Locally Advanced Squamous Carcinoma of the H&N

Question 1

Locally Advanced H&N SCC:

Historically, what was the standard nonsurgical therapy for locally advanced disease?

Answer 1

RT

Question 2

Locally Advanced H&N SCC:

What is the predominant recurrence pattern?

Answer 2

LRF (locoregional failure)

Question 3

Locally Advanced H&N SCC:

What type of RT fractionation leads to an absolute 8% improvement in 5-year survival?

Answer 3

Altered fractionation (Hyperfractionation)

Question 4

Locally Advanced H&N SCC:

Randomized trials of induction cisplatin and 5-fluorouracil (5-FU) chemotherapy
followed by standard fractionation versus laryngectomy and postoperative RT in
advanced larynx and hypopharynx cancer,

initially showed that
larynx preservation could be achieved without compromising overall survival.

TRUE or FALSE?

Answer 4

True.

Veterans
Administration Cooperative Group

European Organization for the
Research and Treatment of Cancer (EORTC)

Question 5

Locally Advanced H&N SCC:

MACH-NC demonstrated that the use of RT and concurrent chemotherapy resulted in __% reduction in the risk of death and an __% improvement in 5-year survival compared to RT alone.

Answer 5

19%
6.5%

A meta-analysis of individual patient data from >17,346 participants in 93
trials conducted from 1965 to 2000 (Meta-Analysis of Chemotherapy in Head
and Neck Cancer [MACH-NC]) demonstrated that the use of radiotherapy and
concurrent chemotherapy resulted in a 19% reduction in the risk of death and an
overall 6.5% improvement in 5-year survival compared to treatment with RT
alone (P < .0001).
This benefit was predominantly attributable to a 13.5% improvement in LRC.

The 2.9% reduction in the risk of distant
metastases was not statistically significant

Question 6

Locally Advanced H&N SCC:

What are the arms of the MACH-NC?

Answer 6

RT alone (control)
CCRT
induction chemotherapy + RT

Question 7

Locally Advanced H&N SCC:

For laryngeal CA, induction cisplatin followed by RT is the most effective means of larynx preservation and provides the best disease control albeit without survival benefit.

TRUE or FALSE?

Answer 7

False.
CRT

(RTOG) conducted a three-arm trial of radiation alone versus radiation and
concurrent cisplatin versus induction cisplatin followed by irradiation in larynx
carcinoma. Concurrent therapy constituted the most effective means of larynx
preservation and provided the best disease control, albeit without a statistically
significant survival benefit.

Question 8

Locally Advanced H&N SCC:

Differentiate synchronous and alternating schemes in the delivery of CRT.

Answer 8

Synchronous
administration results in the delivery of RT and CT on the same
days. Typically, CT will be given for 1 or more days at the initiation
of RT and then repeated in the same fashion several weeks later. Alternating
regimens usually sandwich RT and CT around one another. Radiation and drugs
are therefore not necessarily given on the same days. In such a scheme, CT
would be given during the first week of treatment with RT following in
subsequent week(s) before CT is given again.

Question 9

Locally Advanced H&N SCC:

Describe the differences in the treatment administration in the arms of NCOG and EORTC trials with RT/bleomycin that could have impacted the difference in their results:

The EORTC trial showed no
improvement in DFS or survival, and the RT/bleomycin combination in the
NCOG program led to a statistically significant doubling of LRC
and DFS, as well as a near-significant improvement in overall survival from 24%
to 43%.

Answer 9

Both RT fractionations are similar. (70/18 for NCOG, 64/1.8-2 for EORTC)

EORTC administered 15mg twice weekly for the 1st weeks (150mg)
NCOG only gave 5mg twice weekly (70 mg).

RT was prolonged in the EORTC due to increased toxicity.

Question 10

Locally Advanced H&N SCC:

The Christie Hospital in Great Britain evaluated RT and 100 mg/m2 of singleagent
methotrexate (MTX) given at the commencement of and after 2 weeks of a
3-week course of treatment.27 Most of the 313 patients in this protocol received
50 to 55 Gy in 15 or 16 fractions.

Mucositis was significantly greater in the
patients receiving MTX, but there was no difference in long-term toxicity. The
addition of MTX increased local control from 50% to 70% (P = .02) and
survival from 37% to 47% (P = .07). The greatest benefit was seen in patients
with oropharyngeal primary tumors who constituted one-third of the study
population. Local control with RT/MTX was 78% versus 38% with RT alone (P
= .002) in this patient subset. Survival was 25% with RT alone and 50% with
RT/MTX (P = .009).

