role of chemotherapy in head and neck cancer

• Moderator – Dr.Gunaseelan.,Addl Prof, RT • Presenter – Dr.T.Joseph Rajiv, JR, RT• 5-04-17

ROLE OF CHEMOTHERAPY IN HEAD AND NECK CANCER (LA

–SCC)(excluding nasopharynx)*

OUTLINE

• Introduction• Rationale & Commonly used drugs• Induction Chemotherapy• Concurrent Chemotherapy• Sequential chemotherapy• Post operative chemotherapy• Conclusion

• SCCHN has been considered the sixth most common cancer in the world.

• LASCCHN, non metastatic stage III or stage IV, is the most frequent presentation in 60% of the diagnosed patients.

• For the loco regional diseases local treatment based on surgery and/or radiotherapy (RT).

• 50-60% of patients have local disease recurrence within 2 years, and 20-30% of patients develop metastatic disease if treated by RT alone.

• To improve cure rates and functional outcomes, chemotherapy has been integrated into various multimodality approaches

INTRODUCTION

Currently, three multimodality treatment approaches are used.

The first approach is surgery followed by adjuvant concurrent chemo radiotherapy.

• This enables precise pathologic staging and identification of high-risk features that influence the choice of adjuvant treatment.

• This approach can have limitations, such as poor organ preservation, depending on the anatomic location.

The second approach is definitive concurrent chemo radiotherapy with surgery as an optional salvage or completion treatment.

• Although no pathologic information is obtained with this approach, it has the advantage of improved organ preservation.

• The third approach is the use of IC followed by definitive local therapy

• Advantages include the potential to decrease the risk of distant failure and a rapid reduction in tumor bulk in responders.

• A response to induction appears to predict responsiveness to chemo radiotherapy.

• Nonetheless, this can result in prolonged treatment and additional chemotherapy-related toxic effects from systemic doses.

RATIONALE

• Steel and Peckham (1979) – rationale for chemoradiotherapy in four ways :

• Spatial co-operation• Toxicity independence• Protection of normal tissues,• Enhancement of tumour response

• Bentzen and co-authors(2007) revised Steel’s model

• Proposed five mechanisms :I. Spatial cooperationII. Cytotoxic enhancementIII. Biological co-operationIV. Temporary modulation V. Normal tissue protection

RADIOTHERAPY• Acts in a circumscribed area, a

target volume, locoregionally to eradicate the tumour contained in that area

• Deal with macroscopic and high tumour cell number regions

CHEMOTHERAPY• Tackles the disease beyond the

target volume of radiation, and this requires no interaction between two modalities.

• Scattered micrometastasis,

1.SPATIAL COOPERATION

CHEMOTHERAPY• Tackles the disease beyond the

target volume of radiation, and this requires no interaction between two modalities.

• Scattered micrometastasis,

Different treatment modalities impact on

distinct territories of disease

Spatial cooperation relies on differential

toxicities of radio- and chemotherapy

to use both modalities at effective doses

SPATIAL COOPERATION

2.CYTOTOXIC ENHANACEMENT

• Enhancement of cell killing through the alteration of the induction or repair of DNA damage

• For cytotoxic enhancement, chemotherapeutic agents should be present at the time of irradiation (concurrent chemoradiotherapy)

• Modulating the initial stage of radiation-induced cell killing or repair• Aims at enhancing the local effect of radiotherapy – loco regional control

Efficacy of radiation can be enhanced by :• Radiation effect and resistance• Enhancement of radiation DNA damage• Inhibition of DNA repair• Enhanced activity against hypoxic cells• Prevention of repopulation

CYTOTOXIC ENHANACEMENT

• Platinum analogs :• Cisplatin:• Interacts with nucleophilic sites on DNA and RNA• Introduces intrastrand and interstrand cross-links and forms adducts• Cisplatin adducts + Radiation-induced single strand breaks in close vicinity in

