HOW CHEMO RADIATION EVEOLVED OVER LAST THREE DEADAES

1. Chemo Radiotherapy In Head & Neck Cancers:
Rationale and Relevance
Dr. Ashutosh Gupta
Professor of Radiation Oncology
Regional Cancer Centre
Jammu

2. Our Data: 2017-2018 Published recently (JK science):
Males:
Second most common cancer after lung cancer
 Oral Cavity: 179/2504 7.4%
 Larynx: 154/2504 6.15%
 Pharynx: 111/2504 4.4%
Females:
Does not come in first 10 cancers
 Majority of patients present in locally advanced stage.
 Mortality is high as is the morbidity for those cured.
Head & Neck Cancers
The Jammu perspective:

5. In the past three decades:
Management has undergone a paradigm shift from:
Surgical dominance
To
Non-surgical Organ preservation strategies.
Locally advanced Laryngo-pharyngeal cancers:
Larynx preservation (without compromising survival) is possible
…Against the time tested surgical approach of laryngectomy with adjuvant RT.

6. Chemotherapy!!
All credit must go to…..

7.  Radiation alone
insufficient in many
situations.
 Radio-resistance a big
problem.
Why add Chemotherapy to Radiation?

8. Large tumour cell burden.
 Tumour cell micro-environment/hypoxia.
 Inherent or acquired tumour cell resistance to RT.
 Repopulation of tumour cells during RT.
Radiation failure/Radio-resistance:
Why?

9.  As Radio sensitizer: Improving the probability of local control
and in some cases, survival, by aiding the destruction of radio-
resistant clones.
 Reduction in Distant Metastasis: Act systemically and
potentially eradicate distant micro metastases.
Rationale of adding Chemotherapy to RT:

10. Organ-preservation Intent
Improved cosmesis and function compared
with surgical resection with or without
adjuvant treatment
More importantly….

11. Process affected Mechanism Drug examples
Increased radiation
damage
Incorporation of
chemotherapy drug into
DNA/RNA
5 FU , Cisplatin
Inhibition of DNA repair
processa
Interference with the
DNA repair process after
radiation
5 FU, gemcitabine,
Cisplatin, Methotrexate,
etoposide, hydroxyurea
Cell-cycle interference Accumulation of cells in
the G2 and M phases
Taxanes, nuecleoside
analogs
Enhanced activity
against hypoxic cells
Chemotherapy can help to
eliminate hypoxic cells
Paclitaxel, mitomycin
Radiotherapy
enhancement by
preventing repopulation
Systemic therapy can slow
or stop rapid proliferation
Antimetabolites – 5 FU,
hydroxyurea
Anti EGFRs
Mechanism of Radiation Modulation

12. Early Stage disease:
 Organ preserving
Definitive Surgery.
 Definitive RT.
Management Strategies in H&N Cancers :
Advanced staged Disease:
Un-resectable disease,
Medically inoperable,
Difficult site for surgery.
• Will definitely go for Chemo-
Radiation Protocols.
First Group: Second Group:

13. What about locally Advanced Resectable Disease?
Can we save the Organ & its Functions?
The Third Group…

14. How it started?
Laryngeal Preservation

15. Initial trials demonstrating the potential of
chemotherapy to cause tumor regression as well as
predict response to RT.
Chemo-Radiation & Organ Preservation:
Inception took seed in the early 80’s:

16. Chemotherapy was used in conjunction with RT as an
approach to organ preservation in various combinations:
Neo-adjuvant,
Concurrent,
Alternating
Chemo-Radiation & Organ Preservation:
Since then:

17. 1. Veterans Affairs
2. EORTC
3. RTOG
Subsequently, numerous studies have been designed to evaluate
intensification of treatment as well as study toxicity and tolerability.
Concept got a definite shape primarily based on the findings
of pivotal trials by three pioneer groups:

18.  No sort of chemotherapy—induction/neoadjuvant, concurrent, adjuvant,
or any combination of these approaches—could be considered part of
standard treatment.
 Partial laryngectomy and primary radiation were the recommended
therapeutic options for patients hoping to avoid total laryngectomy.
During the 1980’s….

