Prostate Cancer-Standard Treatment Guidelines

Ministry of Health and Family Welfare released Standard Treatment Guidelines for Prostrate Cancer. Following are its major recommendations

Introduction and Case definition

• Cancer of the prostate (PCa) is now recognized as one of the most important medical problems facing the male population. Prostate cancer is the 2nd most common cause of cancer death in men. Affects 4% of men in undeveloped countries & 15% of men in developed countries


• Risk factors
  Increasing age
  Ethnical origin
  Heredity


• Risk is doubled when one first line relative has prostate cancer. Risk is 5 – 11 fold when two or more first line relatives has PCa[3]

Ministry of Health and Family Welfare, Government of India has issued the Standard Treatment Guidelines for Prostate Cancer. Following are the major recommendations :

INCIDENCE OF THE CONDITION IN OUR COUNTRY

Exact incidence is unknown. Expected to be of same incidence as the western world.

DIFFERENTIAL DIAGNOSIS

1. Benign prostatic hyperplasia


2. Granulomatous Prostatitis


3. Transitional cell carcinoma of prostate


4. Chronic prostatitis


5. Prostatic calculi

PREVENTION AND COUNSELING

1. Mass education about prostate cancer.


2. Opportunistic screening for prostate cancer with serum PSA.


3. Counseling about serum PSA and its implications.


4. Chemoprevention of prostate cancer.


5. Recognizing bladder outflow obstruction and other complications in men due
   to prostate cancer.


6. Thorough examination in elderly men who are at risk.


7. Prompt referral of men with suspicion of prostate cancer to higher centres
   for further evaluation.

OPTIMAL DIAGNOSTIC CRITERIA, INVESTIGATIONS, TREATMENT & REFERRAL CRITERIA

Diagnostic criteria:

Screening & Early detection of prostate cancer Population or mass screening is defined as the examination of asymptomatic men (at risk). It usually takes place as part of a trial or study and is initiated by the screener. In contrast, early detection or opportunistic screening comprises individual case findings, which are initiated by the person being screened (patient) and/or his physician. The primary endpoint of both types of screening has two aspects:

1. Reduction in mortality from PCa.

2. Quality-of-life adjusted gain in life years (QUALYs). Screening for prostate cancer has conflicting results. Based on the results of two large, randomised trials [4,5], it is accepted that at present widespread mass screening for PCa is not appropriate. Rather, early detection (opportunistic screening) should be offered to the well-informed man. Hence

• Early PSA testing should be a shared decision between patient and physician.


• PSA testing & DRE – offered to men >40 years of age & expected life expectancy of atleast 10 years.

Diagnosis –The main diagnostic tools to obtain evidence of PCa include digitial rectal examination (DRE), serum concentration of PSA and transrectal ultrasonography (TRUS).

Investigations:

• DRE: Most prostate cancers are located in the peripheral zone of the prostate and may be detected by DRE when the volume is about 0.2 mL or larger. A suspect DRE is an absolute indication for prostate biopsy. In about 18% of all patients, PCa is detected by a suspect DRE alone, irrespective of the PSA level [6]


• Serum PSA(Prostate-specific antigen) is organ-specific but not cancer-specific. Thus, serum levels may be elevated in the presence of benign prostatic hypertrophy (BPH), prostatitis and other non-malignant conditions. The level of PSA as an independent variable is a better predictor of cancer than suspicious findings on DRE or TRUS [7]. The level of PSA is a continuous parameter: the higher the value, the more likely is the existence of PCa. This means there is no universally accepted cut-off or upper limit.[8] As yet, there is no long-term data to help determine the optimal PSA threshold value for detecting non-palpable, but clinically significant, PCa. Modifications to improve the specificity of PSA in early detection of Ca.P

