|Year : 2010 | Volume
| Issue : 3 | Page : 332-338
From two-dimensional to three-dimensional conformal radiotherapy in prostate cancer: An Indian experience
R Engineer, R Bhutani, U Mahantshetty, V Murthy, SK Shrivastava
Department of Radiation Oncology, Tata Memorial Centre, Mumbai, India
|Date of Web Publication||28-Jun-2010|
Department of Radiation Oncology, Tata Memorial Centre, Mumbai
Source of Support: None, Conflict of Interest: None
Background: Sparse data from India are available regarding the outcome of prostate cancer treatment. We report our experience in treating prostate cancer with radiotherapy (RT). Materials and Methods: This study included 159 men with locally advanced cancer treated with RT with or without hormone therapy between 1984 and 2004. The median RT dose was 70 Gy over 35 fractions. Eighty-five patients received whole pelvic RT and prostate boost, and 74 patients were treated with 3-dimensional conformal radiotherapy (3DCRT) to prostate and seminal vesicles alone. Results: The median follow-up was 25 months and the freedom from biochemical failure for all the patients at 5 years was 76%, disease-free survival (DFS) 59.1%, and overall survival (OAS) was 70.1%. The risk stratification (91% vs 52%, P < 0.03) and RT dose (72.8% for dose > 66 Gy vs 43.5% for dose < 66 Gy; P = 0.01) affected the DFS. DFS at 5 years was better in the group receiving 3DCRT to prostate and seminal vesicles (78% vs 51.5%; P = 0.001) and was reflected in OAS as well (P = 0.01). Conclusion: CRT technique with dose escalation results in significant benefit in DFS and OAS in locally advanced prostate cancer.
Keywords: Three dimensional conformal radiotherapy, India, prostate cancer
|How to cite this article:|
Engineer R, Bhutani R, Mahantshetty U, Murthy V, Shrivastava S K. From two-dimensional to three-dimensional conformal radiotherapy in prostate cancer: An Indian experience. Indian J Cancer 2010;47:332-8
|How to cite this URL:|
Engineer R, Bhutani R, Mahantshetty U, Murthy V, Shrivastava S K. From two-dimensional to three-dimensional conformal radiotherapy in prostate cancer: An Indian experience. Indian J Cancer [serial online] 2010 [cited 2019 Jul 22];47:332-8. Available from: http://www.indianjcancer.com/text.asp?2010/47/3/332/64718
| » Introduction|| |
Prostate cancer is the most common malignancy affecting men in developed countries with an overall incidence of 16.6%. In developing countries, it is considered to be a relatively rare malignancy with only 2684 patients registered by the Bombay Population-based Cancer Registry  from 1986 to 2000 (4.7% of all male cancers).
Although Asians have the lowest incidence and mortality rates of prostate cancer in the world, these rates have risen rapidly in the past 2 decades in most Asian countries,  and the nature of prostate cancer reported is quite different between Asian countries, mainly Japan, and the USA or Europe. , There have been very few reports on survival from cancer in India, mainly because of a poor patient follow-up and inadequate system of registration of death. Also the reported survival by Yeole et al. is much inferior compared with that of the western and other Asian countries since a majority of the patients present in advanced stages. 
Over the last decade, 2 concepts have emerged to improve local control and outcome for men with locoregionally advanced prostate cancer, namely, dose escalation with 3-dimensional conformal radiotherapy (3DCRT) technique and combined treatment with hormonal therapy. Various institutional and multiinstitutional studies of dose escalation with 3DCRT in prostate cancer have consistently shown an improvement in biochemical disease-free survival (bDFS) and local control with increased dose of radiation. ,,,,,
Another recent advancement in the treatment of prostate cancer is the combined treatment using androgen deprivation and radiotherapy (RT) in selected patients, particularly those with locally advanced, unfavorable-risk disease. ,,,,, Both adjuvant  and neoadjuvant hormone therapy (NAHT)  have been shown to improve the outcomes in patients treated with radiation.
