|Year : 2022 | Volume
| Issue : 1 | Page : 17-22
A prospective observational study on Hypo-fractionated Radical Radiotherapy for non-metastatic prostate cancer using Image Guided Radiotherapy: Assessing the toxicity and Quality of life
Beena Kunheri1, JS Lakshmi2, Rajashree Rajan2, Athira Krishnan3, Shabin K Sidhique2, Bibin Rose2
1 National Centre for Cancer Care and Research, NCCCR Hamad Medical Corporation, Doha, Qatar; Department of Radiation Oncology, Amrita School of Medicine, AIMS, Amrita Vishwa Vidyapeetham, Coimbatore, Tamil Nadu, India
2 Department of Radiation Oncology, Amrita School of Medicine, AIMS, Amrita Vishwa Vidyapeetham, Coimbatore, Tamil Nadu, India
3 Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
|Date of Submission||06-Nov-2021|
|Date of Decision||30-Nov-2021|
|Date of Acceptance||09-Dec-2021|
|Date of Web Publication||15-Jun-2022|
Dr. J S Lakshmi
Department of Radiation Oncology, Amrita Institute of Medical Sciences, AIMS, Amrita Vishwa Vidyapeetham, Coimbatore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
BACKGROUND: Prostate cancer is the second most frequent cancer in men. There are no randomized data comparing the outcome, toxicities, and quality of life (QOL) of these patients receiving treatment. This is a prospective study evaluating acute toxicities and QOL of patients receiving radical Radiotherapy (RT) for localized prostate cancer.
MATERIALS AND METHODS: All localized prostate patients reporting for radical radiotherapy were included for this analysis. All patients received image-guided RT. Toxicity analyzed weekly during RT and then at 3 and 6 months. QOL was assessed pre- and post-RT, then at 3 and 6 months.
RESULTS: A total number of 54 patients received radical radiation were included. The median age of presentation was 71 years. Majority of our patients belong to high risk grouping and all patients received image-guided radiotherapy. The highest reported toxicity as Grade 2 and no Grade 3 or 4 genitourinary (GU) or gastrointestinal (GI) toxicities were reported. During RT six patients (11.1%) had Grade 2 GI toxicity and 3 (5.6%) patients had Grade 2 GU toxicity. At 3 months and 6 months, no Grade 2 GI/GU toxicity was recorded. Overall, no Grade 3 or 4 GI and GU toxicity was observed. Regarding QOL, we observed a statistically significant difference in IPSS symptom score between the pre-RT and at completion (P < 0.001) of treatment, 3 months (P < 0.001) and 6 months (P < 0.001) indicating improvement in the symptoms following treatment. Similarly, we noted a significant association in IPSS QOL between the pre-RT and on completion (P < 0.001) of treatment and at 3 months (P < 0.001), 6 months (P < 0.001) indicating improvement in the QOL following treatment.
CONCLUSION: Radical RT is well tolerated with no significant toxicity pattern reported in patients receiving hypo-fractionated RT. QOL assessment showed improvement in IPSS symptom score and QOL scoring and it is well tolerated.
Keywords: Helical tomotherapy, image-guided radiotherapy, prostate cancer, quality of life, toxicity
|How to cite this article:|
Kunheri B, Lakshmi J S, Rajan R, Krishnan A, Sidhique SK, Rose B. A prospective observational study on Hypo-fractionated Radical Radiotherapy for non-metastatic prostate cancer using Image Guided Radiotherapy: Assessing the toxicity and Quality of life. Ann Oncol Res Ther 2022;2:17-22
|How to cite this URL:|
Kunheri B, Lakshmi J S, Rajan R, Krishnan A, Sidhique SK, Rose B. A prospective observational study on Hypo-fractionated Radical Radiotherapy for non-metastatic prostate cancer using Image Guided Radiotherapy: Assessing the toxicity and Quality of life. Ann Oncol Res Ther [serial online] 2022 [cited 2022 Sep 29];2:17-22. Available from: http://www.aort.com/text.asp?2022/2/1/17/347556
| Introduction|| |
Prostate cancer is the fifth most leading cause of cancer death across the world and 2nd most frequent cancer in men. The incidence varies widely around the world, with the highest rates in the USA and Canada and relatively low rates in Asian countries. The incidence increases after the age of 40 years.
