Recommendations  

Strength of recommendations  

Vaccination against hepatitis B reduces the risk of HCC and is recommended for all newborns and high-risk groups .

Strong  

Governmental health agencies should implement policies to prevent HCV/HBV transmission, counteract chronic alcohol abuse, and encourage life styles that prevent obesity and metabolic syndrome.  

Strong  

In general, chronic liver disease should be treated to avoid progression of liver disease.  

Strong  

In patients with chronic hepatitis, antiviral therapies leading to maintained HBV suppression in chronic hepatitis B and sustained viral response in hepatitis C are recommended, since they have been shown to prevent progression to cirrhosis and HCC development.  

Strong  

Once cirrhosis is established, antiviral therapy is beneficial in preventing cirrhosis progression and decompensation. Furthermore, successful antiviral therapy reduces but does not eliminate the risk of HCC development .

Strong  

Patients with HCV-associated cirrhosis and HCC treated with curative intent, maintain a high rate of HCC recurrence even after subsequent DAA therapy resulting in sustained viral response. close surveillance is advised in these patients.  

Strong  

Coffee consumption has been shown to decrease the risk of HCC in patients with chronic liver disease. In these patients, coffee consumption should be encouraged.  

Strong  

Implementation of screening programs to identify at- risk candidate populations should be improved. Such programs are a public health goal, aiming to decrease HCC-related and overall liver-related deaths.  

Strong  

Screening for HCC is warranted in all patients with cirrhosis irrespective of aetiology as long as liver function and co-morbidities allow curative or palliative treatment.  

Strong  

Screening for HCC is warranted for all patients with chronic HBV, regardless of the fibrosis stage.  

Strong

Screening for HCC is warranted in all patients with advanced fibrosis (F3 or F4) with HCV or NAFLD .  

Strong  

Screening of patients at risk of HCC should be carried out by abdominal Us with AFP every 4 months.  

Good practice statement

Patients with  liver nodule(s) < 1cm or 1-2 cm [LI-RADS 1or 2]on abdominal ultrasound should  repeat short-interval ultrasound and AFP  after 3 months.

Strong

In at-risk patients with any suspicious lesion ≥ 1 cm  on ultrasound should undergo diagnostic evaluation with multi-phasic contrast- enhanced CT or contrast-enhanced multi-phasic MRI. 

Strong

All patients with HCC should be carefully discussed and managed by an experienced multidisciplinary team(MDT) with the involvement of hepatologists, diagnostic radiologists, interventional radiologists, surgeons, transplant surgeons ,medical oncologists ,radiation oncologists, pathologists with hepatobiliary cancer expertise ,clinical pharmacists ,nutritionists and palliative care specialists.

Strong

The noninvasive diagnosis of HCC should be based on either multi-phasic contrast- enhanced CT or dynamic contrast enhanced MRI for diagnosis and evaluation of tumor extent(number and size of nodules,vascular invasion,extra-hepatic spread),they should could be performed,interpreted, and reported through the CT/MRI Liver Imaging Reporting and Data System(CT/MRI LI-RADS).

Strong

The diagnosis of HCC can be established if the typical vascular hallmarks of HCC (hypervascularity in the arterial phase with washout in the portal venous or delayed phase) are identified in a nodule of >1 cm diameter using one of the two contrast enhancing imaging techniques, either CT or MRI, in a cirrhotic patient.

strong

The optimal diagnostic method is core biopsy.Indicators for consideration of core needle biopsy include:                                                                                                                                            

     •    lesion> 1cm in cirrhotic patients  but does not meet imaging criteria for HCC in multi-phasic CT and MRI.

    •    lesion meets imaging criteria for HCC but patients is not considered at high risk for HCC development(In non-cirrhotic patients).

    •     lesion meets imaging criteria for HCC but patient has elevated CA19-9 or CEA with   suspicion of iCCA or cHCC-CCA.

Conditional

Repeated bioptic sampling is recommended in cases of inconclusive histological or discordant findings, or in cases of growth or change in enhancement pattern identified during follow-up, but with imaging still not diagnostic for HCC.

Conditional

Staging of HCC is important to determine outcome and planning of optimal therapy and includes assessment of tumor extent,AFP, liver function,portal pressure and clinical performance status.

strong

The Barcelona Clinic Liver Cancer (BCLC) is the commonly accepted staging system for prognostic prediction and treatment allocation.

strong

Multi-phasic contrast-enhanced CT or MRI of the abdomen, CT of the chest, and CT/MRI of the pelvis are also used in the evaluation of the HCC tumor burden to detect the presence of metastatic disease.

Conditional

Initial workup for patients with suspected HCC is a multidisciplinary evaluation including careful review of medical history to identify any potential chronic liver diseases, investigations of the etiologic origin of liver disease, an assessment of the presence of comorbidity, imaging studies to detect the presence of metastatic disease, and an evaluation of hepatic function, including a determination of whether portal hypertension is present.

Conditional

Laboratory evaluation of patients with newly diagnosed HCC include testing to detect  Aetiology of liver disease: HBV (at least HBsAg and anti-HBc), HCV (at least anti-HCV), iron status, autoimmune profile,HbAIc,others as indicated.

Good practice statement

Initial Workup for patient with HCC include an initial assessment of hepatic function involves liver function testing including measurement of serum levels of bilirubin, AST, ALT, ALP, measurement of  PT expressed as INR, albumin, and platelet count (surrogate for portal hypertension). Other recommended tests include CBC, BUN, and creatinine to assess kidney function.

Strong

Endoscopic assessment of any HCC patient: Upper GIT endoscopy is advised before receiving  systemic therapy or surgery.

Conditional

FDG PET-scan is not recommended for early diagnosis of HCC because of the high rate of false negative cases  and  may be considered when there is an  equivocal extrahepatic finding  before liver transplant.

Strong

Partial hepatectomy should be offered to HCC patients without advanced fibrosis and is the treatment of choice as long as an R0-resection can be carried out.  

Strong  

In the case of cirrhosis, surgical treatment is recommended for localized HCC with a single lesion and intact liver function (Child-Pugh A), and in the absence of clinically  significant portal hypertension with the evaluation of the extent of hepatectomy,future liver revenant and patient performance status.

strong  

For patients with chronic liver disease being considered for major resection, preoperative portal vein embolization should be considered.  

strong  

Patients meeting the UNOS criteria [AFP level ≤1000 ng/mL and single lesion ≥2 cm and ≤5 cm, or 2 or 3 lesions ≥1 cm and ≤3 cm and no evidence of macro vascular involvement or extra-hepatic  disease] should be considered for liver transplantation.

strong  

Thermal ablation by RFA or MWA are recommended as an alternative for resection for a single nodule ≤ 3 cm, BCLC stage 0, and those early stages that are not candidates for resection.  

Strong

The number and diameter of lesions treated by RFA in one session should not exceed three lesions, 3 cm each.  

Conditional

Unresectable lesions measuring up to 4 cm are recommended to be subject to local ablative therapy by radiofrequency ablation (RFA) or microwave ablation.  

Strong

Percutaneous ethanol injection is considered an option in some cases of very early HCC with tumor size up to 2 cm when thermal ablation is not technically feasible.  

Strong

EBRT (i.e. IMRT, SRS/SBRT) is recommended as a potential first line single option for patients with liver-confined HCC who are not candidates for curative options (surgery or thermal ablation) and for whom TACE is being considered.  

Strong

Single lesions (4–6 cm) that are beyond local ablative therapy and are ineligible for surgical resection and transplantation could benefit from a combination of heat ablation and chemoembolization and/or radiotherapy.  

Strong

TACE may be considered as an eligible option in intermediate HCC for bridging and down staging before liver transplantation and in case of non-feasibility or failure of other curative options in single lesions up to 8 cm.      

Conditional

TACE is recommended for BCLC-B patients with Child score up to B7 and tumor burden less than 50 % of liver volume  

Strong  

TACE should not be recommended for patients with decompensated liver disease (Child-Pugh score > 7), advanced liver and/or kidney dysfunction, main portal vein or its main branches invasion, extrahepatic spread, or tumor occupying>50 % of the liver size.  

Strong  

TACE should not be repeated after two consecutive sessions, with at least one month interval, and there is no response or there is tumor progression or decompensation of liver beyond Child-Pugh score B7.  

Conditional

Transarterial bland embolization may be used in same indications of TACE as A second choice if TACE is not feasible.  

Conditional

Radiotherapy in HCC is recommended to be integrated in the treatment plan through expert MDT and should be carried out in well trained and equipped centers with image guided, stereotactic radiotherapy, and radiosurgery facilities.  

Strong  

Radiotherapy could be implemented for unresectable or medically inoperable disease irrespective of the location (3D conformal RT, intensity-modulated RT [IMRT], or stereotactic body RT [SBRT]).  

Strong  

To give radiotherapy, there should be no extrahepatic disease or it should be minimal and addressed in a comprehensive management plan. Those with Child-Pugh B (max 7) cirrhosis can be safely treated, but they may require dose modifications and strict dose constraint adherence.  

Strong  

Image-guided RT is strongly recommended to improve treatment accuracy and reduce treatment related toxicity.  

Strong  

SBRT or SRS can be considered after ablation/ embolization techniques have failed or are contraindicated.  

Strong  

SBRT (typically 3–5 fractions) is recommended for patients with 1 to 3 tumors. And could be considered for larger lesions or more extensive disease, if there is sufficient uninvolved liver and liver radiation tolerance can be respected.  

Conditional

SBRT or SRS are recommended for compensated cirrhotic patients with HCC and portal vein thrombosis and when patients are ineligible for other modalities with building-up results.  

Conditional

Palliative RT is indicated for symptomatic control and/or prevention of complications from metastatic lesions as bone or brain, and extensive liver tumor burden.  

Strong  

The recommended doses of radiotherapy should be based on meeting normal organ constraints and underlying liver function as follows: 

           ▪️ SBRT, SRS: 30–50 Gy (typically in 3–5 fractions)

          ▪️ Hypofractionation: 37.5–72 Gy in 10–15 fractions 

          ▪️ Conventional fractionation by IMRT: 50–66 Gy in 25–33 fractions  

Strong

Systemic therapy should be offered to patients with preserved liver function (Child-Turcotte

Pugh A or well-selected Child-Turcotte-Pugh B cirrhosis),ECOG PS0-1,who have BCLC Stage C  HCC,or BCLC Stage B HCC not amenable to or progressing after locoregional therapy.  

Strong  

Sorafenib is the standard of care as first line for patients with advanced HCC and those with intermediate-stage (BCLC B) disease not eligible for, or progressing despite, locoregional therapies. It is recommended in patients with well-preserved liver function and ECOG PS 0-2.  

Strong  

Regorafenib is the standard of care for patients with advanced HCC who have tolerated sorafenib but progressed. It is recommended in patients with well- preserved liver function and ECOG PS 0-1.  

Strong  

Patients with BCLC-Stage-D HCC  should receive the best supportive care (BSC), including pain management, palliative radiotherapy for painful bone metastasis, nutrition optimization, and psychological support  

Conditional  

Follow-up of patients who underwent radical treatments should consist of clinical evaluation with, multi-phasic, high-quality, cross-sectional imaging of the chest, abdomen, and pelvis(ie,CT or MRI) every 3 to 6 months for 2 years, then every 6 months and AFP should be measured every 3 to 6 months for 2 years, then every 6 months. Surveillance imaging and AFP should continue for at least 5 years and thereafter screening is dependent on HCC risk factors.