1. PSA density


2. PSA density of transition zone


3. Age specific PSA


4. PSA molecular forms – PCA3


5. Free / Total PSA ratio (at PSA 4-10ng/ml) <0.10 – 56% biopsy positive


6. PSA doubling time (PSADT)


7. PSA velocity

When in doubt, repeat PSA under standardised conditions

• Transrectal ultrasound of prostate (TRUS) guided biopsy of prostate. Gray-scale TRUS does not detect areas of PCa with adequate reliability. It is therefore not useful to replace systematic biopsies with targeted biopsies of suspect areas. However, additional biopsies of suspect areas may be useful. Transrectal ultrasonography (TRUS) guided biopsy under antibiotic cover with periprostatic nerve block– minimum 10 core laterally and posteriorly directed biopsy is recommended (>12 not significantly more conclusive). [9]The indications for a repeat biopsy (including TZ biopsy) [10] are:

1. Rising and/or persistent PSA, suspicious DRE;


2. Atypical small acinar proliferation (ASAP).


3. Extensive High-grade prostatic intraepithelial neoplasia (PIN)

Complications of biopsy – infection, sepsis < 1%, clot retention, acute urinary retention, bleeding from rectum, hematuria, hemospermia (the last 3 are mostly self limiting).

d. Pathology of prostate cancer:

1. The Gleason score is the sum of the most dominant and second most dominant (in terms of volume) Gleason grade.


2. A diagnosis of Gleason score 4 or lower should not be given on prostate biopsies


3. Gleason score system is the single strongest prognostic

factor for clinical behaviour and treatment response

• TRUS is also useful for staging of prostate cancer, however remains inadequate. [11]

5. MRI – abdomen and pelvis/ MR Urography [12] (risk stratification)

1. Local staging (T-staging)


2. MRI demonstrates higher accuracy for the assessment of uni- or bilobar disease (T2), Extracapsular extension (ECE) and Seminal vesicle invasion (SVI) (T3), as well as the invasion of adjacent structures (T4).


3. Lymph node status (N-staging) is only important when potentially curative treatment is planned.

• Pelvic lymph node dissection remains the only reliable staging method in clinically localized PCa. [13]


• Bone scan - Skeletal metastasis (M-staging) is best assessed by bone scan. This may not be indicated in asymptomatic patients if the serum PSA level is less than 20 ng/mL (risk stratification) in the presence of well or moderately differentiated tumours.[14]


• Serum alkaline phosphatase – if elevated, indicates metastatic bone disease.


• Transurethral resection of prostate- In those men who come with bladder outflow obstruction in an unsuspected fashion and biopsy report may reveal carcinoma of prostate.

Staging of prostate cancer: Based on Tumour Node Metastasis (TNM) classification of carcinoma prostate [15].

• T - primary tumour


• TX Primary tumour cannot be assessed


• T0 No evidence of primary tumour


• T1 Clinically inapparenttumour not palpable or visible by imaging

1. T1a Tumour incidental histological finding in 5% or less of tissue resected


2. T1b Tumour incidental histological finding in more than 5% of tissue resected


3. T1c Tumour identified by needle biopsy (e.g. because of elevated prostate-specific antigen [PSA] level).

T2 Tumour confined within the prostate1

• T2a Tumour involves one half of one lobe or less.


• T2b Tumour involves more than half of one lobe, but not both lobes.


• T2c Tumour involves both lobes.


• T3 Tumour extends through the prostatic capsule.


• T3a Extracapsular extension (unilateral or bilateral) including microscopic bladder neck involvement.


• T3b Tumour invades seminal vesicle(s)

• T4 Tumour is fixed or invades adjacent structures other than seminal vesicles: external sphincter, rectum, levator muscles, and/or pelvic wall.