In the present era, there are various treatment options available for localized prostate cancer such as radical prostatectomy (RP), radical radiotherapy (RT) with or without Hormonal therapy (HT), and brachytherapy with comparable survival. The choice of treatment depends on the stage, risk grouping, age, availability, and patient preference. Patients may require adjuvant RT depending upon the adverse risk factors in the final histopathology and salvage RT for any evidence of biochemical/localized clinical failure. There are no randomized studies comparing the toxicities and outcomes between these different modalities. After the advent of modern RT techniques, there is a significant reduction in toxicity compared with conventional techniques., In the present study, we prospectively evaluated the acute and early delayed toxicity and quality of life (QOL) of patients undergoing radical RT for localized prostate cancer in our center.
The primary objective of this study was to assess the acute and early delayed genitourinary (GU) and gastrointestinal (GI) toxicities. The secondary objective was QOL assessment in patients receiving radical RT.
Acute toxicity refers to those adverse effects occurring during radiation therapy and up to 3 months.
Early delayed toxicity refers to those adverse effects occurring from 3 months to 6 months.
| Materials and Methods|| |
This is a prospective cohort study evaluating the acute and early delayed toxicity and QOL of patients receiving RT for localized prostate cancer during the period May 2018 to October 2019.
All patients reporting to the radiotherapy department for radical radiation therapy were included for this analysis. The study participants were informed about their freedom to withdraw from the study and written informed consent was obtained from each patient. Data collection was done using prediagnosed pro forma. Patients with age ≤85 years, with good performance status with histologically confirmed nonmetastatic prostate cancer patients, were included in this study. Patients with metastatic disease, previous history of any malignancy, or prior radiation to abdomen/pelvis were not included in the study.
Patients on radical RT were treated with radiotherapy ± hormonal treatment (HT), depending on the risk stratification. In general, all low-risk patients received radiation alone whereas intermediate and high-risk patients received HT + RT. The intermediate-risk group of patients received a short course of HT for 6 months and local RT. The high-risk group of patients received 3–6 months of neoadjuvant HT followed by RT and adjuvant HT for a total period of 2 years.
For low-risk patients, extreme hypofractionation using stereotactic body radiotherapy was considered of a total dose of 36.25 Gy, 5 fractions in a week, 725 cGy per fraction. For intermediate and high-risk patients, hypofractionated RT was considered. As institute protocol majority of intermediate patients received a total dose of 60 Gy in 20 fractions, 300 cGy daily 5 days in a week over 4 weeks to the prostate alone, whereas high-risk patients received a total dose of 70 Gy in 28 fractions to the primary and pelvic nodal region to 50.4 Gy/28 fractions, 5 days in a week over 6 weeks using simultaneously integrated boost (SIB).– intensity-modulated radiotherapy.
Simulation and planning
All patients underwent CT simulation with bladder and rectal protocol. All patients received image-guided radiotherapy (IGRT) with either volumetric-modulated arc therapy (VMAT)/helical tomotherapy. Few low to intermediate risk patients received local RT with Cyberknife (CK). Majority of cases, target volume delineation was done as per ESTRO– ACROP consensus guidelines. For high-risk patients, clinical target volume (CTV 70 Gy/28#) includes entire prostate with 3 mm margin and 2.2 cm of proximal seminal vesicles (SV). CTV 50.4 Gy includes the regional nodal stations. For intermediate risk, CTV 60 Gy includes entire prostate with 3 mm margin and 1.4 cm of proximal SV. For low risk, CTV 60 Gy includes entire prostate alone. Daily CT images/weekly CBCT were taken for setup verification. Patients who were treated with extreme hypofractionation using CK underwent gold seed fiducial placement (3–4nos) under ultrasound guidance before simulation. Target volume includes prostate alone and fiducial tracking during treatment execution. Rectum, bladder, femoral heads, bowel bags, bone marrow, and penile bulb were outlined as organs at risk (OAR).
Toxicity was assessed weekly during RT and then at 3 and 6 months using RTOG toxicity grading. QOL assessed pre- and postradiation treatment, then at 3 and 6 months using IPSS. All patients will be followed up long-term for any new toxicity and will be recorded. “Compliance” is assessed based on treatment breaks and completion of the proposed treatment. After completion patients were reviewed every 3 months for the 1st year and then every 4 months for the next 1 year and thereafter every 6 months for the next 2 years and then annually.
The trial was approved by the institutional review board and ethical committee. Informed consent was obtained from all participants. Patients receiving radical RT who gave consent for this study were evaluated for toxicity and QOL and their treatment was not affected by participation in the study and individual patient identity was not revealed.
Statistical analysis was performed using IBM SPSS 20.0 (SPSS Inc, Chicago, USA). For all the continuous variables, the results are given in mean ± standard deviation and for categorical variables as a percentage. To obtain the association of categorical variables, the Chi-square test with correction factor (wherever applicable) was applied. To test the statistical significance of the difference in mean QOL score, Student t-test was applied. P < 0.05 was considered statistically significant.
| Results|| |
A total number of 54 patients diagnosed with carcinoma prostate who received radical radiation were included.