DNA can be difficult for the cell to repair the damage properly

CYTOTOXIC ENHANACEMENT

Complex interaction between Cisplatin and RT :• Presence of radiation-induced free radicals increases toxic platinum

intermediates• Inhibition of DNA repair results in increased incidence of cell cycle disruption

and apoptosis. • Radiation itself increases the cellular uptake of cisplatin

• Common Toxicities:• Mg, Na, Ca, and K alterations• Emesis , diarrhoea• Increased Cr and BUN (cumulative)

• Carboplatin & Oxaliplatin – similar mechanism of action

• 5-FU :• Blocks nucleic acid synthesis through thymidylate

synthase inhibition and deplets the pool of nucleotide triphosphates

•  When 5-FU is incorporated into RNA and DNA it inhibits DNA synthesis and transcription and protein synthesis.

• Decrease in the rate and extent of radiation induced double-strand break repair

• Cytotoxic effect by cell cycle redistribution (More cells in G2 phase)

• Toxicity Profile:• Hepatotoxicity is dose-limiting. • Nausea and vomiting ,Mucositis and diarrhea• Hand-foot syndrome & Myelosuppression.

CYTOTOXIC ENHANCEMENT-ANTIMETABOLITE-BASED CHEMORADIOTHERAPY

• Gemcitabine:

• Cytotoxic riphosphate nucleotide metabolite (dFdCTP)• Incorporation of dFdCTP triphosphate metabolite into DNA resulting in chain

termination and inhibition of DNA synthesis and function• Myelosuppression is dose-limiting.• Flu like symptoms • Transient hepatic dysfunction

• Paclitaxel: High-affinity bonds with microtubules, promoting tubulin polymerization and stabilization

• Cell cycle synchronization:•  Cells remain in the G2–M phase of the cell cycle, leading to synchronization

(cell-cycle pooling) of tumor cells at a point of maximum radiosensitivity• Induce tumor shrinkage, improving perfusion and subsequent

reoxygenation.• Hypoxic areas of the tumor are reoxygenated they become more sensitive

to radiation-induced cell kill• Myelosuppression- Dose-limiting neutropenia• HSR• Neuropathy

CYTOTOXIC ENHANCEMENT-TAXANE-BASED CHEMORADIOTHERAPY

3.BIOLOGICAL COOPERATION

• Aimed at enhancing cell killing or delaying tumour regrowth targeting distinct cell populations.

• Example:• Bioreductive agents- Mitomycin C, selectively target hypoxic cells by being metabolised to toxic intermediates under hypoxic conditions

4.TEMPORAL MODULATION

• Defines the interactions between molecular targeted therapies and radiotherapy

• Combination of EGFR inhibitors (e.g., cetuximab) with radiation• Overexpressed growth factors and growth factor receptors, as well as the increased activity of downstream signalling pathways in tumour cells• Targeted agents can block these pathways

Chemoradiotherapy leads to a shift of both curves to the left Stronger shift of the tumor curve (as indicated by the longer arrow)

Schematic dose–response curves for tumor and normal tissue damage with radiation

therapeutic range.

5.NORMAL TISSUE PROTECTION

1.INDUCTION CHEMOTHERAPY• IC refers to full-dose systemic therapy given as the initial treatment of cancer before definitive local therapy

• Aim : Eradicate small micrometastasesTo reduce the size of the primary tumour• It offers the advantage of increasing local tumour control by radiotherapyReducing the number of tumour clonogenic cells. • Tumour shrinkage can also help to reduce the irradiated volume and therefore,

sparing normal tissues betterA response to induction appears to predict responsiveness to chemo radiotherapy.

Veterans Group Wolf et al 1991

Type of trial Randomized control trial

Aim Laryngeal Preservation with chemotherapy

Study PopulationIntervention

Previously untreated LA laryngeal CancerSurgery + RT Vs Chemotherapy + RT

Sample size S= 166 C = 166

Results Clinical tumor response –Complete = 31% Partial = 54 % PatientsEstimated 2-year survival = 68 % for both treatment groups (P = 0.9846)More local recurrences (p = 0.0005) in C+RTFewer distant metastases (p = 0.016) in the C+RT group than in the surgery group.