However, little data is available regarding the radiotherapeutic management of prostate cancer from India, and the management policies are mainly based on the western literature. Thus, this retrospective study was undertaken at our hospital to evaluate the changing trends of treatment outcome in our scenario. We also evaluated the impact of patient's age, disease (initial prostate-specific antigen [PSA] level, Gleason score, and T stage), and treatment characteristics (NAHT duration, radiation portals, and RT dose) on bDFS and overall survival (OAS) outcomes in patients diagnosed with high-risk prostate cancer and treated with radical RT. The patients were treated before the advent of intensity-modulated radiotherapy at our centre.
| » Materials and Methods|| |
The medical records of 353 patients who presented to radiotherapy department between 1984 and 2004 were reviewed. Patients who presented with metastatic disease were excluded from the analysis; also 15 patients who received brachytherapy as a boost were excluded from the analysis. Thus, out of 353 patients, only 159 were analyzable. All patients had a histologic diagnosis of adenocarcinoma of the prostate. Pretreatment diagnostic evaluations included blood chemistry, digital examination, transrectal ultrasound, chest radiograph, bone scan, and computed tomography (CT) of the abdomen and pelvis in some patients. However, tests to determine the PSA level and Gleason score were routinely available in our hospital since 1992. For the purpose of the present analysis, the patients were stratified according to the available risk group stratification.  (A) Low-risk patients defined as T1-T2 and Gleason < 7 and PSA < 10 ng/mL: 2 cases (1.3%); (B) high-risk patients defined as T3 or Gleason 8-10 or PSA > 20 ng/mL: 138 cases (86.8%); and (C) intermediate-risk patients, including the remaining patients: 19 (11.9%).
The median patient characteristics were age 65 years (range 41-85 years) and pretreatment PSA level determined by radioimmunoassay was 18 ng/mL (range 0-450 ng/mL). The distribution of patients according to 1997 American Joint Committee on Cancer (AJCC) clinical stage was T2: 36 (22.6%), T3: 104 (65.4%), and T4: 19 (11.9%). Gleason score was available for 97 patients: 19.5% had Gleason ≤ 6, 22.6% had Gleason 7, and 19% had Gleason 8-10. The characteristics of the patients are shown in [Table 1]. Among the whole group of 159 patients, 85 patients were treated before the year 1998 and 74 patients after 1998. Those treated before 1998 were mainly treated with 2D planning, whereas patients treated after 1998 mainly received 3DCRT.
All the patients were treated with megavoltage radiation to a total dose of 45-70 Gy (mean dose 66 Gy) with a daily dose of 1.8-2 Gy delivering 5 fractions per week. Five patients could not complete RT, as they died of other causes, mainly cardiac, during the course of radiotherapy. From the year 1984 to 1998, 85 patients received whole pelvic radiotherapy (WPRT; anterior-posterior and opposed lateral portals to a dose of 45-50 Gy) followed by 20 Gy boost to prostate and seminal vesicles. Subsequently, with the availability of better imaging techniques and emerging data, rest of the 74 patients from the year 1998 onward were treated with 3DCRT to prostate and seminal vesicles alone.
Three-dimensional conformal radiotherapy technique
Patients were immobilized using abdominopelvic thermoplastic mould and CT-scanned and treated supine, with emptied rectum and full bladder. The gross tumor volume and clinical target volume incorporated the prostate plus seminal vesicles for all the patients. A 1-cm margin was added to define the planning target volume (PTV), reduced to 0.7 cm in the overlap region with the rectum to minimize rectal toxicity. The block edge was placed 0.7 cm circumferentially around the PTV and 1.0-1.2 cm in the superior and inferior directions. In general, patients receiving doses of 70 Gy were treated with a 3-field (anterior + bilateral) technique. Portal verification was done by electronic portal imaging weekly for all the patients treated with conformal technique.
The endocrine manipulation was done in 110 (69.5%) patients and most of them (84.5%) were from the high-risk group. Of these, 68 (61.8%) patients received medical therapy as a short-term neoadjuvant antiandrogen therapy 2-4 months before and concomitantly with 3DCRT in the neoadjuvant setting. Rest of the 42 patients underwent orchidectomy, which was usually done before being referred to our hospital or in poor socioeconomic conditions. Of the patients who received medical therapy, nonsteroidal antiandrogen was given in 55 patients and in combination with an analog of luteinizing hormone-releasing hormone in only 4.0% patients. Seven patients received luteinizing hormone-releasing hormone only according to the institution policy at the time of administration.
All patients were required to appear for the first follow-up at 2 months from completing the therapy. Subsequent follow-up visits were scheduled at 6 monthly intervals for the first 2 years and annually thereafter. At every follow-up visit, a clinical examination was done, including digital rectal examination and estimation of the serum PSA. Increasing PSA concentrations were monitored by repeat measurements. Acute and late toxicities were scored according to the Radiation Therapy Oncology Group (RTOG) morbidity scoring scale. 
