MEDICAL TREATMENT OF Nasopharynx Carcinoma

dr.Made Putra Sedana SpPD-KHOM Hematologist-Oncologist

Surabaya

Cancer Management

CANCER

SURGICAL MEDICAL TX Radiotx Palliative

Patient Safety in Cancer Management à MULTY DISCIPLINE TEAM (MDT)• THT • Anatomy Pathologic• Radio Diagnostik• Hematologi-Onkologi Medik• Radioterapi• Rehab Medik• Clinical Pathologic

Staging-tumour

• Tx. Tumor primer tidak terdeteksi.• T1 Terbatas pada nasofaring• T2 Meluas ke jaringan lunak orofaring dan/atau fosa nasalis• T2a: Tidak melibatkan parafaringeal• T2b: Melibatkan parafaringeal

• T3 Menginfasi struktur tulang dan/atau sinus para nasalis• T4 Meluas ke intra kranial dan/atau melibatkan nervi

craniales, fosa infratemporal, hipofaring, atau orbita

Staging - Lymphonode

• Nx. KGB regional tidak belum dapat diperiksa• N0 KGB regional tidak terjangkiti• N1 KGB regional unilateral diatas fosa supra- klafikula besarnya £ 6

cm • N2 KGB regional bilateral diatas fosa supraklafikula besarnya £ 6 cm• N3 a. KGB regional uni/bilateral diatas fosa supra- klafikula

besarnya > 6 cmb. Melibatkan fosa supraklafikula

Staging-Metastatic

• Mx. Metastasis belum dapat ditentukan.• M0. Tidak ada metastasis jauh.• M1. Metastasis jauh.

Staging & cytological classification

Stage T N M0 Tis N0 M0I T1 N0 M0

IIA T2a N0 M0

IIBT1

T2aT2b

N1N1

N0/1M0

III T1-2bT3

N2N0-2 M0

IVA T4 N0-2 M0IVB Any N3 M0IVC Any Any M1

Type WHO Former Terminology

1(A). Squamose cells with keratinizing Sel Squamose

2(B). Nonkeratinizing with / without lymphoid stroma

Transitional/Intermediate cellsLimfoepitelial (Regaud)

3(C). Undifferensiated with / without lymphoid stroma

Anaplastic/Clear cellsLimfoepitelial (Schminke)

Cytological classification of NPC

Histopathological grading:Gx. Grading have not yet determinedG1. Well differentiatedG2. Moderately differentiatedG3. Poorly differentiatedG4. Undifferentiated

PROCEDURE PRE CHEMOTHERAPY

A. DIAGNOSTIC1. General Condition: performance status : WHO > 2 karnoffsky > 60%2. Prepare for patient’s emotional condition 3. Prepare the venainsertion and infusion flow, avoid from surgical scars to

prevent oedema4. Integument : Avoid the lession

B. HISTORY AND CLINICAL SYMPTOM1. History taking 2. History of Chemotx : Antracyclin, bleomycin and cisplatin 3. History of drugs allergic 4. Size and shape of the mass, ulcer, bleeding

PROCDURE PRE CHEMOTHERAPY

C. Laboratory examination 1. Laboratory findings: Hb > 10 g/dl, Leukosit ≥ 4000 ml, Trombo >

100.000/ml, SGOT/SGPT : maks 1½ x N; Albumin > 2.5 g/dl, RFT : Cl Creatinin > 70 ml/min with Cisplatin maximal doses

2. Next Pre chemocycle relevant examinations 3. If there are abnormalities

D. Radiology Examination 1. Echocardiograhy : Antracyclin2. Thorax X-RAY : Bleomycin

Chemotherapy Preparation

1. The first chemotx was given should be waited until finished without side effects

2. See the protocols, use general precaution,pregnantwomen are prohibited, prepare emergency kit

3. Pay Attention with extravasasi reaction 4. Pay attention with anaphylaxis allergic reaction

Neoadjuvant

Paliative

1-2a

2b-4b

4c

ESMO GUIDELINES

Annals of Oncology 23 (Supplement 7): vii83–vii85, 2012 doi:10.1093/annonc/mds266