Veterans Group Wolf et al 1991

Type of trial Randomized control trial

Aim Laryngeal Preservation with chemotherapy

Study PopulationIntervention

Previously untreated LA laryngeal CancerSurgery + RT Vs Chemotherapy + RT

Sample size S= 166 C = 166

Results Clinical tumor response –Complete = 31% Partial = 54 % PatientsEstimated 2-year survival = 68 % for both treatment groups (P = 0.9846)More local recurrences (p = 0.0005) in C+RTFewer distant metastases (p = 0.016) in the C+RT group than in the surgery group.

• Total laryngectomy needed in 36% - Chemotherapy group

• Larynx was preserved in : 64 % of the patients overall • Without compromising OS voice preservation can be

done with C+RT

Forastiere el al 2003(RTOG 9111)

Concurrent Chemotherapy and Radiotherapyfor Organ Preservation in Advanced Laryngeal Cancer

Type of trial Randomized control trial

Back Ground Veterans Group TrailAim To compare Induction vs Concurrent Chemotherapy vs Radiation alonePrimary end point Preservation of larynxStudy Population Previously untreated LA laryngeal Cancer

Sample size R+C= 171 C R = 171 R = 171Methods: Induction cisplatin plus fluorouracil followed by radiotherapy.

Radiotherapy with concurrent administration of cisplatin. Radiotherapy alone. Laryngectomy performed - recurrent carcinoma after thecompletion of treatment or who had an inadequateresponse after two courses of induction chemotherapy

Forastiere el al 2003 Concurrent Chemotherapy and Radiotherapyfor Organ Preservation in Advanced Laryngeal Cancer

Type of trial Randomized control trial

Back Ground Veterans Group Trail

Aim To compare Induction vs Concurrent Chemotherapy vs Radiation alone

Primary end point Preservation of larynx

Study PopulationIntervention

Previously untreated LA laryngeal CancerSurgery + RT Vs Chemotherapy + RT

Sample size R+C= 171 C+R = 171 R = 171

Methods: Induction cisplatin plus fluorouracil followed by radiotherapy. Radiotherapy with concurrent administration of cisplatin.Radiotherapy alone.

• Voice preservation :Concurrent Cisplatin (88 %) • Chemotherapy followed by radiotherapy (75 %)(P=0.005)• Radiotherapy alone (70 %)(P<0.001)

• Locoregional control : Significantly better with• CCRT (78 %), vs• Induction Chemo Radiotherapy (61%) vs • Radiotherapy (56%)

• Chemotherapy-based regimens suppressed distant metastases and resulted in better disease-free survival than radiotherapy alone.

• Overall survival rates were similar in all three groups.

• High-grade toxic effects was greater with the chemotherapy-based regimens• 81% - Induction Chemo Radiotherapy • 82 % - radiotherapy with concurrent cisplatin• 61 % - radiotherapy alone

• 10-year results of induction PF followed by RT vs concomitant cisplatin/RT

• Similar efficacy for the overall survival

• Locoregional control and larynx preservation were significantly improved with

concomitant cisplatin/RT compared with the induction arm or RT alone.

Vermorken el al (2007)EORTC 24971/TAX 323

Cisplatin, Fluorouracil, and Docetaxel in Unresectable Head and Neck Cancer

Type of trial Randomized control trial (phase III)

Back Ground Phase 2 studies suggest that the standard regimen of cisplatin and fluorouracil (PF) with taxanes improves outcome

Aim To compare benefit of addition TAXANE to PFPrimary end point Progression free survivalStudy Population Locoregionally advanced, unresectable disease.

4 Cycles of either of chemo f/b Radiation Sample size DCF= 177 PF = 181Methods: DPF (docetaxel and cisplatin, day 1; fluorouracil by continuous

infusion, days 1 to 5 PF every 3 weeks for four cycles. No progression Radiotherapy within 4 to 7 weeks after completing

chemotherapy.

N Engl J Med 2007;357:1695-704.

