Is there a role of digital rectal examination (DRE) in prostate cancer diagnosis?

Literature review: In a case series published by Ghagane et al.,⁵ 87.5% of 471 PCa cases had abnormal DRE and a significant association was observed between DRE and prostate-specific antigen (PSA) level (p=0.0005).⁵ In the study of Jariwala,⁶ PSA was not available in 40 cases and PCa was found in 14 cases on prostate biopsy, 35% being positive only on abnormal DRE. In another study, at multi-ple PSA ranges, suspicious DRE finding significantly increased the cancer detection rates as compared to nonsuspi-cious DRE.⁴ Table 3 shows positive predictive value (PPV) of PSA and DRE in 876 patients who underwent biopsy.⁷ In a retrospective study of 922 patients, DRE examination revealed abnormalities in 158 subjects (17.1%). The relationship between the number of subjects with abnormal DRE findings and their PSA levels is shown in Table 4; as the PSA levels increased the number of prostate cancer cases detected by DRE also increased.⁸

Consensus: Is there a role of DRE in prostate cancer di-agnosis? (yes: 85.7%, no: 3.5%, no response: 10.7%)

Is there a role for prostate cancer screening in India? Literature review: There are no randomized control trials on population-based PCa screening in India. However, in a study conducted by Agnihotri et al.,⁷ of the 4,702 patients, 70.9% had PSA level <4 ng/mL and 29.1% had PSA level >4 ng/mL. Eleven point eight percent had between 4.1-10 ng/mL, 5.4% men had PSA level between 10.1-20 ng/mL, and 11.8% had >20 ng/mL. PSA test positivity rate was 29.1%. In this study, although there was a higher PSA test positivity, the PPV of PSA test in symptomatic men was low. This suggests that an increased number of PSA pos-itive men are unnecessarily put through biopsy.⁷ It is now accepted that PSA screening prevents approximately one PCa death per 1,000 men, each screened several times and followed for 10-15 years.⁹ Overdiagnosis of prostate cancer (estimated to be 35 overdiagnosed cases per 1,000 men screened), a large majority of which are low-risk cancers that would never progress or metastasize, is the most im-portant harm that outweighs the benefits of screening.⁹ Dubey¹⁰ in his review analysed evidences on the usefulness of PSA screening and concluded that there is no scientific rationale to advocate routine use of PSA for early detection of PCa in Indian males. The Government policy in favour of screening for prostate cancer does not exist in India and thus practising population-based screening is difficult.

Consensus: Is there a role for prostate cancer screening in India? (yes: 32.1%, no: 67.9%, no response: 0%)

Should all men have a multiparametric magnetic reso-nance imaging (mp-MRI) of the prostate/pelvis prior to making a decision to proceed to biopsy?

Literature review: In one prospective study conducted in India, the diagnostic performance of mp-MRI was analysed in a group of subjects with serum PSA of ≤10 ng/mL. Receiver operating characteristic (ROC) analysis of Prostate Imaging Reporting and Data System (PIRADS-S) score showed area under the curve of 0.93 (p<0.001) for the de-tection of PCa. Youden selected threshold cutoff was 8 (≥8) with sensitivity, specificity, PPV, and negative predictive value (NPV) of 85%, 87.88%, 68%, and 95.1%, respectively. Mp-MRI showed high NPV with PIRADS-S score cutoff,⁸ which suggest the ability of the test to predict the absence of disease with high confidence. This factor can be used to limit unnecessary biopsy of prostate.¹¹ In another study conducted in 26 patients, sensitivity, specificity, PPV, and NPV of T2, diffusion-weighted imaging, and magnetic reso-nance spectroscopy (MRS) in predicting malignancy was calculated after which transrectal ultrasonography (TRUS) guided biopsy was performed; results of which are de-scribed in Table 5.¹² Prebiopsy mp-MRI should become standard of care as recommended in 2019 NICE guidelines [NG131]. However, its implementation has proved to be difficult in the United Kingdom and certainly in India.

Consensus: Should all men have a mp-MRI of the pros-tate/pelvis prior to making a decision to proceed to biopsy? (yes: 25%, no: 67.8%, no response: 7.1%)

Should transrectal ultrasound-guided biopsies remain the standard approach?