• N - regional lymph nodes


• NX Regional lymph nodes cannot be assessed


• N0 No regional lymph node metastasis


• N1 Regional lymph node metastasis


• M - distant metastasis


• MX Distant metastasis cannot be assessed


• M0 No distant metastasis


• M1 Distant metastasis


• M1a Non-regional lymph node(s)


• M1b Bone(s)


• M1c Other site(s)

• Group I T1a-c N0 M0 PSA < 10 Gleason < 6


• T2a N0 M0 PSA < 10 Gleason < 6


• Group IIA T1a-c N0 M0 PSA < 20 Gleason 7


• T1a-c N0 M0 PSA > 10 < 20 Gleason < 6


• T2a, b N0 M0 PSA < 20 Gleason < 7


• Group IIb T2c N0 M0 Any PSA Any Gleason


• T1-2 N0 M0 PSA > 20 Any Gleason


• T1-2 N0 M0 Any PSA Gleason > 8


• Group III T3a, b N0 M0 Any PSA Any Gleason


• Group IV T4 N0 M0 Any PSA Any Gleason


• Any T N1 M0 Any PSA Any Gleason


• Any T Any N M0 Any PSA Any Gleason

– (Note: When either PSA or Gleason is not available, grouping should be
determined by cT category and whichever of either PSA of Gleason is
available. When neither is available prognostic grouping is not possible,
use stage grouping)

Treatment: Treatment of prostate cancer depends on the stage of the disease and prognostic information available.

• Deferred treatment (Watchful waiting & Active surveillance) [16- 20] Make difference between active survillience and watchful waiting Indications:


• In presumed localisedPCa (Nx-N0, M0):

1. Stage T1a: well and moderately differentiated tumours. In younger
   patients with a life expectancy of > 10 years, re-evaluation with PSA,
   TRUS and biopsies of the prostatic remnant is recommended.


2. Stage T1b-T2b: well & moderately differentiated tumours. In asymptomatic patients with a life expectancy of < 10 years.


3. Inclusion criteria for active surveillance with the lowest risk of cancer.
   

• In presumed localisedPCa (Nx-N0, M0):

1. Stage T1b-T2b patients who are well informed and have welldifferentiated
   (or Gleason 2-4) PCa and a life expectancy of 10-15 years.


2. All patients not willing to accept side-effects of active treatment.


3. Well-informed, asymptomatic patients with high PSA levels for whom
   cure is unlikely.

In locally advanced disease (stage T3-T4):

• Asymptomatic patients with well- or moderately differentiated cancer,PCa and a short life expectancy.


• PSA < 50 ng/mL and PSA doubling time > 12 months.

In metastatic disease (M1) :

– A very rare patient without any symptoms and the possibility of close
follow-up
The criteria for active surveillance have not reached a consensus stage yet. Every institution has different parameters and that should be mentioned. Active surveillance is not the same as watchful waiting.

Radical Prostatectomy [21,22]period between biopsy and surgery

• Indications

In patients with low and intermediate risk localisedPCa (cT1a-T2b and Gleason score 2-7 and PSA < 20) and a life expectancy > 10 years.

• Optional

1. Selected patients with low-volume high-risk localisedPCa (cT3a or Gleason score 8-10 or PSA >20).


2. Highly selected patients with very high-risk localisedPCa (cT3b-T4 N0 or any T N1) in the context of multimodality treatment.

• Recommendations

1. Short-term (3 months) neoadjuvant therapy with gonadotrophin releasing-hormone analogues is not recommended in the treatment of stage T1-T2 disease.


2. Nerve-sparing surgery may be attempted( offered) in pre-operatively potent patients with low risk for extracapsular disease (T1c, Gleason score < 7 and PSA < 10 ng/mL or see Partin tables / nomograms).


3. Unilateral nerve-sparing procedures are an option in stage T2a disease.


4. Recommendation for Lymphadenectomy.


5. Extended PLND is recommended for all patients who have a greater than
   2% chance of having lymph node disease. (NCCN guidelines).

Definitive radiation therapy [23-28]

In localised prostate cancer T1c-T2c N0 M0, 3D-CRT with or without IMRT is recommended even for young patients who refuse surgical intervention. There is fairly strong evidence that low-, intermediate- and high-risk patients benefit from dose escalation.