Why is the data from this trial not applicable to current clinical practice?

Answer 10

Unfortunately, the data from this trial are not generally
applicable to current clinical practice because of the large radiation fraction sizes
that were used.

Question 11

Locally Advanced H&N SCC:

Identify the trial/institution.

A placebo controlled trial that studied the addition of 5-FU with RT.

All 175 patients
received 66 Gy in 2-Gy fractions. 5-FU was given at 1,200 mg/m2/d for the first
3 days of the 1st and 3rd weeks of irradiation. Confluent mucositis was more
frequent in the 5-FU arm than in the placebo arm (32% vs. 11%; P = .001), as
was weight loss >15% from pretreatment baseline (41% vs. 11%; P < .0001).
This increased acute toxicity did not prolong the delivery of RT in the RT/5-FU
arm relative to the RT/placebo arm. Two-year DFS and survival were 30% and
50% for RT/placebo patients and 50% and 63% for RT/5-FU patients (P = .06
and .08), respectively.

Answer 11

NCI of Canada trial

Question 12

Locally Advanced H&N SCC:

Identify the trial/institution.

A study that designed their treatment study according to the hypoxic principle by the addition of Mitomycin C, a cytotoxic agent to hypoxic cells.

They treated 195 patients in two randomized trials with mitomycin C (MMC).
This agent is predominantly metabolized in and preferentially cytotoxic to
hypoxic cells. The Yale treatment program consisted of 68 Gy ± MMC on days 1
and 43 of RT. Local control was improved with the addition of MMC from 54%
to 76% (P = .003). Survival improved from 42% to 48%, but this was not
statistically significant. The majority of patients in these trials received adjuvant
postoperative or preoperative irradiation, however. Only 74 (38%) received
definitive, primary RT, and the benefit from the addition of MMC in this subset
is unclear.

Answer 12

Yale

Question 13

Locally Advanced H&N SCC:

Identify the trial/institution.

This randomized trial assigned patients to receive 66 to 72 Gy ± two cycles of synchronous CDDP (20 mg/m2/d × 4) and infusional 5-FU (1,000
mg/m2/d × 4) during weeks 1 and 4 of RT. The main objective of this study
was primary site organ preservation. Surgical salvage was allowed for patients
with persistent disease. Acute toxicity was significantly greater in the combinedmodality
treatment arm, especially with respect to weight loss. Mucosal recovery
usually required 8 to 12 weeks after completion of RT and chemotherapy. There
were no differences in the total time required for RT delivery, however. Threeyear
DFS was significantly better for the patients receiving chemoradiotherapy
(67% vs. 52%; P = .03). Three-year survival with primary site preservation was
also higher in the combined-modality group (57% vs. 35%, P = .02), although
there was no significant difference in overall survival.

Answer 13

Cleveland Clinic

Question 14

Locally Advanced H&N SCC:

Identify the trial/institution.

MMC and 5-FU were used together in this trial of 209 patients. Patients were treated with continuous-course RT
alone at 2.5 Gy/day to 50 Gy in 28 days. Patients randomized to receive
RT/chemotherapy received the same dose-fractionation scheme as did those
receiving RT alone but over a total time of 56 days because of a planned 4-week
treatment interruption after 25 Gy. Bolus MMC (10 mg/m2) was given on days 1
and 43. Two cycles of continuous infusion 5-FU (1,000 mg/m2/d) were given on
days 1 to 4 and 43 to 46. The intent of the treatment break was to maintain
comparable levels of acute toxicity in the two treatment arms. Acute toxicity
was, in fact, equivalent in the two groups. Unfortunately, however, there was no
difference in 4-year local control (~40%) or survival (~40%).

Answer 14

Princess Margaret Hospital trial

Question 15

Locally Advanced H&N SCC:

A Spanish three-arm randomized trial (N = 859) provides additional
information that is pertinent to the estimation of the radiotherapeutic dose
equivalent provided by the delivery of concurrent chemotherapy.