Vermorken el al (2007)EORTC 24971/TAX 323

Cisplatin, Fluorouracil, and Docetaxel in Unresectable Head and Neck Cancer

Type of trial Randomized control trial (phase III)

Back Ground Phase 2 studies suggest that the standard regimen of cisplatin and fluorouracil (PF) with taxanes improves outcome

Aim To compare benefit of addition TAXANE to PFPrimary end point Progression free survivalStudy Population Locoregionally advanced, unresectable disease.

4 Cycles of either of chemo f/b Radiation Sample size DCF= 177 PF = 181Methods: TPF (docetaxel and cisplatin, day 1; fluorouracil by continuous

infusion, days 1 to 5 PF every 3 weeks for four cycles. No progression Radiotherapy within 4 to 7 weeks after completing

chemotherapy.

N Engl J Med 2007;357:1695-704.

RESULTS: Median follow-up of 32.5 months:

PFS : 11.0 months in the TPF group and 8.2 months in the PF group • HR for disease progression or death in the TPF group, = 0.72; P = 0.007. Median OS : 18.8 months in TPF Vs 14.5 months in the PF group.• TPF resulted in a reduction in the risk of death of 27%(P = 0.02)Toxicities:• TPF group : More grade 3 or 4 events of leukopenia and neutropenia • PF group : More grade 3 or 4 events of thrombocytopenia, nausea, vomiting, stomatitis,

and hearing loss in the PF group.Conclusion: Addition of docetaxel significantly improved PFS & OS in patients with unresectable squamous-cell carcinoma of the head and neck.

• TAX 324 was a phase 3 RCT comparing 3 cycles of TPF induction chemotherapy (docetaxel 75 mg/m(2), followed by intravenous cisplatin 100 mg/m(2) and fluorouracil 1000 mg/m(2) per day, administered as a continuous 24-h infusion for 4 days) with 3 cycles of PF (intravenous cisplatin 100 mg/m(2), followed by fluorouracil 1000 mg/m(2) per day as a continuous 24-h infusion for 5 days) in patients with stage III or IV squamous-cell carcinoma of the head or neck.Both regimens were followed by 7 weeks of chemoradiotherapy with concomitant weekly carboplatin.

• Median follow-up was 72·2 months. • OS was significantly better after treatment with TPF versus PF, with an estimated 5-

year survival of 52% in patients treated with TPF and 42% in those receiving PF. Median survival was 70·6 months in the TPF group versus 34·8 months in the PF group.

• PFS was also significantly better in patients treated with TPF.• No significant difference in dependence on gastric feeding tubes and tracheostomies

between treatment groups. • There was better locoregional control in the TPF group than in the PF group, but the

incidence of distant metastases in the two groups did not differ significantly. • Rates of neutropenia and febrile neutropenia were higher in the TPF group.

We shall focus broadly on the question of neoadjuvant vs chemordiotherapy in locally advanced head and neck cancer. Several meta-analysis are available. The largest one, is ‘‘The Meta Analysis of Chemotherapy on Head and Neck Cancer (MACH-NC)’’ which analyzed individual patient data for more than 17000 patients.

MACH-NC• Initially published in 2000

• Included 63 trials conducted between 1965 and 93 of locoregional treatment with/without chemotherapy

• Included carcinomas of Oral cavity, oropharynx, hypopharynx or larynx

• Overall survival benefit of 4% in the chemotherapy arm – mainly concomitant

• No significant benefit with neoadjuvant and adjuvant chemotherapy

• Due to heterogeneity in the results, the use of chemotherapy remained debatable

• Five trials which represented about 7% of the data explained most of the heterogeneity and when they were excluded the higher benefit of concomitant chemotherapy disappeared

• Therefore the MACH-NC group decided to confirm the results by updating its database with the inclusion of the randomised trials performed between 1994 and 2000.

• The new analysis was published in 2009.

• Effect of INDUCTION : 31 induction chemotherapy trials including 5311 patients (3690 deaths) with a median follow-up of 6.1 years.

• The HR of death - 0.96 ([0.90–1.02] p = 0.18) in favour of induction

• Absolute benefit of 2.4% at 5 years

COMPARISON INDUCTION VS ALTERNATING

• 6 randomised trials used the same drugs in both arms, and compared the timing of their use relatively to radiotherapy.