Literature review: Gupta et al.¹³ reported a false negative rate of approximately 11% with TRUS-guided sextant biopsy. In symptomatic men with negative DRE, Agnihotri et al.⁷ proposed raising the serum PSA cutoff to 5.4 ng/mL for TRUS biopsy in India as this would prevent 10% un-necessary biopsies. This reflects low PCa detection rates of TRUS biopsy in India. It has been observed that compared to other continents, Asian population (including India) have a lower TRUS biopsy yield, especially for serum PSA level <20 ng/mL. Patil et al.,⁴ have confirmed these findings and thus standard serum PSA cutoff of 4 ng/mL followed in Western nations gives lower TRUS biopsy yield for Indian population. Cancer detection rates of TRUS biopsies from Indian studies are shown in Table 6.

Consensus: Should transrectal ultrasound-guided biopsies remain the standard approach? (yes: 85.7%, no: 14.3%, no response: 0%)

What imaging modalities should be used to complement the mp-MRI of the pelvis/prostate when determining the presence/absence of metastatic disease?

Literature review: There are no Indian studies on direct comparison of PSMA-PET-computed tomography (CT) and Isotope bone scan-CT. In the study of Gupta et al.,¹⁴ in their experience of 97 staging prostate cancer patients, PSMA- PET-CT showed 57.41% with only sclerotic metastasis. 33.33% mixed, 7.14% marrow, and 2.3% lytic types of lesions constitute the rest; therefore, bone scan alone in these patients may result in underestimation of bony disease burden.¹⁴ In another study, ⁶⁸ Ga-PSMA PET CT and MRI diagnostic sensitivity, specificity, PPV, NPV, and accuracy for detection of lymph node metastasis in high-risk cases were 66.67%, 98.61%, 85.71%, 95.95%, 95.06%, and 25.93%, 98.61%, 70%, 91.42%, 90.53%, respectively.¹⁵ In a retrospective study of 262 patients having PCa or sus-⁶8 Ga-PSMA scan detected extra-pected recurrent PCa, prostatic disease in 53.2% of subjects when done at baseline prior to starting any treatment. In this study, the sensitivity of ⁶⁸ Ga-PSMA at baseline with histopathological diagnosis was 95% and the PPV was 98%.¹⁶ PSMA-PET-CT is a suit-able replacement for conventional imaging as it provides superior accuracy than CT scan and bone scan.

Consensus: What imaging modalities should be used to complement the mp-MRI of the pelvis/prostate when de-termining the presence/absence of metastatic disease? (PSMA- PET-CT: 57.1%, isotope bone scan+CT scan: 39.2%, no re-sponse: 3.57%)

Should all prostate cancer biopsies be reviewed by a path-ologist with specific experience in the interpretation of pros-tate cancer histology?

Literature review: In the study of Singh et al.,¹⁷ general pathologists scored PCa cases using Gleason grade. For Gleason score (GS) groups (2-4, 5-6, 7, and 8-10) overall agreement with consensus score was 68%. For primary grade 60% of readings were in fair to moderate agreement range; for secondary grade 78% of readings were in slight to fair agreement range. For GS, 80% of readings were in slight to fair agreement range; and for GS groups 68.5% of the readings were in fair to moderate agreement range. In practice, it has been seen that general pathologists often underscore than overscore. In the same study, overscoring was observed in 33.7% and underscoring in 23%.¹⁷ In an-other study, after attending a web-based tutorial, pathologist scored PCa cases independently using the Gleason scoring system. Pathologist overgraded 15% cases of score 7 and 12.5% cases of scores 5-6 in the pretutorial round. In post-tutorial round, this score was reduced to 11.25% and 10.6, respectively.¹⁸

Consensus: Should all prostate cancer biopsies be re-viewed by a pathologist with specific experience in the interpretation of prostate cancer histology? (yes: 89.2%, no: 10.7%, no response: 0%)

Is active surveillance (AS) a viable management option for low-risk prostate cancer in the Indian context?

Literature review: There are no Indian guidelines or studies on the role of AS in prostate cancer. Data of AS in more than 4,000 PCa patients with median follow-up of 4.5 years has been shown in Table 7.¹⁹ In Indian setting, patients gen-erally have insufficient medical knowledge and their treatment outcome expectation is high. In addition, the large Indian population is not regular for AS follow-up. Medical violence is also quite common, thus it is difficult for urolo-gists in India to face the medical disputes caused by PCa progression during AS. Implementing AS in India is there-fore difficult. Even conditions in China are similar to India, which is why radical prostatectomy is still the primary choice of Chinese urologist in low-risk prostate cancer, fol-lowed by AS.²⁰

Consensus: Is AS a viable management option for low-risk prostate cancer in the Indian context? (yes: 42.9%, no: 57.1%, no response: 0%)

Should Gleason Grade Grouping (GG) be adopted across India as a standard for reporting histological grade?