• For patients in the high-risk group, short-term ADT prior to and during radiotherapy results in increased overall survival, but three years of adjuvant ADT are better according to the results of EORTC 22961.


• Transperineal interstitial brachytherapy with permanent implants is an option for


• Patients with cT1-T2a, Gleason score < 7 (or 3 + 4), PSA < 10 ng/mL, prostate volume < 50 mL, without a previous TURP and with a good IPSS Immediate post-operative external irradiation after RP for


• Patients with pathological tumour stage T3 N0 M0 improves overall survival, biochemical and clinical disease-free survival with the highest impact in cases of positive margins (R1).


• An alternative option is to give radiation at the time of biochemical failure, but before PSA rises above 0.5 ng/mL


• In locally advanced prostate cancer T3-4 N0 M0, overall survival is improved by concomitant and adjuvant hormonal therapy for a total duration of 3 years, with external beam irradiation for patients with a WHO 0-2 performance status.


• For a subset of patients with T2c-T3 N0-x and a Gleason score of 2-6, short-term ADT before and during radiotherapy may favourably influence overall survival


• In very high-risk prostate cancer, c-pN1 M0 with no severe co-morbidity, pelvic external irradiation and immediate long-term adjuvant hormonal treatment improve overall survival, disease-specific failure, metastatic failure and biochemical control

Experimental local treatment of prostate cancer[29-32]under invstigations

• Cyrosurgery:

1. Patients with low-risk PCa (PSA < 10 ng/mL, < T2a, Gleason score < 6) or


2. intermediate-risk PCa (PSA > 10 ng/mL, or Gleason score > 7, or stage > 2b) represent potential candidates for CSAP.


3. Prostate size should be < 40 mL at the time of therapy. Long-term results are lacking, while 5-year biochemical progression free rates are inferior to those achieved by RP in low risk patients. Patients must be informed accordingly.

• Cryosurgery - a possible alternative treatment for PCa in patients who are unfit for surgery or with a life expectancy < 10 years.


• All other minimally invasive treatment options – such as HIFU microwave and electrosurgery – are still experimental or investigational.


• Focal therapy of PCa is still in its infancy and cannot be recommended as a therapeutic alternative outside clinical trials.

Hormonal therapy[33-4]

Bone densitometry and bisphosphonates

• In advanced PCa, androgen deprivation therapy (ADT)


• delays progression.


• prevents potentially catastrophic complications.


• palliates symptoms effectively, but does not prolong survival.


• In advanced PCa, all forms of castration used as monotherapy (e.g. orchiectomy, LHRH and DES) have equivalent efficacy.


• Non-steroidal anti-androgen monotherapy (e.g. bicalutamide) is an alternative to castration in patients with locally advanced disease.


• In metastatic PCa, the addition of a non-steroidal anti-androgen to castration (CAB) results in a small advantage in OS over castration alone, but is associated with increased adverse events, reduced QoL, and high costs.


• Intermittent ADT should no longer be regarded as experimental, even though long-term data from prospective clinical trials are still awaited. ‘Minimal’ ADT should, however, continue to be seen as experimental.


• In advanced PCa, immediate ADT (given at diagnosis) significantly reduces disease progression, as well as the complication rate due to progression itself, compared with deferred ADT (delivered at symptomatic progression). However, the survival benefit is at best marginal and not related to cancer-specific survival.


• Bilateral orchiectomy might be the most cost-effective form of ADT, especially if initiated after the occurrence of symptoms from metastatic disease.

Follow-up [47-50]

1. In asymptomatic patients, a disease-specific history & a serum PSA measurement supplemented by DRE - recommended tests for routine follow-up. These should be performed at 3, 6 & 12 months after treatment, then every 6 months until 3 years, and then annually.


2. After radical prostatectomy, a serum PSA level of more than 0.2 ng/mL can be associated with residual or recurrent disease.


3. After radiation therapy, a rising PSA level over 2 ng/mL above the nadir PSA, rather than a specific threshold value, is the most reliable sign of persistent or recurrent disease.