Biochemical failure was assessed using the American Society for Therapeutic Radiology and Oncology consensus guidelines.  The date of PSA failure was established as the date of the first unequivocal increase in PSA. Local failure was defined as persistence of disease or reappearance of disease assessed by digital rectal examination or by transrectal ultrasonography. DFS was defined as failure at locoregional site, distant metastasis, or biochemical failure. An OAS was calculated from the date of registration to the last day of follow-up. A univariate comparison of outcomes was accomplished using the Kaplan-Meier method and Log-rank test, and multivariate analysis was done using Cox regression model.
Variables included in the univariate and multivariate analysis were patient's age, tumor stage, pretreatment PSA, Gleason score, risk groups, addition of hormonal therapy, dose of RT, and the period of treatment (before or after 1998). A P value of 0.05 significance level (2-sided) was considered for all statistical tests. Analyses were carried out using SPSS version 11.5 software (Chicago, Illinois).
| » Results|| |
The median follow-up was 25 months (mean 35.4 months, range 2-195 months). The DFS was 59.1% at 5 years and the OAS was 70.1%. Twenty-one of 159 patients developed biochemical failure as first event with a median time to PSA relapse of 20.5 months (range 2-174 months).
The freedom from biochemical failure for all the patients at 5 years was 76%. Out of 21 patients with biochemical failure, 14 patients had clinical failure also and this was statistically significant (P < 0.01).
Thirty-three patients (20.7%) developed distant metastasis, median time to occurrence being 22.4 months (range 2.6-78.6 months). Four patients had failure both locally as well as at a distant site. At the time of the analysis, 124 patients (78%) were alive; 98 patients alive and free of disease and 29 with disease. Twenty-one (13.2%) patients died due to prostate cancer and 14 patients (8.8%) died of causes other than cancer.
Risk factors for outcome
[Table 2] summarizes the results of univariate analysis carried out to identify clinical and therapeutic variables that can influence the bDFS, DFS, and OAS.
None of the factors, such as patient age, pretreatment PSA, T stage, and Gleason score affected biochemical control.
When DFS was evaluated according to the risk category, the pretreatment PSA significantly correlated with DFS (P = 0.003), with patients with PSA level > 20 ng/mL doing worse. The T stage had a statistically significant (P = 0.03) effect on DFS with smaller T size doing better and this was further evident on risk stratification. The patient with high risk had worse DFS (91% for intermediate vs 52.0% for high risk; P < 0.05; [Figure 1]). The total dose of RT delivered affected DFS (P < 0.02) with improvement on increasing the dose higher than 66 Gy [Figure 2]. When the patients were evaluated on the basis of the period of treatment, it was observed that patients treated after 1998 (localized 3DCRT) had a better DFS as compared with those receiving WPRT before 1998 (78% vs 51.5%, P < 0.001; [Figure 3]). This benefit was even seen in OAS (87.6% vs 47.9%, P = 0.01). While doing subgroup analysis of the patients receiving more than 66 Gy, it was observed that localized RT (3DCRT) had better outcome than WPRT in DFS (84.8% vs 45.8%, P = 0.0002) as well as OAS (87.7% vs 62.4%, P = 0.01). Further subgroup analysis revealed that in patients who received NAHT, localized RT was better than WPRT in DFS (75.2% vs 46% P = 0.001) and OAS (88.6% vs 55.1% P = 0.003). In multivariate analysis, the only independent predictive factor that significantly decreased the rate of DFS was the patients treated with 2D WPRT as against patients treated with 3DCRT technique (P = 0.01) [Table 3].
Early and late morbidities
Thirty-nine (24.5%) patients had grade 2 and 6 patients had grade 3 acute rectal toxicity. Twenty-seven (16.9%) patients had acute grade 2 bladder toxicity. A few patients (5.6%) experienced grade 3 bladder toxicity, and there was no grade 4 toxicity. Patients treated with WPRT with 2D technique prior to 1998 experienced higher incidence of grade 3 genitourinary (GU), gastrointestinal (GI), and skin (9.4% vs 1.3%, 5.8% vs 1.3%, and 10.5% vs 1.3%, respectively) acute toxicity compared with the patients treated after 1998 with 3DCRT [Table 4].
Patients treated with 2D RT had more incidence of late GU and GI toxicity. Eleven patients had grade 3 GU complications of whom 8 patients were treated prior to 1998. GI late complications were observed in 4 patients in 2DRT and 5 patients in the 3DCRT group [Table 5].
| » Discussion|| |
Prostate cancer has been reported to be less common in the Asian subcontinent. The stage distributions of prostate cancer in Asian populations are still unfavorable compared with those of the western and other developed countries. However, a trend toward diagnosing cancer with more favorable prognosis is being seen in most Asian countries.