19.  The Veterans Affairs (VA) Laryngeal Cancer Study group: 1991
 Pivotal study in establishing the role of non-surgical methods of
treatment for advanced laryngeal cancers.
Laryngeal Preservation
First Landmark Trial: 1991

20. The Veterans Affairs (VA) Laryngeal Cancer Study group: 1991

21. Results:
 The chemotherapy/radiation arm yielded survival rates comparable
to those achieved with primary surgical management.
 Two thirds of surviving patients retained their larynx.
The Veterans Affairs (VA) Laryngeal Cancer Study
group: 1991

22. VA study set the stage for further larynx preservation
studies and established induction chemotherapy as
standard of care.
Impact of VA trial:

23.  The results of this trial, like the VA results strongly established the
role of induction chemotherapy in Hypopharyngeal cancers as well.
With similar overall survival, larynx preservation was achieved in
48%.
The EORTC Study 24891: 1996
Locally advanced Hypopharyngeal cancers

24. The 10-year overall survival rate:
Surgery followed by RT arm; 13.8%
Induction chemotherapy followed by RT arm: 13.1%
The 10-year progression-free survival rates:
Surgery followed by RT arm: 8.5%
Induction chemotherapy followed by RT arm: 10.8%
were 8.5% and 10.8%, respectively.
In the chemotherapy arm, the 10-year survival with a functional larynx
rate was 8.7%.
EORTC study 24891
Long term results(10 year updates) 2012:

25.  Induction Chemotherapy followed by RT
 Such was the popularity of larynx preservation approaches that
the study had to be prematurely abandoned due to a strong
patient preference for organ preservation over surgical
resection!!
GETTEC Trial: 2000
Conducted by Groupe d'Etude des Tumeurs de la TeΓ te et du Cou
(GETTEC), Head and Neck Tumor Study French Group.

26. Induction chemotherapy followed by radiation
(with surgery reserved for salvage)….
Came to be considered a new standard treatment for patients with
locally advanced cancer of the larynx.
Thus,
In early years of 2000…..

27. Is giving Chemotherapy before RT(Induction
Chemotherapy) is the best method?
Establishing the best suited Chemotherapy
regimens…

28. Two Issues:

29. RTOG 91-11 study in 2003
Used Chemotherapy in a different way:

30.  Concurrent Cisplatin and radiation: 84%
 Induction cisplatin/fluorouracil followed radiation: 72%.
 Radiation alone: 67%
Median follow up was 3.8 years
RTOG 91-11 Study
Laryngeal preservation Rate:

31.  Established the use of concurrent chemotherapy with radiation as the
superior nonsurgical, larynx preservation strategy.
 Demonstrated that patients with advanced laryngeal cancer receiving
concurrent Cisplatin and radiation had a better larynx preservation.
RTOG study 91-11, 2003

32.  These 10-year results show that induction PF followed by RT and concomitant
Cisplatin/RT show similar efficacy for the composite end point of LFS.
 Loco regional control and larynx preservation were significantly improved
with concomitant Cisplatin/RT compared with the induction arm or RT alone.
 New strategies that improve organ preservation and function with less
morbidity are needed.
RTOG 91-11
Long term results (10 year update): 2013

33. Three armed study:
Locally advanced glottic and supraglottic cancers.
1. Induction chemotherapy,
2.concurrent chemo-radiotherapy (CRT)
3.RT alone
John Hopkin’s study in 2003
Forastiere et al., NEJM

34.  Comparable overall survival in the three arms.
 Larynx preservation was best with concurrent CRT (2 year larynx
preservation rate of 88%, 75% and 70% in the concurrent CRT, induction
chemotherapy and RT alone arm).
 In addition, loco-regional control was significantly better with
concurrent CRT.
John Hopkin’s study in 2003
Forastiere et al., NEJM:

35.  Eighty seven randomized trials performed between 1965 and
2000 included in the present analysis.
 Patients were divided into four categories according to tumour
location: oral cavity, oropharynx, hypopharynx and larynx.
 Individual patient data of 16,192 patients were analysed, with a
median follow-up of 5.6years.
Meta-analysis of chemotherapy in head and neck cancer
(MACH-NC): 2011

36.  The benefit of the addition of Chemotherapy was consistent in all
tumour locations, with hazard ratios between 0.87 and 0.88 (p-value of
interaction=0.99).
 Chemotherapy benefit was higher for concomitant administration for all
tumour locations.
Meta-analysis of chemotherapy in head and neck
cancer (MACH-NC): 2011