• 3 endpoints showed results in favour of the concomitant group

Absolute benefit of 3.5% at5 years

INDUCTION CHEMOTHERAPY -CONCLUSION

• No improvement of the local control rate or OS compared to CCRT

• Clonal selection of radioresistant cells• Chemotherapy-induced accelerated tumour cell repopulation• Important in organ preservation programs particularly in

laryngeal-hypopharyngeal carcinomas

CONCURRENT CHEMO-RADIATION

• Concurrent chemoradiotherapy has assumed a dominant role in the treatment of head and neck cancers.

• Improving local disease control is main goal• Organ preservation• Potential eradication of distant micrometastases

2.CONCURRENT CHEMO-RADIATION

• Al-Sarraf M, Pajak TF, Marcial VA, et al.

• Concurrent radiotherapy and chemotherapy with Cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer 1987; 59:259–265

• The authors concluded that the combination of cisplatin and radiotherapy is an effective and safe treatment in patients with advanced head and neck cancer and needs to be tested against radiotherapy alone.

ARM 1 - RT alone (arm A) ARM 2 - Concurrent RT plus CT (RCT; arm B).

RT was identical in both arms - 70.2GyCT – Cisplatin + 5 – FUConcomitant CT offered improved disease control and survival in advanced head and neck cancer patients..

Wendt, Thomas G., et al. "Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study." Journal of Clinical Oncology 16.4 (1998): 1318-1324.

Adelstein DJ, Saxton JP, Lavertu P, et al. A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck. 1997; 19:567–575

Cleveland Clinic Foundation.

Arm A : RT alone, 68-72 Gy at 1.8-2.0 Gy per day;

Arm B: RT + Infusional chemo of Cisplatin + 5- FU on days 1 and 22 for 4 days

Better DFS, Lesser incidence of distant metastasis, Primary site preservation

Adelstein el al 2003 An Intergroup Phase III Comparison of Standard Radiation Therapy and Two Schedules of Concurrent Chemoradiotherapy in Patients With Unresectable Squamous Cell Head and Neck Cancer

Type of trial Randomized control trial

Aim To test benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer.

Primary end point

Study PopulationIntervention

ARM A = RADIATION ALONEARM B = CRTARM C = SPLIT COURSE RT + CHEMO

Sample size 295 pat randomly divided

Results : Median follow-up of 41 months. 3-year overall survivalA is 23%,B is 37%(P = .014)C is 27%(P = not significant)

Adelstein el al 2003 An Intergroup Phase III Comparison of Standard Radiation Therapy and Two Schedules of Concurrent Chemoradiotherapy in Patients With Unresectable Squamous Cell Head and Neck Cancer

Type of trial Randomized control trial

Aim To test benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer.

Primary end point

Study PopulationIntervention

ARM A = RADIATION ALONEARM B = CRTARM C = SPLIT COURSE RT + CHEMO

Sample size 295 pat randomly divided

Results : Median follow-up of 41 months. 3-year overall survivalA is 23%,B is 37%(P = .014)C is 27%(P = not significant)

The addition of concurrent, single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival.

• Effect of CCRT : Analyses of the 50 concomitant trials including 9615 patients (6560 deaths) with a median follow-up of 5.6 years.

• The hazard ratio of death was 0.81 (95%) confidence interval: 0.78–0.86; p < 0.0001) in favour of chemotherapy with an absolute benefit of 6.5% at 5 years

• Trials were also grouped according to the type of CT (i)Platin (cisplatin or carboplatin) plus fluorouracil(ii)other platin-containing combinations(iii)Multiagent chemotherapy without platin, and(iv) single-agent chemotherapy (platin and others).

• The concomitant trials were also divided into 2 based on the number of chemotherapy agents used – 17 single agent (HR - 0.87)and 9 multiagent (HR – 0.69)- led to 2 heterogenous groups

• New Studies differentiated cancer vs non cancer deaths

• Benefit of chemotherapy effect on deaths related to head and neck cancer (HR 0.78 [0.73–0.84], p < 0.0001

• No effect on non-cancer deaths (0.96 [0.82–1.12], p = 0.62).