The study by Khochikar et al. suggests that despite the "PSA era," most of the prostate cancer patients in India have locally advanced or metastatic disease at presentation. In our study with 42% patients presenting for RT with metastatic disease which due to poor follow-up were not included in analysis, and 77% of the patients had T3 and T4 tumors.
The bDFS is consistent with what has been reported in literature;  however, this has to be interpreted with caution since PSA levels were not done in earlier patients. In our study, the median time for biochemical failure was 21.7 months in 21 patients (13.2%) who developed failure. In the study by Zapatero et al., 11 of the 54 patients (20%) experienced biochemical failure, with the 2-year biochemical control rate being 85%. Several studies with longer follow-up periods have also shown that most patients have an increasing risk of biochemical failure within 36 months, but few fail beyond 4 years. , As expected, the AJCC stage and risk stratification was statistically significant in DFS but not in OAS, probably due to the less number of patients. The reported benefit of combination of radiation therapy and androgen suppression in high-risk patients seen in RTOG and European Organization for Research and Treatment of Cancer (EORTC) trials was not evident in our subset of patients, which could be due to the heterogeneous duration of the treatment. The randomized trial from MD Anderson Cancer Centre  and other sequential prospective studies have revealed that patients with less favorable characteristics are likely to benefit from dose escalation with regard to biochemical freedom from failure. This benefit with higher doses was evident in our study where the DFS was better in patients who received radiation doses more than 66 Gy. The concept of WPRT as compared with localized prostate RT has been a matter of debate with the published results of RTOG 94-13.  This study indicated a significantly better 4-year DFS rate for men treated with WPRT and neoadjuvant and concurrent hormone therapy than localized treatment (60% vs 50%; P = 0.008), although no survival advantage was observed. This was not evident in our study because the patients who received WPRT were treated in the earlier period where a majority of the patients received RT without hormonal manipulation and received lesser doses of RT compared with the patients treated in the latter years, that is, after 1998; also, there were less number of patients (49 [31%]) in the no hormone treatment group.
Our study reveals the impact of better emerging techniques and higher radiation doses (>66 Gy) on the DFS and OAS. This effect is further enhanced in patients who undergo hormonal manipulation. In this subset of patients, radiation-induced complications were generally mild and acceptable but they were significantly less in patients receiving CRT when compared with conventional therapy. ,
This study also highlights the major changes that have evolved during the past decade in the radiotherapeutic management for patients with localized prostate cancer in India.
From 1984 to the present, external beam radiation delivery has become more precise, and treatment planning has moved from a simple 3-field or box arrangement to 3DCRT. This probably reflects the effect of the influence of published reports from western literature in our general practice with improved results. The present radiation dose was generally lower than that in other reports, , and this may have reflected in a relatively poor DFS compared with that of the historical controls. However, the results should be interpreted cautiously because of the inherent bias associated with this retrospective study, especially due to a longer timeperiod of the study, refinement in the diagnostic techniques (namely Gleason score, serum PSA), and treatment on the basis of risk stratification. Also due to failure in the applicability of ASTRO definition of biochemical failure in the earlier years, the assessment of bDFS was relatively difficult.
| » Conclusions|| |
The transition from 2D to 3D CRT technique and higher radiation doses resulted in improved control and decrease in treatment-related morbidity.