The median age of presentation of our patients was 71 years (range 51–82 years). Forty-three patients (79.6%) belong to high risk, 9 (16.7%) belong to intermediate risk and 2 (3.7%) patients belong to low risk. All are patients treated with IGRT, of which 48 (88.9%) received tomotherapy, 1 (1.9%) using VMAT, and 5 (9.3%) patients using CK. Patient characteristics are shown in [Table 1].
During RT, 18 patients (33.3%) had Grade 1 and 6 (11.1%) had Grade 2 GI toxicity and 24 (44.4%) had Grade 1 and 3 (5.6%) patients had Grade 2 GU toxicity. At 3 months, only 1 (1.9%) patient had GI and 9 (16.7%) had Grade 1 GU toxicity. At 6 months, 1 (1.9%) patient had GI and 5 (9.3%) had Grade 1 GU toxicity. At 3 months and 6 months, no Grade 2 GI/GU toxicity was recorded. On subgroup analysis based on stage-wise, three patients belonging to Stage II, 7 from Stage III, eight patients from Stage IV had Grade 1 GI and four patients from Stage III, two patients from Stage IV had Grade 2 GI toxicities during RT. At 3 months and 6 months, only 1 patient from Stage IV had Grade 1 GI toxicity. Similarly, three patients belonging to Stage II, 11 from Stage III, 10 patients from Stage IV had Grade 1 GU and 1 patient from stage III, two patients from Stage IV had Grade 2 GU toxicities during RT. At 3 months four patients from Stage III and five patients' Stage IV had from Grade 1 GU toxicities. At 6 months, two patients from Stage III and three patients from stage IV had Grade 1 GU toxicities. No Grade 2 toxicity reported during the 3rd and 6th month. Overall, no Grade 3 or 4 GI and GU toxicity was observed [Table 2].
Quality of life
QOL assessment done at baseline (before starting RT) at RT completion, at 3 months, and at 6 months. International Prostate Symptom Score (IPSS) symptom score and IPSS QOL scale were used for assessment. For analysis mild and no symptoms were grouped together and moderate to severe symptoms together in the IPSS symptom score. IPSS QOL scale categorization was done as good and average to poor. Good included delighted, pleased, and mostly satisfied. Average to poor included mixed, mostly dissatisfied, unhappy, and terrible.
At RT completion, 38 (70.4%) patients had mild and 10 (18.5%) patients had moderate IPSS symptoms score of which four patients from Stage III and six patients from Stage IV. No severe IPSS symptom score was recorded. At 3 months, 45 (83.3%) patients had mild IPSS scores. No moderate and severe scores were noted. At 6 months, 42 (77.8%) patients had mild and no patients had moderate and severe IPSS symptom scores [Figure 1]a. We observed a statistically significant difference in IPSS symptom score between the pre-RT and on completion (P < 0.001) of treatment and at 3 months (P < 0.001) and 6 months (P < 0.001) indicating improvement in the symptoms following treatment [Table 3].
|Table 3: International prostate symptom score symptom scoring and international prostate symptom score quality of life scale in radical radiation therapy patients|
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Similarly, at RT completion, 31 (57.4%) patients had good QOL, 22 (40.7%) patients had average QOL, of which three patients from Stage II, 8 from Stage III, 11 from Stage IV, and 1 (1.9%) patient from Stage IV had poor QOL. At 3 months, 46 (85.2%) patients had good QOL, 8 (14.8%) had average QOL of which four patients from Stage III and 4 from Stage IV. At 6 months 49 (90.7%) patients had good QOL, 5 (9.3%) had average QOL of which 2 from Stage III and three patients from Stage IV. No poor QOL was noted in both 3 and 6 months [Figure 1]b. We noted a statistically significant association in IPSS QOL between the pre-RT and on completion (P < 0.001) of treatment and at 3 months (P < 0.001), 6 months (P < 0.001) indicating improvement in the QOL following treatment [Table 3].
| Discussion|| |
Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death in men as per the Global Cancer Statistics 2018. There are various treatment options available for localized prostate cancer with almost equivalent local control and survival. Morbidity pattern varies between the modalities and there are no prospective randomized studies comparing the outcome and toxicities between these different modalities. We have done a prospective evaluation of acute toxicities and QOL of localized prostate cancer patients undergoing radical RT.