Conditional

Follow-up of patients with advanced stages of HCC treated with systemic therapies or locoregional treatment , periodic response assessment with cross-sectional imaging including chest, multiphase abdomen, pelvis and serum level of  AFP (every 3 months)

Good practice statement

Using the mRECIST Criteria in the assessment of progression and radiological response after HCC management is recommended.

Conditional

Recommendations

Level Of recommendation

1-Screening for prostate cancer

Early PSA testing (baseline PSA followed by risk-adapted follow-up) can be offered to men >50 years, men >45 years with a positive family history of prostate cancer, and BRCA1/2 carriers >40 years

Conditional

2-Work up for newly diagnosed prostate cancer

History and physical examination

 Personal and family history, Physical examination, DRE , Assessment of ECOG performance status should be done

Strong

Assessment of life expectancy is a very essential tool in the plan of management of prostate cancer , Life expectancy should  be estimated using: The WHO’s Life Tables by country

Strong

Laboratory Studies

Base line tumor marker:  serum PSA (Total, Free )  is the recommended  initial laboratory studies for localized  prostate cancer

Strong

Radiological Studies

TRUS is  the initial imaging studies for diagnosis of  prostate cancer

MRI prostate or mpMRI (if available ) is to be used in the staging and characterization of prostate cancer

Conditional

Radiologists should utilize PI-RADS V 2.1 in the reporting of multi-parametric MRI (mpMRI) imaging

Strong

Standard MRI techniques should be used for examination of the pelvis and/or abdomen for initial evaluation of intermediate and high / very high risk patients and for planning purposes in radiotherapy protocols

Strong

Bone imaging is indicated in the initial evaluation of intermediate and high / very high risk patients to exclude skeletal metastasis

Strong

PSMA-PET if available to be considered as an alternative to standard imaging of bone and soft tissue in high and very high risk patients .

Conditional

Initial Biopsy 

Definitive diagnosis of cancer prostate requires 6- 12 core biopsies of the prostate, using a needle under transrectal / transperineal ultrasound  guidance.

Strong

For biopsy-naïve patients who have a suspicious lesion on MRI, clinicians can perform targeted biopsies of the suspicious lesion either cognitive or software guided 

Conditional

3-Risk stratification and Management of Localized / Locally advanced prostate cancer

Patients with localized prostate cancer should be classified into very low , low , intermediate ( Favourable and unfavourable)  , high and very high risk groups

Strong

Risk stratification of clinically localized prostate cancer facilitate care decisions and guide clinicians in the implementation of selected management options..

Strong

Patients with prostate cancer should be managed through a multidisciplinary team ( Urologist , Medical Oncologist , Radiation oncologist , Radiologist  and Pathologist )

Strong

It is recommended to  use one of the following options in the management of very low/low risk groups (according to MDT decision and patient preference):

If expected patient survival ≥ 10  years,:

Strong

In asymptomatic patients with prostate cancer and < 10 years life expectancy , watchful waiting is recommended

Strong

According to MDT decision and patient preference; It is recommended  to use  one of the following options in the management of favourable intermediate risk groups ( Life expectancy ≥ 10  years):

Strong

It is recommended to use  one of the following options in the management of favourable intermediate risk prostate cancer  (Expected Survival 5-10 Years ):

Strong

Brachytherapy monotherapy  is a recommended  option for patients with very low, low, or favorable intermediate-risk prostate cancer and life expectancy > 10 years  with acceptable 10-year recurrence-free survival rate for LDR/HDR brachytherapy

Strong

RP + PLND  or EBRT + short course ADT ( 6 months ) are the recommended  options for management of unfavourable intermediate risk patients.

Strong

Long term ADT ( 2- 3 years ) combined with EBRT is the recommended  primary treatment for  high risk or very high risk prostate cancer patients  

Strong

RP and PLND is a valid option in very selected cases with high or very high risk prostate cancer based on MDT discussion

Conditional

Locally advanced prostate cancer

Neoadjuvant ADT ( 4-6 months ) followed by ADT + EBRT , then ADT for 2 years  is the recommended treatment option for patients with locally advanced prostate cancer 

Strong

RP and PLND  can be an option in selected cases  of locally advanced prostate cancer according to MDT decision

Conditional

Patients who choose active surveillance program should have regular follow-up with baseline biopsy ,  serum PSA level  , Prostatic MRI  and key principles of active surveillance  include:

 PSA every 3months unless there is an earlier clinical indication

DRE  every 6 months unless there is an earlier clinical indication.

Repeat  radiological examination +/- Prostatic biopsy if there is a clinical indication

Conditional

Watchful waiting  should involve monitoring with a history and physical exam every 12 months (without surveillance biopsies) until symptoms develop.

Strong

Radical prostatectomy

RP +/- PLND is the recommended  therapy for any patient with clinically localized prostate cancer that can be completely excised surgically, Life expectancy of ≥10 years, and  has no serious comorbid conditions that would contraindicate an elective operation

Strong

Extended PLND is recomended when PLND is performed as it provides more complete staging and may cure some patients with microscopic metastases . An extended PLND includes removal of all node-bearing tissue from an area bound by the external iliac vein anteriorly, the pelvic sidewall laterally, the bladder wall medially, the floor of the pelvis posteriorly, Cooper’s ligament distally, and the internal iliac artery proximally.

 Strong

Robotic surgery could be done (if available ) in selected university hospitals after gaining sufficient learning curve

Conditional

Radiotherapy

Indications of Post-prostatectomy ART include Adverse pathologic features : Positive margins, Seminal vesicle invasion, Extracapsular extension) or persistent PSA levels (PSA does not fall to undetectable levels).

 Strong

Radiotherapy is one of the recommended modalities of radical therapy for localized prostate cancer patients without severe complications, where the results of definitive radiotherapy are comparable to radical prostatectomy for patients with similar recurrence risk.

Strong

Radiotherapy in prostate cancer is recommended to be in the treatment plan through an expert MDT and should be carried out in a well-equipped centres with trained personnel and adopting advanced EBRT techniques that include:  IMRT, VMAT , image-guided (IGRT) and SBRT facilities.

Good practice statement

Short-term precise hypo-fractionated radiotherapy can be used as it shortens the treatment course significantly while the treatment results are equivalent to those of conventional high-dose radiotherapy.

Conditional

Addition of a focal boost to the intra-prostatic lesion can be used as it improved disease free survival  for patients with localized intermediate- and high-risk prostate cancer without impacting toxicity and quality of life.

Conditional

Prophylactic nodal radiation should be considered in locally advanced prostate cancer and clinically positive nodes , and it should be dose escalated in the presence of positive nodes by imaging procedures.

Strong

Androgen deprivation therapy

ADT includes LHRH agonist as Goserline or leuprolide , first  generation antiandrogen (Bicalutamide) should be given  at least  7 days  before LHRH agonist only to avoid flare up phenomenon .

Strong

We recommend against Combined androgen blockade (medical or surgical castration combined with an antiandrogen) as it provides modest to no benefit over castration alone in patients with prostate cancer

Strong

ADT should not be used as monotherapy in clinically localized prostate cancer unless there is a contraindication to definitive local therapy, such as life expectancy less than 5 years and presence of comorbidities. Under those circumstances, ADT may be an acceptable alternative if the disease is high or very high risk

Conditional

Follow Up

For patients initially treated with definitive therapy with intent to cure, serum PSA levels should be measured every 3 months for the first 2 years then every  6 months till 5 years and then annually.

Strong

4- Management of biochemical recurrence

Laboratory Studies

 Serum PSA (Total, Free ) , PSA doubling time ( PSA DT )   are the recommended laboratory studies  for patients with biochemical recurrence

Strong

Radiological Studies

Standard MRI techniques for examination of the pelvis and/or abdomen  is recommended as part of workup for recurrence or progression

Strong

Bone imaging should be considered for the evaluation of the patient post-prostatectomy when there is failure of PSA to fall to undetectable levels, or when there is undetectable PSA after RP with a subsequent detectable PSA that increases on 2 or more subsequent determinations.

Strong

Bone imaging should be considered for the evaluation of patients with an increasing PSA or positive DRE after RT

Strong

In patients with a BCR after local therapy, prostate-specific membrane antigen (PSMA)-PET ( if available ) to be done in lieu of conventional imaging or after negative conventional imaging for further evaluation of clinical recurrence.

Conditional

Treatment of biochemical recurrence

Salvage RT in addition to Six months ADT ( concurrent / Adjuvant ) is recommended for patients with BCR following RP and with high-risk features :

( Gleason  Grade Group 4 to 5, PSADT ≤ 6months, persistently detectable post-operative PSA, seminal vesicle involvement). 

 Strong

Salvage radiation for a detectable prostate-specific antigen (PSA) after RP is more effective when given at lower levels of PSA.

Strong

Post-prostatectomy SRT is to treat prostate bed ± pelvic LN  , where PSA cut-off value for SRT (range: 0.2–0.5 ng/ml) and 0.2 ng/ml is the preferable value

Conditional

Immediate rather than deferred ADT is recommended in men with biochemical recurrence after Radiotherapy is recommended  if there are high-risk features for early metastases, including a   clinical Gleason score 8 -10, or an interval to biochemical recurrence ≤18 months after definitive radiotherapy

Strong

Salvage RP and PLND can be offered in selected cases with biochemical recurrence after Radiotherapy according to MDT decision

Conditional

5- Management of Metastatic Hormone Sensitive , Non Metastatic Castrate Resistant , Metastatic Castrate Resistant Prostate Cancer

History and physical examination

Including assessment of ECOG Performance status , Presence of peripheral neuropathy , History of seizures or cerebrovascular problems , History of cardiovascular disease and other comorbidities and  Risk of fall & fractures

Good practice statement

Laboratory Studies

 CBC, KFT’s and LFT’s, Serum Testosterone Level , HbA1c,  serum PSA (Total, Free )  , PSA DT , serum cholesterol /LDL & HDL & S triglycerides , thyroid functions   are the recommended work up for advanced prostate cancer

Good Practice statement

Imaging studies

Standard CT techniques should be used for examination of the chest , abdomen and pelvis as an initial  evaluation of advanced  prostate cancer

Strong

Bone imaging should be considered for the evaluation of patients with advanced prostate cancer

Strong

PSMA-PET if available to be considered as an alternative to standard imaging of bone and soft tissue in patients with advanced cancer prostate  .