Literature review: In a retrospective study comparing the GS of 2005 and 2015 criteria, there was a marked decrease (80%) in GS 6; among these cases, 80% cases were graded as score 7, and 20% cases were graded as score 8. There was also a 28.57% decrease in GS 8 and 60% increase in GS 9 due to the new criteria for pattern 4. The GG 1, 2, 3, 4, and 5 constituted 3.03%, 18.18%, 15.15%, 15.15%, and 48.49% of cases respectively.²¹ In another Indian study, applying World Health Organization 2016 modified Gleason scoring system and prognostic grade grouping criteria to PCa biopsies, there was upgradation of prognostic groups in 7.69% patients. There was also an increase in GS 4+3 from 19.6% to 23.8% and a decrease in GS 3+4 from 13.9% to 9%; After follow-up of 2 years poor prognoses was observed in those patients who were upgraded to the higher prognostic group.²²

Consensus: Should Gleason Grade Grouping be adopted across India as a standard for reporting histological grade? (yes: 100%, no: 0%, no response: 0%)

Does the management and prognosis for high-risk lo-calized and locally advanced prostate cancer differ?

Literature review: The current standard of care in man-agement of high-risk and locally advanced disease is ex-ternal beam radiotherapy (EBRT) in combination with long- term androgen deprivation therapy (ADT); specifically, a 3-dimensional conformal radiation therapy or intensity-mo-dulated radiation therapy (IMRT) radiation therapy techni-que with a dose of 75-80  Gy in conjunction with long-term ADT in a neoadjuvant, concurrent, or adjuvant setting for 2-3 years. In general, brachytherapy is not considered for treatment in high-risk patients; however, in certain scenario brachytherapy boost could be used in conjunction with EBRT, along with consideration of short-term ADT. In ad-dition, surgery could be considered in selected high-risk patients, even though, it is not a popular approach because of it is invasive in nature compared to EBRT. Also, surgery has it's complication which is long-term sexual dysfunction, urinary incontinence etc. It's highly likely that postoperative radiotherapy would be required which will expose patients to toxicities of radiotherapy as well as surgery.²³

Consensus: Does the management and prognosis for high- risk localized and locally advanced prostate cancer differ? (yes: 75%, no: 17.8%, no response: 7.1%)

Should hypo fractionated radiotherapy (60 Gy in 20 fractions) be considered the standard radiotherapy regimen for low-to-intermediate risk prostate cancer?

Literature review: In an Indian study, patients with organ- confined PCa received hypofractionated IMRT. Dose pre-scribed to the prostate was 77 Gy/35 fractions or 60 Gy/20 fractions. After a median follow-up of 26 months, there were 6 biochemical relapses, 1 in intermediate and 5 in high-risk group, of whom 3 deaths occurred due to distant metastasis. In this study, the 2-year biochemical recurrence- free survival (bRFS), prostate cancer-specific survival (pCSS), and overall survival (OS) were 92.3%, 93.9%, and 91.5% respectively. Twenty percent and 13.3% developed acute and late Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal (GI) toxicities respectively. Eight point nine percent and 11.1% developed RTOG grade 2 or worse genitourinary (GU) toxicity respectively. One patient developed grade 3 rectal toxicity, and none developed blad-der toxicity.²⁴ In another Indian study, no significant differ-ence was observed in the incidence of grade 2 GI and GU toxicities between the 2 schedules of 60 Gy in 20 fractions and 65 Gy in 25 fractions.²⁵

Consensus: Should hypo fractionated radiotherapy (60 Gy in 20 fractions) be considered the standard radiotherapy reg-imen for low-to-intermediate risk prostate cancer? (yes: 57.1%, no: 35.7%, no response: 7.1%)

Should radical prostatectomy be considered as a management option for men with high-risk (D’Amico) cN0 cM0 prostate cancer?