37. The 5-year absolute benefits associated with the
concomitant chemotherapy:
Oral cavity: 8.9%
Oropharynx: 8.1%
Larynx: 5.4%
Hypopharynx: 4%
Meta-analysis of chemotherapy in head and neck
cancer (MACH-NC): 2011

38.  Lot of conflicting data in literature.
 Old studies favour concomitant CTRT as the best method of
combining CT with RT.
 Newer studies in 2012, 2013 have challenged the superiority of
concomitant CT RT.
Induction Vs. Concomitant Chemotherapy:

39. Choice of Chemotherapeutic Regimens

40. Toxicity Issues with
Chemo-Radiotherapy

41.  Mucosal
 Haematological
Acute Toxicity

42.  Besides acute mucositis, dysphagia due to fibrosis of
musculature of swallowing is of major concern.
 Radiation causes activation of TGFB1, a peptide invovled in
collagen depostion and degradation.
 Excessive fibrosis results in abnormal mobility of deglutition
muscle may lead to aspiration, dysphagia and stenosis.
Late Toxicity:

43. A 10 year update of the Radiation Therapy Oncology Group (RTOG)
91 11 trial gave some insight into the long-term effect of these
approaches.
Deaths unrelated to cancer or treatment:
 Concomitant chemotherapy arm: 30.8%
 Induction arm: 20.8%
 RT alone arm: 16.9%
Could be attributed to late toxicity related to swallowing
dysfunction along with silent aspiration.
Late Toxicity:
Major Concern

44. RT alone VS.RT concomitant with Cituximab
(A targetted agent):
Loco-regional control Survival
 RT alone: 14.9 months 49 months
 RT with Cituximab: 24.4 months 29.3 months
Results were best seen in the subset of oropharyngeal cancers, there was a
positive trend even in laryngopharynx
Search for alternative treatment strategies:
Bonner Trial 2006(NEJM)

45.  The targeted chemotherapy approach has never been compared
head on to concurrent CRT,
 This approach would seem logical however in elderly patients,
those with compromised renal functions and patients with poor
performance status in whom CRT is not tolerated.
Looking for safer CT RT regimens:

46. Experience from Developing
Nations

47.  Preponderance of advanced cancers in the form of bulky disease and
large nodal burden (Stage IV).
 Larynx preservation studies had limited number of such patients.
 The tumor characteristics of patients in RTOG 91 11 showed that 42-47%
patients were T2 or T3 without cord fixation in all 3 arms.
 Less than 10% of patients had T4 disease in stark contrast to those
presenting in developing nations
Experience from Developing Nations

48.  Poor performance status partially contributed by the preponderance of
hypopharyngeal cancers resulting in dysphagia.
 Hypopharyngeal cancers, which are traditionally known to be poor
performers form the major subsite along with marginal zone cancer
(supraglottis with hypopharynx).
 This is in contrast to the areas from where these trials originated where
the major burden is that of glottic and supraglottic cancers.
Experience from Developing Nations

49. Limited availability of infrastructure and
expertise to administer and monitor such
intensive regimens.
More Importantly…

50.  Weekly low dose chemotherapy (Cisplatin 30 mg/m 2 ) was found
to be a more feasible option with acceptable toxicity and lesser
treatment interruptions (<15%).
 This regimen showed similar control rates when compared to
routinely practiced 3 weekly high dose chemotherapy.
Modifications of Treatment protocols to suit needs of Indian
Patients:

51.  Six day per week RT better than five day regimens.
 Provide better loco regional control rates.
 Strategy seems logistically feasible as all Indian
centres work six days a week.
Making Radiation more effective:

52. More Relevance of Neo Adjuvant CT Protocols:

53. Quality of life issues after CT RT
Survey conducted among patients in TMH in India

54.  Determining molecular biomarkers as predictors for
response to non-surgical treatment.
 Role of epidermal growth factor receptor, E-catherin
and b-catenin Tp53 mutation has been explored
Future Trends:

55. Hope…..
I have not left you more confused!
Thanks

56.  To improve the outcome in advanced un resectable disease chemotherapy was
added in loco-regional treatment in early 70s.
 A large number of the early studies in the 1970s and 1980s were performed
using single agents added concurrently to RT.
 Variety of single drugs (5-FU, bleomycin, cisplatin, methotrexate, mitomycin),
and later drug combinations.
 Over 70 randomized trials were performed to evaluate efficacy of adding
chemotherapy to loco regional treatment.
 Most of these trials were too small to detect even a moderate effect on survival.
 This data was formalized in series of 3 meta-analysis by Pignon et al with
updated individual data.
Pignon Meta-analysis: Lancet 2000; 355: 949–55