Conditional

Echocardiogram should be done to assess the cardiac condition as it can guide further management

Strong

Pathological examination  

 Transrectal US Biopsy is recommended in cases with de novo metastatic prostate cancer

Strong

In previously treated PC with previous biopsy , we recommend against  re-biopsy from the prostate in metastatic setting

Good practice statement

Biopsy from accessible metastatic lesions to identify patients with small  cell/neuroendocrine histomorphologic features can be done in patients with metastatic CRPC

Conditional

Metastatic hormone sensitive prostate cancer

Patients with low-volume metastatic HSPC should be considered for ADT and local radiotherapy to the prostate if not previously given

Strong

ADT plus docetaxel is the standard of care in treatment of patients with high-volume metastatic HSPC

Strong

ADT plus Apalutamide  or Enzalutamide is the standard of care in treatment of patients with high-volume metastatic HSPC who are not candidate for docetaxel

Strong

Radiation therapy to the prostate should NOT be performed in men with high-volume metastatic disease outside the context of a clinical trial unless for palliative intent

Strong

Non Metastatic Castrate Resistant Prostate Cancer

Castrate levels of testosterone should be documented in patients with signs of progression, If serum testosterone levels are <50 ng/dL, the patient should undergo disease workup with bone and soft tissue imaging

Strong

Apalutamide or enzalutamide should be considered for men with non metastatic  CRPC

Strong

Metastatic Castrate Resistant Prostate Cancer

Abiraterone acetate plus prednisone + ADT is the standard of care in the management of patients with metastatic CRPC previously treated with Docetaxel

Strong

Enzalutamide +ADT is the standard of care in the management of patients with metastatic CRPC previously treated with docetaxel and not candidate for Abiraterone acetate + prednisone

Strong

Docetaxel + ADT is the standard of care in the management of patients with metastatic CRPC not previously treated with Docetaxel

Strong

Patients being treated for CRPC should  be closely monitored with radiologic imaging (CT, bone imaging), PSA tests, and clinical exams for evidence of progression.

Strong

Urgent MRI of the spine to detect cord compression is very strongly recommended in men with CRPC with vertebral metastases and neurological symptoms

Strong

6-Special  considerations

Docetaxel should be avoided in patients with ECOG PS≥ 2, IHD, presence of comorbidities, grade III/IV peripheral neuropathy , Absolute neutrophil count < 1000/mm3

Strong

Apalutamide should be avoided in patients with recent cardiovascular disease or  hypothyroidism .

Strong

Enzalutamide should be avoided in seizure prone patients or with history of seizures 

Strong

Abiraterone should be avoided in patients with uncontrolled diabetes , hepatic impairment , cardiovascular disease

Strong

Therapy should be continued until clinical progression or intolerable toxicity 

Strong

Palliative RT is recommended  for symptomatic control and prevention of complications from metastatic lesions as bone or brain .

Strong

Bisphosphonate or denosumab is recommended in patients with bone metastases from CRPC at risk for clinically significant skeletal-related events (SREs)

Strong

The use of a second AR inhibitor (abiraterone after enzalutamide  or vice versa) is not recommended

Strong

Germline testing for BRCA2 and genes associated with cancer predisposition syndromes can be done in patients with positive family history of cancer .

Conditional

Tumor testing for homologous recombination genes and mismatch repair defects (or microsatellite instability) can be considered in patients with mCRPC

Conditional

Small cell/neuroendocrine carcinoma of the prostate should be considered in patients with disease that no longer responds to ADT and are positive for metastases. These relatively rare tumors are associated with low PSA levels despite large metastatic burden and visceral disease.

Strong

Etoposite / platinum is the standard of care in the management of small cell neuroendocrine tumors of the prostate

Strong

Life style measures is recommended  to maintain bone health are recommended for men on ADT: weight-bearing exercise, stop smoking , adequate calcium intake and vitamin D status

Strong

Recommendations

Strength of the recommendation

DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY

Hematuria is the most common presenting symptom in bladder cancer and should in all cases be investigated

Strong

The diagnosis of bladder cancer is based on cystoscopic examination of the bladder and histological evaluation of tissue obtained either with cold-cup biopsy or TURBT, where complete resection of all tumor tissue should be achieved whenever possible and muscle tissue should be included in the biopsies, except when a Ta/LG is expected

Strong

Cross-sectional upper tract imaging (CT/MRI urography) is recommended to screen for synchronous UTUC, in cases of HG bladder cancer

Conditional

Pathological diagnosis should be made according to latest WHO classification

Strong

In addition to stage and grade, presence and percentage of variant histology, lymphovascular invasion and presence of muscularis propria should be reported

Strong

Urine cytology can facilitate the diagnosis of HG UC but cannot be used as the primary method of histological diagnosis

Conditional

STAGING AND RISK ASSESSMENT

Staging of NMIBC

Patients with NMIBC should be classified into four risk categories based on tumor characteristics (low , intermediate , high  and very-high-risk) as shown in table 1.

Strong

Regional and distant staging of MIBC

In patients with invasive disease (>T1), regional and distant staging should be carried out with further imaging studies such as contrast-enhanced CT of chest-abdomen-pelvis or MRI of abdomen/pelvis combined with chest CT

Strong

FDG-PET-CT may aid in the detection of LN and distant metastases, and in cases with impaired renal function.

Conditional

MANAGEMENT OF LOCAL/LOCOREGIONAL DISEASE

Treatment of NMIBC

In patients with low-risk NMIBC and those with small papillary recurrences, detected >1 year after the previous tumor, single, immediate, intravesical chemotherapy instillation, such as mitomycin C, or gemcitabine is recommended, in combination with continued cystoscopic surveillance

Strong

In patients with intermediate-risk NMIBC, additional courses of intravesical therapy are recommended, and is consisting of either instillations of Chemotherapy for a maximum of 1 year, or 12 months of BCG instillation therapy with six BCG instillations at weekly intervals, followed by three BCG instillations each at 3, 6 and 12 months

Strong

In patients with high-risk NMIBC, full dose intravesical BCG for 1-3 years (at least 1 year) is recommended with induction as previously mentioned for 6 weeks followed by instillations at 3, 6, 12, 18, 24, 30 and 36 months

Strong

Planned cystoscopic surveillance per high risk NMIBC schedule should be performed.

Strong

In case of very high risk or BCG unresponsive, radical cystectomy could be offered

Conditional

Treatment of MIBC

RC with standard PLND and protection of small intestine is the standard treatment of MIBC T2-T4a, N0 M0.

Strong

Patients with radiological suspicious node-positive disease (cN1) should be considered for preoperative platinum-based chemotherapy, however surgery can be offered in selected cases (e.g. unfit for systemic therapy, patient preference)

Strong

Organ-preservation therapy with radiotherapy, as part of multimodal schema for MIBC, is a reasonable option for patients with solitary tumors <7cm with no or unilateral hydronephrosis, and no extensive carcinoma in situ, also for patients seeking an alternative to RC and those who are medically unfit for surgery

Conditional

Contemporary organ-preservation protocols should utilize tri-modality combination of TURBT, radiotherapy and chemotherapy

Strong

Following completion of bladder preserving therapy, clinicians should perform regular surveillance with computed tomography (CT) scans, cystoscopy, and urine cytology.

Strong

Three to four cycles of cisplatin-based neoadjuvant chemotherapy should be given for MIBC

Strong

The use of adjuvant cisplatin-based Chemotherapy in patients with pathologic T3, T4, N+ after cystectomy who did not receive neoadjuvant therapy   should be considered

Strong

ddMVAC with growth factor support is the preferred regimen in the neoadjuvant setting , however Gemcitabine and cisplatin is a reasonable alternative

Strong

Carboplatin should not be substituted for cisplatin in the perioperative setting

Strong

For patients who are not candidates for cisplatin , there are no data to support a recommendation for perioperative chemotherapy

Strong

Standard radical cystectomy with curative intent need to obtain negative margins and should include removal of the bladder, prostate, and seminal vesicles in males; bladder in females and should consider removal of adjacent reproductive organs based on individual disease characteristics.

Bilateral pelvic lymphadenectomy should include removal of a minimum, the external and internal iliac and obturator lymph nodes.

Strong

Indications of Adjuvant radiotherapy after cystectomy

1-      P T3 / T4 MIBC

2-      Pathologically node positive

3-      Positive margins 

Strong

Postoperative adjuvant RT

Postoperative adjuvant RT : Treatment field should encompass areas at risk for harboring residual microscopic disease based on pathologic findings at resection and include resection bed, and  lymph nodes. Areas at risk for harboring residual microscopic disease should receive 45–50.4 Gy EBRT. Involved resection margins and areas of extranodal extension should be boosted to 54–60 Gy if feasible based on normal tissue constraints. Areas of gross residual disease should be boosted to 66–70 Gy, if feasible based on normal tissue constraints. Concurrent chemotherapy with regimens used for bladder cancer can be considered for added tumor cytotoxicity

Strong

Treatment of advanced/metastatic disease

First line systemic therapy

For Cisplatin eligible patients, gemcitabine and cisplatin or dd-MVAC (with growth factor support) regimens should be used

Strong

For Cisplatin ineligible patients, gemcitabine and carboplatin regimens should be used

Strong

Second and subsequent lines of therapy

Patients with good PS  

Second  line of therapy should  include either single agents as  gemcitabine, paclitaxel or docetaxel, or combination regimens as Gemcitabine and paclitaxel, or Ifosfamide, doxorubicin, and  gemcitabine   or other combinations

Strong

In patients with  progression free survival > 12 months after platinum ( cisplatin or carboplatin ), consider re-treatment with platinum if the patient is still platinum eligible

Conditional

 Palliative RT can be offered for palliation (bleeding, pain).

Strong

Recommendation

Strength of recommendation

     Diagnosis

· Labs

· Routine labs including LFTs, KFTs, and CBC should be included in the primary diagnosis of pancreatic cancer. 

Good practice statement

· CA 19-9 can be used as a serum marker to measure disease burden and potentially guide treatment decisions.

Good practice statement.         

· Cytology in localized pancreatic lesion, preferably by EUS guidance or biopsy from metastatic site “preferred” should be obtained before initiation of chemotherapy.

Strong

· Imaging

· Multiphasic contrast-enhanced thoracic-abdominal and pelvic CT, including late arterial phase and portal venous phase, should be used as the first-line imaging modality for suspected PC.

Strong

· We recommend imaging before biliary drainage or stenting in case of jaundice due to an obstructive head PC.

 Strong

·Imaging should be carried out in the 4 weeks before starting treatment.

Strong

·  Abdominal MRI may be used when CT cannot be carried out, or inconclusive or for pancreatic cystic lesions.

Conditional

· We do not recommend PET/CT for diagnosis of primary tumors but may be useful for staging localized tumors and in cases where the presence of distant metastases is uncertain (e.g. Doubtful imaging or high CA 19-9).

Conditional

·  Hepatic MRI is recommended before surgery to confirm the absence of small liver metastases

Strong

Pathology and immunophenotyping

· CA19-9 (or CK19 according to availability), Chromogranin (or synaptophysin according to availability) are recommended for pathologic diagnosis.

Conditional

Staging and Risk assessment

· MDT discussion in expert centers is required to define a recommended treatment strategy for patients with PC.

Good clinical practice

· Tumors should be staged according to the AJCC staging system

Strong

·  We recommend assessing resectability by anatomical NCCN criteria.

Strong

· We prefer staging laparoscopy in patients who meet any of the followings:

CA19.9 > 150U/ml, low volume ascites, tumor in the body or tail of pancreas, borderline resectable tumor (after neoadjuvant treatment), or tumor > 3 cm in size.

Conditional

Treatment of resectable PC

· We suggest performing frozen section analysis of pancreatic neck transection and of common bile duct transection margins.

Conditional

·  Tumour clearance should be defined for all margins identified by the surgeon

Good clinical practice

· For adenocarcinomas of the pancreas head and uncinate, a pancreatoduodenectomy (Whipple procedure) should be done.

Strong

· For patients with tumours in the body or tail, radical anterograde modular pancreatosplenectomy with dissection of the left hemi-circumference of the SMA to the left of the coeliac trunk is recommended.