4. Both a palpable nodule and a rising serum PSA level can be signs of local disease recurrence.


5. Detection of local recurrence by TRUS and biopsy is only recommended if it will affect the treatment plan.


6. In most cases TRUS and biopsy are not necessary before second-line therapy.


7. Metastasis may be detected by pelvic CT/MRI or bone scan. In asymptomatic patients, these examinations may be omitted if the serum PSA level < 120 ng/mL.


8. Routine bone scans & other imaging studies are not recommended in asymptomatic patients. If a patient has bone pain, a bone scan should be considered irrespective of the serum PSA level.

After hormonal therapy [51-53]

Patients should first be evaluated at three & six months after the initiation of treatment. (one month and 3 months after initiating treatment)

As a minimum.

• serum PSA measurement.


• digital rectal examination (DRE).


• serum testosterone and careful evaluation of symptoms in order to assess the treatment response and the side-effects of the treatments given.


• Follow-up should be tailored for the individual patient, according to symptoms, prognostic factors and the treatment given.


• In patients with stage M0 disease with a good treatment response, follow-up is scheduled every six months, and should include as a minimum a disease-specific history, DRE and serum PSA determination.


• In patients with stage M1 disease with a good treatment response, follow-up is scheduled for every three to six months.


• As a minimum, this should include a disease-specific history, DRE and serum PSA determination, and is frequently supplemented with haemoglobin, serum creatinine and alkaline phosphatase measurements.


• Patients (especially if M1b status) should be advised on the clinical signs that could suggest spinal cord compression.


• When disease progression occurs, or if the patient does not respond to the treatment given, the follow-up needs to be individualised.


• Routine imaging of stable patients is not recommended.

Treatment of biochemical failure after treatment with curative intent [54- 61]

Presumed local failure after radical prostatectomy

• Patients with presumed local failure only may be candidates for salvage radiotherapy. At least 64 Gy given and preferably before PSA has risen above 0.5 ng/mL.


• Other patients are best offered a period of watchful waiting (active monitoring), with possible hormonal therapy later on.

Presumed local failure after radiotherapy

• Selected patients may be candidates for salvage radical prostatectomy and patients should be informed about the higher risk of complications, such as incontinence and erectile dysfunction.


• Salvage prostatectomy should only be performed in experienced centres. Other patients are best offered a period of watchful waiting (active monitoring), with possible hormonal therapy later on.

Presumed distant failure

• There is some evidence that early hormonal therapy may be of benefit in +/- local failure, delaying progression, and possibly achieving a survival benefit in comparison with delayed therapy.


• Local therapy is not recommended except for palliative reasons.

Castration refractory prostate cancer (CRPC or HRPC)-

Definition:

• Serum castration levels of testosterone (testosterone < 50 ng/dL or < 1.7 nmol/L).


• Three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA > 2 ng/mL.


• Anti-androgen withdrawal for at least 4 weeks.
  PSA progression, despite consecutive hormonal manipulations.


• Either anti-androgen withdrawal or one secondary hormonal manipulation should have been done in order to fulfil the criteria for CRPC.


• Progression of osseous lesions: progression or appearance of two or more lesions on bone scan or soft tissue lesions using RECIST (Response Evaluation Criteria in Solid Tumours) and with nodes > 2 cm in diameter.

CRPC

Recommendation of treatment after hormonal treatment

• It is recommended to stop anti-androgen therapy once PSA progression is documented.


• Four to six weeks after discontinuation of flutamide or bicalutamide, an eventual anti-androgen withdrawal effect is apparent.


• No clear-cut recommendation can be made for the most effective drug for secondary hormonal manipulations. Secondary hormonal manipulations possibilities.


• Abiraterone and Cabazitaxel have shown to prolong survival in CRPC after docetaxel chemotherapy. Sipuleucel T is prostate vaccine which is used and has been approved in the west for CRPC which is minimally symptomatic or asymptomatic. Not yet available in India.