Patients were
assigned to receive one of the following regimens:
A. 2 Gy/day to 60 Gy/42 days
B. 1.1 Gy twice daily to 70.4 Gy/44 days
C. 2 Gy/day to 60 Gy/42 days with concurrent bolus 5-FU 250 mg/m2 given
every other day
Progression-free survival and overall survival were significantly worse in arm
A as compared with arms B and C, as one would expect. Arms B and C were
equally efficacious. Not accounting for the different fractionation in arms B and
C and the unconventional administration of chemotherapy, it is still clear that the
addition of 5-FU was comparable to dose escalation of approximately 10 Gy. A
recent modeling analysis of phase III trials comparing CRT with RT only
suggests that concurrent chemotherapy provides the equivalent of a _______Gy
dose escalation.

Answer 15

10 to 12 Gy

Question 16

Locally Advanced H&N SCC:

Identify the trial/institution.

The ___________ conducted a phase III trial
comparing RT with alternating RT and chemotherapy in 157 patients with
unresectable HNC.

The RT arm was designed to give 70 Gy/7 weeks via
standard fractionation. The combined-therapy arm scheduled chemotherapy on
weeks 1, 4, 7, and 10 and radiation (60 Gy) on weeks 2 to 3, 5 to 6, and 8 to 9.
Each 2-week cycle of radiation consisted of 20 Gy/10 fractions. Each cycle of
chemotherapy included 5 days of bolus CDDP (20 mg/m2/d) and bolus 5-FU
(200 mg/m2/d). The incidence of grade 3/4 mucositis (18% to 19%) was the
same in both treatment groups. However, RT treatment delays occurred more
often in the RT-alone patients: 32% with a 1-week prolongation and 25% with a
≥2-week prolongation. Corresponding delays in the combined-modalitytreatment
group were 11% and 15%, respectively. The median dose of RT
delivered in the combined-modality-treatment group matched the planned dose
of 60 Gy, but it was only 62 Gy in the RT-alone group. Five-year actuarial
survival was significantly better in the combined-modality-treatment patients
(24% vs. 10%; P = .01), as were DFS (21% vs. 9%; P = .008) and local control
(64% vs. 32%; P = .04).

Answer 16

National Institute for Cancer Research in Italy

Question 17

Locally Advanced H&N SCC:

Identify the trial/institution.

This trial was performed in patients
who had stage III/IV oropharyngeal carcinoma.20,42 Radiotherapy consisted of
conventional 2 Gy, once-daily fractionation to 70 Gy. Patients on the CRT arm
also received three cycles of concurrent carboplatin (70 mg/m2) and continuous
infusion 5-FU (600 mg/m2/d × 4 days). Two hundred twenty-six patients were
enrolled in the trial. CRT resulted in significant improvement in 5-year
locoregional control (48% vs. 25%; P = .002), DFS (27% vs. 15%; P = .01), and
survival (23% vs. 16%; P = .05). This improvement in efficacy was
accompanied by a significant increase in acute mucositis (grade ≥ 2) from 39%
to 71% (P = .005). Severe acute cutaneous and hematologic toxicity and worse
nutritional status were also significantly more prevalent in the patients who
received combined-modality therapy. Severe late toxicity, primarily cervical
fibrosis, occurred in 27% of the combined-modality patients and in 12% of those
treated with RT alone (P = .04). Severe dental complications were twice as
frequent in the combined-modality patients (37% vs. 18%; P = .01).

Answer 17

French cooperative group trial, GORTEC 94-01

Question 18

Locally Advanced H&N SCC:

MUST KNOW:

Describe the entire study:

INTERGROUP 0099

Answer 18

Treatment of advanced NPC with CCRT was the subject of an intergroup study in which patients in both arms received conventionally fractionated RT (1.8 to 2.0 Gy/day) to a total dose of 70 Gy.
Those patients who were randomized to concurrent chemotherapy also received 3 cycles of cisplatin during RT at a dose of 100 mg/m2.
After completion of RT, they received an additional 3 cycles of adjuvant cisplatin at 80 mg/m2 and 4-day continuous infusions of 5-FU at 1,000 mg/m2/d.
All patients had stage III/IV, M0 disease.
In spite of an initial plan of enrolling 270 patients, the trial was terminated early when an interim analysis demonstrated the superiority of the CMT.
193 patients were enrolled, and the median follow-up was 2.7 years.
Three-year PFS favored the CMT patients (69% vs. 24%; P < .001).
Similaly, 3-year survival was 78% versus 47% (P = .005) in favor of the patients who received CCRT (Fig. 43.3).
Approximately, one-third of the patients in the CMT arm did not receive some or all of their adjuvant chemotherapy.