Due to the increasing workload and logistic issues in a country like India, it becomes important to reduce treatment time whenever possible. Prostate cancer with a low α/β value is one tumor that can be treated using hypofractionation. Long-term follow-up results of hypofractionated studies such as conventional versus hypofractionated high dose intensity-modulated radiotherapy for prostate cancer-CHHiP (60 Gy in 20 fractions) and Cleveland clinic dose schedules (70 Gy in 28 fractions) did show improved control rates with acceptable toxicity. In the CHHiP trial, 38% Grade II or more GI and 49% Grade II or more GU acute toxicities were reported, whereas at 18 weeks (early delayed toxicity), they noted a decreasing trend, 3% GI and 5% GU toxicities were reported. Similarly, in the Cleveland clinic 40% Grade I and 9% Grade II GI and 48% Grade I, 18% Grade II and 1% Grade III GU acute toxicities were reported.
The role of whole pelvic radiation therapy (WPRT) in prostate cancer has always been controversial. While two landmark studies, the RTOG 9413 and the GETUG 01 trial did not report the benefit of the addition of WPRT radiation therapy over prostate only RT; a recent Phase III study published in 2021 have shown improved biochemical failure-free survival and disease-free survival with prophylactic pelvic RT in high risk and very high risk group. Using newer techniques, we are able to produce more conformal plans minimizing dose to the adjacent OARs while ensuring good target coverage. Thus, we routinely treat high-risk prostate cancer patients with whole pelvic radiotherapy and boost to the prostate using SIB.
In the present study, 11.1% of patients had ≥Grade 2 GI and 5.6% patients had ≥Grade 2 GU acute toxicities. [Table 4] shows the toxicity pattern comparison of the current study with literature in radical RT. The low rates of toxicity could be explained by the high conformality achieved in our plans, thereby limiting the dose to the OARs. Lower toxicity could be expected in patients being treated with moderate hypofractionated radiation therapy. Of course, this claim will have to be validated in a significantly larger cohort with longer follow-up to account for late toxicity. We could achieve significantly lower planning constraints compared to the constraints achieved in the reported literature.
|Table 4: Toxicity pattern comparison of the current study with relevant study in|
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QOL is an important hallmark in prostate cancer management, especially considering that men are likely to survive for a considerable number of years after diagnosis. The Prostate Cancer Outcomes Study on QOL examined 1655 men who were diagnosed with prostate cancer from 1994 to 1995 and who underwent either RP (1164 men) or radiotherapy (491 men). The study found that those undergoing surgery were significantly more likely to have urinary incontinence and erectile dysfunction (ED) at 2 (odds ratio [OR] 6.2; 95% confidence interval [CI] 1.9–20.3) and 5 (OR 5.1; 95% CI 2.3–11.4) years follow-up monitoring. However, bowel urgency at the 2-year (OR 3.5; 95% CI 1.93–6.2) and 5-year (OR 2.0; 95% CI 1.1–3.6) follow-up points were significantly more likely in those undergoing radiotherapy. Notably, when follow-up duration was extended to 15 years, the burden of urinary incontinence, ED, and bowel urgency was comparable between the treatment modalities.
We observed a statistically significant difference in IPSS symptom score between the pre-RT and on completion (P < 0.001) of treatment and at 3 months (P < 0.001) and 6 months (P < 0.001) following treatment. Similarly, a significant association was noted in IPSS QOL between the pre-RT and on completion (P < 0.001) of treatment and at 3 months (P < 0.001), 6 months (P < 0.001) following treatment.
The reason for worse QOL at the baseline before starting RT was due to the presence of bulky and high burden disease and after radiation QOL improved because of local tumor control and symptomatic measures. Toxicity due to RT did not contribute significantly to QOL worsening because of lower rates of higher-grade toxicities reported, this being due to highly conformal techniques of radiation.
The limitation of this study is the interim findings of an ongoing study. Hence, the data have the limitation of sub-optimal patient numbers and short follow-up period. Acute and early delayed toxicities were only reported, and longer follow-up is needed for late toxicities.
| Conclusion|| |
Our study reported a low rate of acute toxicity compared to the literature, and revealed no significant Grade 3 and 4 toxicities. Pre RT QOL was compromised in radical RT patients due to bulky local disease-causing symptoms and there was an improvement in QOL after RT.
We thank the faculty and staff of the department of Radiation Oncology, department of Medical Oncology and Department of Uro-oncology of the Amrita School of Medicine, Amrita Vishwa Vidyapeetham, AIMS Ponekkara PO, Kochi, Kerala, Pincode 682041 for the cooperation extended to this study.
The manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met, and that each author believes that the manuscript represents honest work.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]