Strong

· Standard lymphadenectomy is recommended and should involve the removal of >16 lymph nodes to allow adequate pathological staging of the disease.

Strong

· The total number of lymph nodes examined and lymph node ratio (number of involved lymph nodes as a proportion of the number of lymph nodes examined) should be reported in the pathological analysis.

Strong

· Patients undergoing surgery should receive perioperative thromboprophylaxis with either unfractionated heparin or low-molecular-weight heparin (LMWH), unless contraindicated.

Strong

· If the bilirubin level is >14 mg/l (250 mmol/l), endoscopic drainage is recommended for those planned to receive neoadjuvant treatment or those in whom surgery will be delayed for longer than 2 weeks.

Strong

· Neoadjuvant therapy is not recommended for resectable PC.

Conditional

· Following resection of PC, completion of 6 months of adjuvant Chemotherapy is strongly recommended.

Strong

·  Adjuvant mFOLFIRINOX is recommended for patients with resected PC and ECOG PS 0-1.            

Strong

· In patients who are not candidates for mFOLFIRINOX (age >75 years, ECOG PS 2 or contraindication to mFOLFIRINOX), we recommend gemcitabine-capecitabine as an alternative option.

Strong

· Adjuvant gemcitabine or 5-FU-LV should be limited to frail patients.

Strong

· Adjuvant CRT is not recommended and should not be given to patients following surgery.

Strong

Treatment of borderline resectable tumors (BRPC)

· Patients with BRPC have a high probability of an R1 resection and should be considered for induction treatment.

Strong

·  A period of induction chemotherapy (FOLFIRINOX) followed by CRT on a case-by-case basis and subsequent surgery, is recommended according to MDT recommendations

Strong

· Gemcitabine combined with oxaliplatin or capecitabine may be considered, when FOLFIRINOX is not feasible.

Strong

· CRT with capecitabine may be considered after induction Chemotherapy.

Conditional

 ·  Following induction therapy, medically fit patients without disease progression and with a decrease in CA 19-9 should undergo surgical exploration, unless contraindicated.

Strong

Treatment of locally advanced pancreatic cancer (LAPC)

· A conversion surgery strategy utilizing the standard of care of up to 6 months of combination Chemotherapy (e.g. FOLFIRINOX) should be chosen.

Strong

·  Arterial resection after induction therapy is not recommended but can be considered as a possibility in experienced centers on a case-by-case basis in selected patients according to MDT recommendations.

Conditional

Treatment of advanced pancreatic cancer

First-line treatment

· Options to treat patients with metastatic PC should be dependent on PS:

o In patients with ECOG PS 0-1 and bilirubin level <1.5 times the ULN, the regimen  

   FOLFIRINOX should be considered.

             Strong recommendation, high grade evidence (34)

o For patients with ECOG PS 2, Karnofsky PS (KPS) >70 and bilirubin level <1.5 times

   the ULN, gemcitabine-cisplatin can be considered.

             Strong recommendation, high grade evidence (34).

o For patients with ECOG PS 2, KPS <70 and/or bilirubin level >1.5 times the ULN,   

   gemcitabine monotherapy should be considered.

             Strong recommendation, high grade evidence (34).

o For patients with ECOG PS 3-4, symptom-directed and palliative care should be

   considered

              Strong recommendation, high grade evidence (34).

Strong

· The efficacy of treatment should be typically evaluated every 8-12 weeks and should be based on clinical status, CA 19-9 trajectory and imaging.

Strong

Second-line treatment

· After FOLFIRINOX treatment, gemcitabine alone may be offered to patients with ECOG PS 0-1 and a favorable comorbidity profile.

Conditional

·  Oxaliplatin-based second-line treatment (mFOLFOX6 or OFF) may be considered as an alternative in patients with ECOG PS 0-2 if not given previously.

Conditional

· For patients with ECOG PS 3-4, symptom directed, and palliative care is recommended.

Strong

· Maintenance therapy with capecitabine (after discussion with patient) may be indicated till disease progression or unacceptable toxicity on a case- by case basis according to MDT recommendations.

Conditional

Diagnostic and Staging Work up

The standard work-up for patients suspected of having EOC (Epithelial Ovarian Carcinoma) should include detailed history and clinical examination, LFTs, KFTs, serum CA-125, serum CEA and CA 19-9 in case of mucinous carcinoma and endoscopy if either or both are elevated, as well as transabdominal and transvaginal US (should be done by an expert examiner), as well as CT of thorax, abdomen and pelvis.

Strong

Pathological examination of adequate tumor sample from diagnostic biopsy or surgical specimen should be done. In case of the presence of pleural effusion, cytological assessment should be done.

Strong

The revised 2017 FIGO staging system for EOC should be used.

Strong

Management of early EOC (FIGO STAGE I-II)

Surgical staging is recommended in presumed early-stage ovarian cancer for

classification and recommendation of optimal systemic therapy.

Strong

The aim of surgery for early EOC is complete resection of the tumour and to undertake adequate staging, which should be performed by midline laparotomy and should include:

–   Inspection and palpation of the whole abdominal cavity

–   Peritoneal washing with cytological examination
–   Biopsies from all visible lesions and all abdominal fields
–   Bilateral salpingo-oophorectomy
–   Hysterectomy
–   Omentectomy
–   Appendicectomy in MC
–   Systematic pelvic and para-aortic lymphadenectomy

Strong

Fertility-sparing surgery should be considered in young patients, but always after full discussion with the patient about potential risks.

Strong

Patients with any stage IA histotype or stage IC1-2 with unilateral ovarian involvement and favorable histology (i.e. low-grade tumors) would be amenable to contralateral ovary and uterus preservation, in combination with the other recommended surgical staging procedures.

Strong

Adjuvant chemotherapy in early-stage ovarian cancer is generally recommended for FIGO stage I-IIB (see exceptions below), either paclitaxel-carboplatin or carboplatin alone (six cycles).

Strong

The benefit of adjuvant chemotherapy is uncertain and can be considered as optional for:

– Low grade serous carcinoma (LGSC) stage IB-IC

– Clear cell carcinoma (CCC) stage IA-IC1

– Low-grade endometrioid carcinoma (EC) stage IB-IC

– Expansile mucinous carcinoma (MC) stage IC

– Infiltrative MC stage IA

Conditional

For patients receiving paclitaxel-carboplatin, a minimum of three cycles are recommended except for high grade serous carcinoma (HGSC) /high-grade endometrioid carcinoma (EC) or any stage IC-II regardless of histotype, for which six cycles should be administered.

Strong

Adjuvant chemotherapy is not recommended in completely staged patients with LGSC stage IA, low-grade EC stage IA or expansile MC stage IA-IB.

Conditional

Management of advanced EOC (FIGO STAGE III-IV)

Patients with advanced EOC should be evaluated for primary cytoreductive surgery (PCS) by a specialized team, with the aim of achieving complete cytoreduction (absence of all visible residual disease).

Strong

When complete cytoreductive surgery is feasible, PCS is recommended; otherwise, obtaining adequate biopsy tissue for histology and molecular testing is recommended.

Strong

PCS should aim to maximal surgical effort and may require intestinal resection, diaphragmatic and peritoneal stripping, splenectomy and removal of bulky para-aortic lymph nodes and, in some cases, extra-abdominal disease.

Strong

We recommend against systematic lymphadenectomy in patients with macroscopic complete resection and clinically negative nodes as this may lead to unnecessarily increases the rate of post-operative complications and mortality and should not be done.

Strong

PCS is also recommended in patients with less chemo-sensitive subtypes (e.g. MC or LGSC), even if uncertainty about achieving complete resection exists and a small residual tumour (<1 cm) is likely to remain.

Strong

When complete cytoreductive surgery is not feasible, neoadjuvant chemotherapy (NACT) for three cycles followed by interval cytoreductive surgery (ICS) and three cycles of paclitaxel-carboplatin are recommended, + staging laparoscopy. 

Strong

Consider the use of bevacizumab in the neoadjuvant setting, before interval cytoreductive surgery (ICS).

Conditional

When ICS is not possible, and in the absence of overt disease progression, three additional cycles of paclitaxel-carboplatin alone or with bevacizumab are recommended.

Strong

Paclitaxel (175 mg/m2)-carboplatin (AUC 5-6) every 3 weeks for six cycles is the standard first-line chemotherapy in advanced ovarian cancer.

Strong

We recommend the schedule of weekly chemotherapy with paclitaxel (60 mg/m2)-carboplatin (AUC 2) as an alternative in frail patients.

Strong

Bevacizumab may be considered in addition to paclitaxel-carboplatin in high-risk patients, (defined as patients with stage III and macroscopic residual tumour >1 cm or stage IV).

Conditional

Bevacizumab dose, if given, should be 7.5 mg/kg and the duration of treatment is 12 months.

Strong

Intraperitoneal chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) are not considered a standard of care in first-line treatment.

Conditional

Maintenance with anti-estrogen therapy after first-line platinum-based chemotherapy can be considered in ER positive low grade serous carcinoma (LGSC) or grade I endometrioid carcinoma.

Conditional

Other recommended regimens (other than paclitaxel/carboplatin regime) such as docetaxel/carboplatin or 5FU/ calcium leucovorin/oxaliplatin or Capecitabin/Oxaliplatin specially in mucinous carcinoma may be used

Conditional

Management of recurrent EOC.

The following should be assessed when selecting treatment for patients with recurrent disease:

– Histotype

– Number of prior lines of treatment

– Exposure and response to prior treatment

– TFIp (treatment-free interval from last platinum)

– Possibility of achieving a complete secondary surgical cytoreduction

– Residual chemotherapy toxicity

– The patient’s general condition and preferences

Good Practice Statement

Patients with first relapse of ovarian cancer after >6 months of last platinum administration should be evaluated by a team experienced in surgery for ovarian cancer to identify potential candidates for surgical cytoreduction.

Strong

Patients who have previously responded to platinum without early symptomatic relapses (after >6 months) should be treated with either a platinum-based doublet (paclitaxel or gemcitabine with bevacizumab) or single agent (liposomal doxorubicin).

The selection should be based on safety and patient preference.

Strong

If combination therapy is contraindicated, carboplatin monotherapy remains an option.

Strong

Treatment is usually recommended for four to six cycles.

Strong

Bevacizumab should be continued until disease progression (symptomatic) or the next line of treatment is started, as continuation of bevacizumab beyond progression has not been evaluated in the recurrent setting.

Strong

Platinum rechallenge following treatment with a platinum regimen (monotherapy or combination) should be considered if the tumour is not refractory or resistant.

Strong

Patients with relapsed EOC for whom platinum is not an option should be defined by:

– Proven refractory (progression during platinum)

– Expected resistance (early symptomatic progression

post-platinum, response to rechallenge unlikely)

– Platinum intolerance

– Patient choice

– QoL issues

Good Practice Statement

For patients who are not candidates to receive platinum, integrating palliative care early in the treatment pathway is strongly recommended.

Good Practice Statement

Single-agent non-platinum options that are recommended include weekly paclitaxel, a combination of gemcitabine and oral etoposide, navelbine, or metronomic cyclophosphamide.

Strong

Bevacizumab should be recommended in combination with weekly paclitaxel, or topotecan in patients without contraindications to bevacizumab (e.g. increased risk of intestinal fistulae, history of bowel obstruction or serosal invasion).