Literature review: Most patients in India present with locally advanced disease or metastatic disease due to lack of medical education and awareness. Even those patients pre-senting with localized disease who could be managed with RP, are in the high-risk group. In an Indian study, patients underwent robotic-assisted radical prostatectomy (RARP) and it was observed that 39.6% were in high-risk group. After a follow-up of 12 months post-RARP, 27.8% had bio-chemical recurrence (BCR), and 92% patients were continent.²⁶ Kulkarni et al.²⁷ studied the outcome of upfront RP in Indian patients with high risk PCa. From 1996 to 2010, 208 PCa patients (high-risk category D’Amico's criteria) underwent open RP with bilateral pelvic lymphadenectomy. At 7 and 10 years, pCSS was found to be 79.7% and 65%, respectively, bRFS was 42.4% and 36.7%, respectively and the metastasis-free survival (MFS) was 71.1% and 64.4% respectively.²⁷ In another study, out of 192 patients who un-derwent RP 109 had D’Amico high-risk (HR) disease. The 2- and 5-year bRFSs were 45% and 35%, respectively. It was also observed that the 2-year bRFS was 63%, 23%, and 22%, for 1HR, 2HR, and 3HR respectively (log rank, p<0.0001).²⁸ In the study of Mishra et al.,²⁹ after undergoing laparoscopic radical prostatectomy for a clinical T2 lo-calized disease, patient's 5-year progression-free probability with low-, intermediate-, and high-risk PCa was 91%, 82%, and 58%, respectively.²⁹

Consensus: Should radical prostatectomy be considered as a management option for men with high-risk (D’Amico) cN0 cM0 prostate cancer? (yes: 85.7, no: 7.1%, no re-sponse: 7.1%)

Should lymph node dissection be recommended in all men with high-risk (D’Amico) cN0 cM0 prostate cancer un-dergoing a radical prostatectomy?

Literature review: Lymph node positivity is detected in 5%-6%, 20%-25%, and 30%-40% of low-, intermediate-, and high-risk PCa patients respectively who undergo RP and extended pelvic lymph node dissection (ePLND).³⁰ In contrast to the Western countries, most Indian patients are detected with higher stage of PCa and with greater proba-bility of lymph node involvement. Results of the study of Batra et al.³¹ showed that 7% and 45% of patients had low-risk and high-risk disease respectively and positive lymph node was found in 20% of these high-risk patients on ePLND. This demonstrates how much important pelvic lymphadenectomy is in patients undergoing RARP in the Indian subcontinent. Abdollah et al.³² studied the practice patterns in the utilization of pelvic lymph node dissection in Indian and United States (US) practices. Even this study confirmed that Indian patients had a higher risk distribution compared to US (53.4% in India vs. 27% in the US; p<0.001). It was also observed that Indian patients with low risk more frequently underwent PLND (81.0% vs. 41.4%). In addition, the study showed that the probability of Indian patients undergoing PLND was 2.57-fold higher than their US counterparts.³²

Consensus: Should lymph node dissection be recommen-ded in all men with high-risk (D’Amico) cN0 cM0 prostate cancer undergoing a radical prostatectomy? (yes: 92.8, no: 0%, no response: 7.1%)

In men undergoing lymph node dissection during radical prostatectomy for high-risk (D’Amico) cN0 cM0 prostate cancer, which lymph node regions should be dissected?

Literature review: With the absence of Indian literature, evidences from international studies have been evaluated. In high-risk men with lymph node positive disease after RP and ePLND, Bader et al.³³ found that the common sites for metastasis in patients were obturator fossa (60%) followed by internal iliac (hypogastric) (58%) and external iliac nodal areas (36%). Nineteen percent of the patients had metastasis in the hypogastric region alone. In another study, 470 lymph nodes were detected scintigraphically and 46% pos-itive nodes were found in patients during ePLND. If ePLND went only up to the common iliac chain, 94% would have been correctly staged, but only 77% would have had all their metastasised sites removed.³⁰ A recent study of PLND versus ePLND evaluated bPFS outcomes in localized PCa patients undergoing open RP. The 5-year bPFS in low risk, intermediate-risk, and high-risk patients undergoing PLND and ePLND were found out to be 90.1% and 91.3%, 73.1% and 85.7%, 51.1%, and 71.4% respectively.³⁴

Consensus: In men undergoing lymph node dissection during radical prostatectomy for high-risk (D’Amico) cN0 cM0 prostate cancer, which lymph node regions should be dissected? (below common illiac bifurcation: 64.2%, above common iliac bifurcation: 32.1%, no response: 3.5%). In the discussion during Consensus Board Meeting (CBM), expert committee was of the opinion that the statement derived from this question should have a strong recommendation.

Which staging investigations should be performed in a man with high-risk (D’Amico) cN0 cM0 prostate cancer prior to confirming suitability for surgery?