Recommendation of cytotoxic therapy

1. Ideally, patients with CRPC should be counselled, managed and treated in a multidisciplinary team.


2. In non-metastatic CRPC, cytotoxic therapy should only be considered in clinical trials.


3. In patients with a PSA rise only, two consecutive increases of PSA serum levels above a previous reference level should be documented.


4. Prior to treatment, PSA serum levels should be > 2 ng/mL to assure correct interpretation of therapeutic efficacy.


5. Potential benefits of cytotoxic therapy and expected side-effects should be discussed with each individual patient.


6. In patients with metastatic CRPC, and who are candidates for cytotoxic therapy, docetaxel at 75 mg/m2 every 3 weeks has shown a significant survival benefit.


7. In patients with symptomatic osseous metastases due to CRPC, either docetaxel or mitoxantrone with prednisone or hydrocortisone are viable therapeutic options.


8. Second-line docetaxel should be considered in previously responding patients to docetaxel.


9. Otherwise, treatment is tailored to the individual patient.


10. Cabazitaxel should be considered as effective second-line treatment following docetaxe.


11. Chemotherapeutic drugs/ targeted therapy for cancer prostate patients should be decided and administered under supervision of a Urologist.

Recommendation of palliative management

• Patients with symptomatic and extensive osseous metastases cannot benefit from medical treatment with regard to prolongation of life.


• Management of these patients has to be directed at improvement of QoL and mainly pain reduction.


• Effective medical management with the highest efficacy and a low frequency of side-effects is the major goal of therapy.


• Bisphosphonates may be offered to patients with skeletal masses (mainly zoledronic acid has been studied) to prevent osseous complications. However, the benefits must be balanced against the toxicity of these agents, in particular jaw necrosis must be avoided.


• Palliative treatments such as radionuclides, external beam radiotherapy, adequate use of analgesics should be considered early in the management of painful osseous metastases.


• Spinal surgery or decompressive radiotherapy are emergency surgeries which have to be considered in patients with neurological symptoms might be an emergency.

Denosumab is more efficacious in preventing skeletal related events than Zoledronic acid with no need to adjust dose for mild to moderate renal dysfunction.

Referral criteria for Urologist :

• Men who come with LUTS with DRE showing hard nodular prostate.


• Localized prostate cancer.


• Men with advanced prostate cancer / metastases.

Situation 1: At Secondary Hospital / Non-Metro Situation: Optimal Standards Of Treatment In Situations Where Technology And Resources Are Limited.

Clinical diagnosis:Hard, nodular, asymmetric prostatic enlargement in digital rectal examination.

Investigations: Ultrasound of abdomen and pelvis (preferably by trans rectal ultrasound) – to assess the size and echotexture of prostate and to assess the tumour factors.

Treatment:According to the stageof the disease.

Standard operating procedure:

Inpatient:
Outpatient
Daycare:

Referral criteria:

Men who come with LUTS with DRE showing hard nodular prostate
Localized prostate cancer
Men with advanced prostate cancer / metastases

Situation 2: At super speciality facitlity in metro location where higher end technology is available.

Clinical diagnosis: DRE and look for metastatic lesions.

Investigations: All the possible investigations mentioned.

Treatment:According to the stage of the disease and the treatment options selected by the patient after counseling.

Standard operating procedure

a) Inpatient
b) Outpatient
c) Daycare

Referral Criteria:

• For diagnosis and staging – TRUS guided biopsy of prostate (depending on centers of excellence).


• Evaluation of metastatic disease – bone scan.


• Extensive metastatic disease requiring advanced speciality care like radiopharmaceuticals, spine decompression surgery and neurosurgery.

Guidelines by The Ministry of Health and Family Welfare :

Prof. Rajesh Ahlawat
Chairman,
Department of Urology & Kidney Transplant,
Medanta Medicity
Reviewed By:
Dr Anup Kumar Gupta
Head of Department
Department of Urology
VMMC and Safdarjang Hospital,
New Delhi