Stage INasopharyngeal Cancer

Standard treatment options:• High-dose radiation therapy to the primary tumor site and

prophylactic radiation therapy to the nodal drainage. [1-3]

Stage IINasopharyngeal CancerStandard treatment options: • Concurrent Chemoradiotherapy.[1] àLevel of evidence:

3A• High-dose radiation therapy to the primary tumor site and

prophylactic radiation therapy to the nodal drainage.[2- 4]

Phase I/II Studies of Taxotere/Cisplatin or Taxotere/Irinotecan + Radiation

TXT = Taxotere; CDDP = cisplatin; CT = chemotherapy; RT = radiation therapy. *Number evaluable for response. †For the evaluable population.

Budach W et al. Proc Am Soc Clin Oncol 2000;19:418a. Abstract 1649.Koukourakis MI et al. Anticancer Res 1999;19:2305-2310.

Varveris HC et al. Proc Am Soc Clin Oncol 1999;18:443a. Abstract 1707.

Principal Gr 3/4Study (Eval Pts*) Treatment ORR (CR)† Toxicity (% of Pts)Budach et al 2000 TXT 60 mg/m2 IV d1; 92% (46%) Leukopenia (47) (n=13)

CDDP 15 mg/m2 IV d2-5 Mucositis (20)

CT q 4 wk ´ 3Phase II Alternating RT 2 Gy/d for 5 d/wk

on Wks 2, 3, 5, 6 (total dose, 40 Gy)

Varveris et al 1999 TXT 15-30 mg/m2 IV; 100% (59%) Gr 2-4 mucositis (85)(n=54) CDDP 15-30 mg/m2 IV

CT twice weekly ´ 7 wkPhase II Concurrent RT 1.15 Gy bid for

5 d/wk ´ 7 wk (total dose, 80.5 Gy)

Koukourakis et al TXT 20-25 mg/m2 IV d1; 100% (75%) Mucositis (42%)1999 (n=12) Irinotecan 25-55 mg/m2 IV d3

RT 2 Gy/d for 5 d/wkPhase I/II (total dose, 66-70 Gy)

CT/RT q 7 d ´ 7 wk

Stage IIINasopharyngeal Cancer

Standard treatment options:• Chemo and radiotherapy.[1,2,3,4]

• High-dose or superfractionated radiation therapy to the primary tumor site and bilateral neck nodes that are clinically positive. [5-8]

• Neck dissection may be indicated for persistent or recurrent nodes if the primary tumor site is controlled. [7]

Treatment options under clinical evaluation:• Induction chemotherapy.• Two randomized prospective trials compared combination chemotherapy plus radiation

therapy to radiation therapy alone :• cisplatin and epirubicin à Level of evidence: 1A, or• cisplatin plus fluorouracil [5-FU] injections à Level of evidence: 1D• Although disease-free survival was improved in the chemotherapy group for both groups,

improvement in overall survival was reported only from the intergroup.[1]

Induction Therapy:Docetacel-CDDP and Docetacel-5FU

Principal Gr 3/4Toxicity

Neutropenia (31% of patients)

Neutropenia(35% of cycles)

Neutropenia(28% of cycles)

Neutropenia(19% of cycles)

Study (Eval Pts*)

Manzione et al 1999(n=26)

Mel et al 1999(n=37)

Biakhov et al 2000(n=49)

Treatment

TXT 75 mg/m2 IV;CDDP 100 mg/m2 IVq 3 wk ´ 3 cycles Þ RT

TXT 75 mg/m2 IV;CDDP 75 mg/m2 IVq 3 wk ´ 3 cycles Þ RT ± Surgery

TXT 75 mg/m2 IV;CDDP 75 mg/m2 IVq 3 wk ´ 4 cycles Þ RTor

TXT 85 mg/m2 IV d1;5-FU 750 mg/m2/d CIVI d1-5q 3 wk ´ 4 cycles Þ RT

ORR (CR)†

46% (15%)

55% (30%)

65% (17%)

54% (19%)

TXT = Taxotere; CDDP = cisplatin; RT = radiation therapy. *Number evaluable for response. †For the evaluable population.Biakhov M et al. Proc Am Soc Clin Oncol 2000;19:419a. Abstract 1657.