Literature review: There are no Indian studies on compar-ison of various investigations in high-risk (D’Amico) cN0 cM0 prostate cancer prior to confirming suitability for surgery. However, Indian data on different investigations in prostate cancer are mentioned in statement No. 5 under the diagnosis section of consensus opinion. Due to lack of Indian data, evidences from other literature were assessed. In a study conducted in Jordan, ⁶⁸ Ga PSMA PET/CT scan in high-risk disease patients showed a higher concordance rate of 90% as compared to the bone scan (75%) followed by MRI scan (73%), and CT scan (60%). The study also demonstrated that ⁶⁸ Ga PSMA PET/CT was more accurate in detecting suspicious pelvic lymph nodes than MRI scan (95.2% vs. 80%) but it had almost same accuracy to MRI in detecting PCa lesions. In this study ⁶⁸ Ga PSMA PET/CT also performed better than CT scan in identifying suspicious lymph nodes (95.2% vs. 75%) and extrapelvic nodes (100% vs. 75%), as well as bone lesions via bone scan (100% vs. 62.5%). Intriguingly the management of PCa was changed by ⁶⁸ Ga PSMA PET/CT in 52% patients.³⁵

Consensus: Which staging investigations should be per-formed in a man with high-risk (D’Amico) cN0 cM0 pros-tate cancer prior to confirming suitability for surgery? (multiparameteric MRI+bone scan: 35.7%, PSMA-PET: 60.7%, no response: 3.5%)

Should neoadjuvant ADT be considered for men with high-risk (D’Amico) cN0 cM0 prostate cancer prior to radi-cal prostatectomy?

Literature review: Indian studies are lacking on this sub-ject, thus other available literature was reviewed for this statement. Narita et al.³⁶ studied the outcomes in patients having high-risk disease treated with neoadjuvant chemohormonal therapy (NCHT) with RP alone. In this study, 10% patients had pathologic complete response and 3.3% had positive surgical margins. The BCR-free survival rates for 2 years and 5 years were 69.2% and 60.1%, respectively. After propensity score matching, it was observed that the BCR rate in patients remained significantly lower in the NCHT+RP group than RP group alone.³⁶ In 2006 a Cochrane review published that neoadjuvant ADT improved patho-logical outcomes but not overall or disease-free survival.³⁷

Consensus: Should neoadjuvant ADT be considered for men with high-risk (D’Amico) cN0 cM0 prostate cancer prior to radical prostatectomy? (yes: 28.5%, no: 64.2%, no response: 7.1%)

Is there a role for trimodality therapy (ADT+radical pros-tatectomy+adjuvant radiotherapy [ART]) for men with high-risk (D’Amico) cN0 cM0 prostate cancer?

Literature review: Trials have demonstrated that combination therapies improve survival and cancer outcomes when compared to monotherapy for men with high-risk PCa. To date, only one prospective randomized trial comparing RP plus ADT with EBRT plus ADT in the treatment of patients with high-risk PCa has been published; men with T2b-3N0M0 tumours were included in this trial, regardless of serum PSA level. After a follow-up of 102 months, the 10-year OS rate in the patients who underwent surgery tend-ed to be better than the rate observed in the radiation group (76.2% vs. 71.1%). Furthermore, other outcomes were im-proved in the surgery cohort compared to radiotherapy co-hort: bPFS was 83.5% versus 66.1%, clinical progression- free survival rates were 85.7% versus 77.1%, and disease- specific survival (DSS) rates was 67.9% versus 60.9%. However, none of these survival advantages reached stat-istical significance.³⁸ In another retrospective study, the out-come in PCa patients receiving combination of ART and ADT after RP was evaluated. After a median follow-up of 61 months, the 5- and 7-year bRFS rates were 90.5 and 77.2%, respectively. Distant relapse occurred in 5 patients, resulting in 5- and 7-year MFS of 95.9% and 81.7%, respectively. During follow-up, 7 patients died (2 PCa deaths), resulting in 5- and 7-year DSS and OS rates of 100% and 94.7% and 90.6 and 81.5%, respectively.³⁹

Consensus: Is there a role for trimodality therapy (ADT+radical prostatectomy+ART) for men with high-risk (D’Amico) cN0 cM0 prostate cancer? (yes: 53.5%, no: 42.8%, no response: 3.5%). During CBM, the expert com-mittee was of the opinion that the statement derived from this question should have a strong recommendation and the terminology trimodality is to be replaced with multimo-dality.