• Oral Cavity :4331 patients analysed , HR for death with chemotherapy – 0.87 with absolute 5.1% survival benefit.

• 5878 patients with oropharyngeal cancer and 82 comparisons

• The HR of death associated with chemotherapy is 0.88

• Absolute 5-year overall survival benefit of 5.3%

• 5878 patients with oropharyngeal cancer and 82 comparisons are included.

• The HR of death associated with chemotherapy is 0.88

• Absolute 5-year overall survival benefit of 5.3%

• 2767 patients with hypopharyngeal cancer and 66 comparisons are included.

• The HR of death associated with chemotherapy is

0.88• Absolute 5-year overall survival benefit of 3.9%

SEQUENTIAL RT

• To exploit the benefits of both induction and CCRT• INDUCTION CHEMO – Decreased distant metastasis (no survival benefit)• With aggressive concurrent chemoradiotherapy schedules, locoregional

improved, • The impact of distant metastatic disease – OS again become important• Rationale - current sequential treatment schedules.

CCRT- CONCLUSION

• Concurrent CRT widely accepted and standard of care • Issues without consensus:• Defining the optimal platinum-based regimen to be administered• Ttype of platinum agent used (cisplatin vs Cb)• The total platinum dose, the number of cycles• The best schedule of administration (daily, weekly, every 3 weeks)

A. Paccagnellal el al Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study

Type of trial Randomized control trial (phase II)

Back Ground Concomitant chemoradiotherapy (CT/RT) is the standard treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Aim To compare benefit of induction + CRT over CRTPrimary end point Radiologic complete response (CR) at 6–8 weeks after the end of CT/RT.Study Population Stage III–IVM0 SCCHN,

Sample size 50 Patients in each armMethods: Arm A: 2 of cisplatin 20 mg/m2 , days1–4, plus 5-FU

800continuous infusion, during weeks 1 and 6 of radiotherapy) three cycles of TPFArm B: docetaxel 75 mg/m2 and cisplatin 80 mg/m2 , day 1, and 5-fluorouracil 800 mg/m2 /day 96 h continuous infusion, every 3 weeks) followed by the same CT/RT

Annals of Oncology 21: 1515–1522, 2010

A. Paccagnellal el al Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study

Type of trial Randomized control trial (phase II)

Back Ground Concomitant chemoradiotherapy (CT/RT) is the standard treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Aim To compare benefit of induction + CRT over CRTPrimary end point Radiologic complete response (CR) at 6–8 weeks after the end of CT/RT.Study Population Stage III–IVM0 SCCHN,

Sample size 50 Patients in each armMethods: Arm A: 2 of cisplatin 20 mg/m2 , days1–4, plus 5-FU

800continuous infusion, during weeks 1 and 6 of radiotherapy) three cycles of TPFArm B: docetaxel 75 mg/m2 and cisplatin 80 mg/m2 , day 1, and 5-fluorouracil 800 mg/m2 /day 96 h continuous infusion, every 3 weeks) followed by the same CT/RT

Annals of Oncology 21: 1515–1522, 2010

Conclusion: Induction TPF followed by CT/RT was associated with higher radiologic CR in patients with locally advanced SCCHN with no negative

impact on CT/RT feasibility.

CCRT SEQUENTIALCR 21% 50% (P =0.0001PFS 19.7 30OS 33 39TOXICITIES SAME SAME

Adult patients with previously untreated, non-metastatic, newly diagnosed head and neck cancer were • eligible if their tumour was either unresectable

or• low surgical curability

or• regional-node stage (2 or 3, except T1N2)

• Patients were randomly assigned (in a 1:1 ratio) to receive either

• Arm A :IC with three cycles of TPF followed by concurrent chemo radiotherapy with either docetaxel or carboplatin

or • Arm B :CRT alone with two cycles of cisplatin.

• Stratification factors were WHO performance status, primary disease site, and stage.

• The primary endpoint was overall survival.

3-year overall survival was 73% in the induction therapy followed by chemo radiotherapy group and 78% in the chemo radiotherapy alone group .

