion criteria

  1. All patients diagnosed with osteosarcoma of the extremity who underwent NACT followed by limb salvage surgery in Malabar Cancer Center
  2. Patients who have undergone NACT according to our institutional protocol from regional cancer center, Thiruvananthapuram and referred to MCC for surgery.


Exclusion criteria

  1. Patients treated for a cancer except cutaneous malignancy other than melanoma
  2. Patients whose case records are not complete and the relevant data cannot be compiled.


Statistical analysis

IBM SPSS Statistics for Windows, version 20.0. Armonk, NY, USA: IBM Corp., will be used for the analysis. Descriptive and inferential statistics will be used for data analysis. Kaplan–Meier method will be utilized for calculating the recurrence free and overall survival and log-rank test for comparing survival functions. Spearman and Karl Pearson's methods will be used for correlation analysis. Five percent level of significance was used for statistical test. Cox regression will be used to assess the influence of the various factors on survival.

Ethics considerations

The permission from the Institutional Review Board/Institutional Scientific Committee will be obtained for the study.

The process of data collection will not pose any risk or harm to the subjects as no kind of intervention or any interference with treatment is undertaken in this study.

Data confidentiality – The names of the patients will not be entered anywhere in the study.


  Publication of the results Top


The results will be published in peer-reviewed national and international journals and conferences, increasing the body of knowledge and informing the larger scientific/medical body.



 
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