Strong

Hormonal therapy ((e.g. aromatase inhibitors, tamoxifen or luteinising hormone-releasing hormone agonists) is recommended for relapsed LGSC with ER and/or PgR expression.

Strong

Surveillance

Surveillance of ovarian cancer patients can include CA-125 determination, physical examination and CT scan evaluation, first year: every three months, second year: every six months, and annually thereafter.

Good Practice Statement

Diagnostic and Staging Work up

Diagnostic and staging work up should include history and

physical examination, complete blood count, as well as liver function and renal function studies.

Good practice statement

We recommend cervical cytology or Papanicolaou (Pap) smears and cervical biopsies for diagnosis.

Strong recommendation

We recommend cone biopsy (i.e., conization) if the cervical biopsy is inadequate to define invasiveness or if accurate assessment of microinvasive disease is required.

Strong recommendation

Recommended radiologic imaging includes pelvic MRI, and FDG-PET/CT.

Strong recommendation

Consider examination under anesthesia (EUA) cystoscopy/proctoscopy for cases having ≥ stage IB.

Good practice statement

Consider options for fertility sparing or referral to reproductive endocrinology and infertility.

Conditional recommendation

Staging and risk assessment.

Tumor risk assessment should include tumor size, stage, depth of tumor invasion, lymph node status, LVSI and histological subtype.

Strong recommendation

Management of local/locoregional disease,

Surgery

Surgical therapy in cervical cancer should be adapted to the stage of disease according to FIGO and TNM classification (Appendix).

Good practice statement

Surgery should only be considered in patients with earlier stages of cervical cancer (up to FIGO IIA) without risk factors necessitating adjuvant therapy, which results in a multimodal therapy without improvement of survival but increased toxicity.

Strong recommendation

Microinvasive cervical cancer (stage IA1) without LVSI should be managed with conisation or simple trachelectomy to preserve fertility, and simple hysterectomy is recommended if the patient does not wish to preserve fertility.

Strong recommendation

In stage IA1 with LVSI, surgical assessment of pelvic lymph nodes is recommended.

Strong recommendation

In patients with FIGO stage IA2, IB and IIA, radical hysterectomy with bilateral lymph node dissection (with or without SLN) is standard treatment, if the patient does not wish to preserve fertility.

Strong recommendation

Adjuvant/neoadjuvant treatment

Consider NACT with surgery as this may reduce the need for adjuvant RT.

Conditional recommendation

Intermediate-risk surgicopathologic findings, frequently referred to as Sedlis criteria, are defined by a combination of lymphovascular space involvement, depth of stromal invasion, and tumor size (Table 5, appendix), and they should be treated by whole pelvic RT delivered to a total dose of 4500 to 5040 cGy, in 180 Gy per fraction or 4000 to 4400 Gy in 200 Gy per fraction.

Strong recommendation

Adjuvant CRT is recommended in high-risk patients (one or more negative prognostic factors such as positive or close surgical margins, positive lymph nodes or microscopic parametrial involvement). For these patients, whole pelvic RT should be delivered to a total dose of 4500 to 5040 cGy, in   180 cGy fractions, with concurrent weekly cisplatin (40mg/m2).

Strong recommendation

Chemoradiotherapy in locally advanced cervical cancer

We recommend CRT  for patients with bulky IB2–IVA disease, and the most commonly used regimen is weekly cisplatin 40 mg/m2.

Strong recommendation

Patients not eligible to cisplatin may receive carboplatin or gemcitabine.

Strong recommendation

Brachytherapy is needed to obtain a sufficiently high dose to ensure a high rate of local control in advanced cases.

Good practice statement

Management of advanced/metastatic disease

Palliative chemotherapy with the aim of relieving symptoms and improving quality of life is recommended if the patient has a PS< 2 and no formal contraindications.

Strong recommendation

Cisplatin-based doublets with paclitaxel or topotecan have demonstrated superiority to cisplatin monotherapy in terms of response rate and PFS.

Strong recommendation

Paclitaxel and cisplatin combined with bevacizumab is recommended as the preferred first-line regimen in metastatic or recurrent cervical cancer based on the balance between efficacy and toxicity profile.

Strong recommendation

The combination of paclitaxel and carboplatin is recommended as an alternative for patients that are not candidates for cisplatin.

Strong recommendation

Some patients develop small lung metastases only, which do not rapidly progress and can be managed with stereotactic RT and/or a watchful waiting policy, frequently delaying systemic chemotherapy for a significant period of time.

Conditional recommendation

Local recurrence of cervical cancer following radical surgery

Higher doses of RT can be delivered with brachytherapy and increase the likelihood of local control for patients with small volume central recurrences.

Strong recommendation

Clinical indicators  

Follow-up visits with a complete physical examination including a pelvic–rectal exam and a patient history should be conducted by a physician experienced in the surveillance of cancer patients.

Good practice statement

CT or PET/CT scan should be carried out as clinically indicated. A reasonable follow-up schedule involves follow-up visits every 3–6 months in the first 2 years and every 6–12 months in years 3–5.

Good practice statement

Patients should return to annual population-based general physical and pelvic examinations after 5 years of recurrence-free follow-up.

Good practice statement 

Recommendations

Strength of recommendations  

Diagnosis, initial staging and risk assessment

Diagnosis, initial staging and risk assessment should include physical examination, full and differential blood count, liver and renal function tests, endoscopy and contrast enhanced CT scan with oral and IV contrast of the thorax, abdomen and pelvis.

Strong

Diagnosis should be made from multiple (5-8) endoscopic biopsies to guarantee an adequate representation of the tumour.

Strong

The histological diagnosis should be reported according to WHO criteria.

Strong

HER2 expression by IHC and/or amplification by in situ hybridisation is a validated predictive biomarker for drug therapy and is recommended in case of adenocarcinoma and metastatic disease.

Strong

Accurate assessment of T and N stage by EUS in potentially operable tumours to determine the proximal and distal extent of tumour is preferred

Conditional

Assessment of nutritional status to detect relevant dietary and nutritional deficiencies in both localised and advanced disease settings is recommended.

Good practice statement.

FDG/PET/CT may be used as problem solving tool only

Conditional

Diagnostic laparoscopy and peritoneal washings for cytology are recommended for patients with resectable gastric cancer who are also candidates for perioperative chemotherapy as patients with cytology positive samples are uncertain candidates for curatively-intended surgical resection.

Strong

Management of local and locoregional disease

Multidisciplinary treatment planning before any treatment decision is mandatory.

Good practice statement

Surgery

Endoscopic or surgical resection alone is appropriate for selected very early tumours (stage Tis, IA).

Strong

For stage IB-III gastric cancer, peri-operative therapy and radical gastrectomy is recommended.

Strong

Patients should undergo D2 resection in a high-volume surgical centre.

Strong

En bloc resection of involved structures should be done for T4b tumors.

Strong

Routine splenectomy is not indicated unless the spleen is involved or extensive hilar adenopathy is noted.

Strong

Consider placing feeding tube in selected patients undergoing total gastrectomy (especially if postoperative chemoradiation appears a likely recommendation).

Good practice statement

Peri-operative chemotherapy

Peri-operative (pre- and post-operative) chemotherapy is recommended for patients with stage >IB resectable gastric cancer.

Strong

A triplet chemotherapy regimen including a fluoropyrimidine, a platinum compound and docetaxel should be given in case of good perforance status (ECOG PS 0-1).

Strong

Peri-operative use of FLOT is standard of care for patients who are able to tolerate a triple cytotoxic drug regimen (ECOG PS 0-1).

Strong

For patients unfit for triplet Chemotherapy, a combination of a fluoropyrimidine with cisplatin or oxaliplatin is recommended.

Strong

Adjuvant treatment

For patients with stage >IB gastric cancer who have undergone surgery without administration of preoperative chemotherapy, adjuvant chemotherapy is recommended.

Strong

For patients undergoing peri- or post-operative chemotherapy, we recommend against the addition of post-operative RT.

Strong

For patients who have not received preoperative chemotherapy and have not undergone an appropriate D2 lymphadenectomy, adjuvant CRT (see annex 3) can be considered.

Conditional

For patients who have undergone surgery with involved margins (R1), adjuvant RT or CRT (see annex 3) might be considered as an individual recommendation, but is not standard.

Conditional

Management of advanced and metastatic disease

First-line systemic therapy

First-line chemotherapy with a platinum and fluoropyrimidine is recommended. Oxaliplatin is preferred, especially for older patients.

Strong

Irinotecane 5-FU can be considered an alternative option for patients who do not tolerate platinum compounds.

Strong

Trastuzumabe chemotherapy is recommended in patients with adenocarcinoma HER2-positive tumours.

Strong

Second- and later-line treatment

Treatment with trastuzumab is not recommended after first-line therapy in HER2-positive advanced gastric cancer.

Strong

Alternative treatments include a taxane, irinotecan, or capecitabine.

Strong

Surgery for metastatic gastric cancer

Gastrectomy is not recommended in metastatic gastric cancer unless required for palliation of symptoms.

Conditional

Resection of metastases cannot be recommended in general, but might be considered as an individual approach in highly selected cases with oligometastatic disease and response to chemotherapy.

Conditional

Supportive care and nutrition

Care for patients with gastric cancer should include an early palliative care referral and nutritional support.

Strong

Surveillance   

Regular follow-up is recommended for investigation and treatment of symptoms, psychological support and early detection of recurrence

Strong

Follow-up should be tailored to the individual patient and stage of disease

Strong

Dietary support is recommended with attention to vitamin and mineral deficiencies

Strong

In the advanced disease setting, regular follow-up is recommended to detect symptoms of disease progression before significant clinical deterioration

Strong

Radiological investigations, specifically CT with oral and IV contrast of the thorax and abdomen, and pelvis should be carried out every 6-12 weeks in patients who are candidates for further cancer specific therapies

Strong

Recommendations

Strength of the recommendation

Diagnosis, pathology and molecular biology

At first diagnosis of MBC, a biopsy should be carried out to confirm histology and assess/re-assess tumour biology including ER, PgR, HER2 status & KI 67.

Strong

Staging and risk assessment

The minimum imaging work-up for staging includes computed tomography (CT) of the chest and abdomen, and bone scintigraphy.

Strong

18F-FDG-PET)/CT may be used instead of CT and bone scans only as problem solving tool.

 Conditional

 The interval between imaging and starting treatment should be ≤4 weeks.

Good practice statement.

Evaluation of response should generally occur every 2-4 months depending on disease dynamics, location, extent of metastasis and type of treatment.

Good practice statement.

Disease monitoring intervals should not be shortened as there is no evidence of an OS benefit but potential for emotional and financial harm. Less frequent monitoring is acceptable, particularly for indolent disease.

Good practice statement.

If progression is suspected, additional tests should be carried out in a timely manner irrespective of planned intervals.

Good practice statement.

Repeat bone scans are a mainstay of evaluation for bone-only/predominant metastases, but image interpretation may be confounded by a possible flare during the first few months of treatment. MRI may be added to define response in specific locations.

 Conditional

 Impending fracture risk should be evaluated by CT or X-rays. In the case of suspected cord compression, MRI is the modality of choice.

Strong

Symptomatic patients should always undergo brain imaging, preferably with MRI.