57. 1. The effect of chemotherapy—LR treatment was
compared with LR treatment plus chemotherapy.
2. The timing of chemotherapy—NACT plus
radiotherapy was compared with concomitant or
alternating RadioChemotherapy with the same
drugs.
3. Larynx preservation with neo adjuvant
chemotherapy—radical surgery plus radiotherapy
was compared with neo adjuvant chemotherapy
plus radiotherapy in responders or radical surgery
and radiotherapy in non-responders.
Three comparisons;

58.  Trials were divided according to timing of chemotherapy:
Adjuvant, neoadjuvant, and concomitant or alternating with
radiotherapy.
 Trials were also grouped according to the type of
chemotherapy:
 platin (cisplatin or carboplatin) plus fluorouracil,
 platin-containing combinations,
 multiagent chemotherapy without platin,
 single-agent chemotherapy (platin or others).

59.  The first meta-analysis included 63 trials.
Effect of Chemotherapy on survival

60.  Concomitant trials - grouped according to number of
chemotherapuetic agents used.
 Single 17 trials (2634 pts) v/s multiple 9 trials (1093 pts)
 The effect of concomitant chemotherapy was significantly
(p<0.01) greater with multiagent chemotherapy than with
single-agent chemotherapy (hazard ratio 0.69 v/s 0.87).
 The only significant observation was a decreasing effect of
chemotherapy on survival with increasing age (trend test,
p=0·05

61.  The second meta-analysis – 6 RCTs
 861 patients
 The pooled HR of death was 0.91 in favour of alternating or
concomitant radiochemotherapy, but this did not reach the
statistical significance (p=0.23)
 This reduction in the risk of death translated into an absolute,
but not statistically significant, survival benefit of 3%, both at
2 years (43 vs 40%) and 5 years (27 vs 24%).
Effect of Timing of Chemotherapy on survival
Neoadjuvant plus Radiotherapy
with or without Adjuvant
chemotherapy
concomitant or
alternating
Radiochemotherapy.

62.  The addition of chemotherapy to locoregional
treatment- the most important result was a small, but
statistically significant, overall benefit in survival with
chemotherapy (the absolute benefit at 2 and 5 years was
4%).
 No significant benefit of adjuvant or neoadjuvant
chemotherapy but a significant benefit of concomitant
chemotherapy (absolute benefit at 2 and 5 years of 8%)
Conclusion

63. EVIDENCE
LOCALLY ADVANCED
NASOPHARYNGEAL
CANCERS

64. 284 pts stage III/IV Nphx Ca 1993 – 99
Two arm with RT 70 – 74 Gy @ conventional
fractionation
Cisplatin 20 mg/m2/d and fluorouracil (FU) 400
mg/m2/d as a 96-hour continuous infusion during
weeks 1 and 5 of RT.
Phase III Study of Concurrent Chemoradiotherapy Versus
Radiotherapy Alone for Advanced Nasopharyngeal Carcinoma:
Positive Effect on Overall and Progression-Free Survival
Jin-Ching Lin, Jian-Sheng Jan J Clin Oncol 21:631-637. © 2003

65. TOXICITIES

66. CCRT RT Significance
5 yr progression free
survival 71.6 % 53 % P = .0012
5 yr overall survival
72.3 % 54.2 % P = .0022
5 yr Nphx disease
free survival 89.3 % 72.6 % P = .0009
5 yr neck disease
free survival 96.8 % 92.1 % P = .1716
5 yr DMFS 78.7 % 69.9 % P = .0577
Results
Conclusion: We conclude that CCRT is superior to RT
alone for patients with advanced NPC in endemic areas.