Manzione L et al. Proc Am Soc Clin Oncol 1999;18:398a. Abstract 1537.Mel JR et al. Proc Am Soc Clin Oncol 1999;18:401a. Abstract 1549.

Stage IVNasopharyngeal Cancer

Standard treatment options:• Chemo and radiotherapy.[1-5]

• High-dose or superfractionated radiation therapy to the primary tumor site and bilateral lymph nodes that are clinically positive.[6-9]

• Neck dissection should be reserved for persistent or recurrent nodes.[8]

• Chemotherapy for patients with stage IVC disease.[10]

Treatment options under clinical evaluation:• Neoadjuvant chemotherapy as given in clinical trials has been used to shrink tumors,

thereby rendering them more definitively treatable with radiation.• Chemotherapy is given prior to the other modalities, hence the designation neoadjuvant to

distinguish it from standard adjuvant therapy, which is given after or during definitive therapy with radiation or after surgery.Many drug combinations have been used in neoadjuvant chemotherapy.

• Two randomized prospective trials compared combination chemotherapy plus radiation therapy to radiation therapy alone:

• cisplatin, epirubicin, and bleomycin à Level of evidence 1A, or• cisplatin plus fluorouracil [5-FU] injections à Level of evidence: 1D• Although disease-free survival was improved in the chemotherapy group for both groups,

improvement in overall survival was reported only from the intergroup.[1]

RecurrentNasopharyngeal Cancer

Standard treatment options:• Selected patients may be re-treated with moderate-dose external-beam

radiation therapy using limited ports and an intracavitary or interstitial irradiation boost to the site of recurrence.[1-4]

• In highly selected patients, surgical resection of recurrent lesions may be considered.

• If a patient has metastatic disease or local recurrence that is no longer amenable to surgery or radiation, chemotherapy should be considered.[5-7]

Treatment options under clinical evaluation:• Clinical trials such as those evaluating chemotherapy and interferon

should be considered.[8]

• Information about ongoing clinical trials is available from the NCI Cancer.gov Web site.

Phase II Studies of Single-Agent Taxotere in recurrent NPC

Study (Enrolled Pts)Couteau et al 1999(N=24)

Inuyama et al 1999 (N=63)

Dreyfuss et al 1996(N=31)

Catimel et al 1994(N=43)

ORR*21%

22%

42%

28%

Catimel G et al. Ann Oncol 1994;5:533-537.Couteau C et al. Br J Cancer 1999;81:457-462.Dreyfuss AI et al. J Clin Oncol 1996;14:1672-1678.Inuyama Y et al. Gan To Kagaku Ryoho 1999;26:107-116.

TreatmentTXT 100 mg/m2 IV q 3 wk

TXT 60 mg/m2 IV q 3-4 wk

TXT 100 mg/m2 IV q 3 wk

TXT 100 mg/m2 IV q 3 wk

TXT = Taxotere.*For the intent-to-treat population.

Principal Gr 3/4 Toxicity (% of Pts)Neutropenia (79)

Neutropenia (79)

Febrile neutropenia (53)

Neutropenia (87) Leukopenia (74)

Phase II Studies of Taxotere-Cisplatin in recurrent NPC

Study (Eval Pts*)Specht et al 2000(n=24)

Schöffski et al 1999 (n=9 pretreated pts)

Forastiere et al 1998(n=12)

TreatmentTXT 75 mg/m2 IV;CDDP 75 mg/m2 IVq 3 wk ´ 8

TXT 100 mg/m2 IV; CDDP 75 mg/m2 IVq 3 wk ´ 6

TXT 75 mg/m2 IV; CDDP 75 mg/m2 IVq 3 wk

Principal Gr 3/4 Toxicity (% of Pts)Neutropenia (75)

Neutropenia (67% of cycles)

Febrile neutropenia (16)

ORR†33%

33%

42%

TXT = Taxotere; CDDP = cisplatin.*Number evaluable for response.†For the evaluable population.

Forastiere A et al. Proc Am Soc Clin Oncol 1998;17:399a. Abstract 1540.Schöffski P et al. Ann Oncol 1999;10:119-122.Specht L et al. Ann Oncol 2000;11:845-849.