Strong

HR-positive, HER2-negative breast cancer

First Line.

A CDK4/6 inhibitor combined with endocrine therapy (ET) may be used as first-line therapy for patients with ER-positive, HER2-negative MBC. However this depends  on the availability, access-ability, patient comorbidity, and budget impact.

Conditional

Pre- and perimenopausal women should be offered OFS or ovarian ablation in addition to all endocrine-based therapies.

Strong

Second-line treatment.

Selection of second-line therapy (chemotherapy versus further endocrine-based therapy) should be based on disease aggressiveness, extent and organ function, and consideration of the associated toxicity profile.

Good practice statement.

Everolimus- exemestane is a recommended option.

Strong

Tamoxifen or fulvestrant can also be combined with everolimus and is recommended. If everolimus is used, stomatitis prophylaxis must be used.

Strong

At least two lines of endocrine-based therapy are preferred before moving to chemotherapy in the absence of endocrine refractory disease and/or imminent organ failure.

Strong

 In patients with imminent organ failure, chemotherapy is the preferred option.

Strong

For patients with endocrine-sensitive tumours, continuation of ET with agents not previously received in the metastatic setting is recommended.

Strong

Beyond second-line treatment

Patients with tumours that are endocrine resistant should be considered for chemotherapy.

Strong

Sequential single-agent chemotherapy is generally preferred over combination strategies. In patients where a rapid response is needed due to imminent organ failure, combination chemotherapy is preferred.

Strong

Available drugs for single-agent chemotherapy include anthracyclines, taxanes, capecitabine, vinorelbine, and platinums.

Strong

HER2-positive breast cancer

Standard first-line treatment of HER2-positive MBC should be trastuzumab-docetaxel regardless of HR status.

Strong

Docetaxel should be given for at least six cycles, if tolerated, followed by maintenance trastuzumab until progression.

Strong

An alternative taxane (paclitaxel) can be substituted for docetaxel.

Strong

ET can be added to trastuzumab maintenance after completion of chemotherapy for HER2-positive, HR-positive .

Strong

If chemotherapy is contraindicated in patients with HER2-positive, HR-negative MBC, HER2-targeted therapy without chemotherapy (e.g. trastuzumab) is recommended.

Strong

if taxane chemotherapy is contraindicated, a less toxic chemotherapy partner (e.g. capecitabine or vinorelbine) should be considered.

Strong

In selected cases of HER2-positive, HR-positive MBC where the patient is not suitable for first-line chemotherapy, ET (e.g. an AI) in combination with an HER2-targeted therapy, such as trastuzumab, or lapatinib, can be recommended.

Strong

The use of single-agent ET without HER2-targeted therapy in HER2-positive, HR-positive MBC is not routinely recommended unless comorbidities (e.g. cardiac disease) preclude the safe use of HER2-directed therapies.

Conditional

 Patients with metastatic recurrence within 12 months of receiving adjuvant trastuzumab should follow the second-line therapy recommendations.

Strong

In later lines of therapy, lapatinib is an evidence-based therapy option to be used preferably in combinations (e.g. with capecitabine, trastuzumab or ET).

Conditional

TNBC

In cases of imminent organ failure, combination therapy is preferred based on a taxane and/or anthracycline combination.

After progression, all chemotherapy recommendations for HER2-negative disease also apply for TNBC, e.g. capecitabine, and vinorelbine.

Site-specific management

Primary stage IV disease

For patients with newly diagnosed stage IV breast cancer and an intact primary tumour, therapeutic decisions should ideally be discussed in a multidisciplinary context.

Good practice statement.

Locoregional treatment of the primary tumour in the absence of symptomatic local disease does not lead to an OS benefit and is not routinely recommended.

Good practice statement.

 In patients with local symptoms caused by the primary tumour or metastatic disease, the use of local treatment modalities should be evaluated.

Strong

Surgery of the primary tumour is recommended for patients who may benefit from salvage surgery (e.g. those with bone-only metastases, a good response to initial systemic therapy, HR-positive tumours, HER2-negative tumours, age <55 years and those with OMD).

Strong

Surgery or RT of the primary tumour should be carefully considered for circumstances in which they provide added value for symptom palliation or prevention of complications.

Conditional

Oligometastatic disease

A multidisciplinary approach is essential to manage patients with bone metastases and prevent skeletal-related events (SREs).

Good practice statement.

Patients with OMD should be discussed in a multidisciplinary context to individualise management.

Good practice statement.

Multimodality treatment approaches involving locoregional therapy [e.g. high conformal radiotherapy (RT), image-guided ablation,selective internal RT and/or surgery] combined with systemic treatments are recommended, and should be tailored to the disease presentation in the individual patient.

Strong

Local ablative therapy to all metastatic lesions may be offered on an individual basis after discussion in a multidisciplinary setting.

Conditional

Bone metastases and bone-modifying agents

A multidisciplinary approach is essential to manage patients with bone metastases and prevent skeletal-related events (SREs).

Strong

 An orthopaedic evaluation is advised in the case of significant lesions in the long bones or vertebrae as well as in patients with MSCC to discuss the possible role of surgery.

Strong

RT is recommended for lesions at moderate risk of fracture and those associated with moderate to severe pain.

Strong

A single 8-Gy RT fraction is as effective as fractionated schemes in patients with uncomplicated bone metastases.

Strong

RT should be delivered after surgery for stabilisation or separation surgery for MSCC.

Strong

Bone-modifying agents (BMAs) are recommended for patients with bone metastases,regardless of symptoms.

Strong

Before the initiation of BMAs, patients should have a complete dental evaluation and ideally complete any required dental treatment. Calcium and vitamin D supplements should be prescribed.

Strong

 The optimal duration of BMA therapy has not been defined but it is reasonable to interrupt therapy after 2 years for patients in remission.

Good Practice Statement

The ideal sequence of therapies has not been defined but it seems reasonable to document tumour response with a systemic treatment before suggesting locoregional therapy.

Conditional

Brain metastases and leptomeningeal metastases

Brain metastases should be managed according to the recommendations outlined in the European Association of Neuro-Oncology-ESMO (EANO-ESMO) Clinical Practice Guideline (CPG) for the management of patients with brain metastases from solid tumours.

Strong

Leptomeningeal metastases should be treated according to the recommendations outlined in the EANO-ESMO CPG for the management of patients with leptomeningeal metastases from solid tumours.

Strong

Long-term implications and survivorship

An interdisciplinary approach is critical, including specialised oncology and/or breast care nurses to proactively screen for and manage treatment-emergent toxicities.

Good practice statement.

Patients should be informed about treatment choices and side-effect profiles of recommended systemic treatments.

Good practice statement.

All treatments should include formal patient education regarding side-effects of  management.

Strong

All efforts should be done to encourage integrated electronic medical records (EMR) in different hospitals.

Strong

QoL assessments should be incorporated into the evaluation of treatment efficacy.

Strong

Dose reduction and delay are effective strategies to manage toxicity in advanced disease.

Strong

Recommendations

Strength of the recommendation

DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY

l  From diagnosis, a dedicated multidisciplinary team (MDT) of expert medical oncologists, radiologists, surgeons, radiation oncologists and pathologists should attend regular meetings to discuss patients

Good practice statement.

l  A full medical history and physical examination, including digital rectal examination (DRE), complete blood count, liver and renal function tests and measurement of serum CEA, should be carried out

Good practice statement.

l  Preoperative colonoscopy to the caecal pole and MRI are recommended to determine tumour level. Tumor height must be defined: low = 0 to <5 from anal verge , mid 5 to <10 cm, upper >10 cm.

Strong

l  ERUS (if available) is recommended for T staging of localized tumors in cases of cT1 versus cT2.

Conditional

l  MRI (rectal protocol) is mandatory as part of the staging work-up to stratify for risk-adapted treatment

Strong

l  MRI reports should include description of tumour infiltration depth, node status, lateral lymph nodes, EMVI status and MRF status

Strong

l  The recommended high-risk criteria are cT4a or cT4b, involved or threatened mesorectal fascia (MRF+), cN2 (4 uspicious nodes), EMVI + and lateral lymph node enlargement of 7 mm .

Strong

l  Contrast-enhanced CT of the chest and abdomen is recommended for distant staging (if possible)

Strong

l  Fertility risk discussion is recommended in appropriate patients.

Good practice statement.

MANAGEMENT OF LOCALISED DISEASE

RT and CRT

For lower or middle third tumours when surgery is intended:

l  Preoperative RT followed by LE cannot generally be recommended in patients with cT2 N0 tumours <4 cm  but may be considered for selected patients (e.g. elderly or frail patient at high surgical risk).

Conditional

l  Neoadjuvant SCRT or CRT (not TNT) is recommended for patients with cT2 N+, cT3 N0 or cT3 N1 tumours.

Strong

For lower or middle third tumours when watch-and-wait approach is intended:

l  SCRT or CRT is recommended for patients with cT1-cT2 N0 tumours.

Strong

Total neoadjuvant therapy (TNT).

l  RT should be offered as long-course CRT (50-50.4 Gy in 25-28 fractions with concomitant capecitabine or infusional 5-FU) or SCRT (25 Gy in five fractions)

Strong

l  Consolidation or induction chemotherapy (CAPOX or FOLFOX) should be administered for 4-6 cycles (i.e. 3-4.5 months)

Strong

l  If FOLFIRINOX regimen is used, it may be administered in line with the protocol of the PRODIGE 23 trial (indications and doses), see Annex.

Conditional

For upper third tumours:

l  TNT should be offered to patients with cT4 or involved or threatened MRF.

Strong

l  CRT or SCRT should be considered if TNT is not feasible.

Strong

For lower or middle third tumours when surgery is intended:

l  TNT should be offered to patients with high-risk criteria.

Strong

For lower or middle third tumours when watch-and-wait approach is intended:

l  TNT is recommended for patients with high-risk criteria and patients with cT2 N+ or cT3 any N

Strong

l  Upfront CRT followed by consolidation chemotherapy is recommended to increase the likelihood of cCR.

Strong

Neoadjuvant Chemtherapy

l  When considering neoadjuvant chemotherapy, the inclusion criteria of the PROSPECT study should be used (T2 N+, T3 any N, distance to the CRM ≥3 mm, continence-preserving surgery possible).

Strong

l  Neoadjuvant chemotherapy should comprise 3 months of CAPOX or FOLFOX .

Strong

For upper third tumours:

l  Neoadjuvant chemotherapy is recommended for patients with cT2 N+ or cT3 any N disease.

Strong

l  Neoadjuvant chemotherapy is recommended for patients with cT4 any N disease.

Strong

For lower or middle third tumours when surgery is intended:

l  Neoadjuvant chemotherapy is recommended for patients with cT2 N+, cT3 N0 or cT3 N1 disease.

Strong

l   Salvage RT is recommended in case of intolerance to, or progression on, neoadjuvant chemotherapy.

Strong

Restaging before surgery or watch-and-wait approach

l  Restaging should comprise MRI, endoscopy and DRE.

Strong

l  In case of a cCR, biopsies are not recommended to determine a watch-and-wait approach, as their value in this setting is unclear.

Strong

Surgery

l  PME and TME are the recommended surgical procedures for rectal cancer

Strong

l  Open surgery and minimally invasive approaches are both recommended as they lead to similar oncological results

Strong

l  A distance of >1 mm from tumour to CRM and other organs is recommended.  In case of MRF + or T4b, beyond TME surgery is recommended.