| » References|| |
|1.||Sunny L, Yeole BB, Kurkure AP, Hakama M, Shiri R, Mathews S, Cumulative risk and trends in prostate cancer incidence in Mumbai, India. Asian Pac J Cancer Prev 2004;5:401-5. |
|2.||Sim HG, Cheng CW. Changing demography of prostate cancer in Asia. Eur J Cancer 2005:834-45. [PUBMED] [FULLTEXT] |
|3.||Akaza H. Advanced prostate cancer treatment guidelines: a global perspective; trends of hormone therapy in Japan. BJU Int 2004;94:5. [PUBMED] |
|4.||Watanabe M, Nakayama T, Shiraishi T, Stemmermann GN, Yatani R. Comparative studies of prostate cancer in Japan versus the United States. Urol Oncol 2000;5:274-83. [PUBMED] [FULLTEXT] |
|5.||Yeole BB, Sunny L. Population based survival from prostate cancer in Mumbai (Bombay), India. Indian J Cancer 2001;38:126-32. |
|6.||Zelefsky MJ, Leibel SA, Gaudin PB, Kutcher GJ, Fleshner NE, Venkatramen ES, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491-500. [PUBMED] [FULLTEXT] |
|7.||Zelefsky MJ, Fuks Z, Hunt M, Lee HJ, Lombardi D, Ling CC, et al. High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol 2001;166:876-81. |
|8.||Fiveash JB, Hanks G, Roach M, Wang S, Vigneault E, McLaughlin PW, et al. 3D conformal radiation therapy (3DCRT) for high grade prostate cancer: a multi institutional review. Int J Radiat Oncol Biol Phys 2000;47:335-42. [PUBMED] [FULLTEXT] |
|9.||Vicini FA, Abner A, Baglan KL, Kestin LL, Martinez AA. Defining a dose response relationship with radiotherapy for prostate cancer: is more really better? Int J Radiat Oncol Biol Phys 2001;51:1200-8. [PUBMED] [FULLTEXT] |
|10.||Hanks GE, Hanlon AL, Epstein B, Horwitz EM. Dose response in prostate cancer with 8-12 years' follow-up. Int J Radiat Oncol Biol Phys 2002;54:427-35. [PUBMED] [FULLTEXT] |
|11.||Roach M III, Lu J, Pilepich MV, Asbell SO, Mohiuddin M, Terry R, et al. Predicting long-term survival, and the need for hormonal therapy: a meta-analysis of RTOG prostate cancer trials. Int J Radiat Oncol Biol Phys 2000;47:617-27. |
|12.||Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 2002;360:103-6. [PUBMED] [FULLTEXT] |
|13.||Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, et al. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;50:1243-52. [PUBMED] [FULLTEXT] |
|14.||Lawton CA, Winter K, Murray K, Machtay M, Mesic JB, Hanks GE, et al. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;49:937-46. [PUBMED] [FULLTEXT] |
|15.||Laverdiere J, Gomez JL, Cusan L, Suburu ER, Diamond P, Lemay M, et al. Beneficial effect of combination hormonal therapy administered prior and following external beam radiation therapy in localized prostate cancer. Int J Radiat Oncol Biol Phys 1997;37:247-52. |
|16.||Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, et al. Radiation Therapy Oncology Group phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol 2003;21:3972-8. [PUBMED] [FULLTEXT] |
|17.||American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997;37:1035-41. [PUBMED] [FULLTEXT] |
|18.||Zapatero A, Valcαrcel F, Calvo FA, Algαs R, Bιjar A, Maldonado J, et al. Risk-adapted androgen deprivation and escalated three-dimensional conformal radiotherapy for prostate cancer: Does radiation dose influence outcome of patients treated with adjuvant androgen deprivation? A GICOR study. J Clin Oncol 2005;23:6561-8. |
|19.||Khochikar M. Hormone refractory prostate cancer: Current understanding and future perspectives. Indian J Urol 2007;23:34. [PUBMED] |
|20.||Dearnaley DP, Sydes MR, Graham JD; RT01 collaborators. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: First results from the MRC RT01 randomized controlled trial. Lancet Oncol 2007;6:475-87. |
|21.||Roach M 3rd, Hanks G, Thames H Jr, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965-74. [PUBMED] [FULLTEXT] |
|22.||Zapatero A, Rύos P, Marύn A, Mύnguezy R. Dose escalation with three-dimensional conformal radiotherapy for prostate cancer: Is more dose really better in high-risk patients treated with androgen deprivation. Clin Oncol 2006;18: 600-7. |
|23.||Pollack A, Zagars GK, Starkschall G, Antolak JA, Lee JJ, Huang E, et al. Prostate cancer radiation dose response: Results of the M.D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53:1097-105. |
|24.||Roach, DeSilvio M, Lawton C, Uhl V, Machtay M, Seider MJ, et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation therapy oncology group 9413. J Clin Oncol 2003;10.1904-11. |
|25.||Koper PC, Stroom JC, van Putten WL, Korevaar GA, Heijmen BJ, Wijnmaalen A, et al. Acute morbidity reduction using 3DCRT for prostate carcinoma: A randomized study. Int J Radiat Oncol Biol Phys 1999;43:727-34. [PUBMED] [FULLTEXT] |
|26.||Zelefsky MJ, Moughan J, Owen J, Zietman AL, Roach M 3rd, Hanks GE. Changing trends in national practice for external beam radiotherapy for clinically localized prostate cancer: 1999: Patterns of care survey for prostate cancer. IJROBP 2004;59:1053-61. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]