Targeting of treatmentStage Grade Goal Therapy

I, IIa Any G Cure Radiation

IIb G3-4 Cure Radiation

IIb G1-2 Cure ** Concurrent chemoradiation

III G3-4 Cure ** Radiation + adjuvant chemotherapy

III G1-2 Palliative Concurrent chemoradiation

IVa G3-4 Cure ** Induction chemo-radiotherapyIVb G3-4 Cure ** Neoadjuvant chemoradiation

IVa/b G1-2 Palliative Neoadjuvant or concomitant*) chemoradiation

IVc G3-4 Palliative Palliative chemotherapy orconcomitant*) chemoradiation

IVc G1-2 Palliative Best supportive care

*) on going trial phase III, **) improved DFS & survival

Concurrent chemoradiation

• Single agent• Cisplatin 40 mg/m2 weekly• Paclitaxel 60 mg/m2 weekly• Docetaxel 36 mg/m2 weekly

• Double agent• Cisplatin 25-30mg/m2 weekly +

• 5FU 500 mg/m2 weekly, or• Paclitaxel 45 mg/m2 weekly, or• Docetaxel 25 mg/m2 weekly.

• Radioterapi 200 cGy/d for 5d/week

Concurrent chemoradiation

• Cisplatin-Gemcitabine• Phase II trial• 24 hours before irradiation• Cisplatin 25-30mg/m2 weekly +

• Gemcitabine 200 mg/m2 weekly.

• Radioterapi 200 cGy/d for 5d/week

Induction chemo-radiotherapy

• Cisplatin-Epirubicine• Cisplatin 80-100 mg/m2 on d1, and• Epirubicine 80 mg/m2 on d1• For 3 cycle (3weekly/cycle)• Radiotherapy 6600 cGy

OR• Cisplatin-Docetaxel• Cisplatin 75-80 mg/m2 on d1, and• Docetaxel 75 -100 mg/m2 on d1• For 3 cycle (3weekly/cycle)• Radiotherapy 6600 cGy

Adjuvant chemotherapy

• Cisplatin 80-100 mg/m2 on d1, and• 5FU 1000 mg/m2 24h infusion on d1 until d4 or d5, or• Paclitaxel 175 mg/m2 on d1, or• Docetaxel 85-100 mg/m2 on d1

Concomitant chemoradiation

• Double agent• Cisplatin 40 mg/m2 weekly +

• 5FU 800-1000 mg/m2 weekly, or• Paclitaxel 60 mg/m2 weekly, or• Docetaxel 36 mg/m2 weekly.

• Radiotherapy 200 cGy/d (5d/week)

Treatment Monitoring

• Complete respon• Partial Respon• Stationary Disease • Progressive Disease

ADVERSE REACTION OF CHEMOTERAPHY

I. Onset 1. Acute < 1 hours after chemotherapy2. Early : 1 – 48 hours 3. Delayed 2 days – 2 months 4. Late after 2 months

II. Targeted Organ

III. Severity 1. Grade 0-2 : quite safe, no need therapy 2. Grade 3 : Watch out, sometimes need therapy 3. Grade 4 : warning sign, adequate therapy 4. Grade 5 : died

Acute SIDE EFFECTS (< 1 hour)

A. FEBRIS and HypertensionEg : after Bleomycin i.v had febris, moderate-high. Incidence 10% Prevention : Slowly injection or continuous iv , tx : anti piretic

B. HYPOTENSION Bleomycin or Cisplatin rapid IV hypotension until shock incidence +

10%. Prevention : slowly injection or drip 1-2 hours tx : fluid treatment, adrenalin

dopamine and steroid if needed

C. VomittingIncidence : 30 – 80%

DELAYED SIDE EFFECTS 24 HOURS– 2 MONTHS

Targeted Organ

• Gastro-intestinal (GI) System• Hematological system• Central Nervous System (CNS) • Hepatobilier system• Cardiovascular system • Respiratory system• Urinary system

THANK YOU FOR YOUR ATTENTION

“ The good physician treats the disease, The great physician treats the patient who has the disease”– William Osler