More patients had febrile neutropenia in the induction chemotherapy followed by chemo radiotherapy group (16 patients) than in the chemo radiotherapy alone group (one patient).

(DeCIDE [DocetaxelBased Chemotherapy Plus or Minus IC to Decrease Events in Head and Neck Cancer]

Treatment naive and pathologically confirmed HNSCC; N2/N3 disease without metastases; KPS >70, Intact organ & marrow function.Patients were randomized to one of the following:

CRT alone with Docetaxol (25 mg/m2), continuous infusion 5-FU (600 mg/m2), hydroxyurea (500 mg BID) immediately preceding radiation, and hyperfractionated twice daily radiation at 150 cGy/ fraction (DFHX).

versus

Two 21-day cycles of IC (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and fluorouracil 750 mg/m2 on days 1 to 5) followed by the same CRT regimen (IC -CRT arm).

• 280 subjects were accrued from 2004-09.• 142 patients were randomized to the IC arm • 138 patients were randomized to the concurrent CRT arm.

Older age at diagnosis, lower Karnofsky performance score, and higher stage were associated with worse outcomes.Results

The most common grade 3 to 4 toxicities during IC were febrile neutropenia (11%) and mucositis (9%); during CRT (both arms combined), they were mucositis (49%), dermatitis (21%), and leukopenia (18%). Serious adverse events were more common in the IC arm (47% v 28%; P.002).

With a minimum follow-up of 30 months, there were no statistically significant differences in OS,RFS, or DF-free survival.

Fewer distant recurrences occurred in the ICCRT group, but the difference was not statistically significant (19 v 29; P .11).

Study detailsType of study Meta analysisNumber of studies

5 RCT ; n = 1022

Disease Advanced squamous cell carcinoma of the head and neck (HNSCC)51.3% = Oropharyngeal ; 7.3% = Hypoharyngeal; 18.7% =‘Laryngeal; 19.4% = Oral cavity 3.5% = other HNSCC

Intervention TPF Induction chemotherapy followed by concurrent radio-chemotherapyVs concurrent radio-chemotherapy alone (Platin/Taxane)

Methodology Meta analysis of effect size of Overall Survival (OS) and progression free survival (PFS) was done

Results No significant improvement in OS or PFS was noted by addition of TPF induction chemotherapy

META-ANALYSIS OF RANDOMIZED TRIALS : OS

Hazard Ratio: 1.01095% confidence limits (CL) = 0.84–1.21p = 0.92

META-ANALYSIS OF RANDOMIZED TRIALS : PFS

Hazard Ratio: 0.9195% confidence limits (CL) = 0.75–1.1p = 0.32

• Conclusion :• Currently Sequential CRT is not superior to CRT• Longer treatment time & • Higher rates of hematological toxicities• Clinicians should still use judgement for disease with high risk for local or

distant failure

POST OPERATIVE CHEMORADIOTHERAPY

Study populationinclusion

Pts with squamous-cell carcinoma arising in the oral cavity, oropharynx, larynx, or hypopharynx - macroscopically complete resection High-risk characteristics (any or all of the following)Histologic evidence of invasion of two or more regional lymph nodes, extracapsular extension of nodal diseaseMicroscopically involved mucosal margins of resection)Those who could tolerate chemotherapy

Hypothesis Concurrent postoperative administration of cisplatin and radiotherapywould improve the rate of local and regional control

Intervention 231 = Radiotherapy alone (60 to 66 Gy in 30 to 33 fractions to 6-6.6 weeks)228 = identical treatment plus concurrent cisplatin(100 mg per square meter of body-surface area intravenously on days 1, 22 & 43)

Jay S. Cooper,

• Rate of local and regional control – significantly higher in the combined-therapy group Vs RT group (HR = 0.61; 95 % CI = 0.41 - 0.91; P=0.01).