67.  Phase III RCT – CTRT v/s RT alone
 350 pts
 Cisplatin 40 mg/m2 weekly
 Median f/u 5.5 yrs
 5 yr OS 58.6 % for RT alone arm compared to 70.1 % for CRT arm.
 Subgroup analysis- no difference in OS for T1/T2 stage whereas there was a difference
between the arms for T3/T4 stage ( P =.013) favoring the CRT arm.
 Conclusion - The regimen of weekly concurrent CRT is a promising standard treatment
strategy for locoregionally advanced nasopharyngeal carcinoma patients.
Overall Survival After Concurrent Cisplatin Radiotherapy Compared With
Radiotherapy Alone in Locoregionally Advanced Nasopharyngeal Carcinoma
J Natl Cancer Inst 2005;97:536–9

68.  CTRT is better that RT alone
 Hyperfractionated RT is better than conventional
 Is CTRT better than hyperfractionated RT for
locally advanced head neck cancers
QUESTION

69.  122 patients with advanced head neck cancers
 Hyperfractionated RT 75Gy @1.25Gy BD over 6wk
 Combined modality arm
RT 70 Gy @same fractionation with planned treatment interruption of 7 days
after 40 Gy to manage mucosities
 Chemotherapy – wk 1 and wk 6
5 FU 600 mg/m2 /day cont. infusion for 5 days
cisplatin 12 mg/m2/day iv bolus for 5 days
 2 more cycles of chemotherapy were given to all patients after completion of
local therapy
HYPERFRACTIONATED IRRADIATION WITH OR WITHOUT
CONCURRENT CHEMOTHERAPY FOR LOCALLY ADVANCED
HEAD AND NECK CANCER
DAVID M. BRIZEL The New England Journal of Medicine, 1998

71.  Compared induction chemotherapy versus concurrent CRT in hypopharyngeal
cancers.
 The induction chemotherapy regimen comprised of two drugs Cisplatin/5 FU.
 Amongst 71 patients with advanced pyriform sinus cancer, larynx preservation
was superior for concurrent CRT group (2 year larynx preservation 92%)
compared with induction chemotherapy (68%).
 However, there was no survival benefit with concurrent CRT.
Randomized phase III trial comparing induction chemotherapy followed
by radiotherapy to concomitant chemoradiotherapy for laryngeal
preservation in T3M0 pyriform sinus carcinoma.
French group Prades et al; 2010

72.  Median follow up 41 months
 Conclusions Combined treatment for advanced head and neck
cancer is more efficacious and not more toxic than
hyperfractionated irradiation alone.
Results
Combined
modality
Hyperfractio
nated RT
Relapse free
survival rate 61 % 41 %
Locoregional
control 70 % 44 %
Overall
survival 55 % 34 %

73. 298 pts enrolled 1989-93 with locoregionally
advanced head neck cancers
2 arms with RT alone and CTRT
RT – 3 courses of 13 fractions of 1.8 Gy twice daily.
Total dose 70.2 Gy
CT – CDDP 70 mg /m2, 5 FU 350 mg/m2 from day
2 to 5 repeated on day 22 and 44
Simultaneous radiochemotherapy versus radiotherapy alone in
advanced head and neck cancer: a randomized multicenter study
TG Wendt Journal of Clinical Oncology, Vol 16, 1318-1324

74. arm A arm B
3 yr locoregional
control rate 17 % 36 % P = .004
3 yr overall
survival 24 % 46 % P = .0003
Distant failure
rates 10 % 10 %
Serious late side
effects 6.4 % 10 %
Results
CONCLUSION: Concomitant CT offeredimproved disease control and survival in
advanced head and neck cancerpatients. Due to increased acute toxicity, more
supportive care is demandedwhen CT is given simultaneously. Increased total
treatment time does not exert a negative impact on outcome in this combined
modality regimen.

75. 130 patients with locally advanced head neck cancers
Arm 1- Hfx RT 77 Gy @ 1.1 Gy/ fraction twice a day over 35
days
Arm 2 – Hfx RT + low dose daily Cisplatin
6 mg/m2 1-2 hr before 2 nd fraction
In case of acute high grade reactions treatment interruption of
2 wk was allowed with no dose reduction.
Hyperfractionated Radiation Therapy With or Without Concurrent Low-Dose
Daily Cisplatin in Locally Advanced Squamous Cell Carcinoma of the Head and
Neck: A Prospective Randomized Trial
Branislav Jeremic, J Clin Oncol 18:1458-1464. © 2000

76. Toxicities
All 130 pts completed planned treatment.
Total treatment time were identical.
Treatment interruption because of toxicity were similar.