Strong

l  The distal mesorectal margin should be >5 cm.

Strong

l  A distal resection margin of  >1 cm is recommended.

Strong

l  Lateral lymph nodes with a short axis of >7 mm should be resected after neoadjuvant treatment

Strong

For upper third tumours:

l   PME and TME are both equally recommended.

Strong

l  LE is recommended as an alternative to PME or TME for low-risk tumours (pT1 without unfavourable pathological features).

Strong

For lower or middle third tumours when surgery is intended:

l  TME is the recommended surgical procedure.

Strong

l  LE should be considered as an alternative to TME for low-risk tumours (pT1 without unfavourable pathological features).

Strong

For lower or middle third tumours when watch-and-wait approach is intended:

l  Surgery, with the resection method depending on clinical assessment, is recommended for patients who do not achieve a cCR following CRT or TNT

Strong

l  In case of local (endorectal) regrowth after a watch-and-wait procedure, salvage resection should be offered to all patients.

Strong

Watch and wait approach

l  For lower or middle third tumours, a watch-and-wait strategy is recommended in patients with cCR when organ preservation is intended.

Strong

l  Discussion with patients about the importance of adherence to strict follow-up investigations is mandatory.

Good Practice Statement

l  Follow-up examinations should comprise MRI, endoscopy and DRE every 3 months for the first 2 years and every 6 months thereafter. CT scans of the chest and abdomen should be carried out every 6 months for the first 2 years and annually thereafter.

Strong

Adjuvant therapy

For upper third tumours:

Adjuvant Chemotherapy with a fluoropyrimidine and (potentially) oxaliplatin should be offered (according to clinical risk assessment) following PME or TME alone.

Strong

In patients who did not receive preoperative RT, adjuvant CRT should be offered in case of CRM positivity, pT4b, pN2 with extracapsular spread close to the MRF or poor-quality TME.

Strong

For lower or middle third tumours after surgery:

l  Adjuvant therapy with a fluoropyrimidine and (potentially) oxaliplatin should be offered (according to clinical risk assessment) following TME alone.

Strong

l  Adjuvant therapy with a fluoropyrimidine and (potentially) oxaliplatin is recommended after neoadjuvant CRT or SCRT.

Strong

l  In patients who did not receive preoperative RT, adjuvant CRT should be offered in case of CRM positivity, pT4b, pN2 with extracapsular spread close to the MRF or poor-quality TME.

Strong

For lower or middle third tumours for watch-and-wait approach:

l  An adjuvant fluoropyrimidine oxaliplatin combination can be offered on a case-by-case basis after RT or fluoropyrimidine-based CRT in patients achieving cCR with initial cN+ disease

 Conditional

l  Post-neoadjuvant systemic treatment following TNT (irrespective of surgical or nonsurgical local approach) cannot be generally recommended due to toxicity considerations. This approach should be discussed individually within an MDT.

Conditional

FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP

l  Proactive surveillance for local recurrence can be considered in patients at high risk of recurrence (e.g. involved CRM).

Good practice statement.

l  Clinical assessment should be carried out every 3 months for 2 years

Good practice statement.

l  Serum CEA measurements can be recommended every 3-4 months for the first 3 years.

Good practice statement.

l  Annual (minimum) CT scan of the chest, abdomen and pelvis can be recommended after the first 2 years for detection of distant metastases.

Good practice statement.

l  A completion colonoscopy is recommended within the first year (preferably after 6 months) if not carried out at the time of diagnostic work-up (e.g. if an obstruction was present)

Good practice statement.

l  Medical history and colonoscopy with resection of colonic polyps can be recommended every 5 years up to the age of 75 years

Good practice statement.

l  Long-term side-effects of treatment should be monitored

Good practice statement.

Recommendations

Strength of the recommendation

Diagnostic work-up for localized colon cancer

In the absence of a bowel obstruction or massive haemorrhage, which may constitute indications of an urgent tumour resection, a total colonoscopy is recommended for diagnostic confirmation of colon cancer as there are many advantages of endoscopy  including determination and marking of the exact tumour location, biopsy of the lesion, and detection and removal of (further) synchronous precancerous or cancerous lesions.

Strong

In cases where complete colonic exploration cannot be carried out before surgery, a complete colonoscopy should be carried out within 3 to 6 months.

Strong

A complete work-up should be carried out to achieve an accurate histological diagnosis of the primary tumor, assess the baseline characteristics of the patient and determine the extent of the disease.

 Strong

Besides a comprehensive physical examination, blood tests including complete blood count and chemistry profile should be performed.

Strong

In addition, serum levels of CEA (although not sufficient for colon cancer diagnosis themselves in the absence of a confirmatory tumor biopsy) should be evaluated before surgery and monitored during the follow-up period to help the early detection of metastatic disease.

Strong

CT of the thoracic, abdominal and pelvic cavities with i.v. contrast administration is the preferred radiological method for the evaluation of the extent of CRC.

Strong

Contrast-enhanced MRI constitutes the reference test for evaluation of the relationship of locally advanced tumors with surrounding structures or in defining ambiguous hepatic lesions.

Strong

FDG/PET,with or without integrated CT (PET/CT), does not add significant information to the CT scans on preoperative staging of CRC and is not recommended for routine use in staging of localized CRC except if assisting in interpretation of ambiguous findings.

Strong

MANAGEMENT OF LOCAL/LOCOREGIONAL DISEASE

General recommendations

En bloc endoscopic resection of the polyp is recommended and sufficient for non-invasive (pTis, i.e. intraepithelial or intramucosal) adenocarcinomas.

Strong

The presence of invasive carcinoma (pT1) in a polyp should require a thorough review with the pathologist and surgeon. High-risk features mandating surgical resection with lymphadenectomy include lymphatic or venous invasion, grade 2 or 3 differentiation, or tumour budding.

Strong

Laparoscopic colectomy can be safely carried out for colon cancer when technical expertise is available in the absence of contraindications, in view of reduced morbidity, improved tolerance and similar oncological outcomes.

Conditional

Obstructive CRCs can be treated in one- or two-stage procedures, as indicated.

Strong

A standard surgical/pathological report should include specimen description and surgical procedure, tumour site and size, macroscopic tumour perforation, histological type and grade, extension into the bowel wall and adjacent organs, distance of cancer from resected margins (proximal, distal and radial), presence or absence of tumour deposits, lymphovascular and/or perineural invasion, tumour budding, site and number of removed and involved regional lymph nodes, and involvement of other organs.

Strong

Adjuvant therapy options should be fully discussed with the patient, taking into consideration tumour risk of recurrence, expected benefit from chemotherapy and risk of complications.

Good Practice Statement

The risk of relapse after a colon cancer resection should be assessed by integrating the TNM staging, biologic profile and number of lymph nodes sampled.

Strong

Other additional clinicopathological features such as the histological subtype and grading, lymphatic or venous or perineural invasion, lymphoid inflammatory response ,involvement of resection margins and bowel obstruction should be taken into consideration for refining the risk assessment on stage II tumours.

Strong

It can be generalised that benefits of treatment with fluoropyrimidines alone or with oxaliplatin, seems to be more limited with a higher likelihood for toxicity in older patients.

Conditional

Management of stage II and III disease

Stage III disease

Combinations of fluoropyrimidines, either 5-FU or capecitabine, and oxaliplatin constitute the basis for stage III colon cancer adjuvant treatment.

Strong

Further adaptation of the treatment according to risk subgroups: 3 months for CAPOX or 3-6 months for folfox (T 1-3 N1 disease), 3-6 months for CAPOX or 6 months for FOLFOx (T4 or N2 disease)based on IDEA collaboration should be made with caution, since this was based on a post-hoc analysis, non-significant for interaction (see Annex 4).

Strong

The length of oxaliplatin-based adjuvant treatment of stage III colon cancer based on the IDEA data should be tailored to 3 or 6 months for CAPOX or 6 months for FOLFOX, and  also taking into consideration pathological risk characteristics, patient comorbidity and risk assessment (see Annex 4).

Strong

For patients not fit for or not tolerating oxaliplatin, either capecitabine or LV5FU2 (de Gramont) infusion are acceptable alternative adjuvant regimens for a 6-month duration.

Strong

Stage II disease

For patients with low-risk stage II colon cancer (see Annex 3), follow-up is recommended or consider capecitabine (6 mo) or                        5-FU/leucovorin (6 mo)

Strong

For patients with intermediate risk (non-MMR/MSI + any risk factor except pT4 or multiple intermediate risk factors, regardless of MSI) consider the addition of oxaliplatin (see Annex 3).

Conditional

Patients with high-risk stage II colon cancer (see Annex 3) are to be  considered for 3 months of CAPOX, as the IDEA-pooled analysis showed non-inferiority of 3 months of CAPOX and inferiority of 3 months of FOLFOX when compared with 6 months of FOLFOX, with all the limitations of post-hoc analyses (see Annex 4).

Strong

Follow up

Intensive follow-up allows earlier detection of relapses in patients at risk

Strong

History and physical examination and CEA level determination are advised every 3-6 months for 2 years and every 6 months for the following 3 years.

Strong

Colonoscopy must be carried out at year 1 and if advanced adenoma, repeat in 1 year, but if no advanced adenoma,  repeat after 3 years, then every 5 years

Strong

Perform CT scan of chest and abdomen every 6-12 months from date of surgery for a total of 5 years.

Strong

Other laboratory and radiological examinations are of unproven benefit and must be restricted to patients with suspicious symptoms.

Conditional

Long-term follow-up, rehabilitation and survivorship care programmes should be implemented, aiming at detection of recurrent or new cancers, assessment and management of late and psychosocial effects and implementation of health promotion measures.

Strong

Recommendations

Strength of the recommendation

1.      DIAGNOSTIC WORK UP FOR ADVANCED/METASTATIC DISEASE

 Complete work-up should be carried out to achieve an accurate histological diagnosis of the primary tumor, assess the baseline characteristics of the patient and determine the extent of the disease.

 Strong

Besides a comprehensive physical examination, request blood tests including complete blood count and chemistry profile.

Strong

In addition, serum levels of CEA should be evaluated and monitored during the follow-up period to help evaluate response to treatment.

Strong

CT of the thoracic, abdominal and pelvic cavities with i.v. contrast administration is the preferred radiological method for the evaluation of the extent of CRC.

 Strong

A  Triphasic CT or Dynamic liver MRI is recommended to characterise non-typical liver lesions on CT scans or when liver metastases seem resectable or potentially resectable.

Strong

FDG-PET/CT scan can be useful, particularly in patients with increased tumour markers without evidence of metastatic disease, or to define the extent of metastatic disease on potentially resectable metastases.

Conditional

FDG-PET/CT is NOT USEFULL in mucinous and sigent ring differentiation.

 Strong

Testing for KRAS, NRAS exon 2, 3 and 4 and BRAF mutations is recommended in all patients at the time of mCRC diagnosis

Strong

RAS testing is mandatory before treatment with antiEGFR monoclonal antibodies and can be carried out on either the primary tumour or other metastatic sites.

Strong

BRAF mutation status should be assessed simultaneously with the evaluation of RAS, for prognostic assessment and for the option of treatment with antiEGFR mAbs.