• Disease-free survival significantly longer in the combined-therapy group Vs RT group (HR = 0.78; 95 % CI = 0.61 - 0.99; P=0.04)

• No significant difference in overall survival

• EORTC Study (Bernier et al. 2004)

• 334 patients with high risk head and neck tumors randomly assigned to post op RT vs. post op Chemo-RT– High Risk = Vascular invasion, Perineural invasion, Stage III/IV

disease, Microscopically + Margins, extracapsular spread– Progression free survival of 55 vs. 23 months– Locoregional recurrence of 31% vs. 18%– OS significantly higher in Chemo-RT than in RT alone (53% vs

40%)– No Significant change in toxicity

SUMMARY

• ECE and/or Margin +, definitive indications for adjuvant chemo radiation.• Other factors shown in the two trials (EORTC and RTOG)- hypothesis

generating• Research question:

• Node positive and number of positive nodes – as risk factor and benefit of chemo radiation in this subgroup with no ECE or margin +

ALTERED FRACTIONATION VS CHEMO RT

Study detailsType of study Meta analysisNumber of studies 5 RCT ; n = 1100Disease LA H& N CancersIntervention conventionally fractionated CCRT with AFRT alone were

included.Methodology Meta analysis of effect size of Overall Survival (OS) and progression free

survival (PFS) was doneResults Hazard ratio of death was 0.73 (95% confidence interval ¼ 0.62e0.86), which

significantly favoured conventionally fractionated CCRT over AFRT alone (P < 0.0001)

Clinical Oncology 28 (2016) 50e61

CONCLUSION :No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy

BIOLOGIC AGENTS IN FRONTLINE THERAPY

Bonner et al2006

Radiotherapy plus Cetuximab for Squamous- Cell Carcinoma of the Head and Neck

Study design multinational, randomized study

Aim To compare radiotherapy alone with radiotherapy plus cetuximab

Disease Unresectable, nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN)

Intervention

Primary

Secondary

Duration of control of locoregional disease.

Overall survival, progression-freesurvival, the response rate, and safety

Hitt et al., 2014

Bonner et al2006

Radiotherapy plus Cetuximab for Squamous- Cell Carcinoma of the Head and Neck

Study design multinational, randomized study

Aim To compare radiotherapy alone with radiotherapy plus cetuximab

Disease Unresectable, nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN)

Intervention

Primary

Secondary

Duration of control of locoregional disease.

Overall survival, progression-freesurvival, the response rate, and safety

Hitt et al., 2014

• RESULTS• Median duration of locoregional control• 24.4 months with cetuximab plus radiotherapy • 14.9 months among those given radiotherapy alone • Hazard ratio for locoregional progression or death, 0.68; P = 0.005.• Safety:• Toxic effects, including mucositis, did not differ significantly between the two

groups.

• Cetuximab plus RT has never been compared prospectively to CRT,• CRT remains the standard treatment for patients with locoregionally

advanced SCCHN for whom surgery is not considered the optimal treatment.• The addition of cetuximab to platinum-based chemotherapy prolongs

survival in patients with recurrent or metastatic SCCHN.

Pol Specenier et, al.

• Absolute benefit of addition of chemotherapy to radiation LA-SCCHN -4.5% at 5 yrs

• Induction chemotherapy – 2.4%• Concurrant chemotherapy – 6.5%• Adjuvant chemotherapy – (-1%)

• Subsite wise:• Oral cavity : 5.1%• Oropharynx :5.3%• Larynx – 4.5%• Hypopharynx- 3.9%

MODE OF TREATMENT

IMPORTANT TRAILS

OUTCOME CURRENT STATUS

CCRT MACH-NC Metanalysis

Over all survival benefit of 6.5% (Significant )

Standard Treatment

Induction Chemotherapy

Veterans groupRTOG 9111MACH-NCTAX323

Insignificant Improvement in survivalTaxane + PF better than PF

Not recommended at presentCan be considered in advanced nodal disease

Post operative chemotherapy

EORTC (#22931)RTOG (#9501)

Benefit in margin +ECE

Recommended

Sequential Chemotherapy

DECIDE PARADIGM

No survival advantage compared to CCRT

Not recommendedInvestigational

Targeted agents Bonner et al Cetuximab + RT > RT

Investigational stage

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