77.  Median
followup 79
months.
Results
Combined
modality
Hfx RT alone Significance
Complete
Response 75 % 48 % p = .002
2 yr Survival
rate 68 % 49 %
5 yr Survival
rate 46 % 25 % p = .0075
5 yr
Progression
free survival
46 % 25 % p = .0068
5 yr DMFS 86 % 57 % P = .0013
Conclusion: As compared with Hfx RT alone, Hfx RT and
concurrent low-dose daily CDDP offered a survival advantage, as
well as improved LRPFS and DMFS.

78.  The EGFR, a member of the ErbB family of receptor tyrosine
kinases, is abnormally activated in epithelial cancers, including
head and neck cancer.
 Radiation increases the expression of EGFR in cancer cells,
and blockade of EGFR signaling sensitizes cells to the effects
of radiation.
 Cetuximab, an IgG1 monoclonal antibody against the
ligandbinding domain of EGFR, enhances the cytotoxic
effects of radiation in squamous-cell carcinoma.
Anti EGFR as a Radiomodulator

79.  424 pts, multinational study
 RT v/s RT + Cetuximab
 Cetuximab 400 mg/m2 at initial dose followed by 250 mg / m2 weekly for rest RT.
 The median duration of LRC was 24.4 months for cetuximab plus RT and 14.9 months for RT
alone ( P = 0.005)
 median f/u of 54.0 mths
 The median duration of OS was 49.0 months among patients treated with combined therapy
and 29.3 months among those treated with radiotherapy alone ( P = 0.03)
 With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater
toxic effects, including mucositis, did not differ significantly between the two groups
Radiotherapy plus Cetuximab for Squamous- Cell
Carcinoma of the Head and Neck
N Engl J Med 2006;354:567-78
James A. Bonner

80. CONCURRENT
CHEMORADIATION IN
ADJUVANT SETTING

81.  RT - standard adjunctive treatment in completely
resected patients with stage III or IV disease.
 Even more essential in resected patients with gross or
microscopic residual disease.
 Based on the benefit demonstrated for patients with
unresectable HNC, several trials have assessed the
benefit of chemotherapy added to RT in the
postoperative setting

82.  Haffty BG. Yale Mitomycin Randomized Trials. J Clin Oncol
15:268-276, 1997
 Bachaud JM. Int J Radiat Oncol Biol Phys 36:999-1004, 1996
 Bernier J. EORTC phase III trial 22931. Int J Radiat Oncol Biol
Phys 51:1, 2001.
 Cooper JS. RTOG 9501/intergroup phase III trial. Proc Am Soc
Clin Oncol 21:903, 2002

83. Patient Selection Criterion
EORTC 22931 only EORTC 22931 and RTOG 9501 RTOG 9501 only
Stage III/IV disease
Surgical margins microscopically
involved
Two or more positive lymph
nodes
Positive lymph nodes at levels IV or
V in patients
with tumors arising from oropharynx
or oral cavity
Extracapsular extension in positive
lymph nodes
Vascular embolisms
Perineural infiltration

84.  Post op RT alone
 Post op RT + Cisplatin 100 mg/m2 on weeks 1, 4 and 7
 EORTC Trial 334 patients were treated. There was a significant benefit for 3 yr
overall survival ( 61% v 49%)
 DFS, LRC, and time to progression favoring the CRT arm.
 Although acute functional mucosal reactions were worse in the CRT arm than the
RT arm, there were no differences seen in late toxicities.
 RTOG 459 high risk patients
 Similar results

86. In summary, the bulk of the data from the two most recent trials, along with two
earlier trials, support the use of postoperative CRT for patients with high risk for
recurrence, as defined for these trials.

87.  As toxic deaths can occur, it is imperative that close
monitoring, appropriate drug dose reductions, and
optimal supportive care be used.
 Most patients studied in these trials were <70 years of
age and all with good to excellent functional status;
therefore, the application of adjuvant
chemoradiotherapy to patients >70 and of poorer
functional status should be carried out with caution.
Word of Caution

88. CONCURRENT CHEMORADIATION
FOR RESECTABLE HEAD NECK
CANCER
ORGAN AND FUNCTION
PRESERVATION

89.  The landmark Veterans Affairs LCS group trial demonstrated
that induction Cisplatin / 5 FU followed by RT resulted in 64 %
laryngeal preservation without decrementing OS.
 Despite this high rates of local failures were seen.
 To address whether addition of conc chemoth to RT
improves the outcome RTOG 9111 was conducted.