 Strong

Identification of HER2 amplification by IHC or FISH is recommended in RAS-wt patients to detect those who may benefit from HER2 blockade.

 Strong

2.TREATMENT OF POTENTIALLY RESECTABLE ADVANCED AND METASTATIC DISEASE

In patients with resectable metastases, favorable prognostic criteria and a feasible  surgical approach, preoperative / post-operative systemic treatment may not be needed.

Conditional

In patients with resectable metastases, the use of perioperative oxaliplatin-based chemotherapy is recommended where the prognostic situation is unclear.

Strong

Anti-EGFR monoclonal antibodies in left-sided RAS-wt patients should be used as conversion therapy, when complete resection is the aim.

Strong

In patients with right-sided and RAS-mutant disease, FOLFOXIRI-bevacizumab and, to a lesser extent, a cytotoxic doublet-bevacizumab should be considered the best choice depending on patients’ ability to tolerate triplet chemotherapy.

Strong

Patients unresponsive to first-line chemotherapy should not be denied resection or ablation of metastases since the outcome of resected patients after second-line treatment could be also favorable

Conditional

In case of peritoneal metastasis only, complete cytoreductive surgery may be carried out.

Conditional

Intent and choice of local treatment.

Local treatment can be used  primarily as a  metastasis-directed  treatment to halt local failure , further dissemination, and/or following systemic therapy as a consolidation treatment, to delay or pause further treatment.

Conditional

Frequent radiological reevaluations of the potential applicability of surgery or other local treatment techniques should be carried out, generally every 8-12 weeks. 

Strong

Local ablation treatment

In patients with unresectable CRLMs only, or OMD in the liver, thermal Ablation can be considered for small metastases.

Conditional

Thermal Ablation is a valid treatment option for recurrent disease after surgical resection for small CRLMs.

Strong

In patients with lung-only metastases or OMD including lung lesions, thermal ablation may be considered along with resection, according to tumor size, number, location, the extent of lung parenchyma loss, or other comorbidities.

Conditional

SBRT may be considered as  a local treatment option.

Conditional

3.MANAGEMENT OF ADVANCED AND METASTATIC DISEASE WITHOUT POTENTIAL CONVERSION

First-line therapy

Determining the RAS mutational status on a tumour biopsy is mandatory to guide the best treatment decision.

Strong

Delivering a biological therapy in combination with chemotherapy in the first-line setting is recommended, unless contraindicated.

Strong

First-line treatment will consist of  doublet of chemotherapy (FOLFOX, FOLFIRI, CAPOX)  combined with an anti-VEGF or anti-EGFR mAbs  unless contraindicated..

Strong

In RAS-wt and BRAF-wt left-sided tumours, doublet chemotherapy  plus an anti-EGFR mAbs is the preferred option.

Strong

In RAS-wt right-sided tumours, chemotherapy +  bevacizumab is the recommended treatment unless contraindicated

Strong

Anti-EGFR mAbs should be combined with the doublets FOLFOX or FOLFIRI.

Strong

Bevacizumab should be combined with single fluoropyrimidines, irinotecan or oxaliplatin-based doublet of ChT (FOLFOX, CAPOX, FOLFIRI) or triplets (FOLOXIRI).

Strong

A triplet with FOLFOXIRI plus bevacizumab could also be an option for selective patients with good PS and without comorbidities.

Conditional

Triplets including FOLFOXIRI should not be used in patients >75 years old, with PS2 or in patients with significant comorbidities.

Strong

In patients with comorbidities, older age or with metastatic disease not amenable to a curative treatment strategy and no significant disease-related symptoms, monotherapy with a fluoropyrimidine  bevacizumab is recommended

Strong

In frail or elderly patients unable to tolerate chemotherapy, whose tumours are left-sided and RAS-wt, monotherapy with anti-EGFR mAbs can be considered.

Conditional

Maintenance and subsequent therapy

After first-line therapy with ChT based on oxaliplatin and  bevacizumab, maintenance therapy with a fluoropyrimidine  is recommended in nonprogressive patients after at least 6 months of treatment.

Strong

Reintroduction of an initial successful induction therapy may be done after progressive disease while on maintenance therapy.

Conditional

After failure of  first-line oxaliplatin-based therapy, second-line treatment with irinotecan-based or monotherapy is recommended unless contraindicated

Strong

After failure of first line irinotecan-based therapy , second line treatment with  oxaliplatin-based therapy (FOLFOX or CAPOX) is recommended unless contraindicated .

Strong

In RAS-wt patients not previously treated with an anti- EGFR moAb, treatment with chemotherapy (FOLFIRI or irinotecan) and cetuximab or panitumumab is recommended  for left-sided colon tumours.

Strong

In patients previously treated with chemotherapy alone, a combination of doublet chemotherapy + bevacizumab or anti EGFR (Left side) is recommended.

Strong

Bevacizumab can be combined with a fluoropyrimidine doublet with oxaliplatin or irinotecan, depending on the first-line chemotherapy backbone delivered.

Conditional

Reintroduction of the initial induction therapy can be considered after second-line therapy, as long as the patient did not progress during the induction course of first-line chemotherapy. Treatment should be based upon previous treatment lines, AEs, and PS.

Conditional

Follow up and monitoring

History and physical examination and CEA level determination are recommended  every 3-6 months for 3 years and every 6-12 months at years 4 and 5 after surgery.

Strong

Colonoscopy must be carried out at year 1 and every 3-5 years thereafter, looking for metachronous adenomas and cancers.

Strong

CT scan of chest , abdomen and pelvis  every 6-12 months for the first 3 years is recommended  in patients who are at higher risk of recurrence according to the TNM classification.

Strong

Long-term follow-up, rehabilitation and survivorship care programmes should be implemented, aiming at detection of recurrent or new cancers, assessment and management of late and psychosocial effects and implementation of healocal treatmenth promotion measures.

Strong

Recommendation

Strength of recommendation

Diagnosis and Risk Assessment

Initial assessment should include smoking history, physical examination, complete blood count, liver enzymes, sodium, potassium, calcium, glucose, LDH and creatinine (pulmonary function tests if localized disease).               

Good practice statement

Attention drawn towards potential autoimmune-mediated paraneoplastic  symptoms is advised .

Conditional

Combined approach of using the AJCC TNM staging system (9th edition) and the older Veterans Administration (VA) Lung Study Group’s 2-stage classification VA scheme for SCLC staging should be used (appendix 1).

Good practice statement

The effusion should be excluded as a staging element if: 1) multiple cytopathologic examinations of the pleural fluid are negative for cancer; 2) the fluid is not bloody and not an exudate; and 3) clinical judgment concludes that the effusion is not directly related to the cancer.

Good practice statement

Pericardial effusions are classified using the same criteria mentioned above.

Good practice statement

A contrast-enhanced CT of the chest and abdomen is recommended.

Strong

Brain MRI is recommended for all patients. However, contrast enhanced CT is an option when MRI is not available.

Strong

FDG–PET–CT is optional for staging in limited-stage disease, and FDG–PET findings that modify treatment decisions should be pathologically confirmed.

Conditional

FDG–PET–CT is advised to assist in RT volume delineation.

Conditional

In limited-stage disease, additional bone scintigraphy is recommended when no FDG–PET–CT has been carried out.

Strong

In limited-stage disease, a bone marrow aspiration and biopsy are advised in the case of abnormal blood counts suggesting bone marrow involvement only if it changes clinical management.

Conditional

The workup for SCLC should not delay the onset of treatment for >1 week because of the aggressive nature of SCLC.

Good practice statement

Tobacco smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and patients who previously smoked tobacco should be strongly encouraged to remain abstinent.

Good practice statement

Treatment

Management of limited-stage disease (i.e. stages I-III SCLC eligible for treatment of curative intent)

Surgery should be considered in patients with clinical stages I and II (cT1-2N0) SCLC in the context of a multimodal treatment concept and following a multidisciplinary board decision.

Strong

The aim of surgical treatment should be achieving an R0 resection.

Strong

When considering surgical treatment for SCLC, pathological mediastinal staging should be done.

Strong

Sublobular resection is not recommended for SCLC.

 Conditional

After surgical resection, in case of pT1-2N0-1, R0 resection, adjuvant chemotherapy should be given.

Strong

After surgical resection, in case of R1-R2 resection or positive mediastinal lymph nodes (N2), adjuvant chemotherapy should be combined with RT, preferably concurrently.

Strong

The preferred Chemotherapy for patients with limited-stage (stage I-III) SCLC is platinum plus etoposide.

Strong

G-CSF is a treatment option to prevent haematological toxicity.

Good practice statement

Patients with T1-4N0-3M0 tumours and a good PS (0-1) should be treated with concurrent platinum-salt based chemotherapy and thoracic RT.

 Strong

The recommended dose fractionation schedule is 66 Gy. in 33 fractions or equivalent doses

 Strong

Thoracic RT should be initiated as early as possible, starting on the first or second cycle of Chemotherapy.

 Strong

When the patient PS (≥2) or dose to the organs at risk do not allow for the early administration of thoracic RT, it should be postponed until the start of the third cycle of Chemotherapy.

 Strong

Sequential CRT is the preferred option for patients who are not candidates for concurrent CRT due to poor PS, comorbidities and/or disease volume.

 Strong

In case of response to Chemotherapy, the post-Chemotherapy primary tumour should be included in the radiation field.

 Strong

In case of response to Chemotherapy, the pre-Chemotherapy nodal stations should be included in the radiation field.

 Strong

Selective node irradiation is recommended (i.e. involved nodes defined as FDG avid on PET–CT, enlarged on CT and/or biopsy-positive).

 Strong

Patients with stage III SCLC with a response after treatment (CRT) and a PS of 0-1 should be offered PCI.

 Strong

PCI can be considered in patients with a PS of 2.

Conditional

The role of PCI is not as well defined in patients with stage I-II SCLC or in those >70 years of age or who are frail. In such cases, shared decision making is advised.

 Conditional

The recommended PCI regimen is 25 Gy/10 fractions.

 Strong

Management of extensive-stage disease (i.e. stage IV or stage III SCLC not eligible for treatment of curative intent)

The preferred first-line treatment of extensive-stage SCLC          (PS 0-2) is four to six cycles of a platinum plus etoposide

Strong

Cisplatin with irinotecan or topotecan are alternative treatment options.

 Conditional

In poor prognosis patients, gemcitabine plus carboplatin is an alternative treatment option.

 Conditional

In patients achieving a response after Chemotherapy and a PS of 0-2, RT to the residual primary tumour and lymph nodes (30 Gy/10 fractions) is a treatment option.

 Conditional

PCI (20 Gy/5 fractions and 25 Gy/10 fractions) is justified without prior MRI staging or follow-up in patients <75 years of age and a PS of 0-2 who achieved a response after Chemotherapy.

Strong

In patients with extensive-stage SCLC without brain metastases on brain MRI after Chemotherapy and who can be followed-up with regular brain MRI, PCI may be omitted.

Strong

Patients with platinum-refractory SCLC have a poor prognosis and BSC is recommended.

 Conditional

Topotecan is recommended for patients with platinum-resistant or -sensitive relapse; CAV , texans, gemcitabine, and oral etoposide are alternative options.                      

Strong

In patients with platinum-sensitive SCLC, rechallenge with first-line platinum plus etoposide can be considered.

Strong