90.  546 pts
 3 arms
 Induction Cisplatin + 5 FU followed by RT
 Radiotherapy with concurrent cisplatin.
 Radiotherapy alone
 Median f/u 3.8 yrs
Concurrent Chemotherapy and Radiotherapy
for Organ Preservation in Advanced Laryngeal Cancer
Arlene A. Forastiere, N Engl J Med 2003;349:2091-8
NACT-RT CTRT RT
2yr intact
larynx 75 % 88 % 70 %
LRC 61 % 78 % 56 %

91.  55 patients March 1999 and May 2002.
 Evaluated for their ability to resume oral feeding following treatment.
 Modified barium swallow (MBS) studies were performed if the patients complained of dysphagia or if
there was clinical suspicion of aspiration.
 The severity of dysphagia was graded on a scale of 1–7.
 At a median follow-up of 17 months.
 25 patients (45%) developed severe dysphagia requiring prolonged tube feedings or repeated dilatation.
 Among 33 patients who underwent MBS following treatment, 12 patients (36%) had silent aspiration.
 Most patients had severe weight loss (0–21 kg) during treatment, likely due in part to mucositis in the
orodigestive tube
Dysphagia following chemoradiation for locally advanced head and
neck cancer. Annals of Oncology 15: 383–388, 2004
N. P. Nguyen

92.  Dysphagia is a common, debilitating and potentially life-threatening
sequela of concurrent chemoradiation for head and neck malignancy.
 Physicians should be aware that the clinical manifestations of aspiration
may be unreliable and insidious, because of the depressed cough reflex.
 Modified and traditional barium swallows should be performed following
treatment to assess the safety of oral feeding and the structural integrity
of the pharynx and esophagus.
 Tube feeding should be continued for those with aspiration.
CONCLUSION

93.  High dose Cisplatin 100 mg/ m2 every 3 weekly was initially
adopted as single modality CT regimen.
 Alternatives were developed to decrease the toxicity- renal,
mucosal, ototoxicity.
 Daily (6mg/m2) and weekly (40mg/m2) dosing schedules were
tried and demonstrated LCR control and OS benefits.
 But these schedules never been adequately compared with
100mg/m2 schedule.
What is the optimal chemotherapy
ragimen?

94.  MACH-NC 2000 reported significant survival benefit for multiagent
chemotherapy over single agent regimen.
 However updated analysis 2007 did not show this benefit compared with
single agent regimen.
 Only difference shown was platinum and 5FU containing regimen were
superior to others.
 Direct comparison between cisplat v/s cisplat and 5FU made by
Aldenstein ( Intergroup Randomised trial) but results were confounded
by spilt course of RT
Single agent or Multiagent

95. Although Cetuximab/RT improves OS over RT alone
but no direct comparison with RT + CT.
Cetuximab – less mucosal toxicity but COST.
Ongoing trial
 RTOG randomizing betn Cisplat v/s Cisplat + Cetuximab
 Phase II studies to integrate Cetuximab into post op regimen.
 Integration of antiangiogenic antibody Bevacizumab is being
evaluated
 Separate and combined angiogenic and EGFR blocade
integrated into concomitant Cisplatin and hyperfrationated
RT is being evaluated (NCT 00140556)
Targeted Agents

96.  Applicability of these trials out of a protocol setting was a cause of
concern more so in the developing nations.
 Therefore, individual centers have adopted these protocols some of
them with certain modifications to increase their applicability.
 However, there remains a paucity of robust data from the
developing world on non-surgical organ preservation strategies.
However:

97.  The group essentially concluded that larynx preservation protocol was a
feasible option in Hypopharyngeal cancers in the form of induction
chemotherapy and RT.
 The authors however noted that the response was more favorable for
T2 disease when compared to T3 and T4 disease.
 The 10 year update done in 2012 suggests similar overall survival in both
the arms and survival with a functional larynx in 8.7%.
The EORTC Study 24891: 1996
Locally advanced Hypo-Pharyngeal cancers

98. Although early Stage cancers (I and II) are
usually managed with definitive RT or Surgery alone…
……Patients with more-advanced Stages( III & IV) will need
the use of Chemotherapy along with Surgery and
Radiation.
Place of Chemo-Radiotherapy in managing H&N
Cancers: