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Corso Integrato di Clinica Medica ONCOLOGIA MEDICA AA LUNG CANCER. VIII. THERAPY. V. SMALL CELL LUNG CANCER Prof.

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(1)

Corso Integrato di Clinica Medica

ONCOLOGIA MEDICA

AA 2010 - 2011

LUNG CANCER. VIII.

THERAPY. V.

SMALL CELL LUNG CANCER

(2)

* limited stage (good performance status) = combination CT + chest RT;

* extensive stage (good performance status) =

combination CT;

- complete responders (all stages): prophylactic cranial RT;

* poor - performance - status pts (all stages): - modified - dose combination CT;

- palliative RT

SMALL CELL LUNG CARCINOMA

(3)

* SCLC = chemotherapy - sensitive disease;

- with limited stage disease → response rates = 60 - 80%, with 10 - 30% complete response);

- with extensive disease → response rates = 50%, usually partial responses;

- tumor regressions usually quick, within first 2 cycles of treatment, providing rapid palliation of tumor - related symptoms

TREATMENT

(4)

* chemotherapy significantly prolongs survival;

* untreated pts with limited - stage SCLC → median survival = 12 wks;

- with chemotherapy, median survival = 18 mos and long - term (> 3 yr) survival = 30 - 40%;

- median survival of extensive - stage pts = 9 mos and < 5% of pts survive 2 yrs;

although initially responsive, most pts relapse (due to emergence of chemotherapy resistance)

TREATMENT

(5)

INFLUENCE

OF MODERN COMBINATION CHEMOTHERAPY ON SURVIVALOFPTSWITHSCLC

era survival

limited disease

extensive disease prechemotherapy

supportivecare (median) 3 mos 1,5 mos

surgery(5yr) < 1%

-radiotherapy(5yr) 1 -3%

-chemotherapy

singleagent (median) 6 mos 4 mos combination

median 10 -14mos 7 - 11mos

5 yr 2 -8% 0 -1%

chemotherapy+ RT

(6)

*

goal of treatment

= obtaining

complete clinical

response - regression

(after 6 - 12 wks, by repeating

initial positive staging procedures, especially

fiberoptic bronchoscopy with washings and biopsies);

*

quality of initial response

predicts both median and

long - term survivals and potential cure;

-

complete responders survive longer

(with > 3 yrs

response, some pts are cured)

than partial responders

(tumor

> 50% of visible disease) and of no

responders

TREATMENT OF SMALL CELL LUNG CARCINOMA

I. Combination chemotherapy

(7)

* pts with

both limited or extensive disease

evaluated as

physiologically able

or not able

to

tolerate combination chemotherapy

(or chemo -

radiotherapy);

*

mortality

~ 1 -

5%

even in “able” pts (as for

pulmonary resection = need for physiologic staging)

and kept low by attention to day by day management

through initial 6 - 12 wks

TREATMENT OF SMALL CELL LUNG CARCINOMA

II. Combination chemotherapy

(8)

* reserved to

ambulatory pts

with no prior CT or RT

,

no other major medical problems

, and

adequate

heart

,

liver

,

renal

,

lung and bone marrow functions

;

- arterial P

O2

on room air > 6.6 kPa (50 mmHg),

without CO

2

retention;

*

chemotherapy modified

(to prevent undue toxicity)

in pts

with some health limitations

;

*

in all pts

, treatment coupled with

supportive care

(for infectious, hemorrhagic and other complications)

TREATMENT OF SMALL CELL LUNG CARCINOMA

(9)

*

most widely combination chemotherapy used =

etoposide plus cisplatin or carboplatin (/ 3 wks, on outpatient basis for 4 - 6 cycles)

TREATMENT OF SMALL CELL LUNG CARCINOMA

IV. Combination chemotherapy

(10)

* other

combination chemotherapy regimens

(effective with adequate drug dose and schedules)

include

etoposide + cisplatin + paclitaxel

,

irinotecan +

etoposide

(

median survival, but > toxic than

etoposide + cisplatin

), given / 3 wks for 4 - 6 courses;

-

dose intensity chemotherapy

adds toxicity

without clear survival benefit;

* on other hand,

oral single agent etoposide

of

clinical benefit in initial treatment of pts who are

elderly or with very poor performance status

TREATMENT OF SMALL CELL LUNG CARCINOMA

V. Combination chemotherapy

(11)

* appropriate

supportive care

(antiemetic therapy,

fluid and saline boluses with cisplatin, monitoring

blood counts and chemistries, attention for bleeding

or infection, and, as required, administration of

erythropoietin and granulocyte colony - stimulating

factors, CSFs);

*

adjustment of chemotherapy

doses

from nadir

granulocyte counts

[initial chemotherapy often

results in moderate / severe

granulocytopenia

(i.e.,

granulocytes < 500 - 1000 /

µ

l, respectively) and

thrombocytopenia

(platelets < 50,000 - 100,000 /

µ

l)

TREATMENT OF SMALL CELL LUNG CARCINOMA

(12)

*

following initial 4 - 6 courses

,

restaging

for

complete clinical remission

” (= complete

disappearance of all clinically evident lesions and

paraneoplastic syndromes), or “

partial remission

”, or

no response

”, or “

tumor progression

” (10 - 20% of

pts);

-

chemotherapy stopped in responding pts

(continuing CT not of value

TREATMENT OF SMALL CELL LUNG CARCINOMA

VII. Combination chemotherapy

(13)

*

complete remission

in

~

50 and 30% of pts with

limited - and extensive - stage, respectively. and

partial response

in 90 - 95% of all pts

TREATMENT OF SMALL CELL LUNG CARCINOMA

VIII. Combination chemotherapy

(14)

* responses median survival from 2 - 4 mos for

untreated pts to 14 - 18 and 10 - 12 mos for limited and extensive stage for pts, respectively;

* potential cure = 30 - 20% and 5 - 1% for limited and extensive stage SCLC, respectively;

- for most pts, improvement of symptoms and

performance status (physician be able at administering out - pt chemotherapy with avoiding undue therapeutic toxicity)

TREATMENT OF SMALL CELL LUNG CARCINOMA

IX. Combination chemotherapy

(15)

* poor prognosis for pts who relapse;

- patients who relapse > 3 mos since completion of initial chemotherapy (“chemosensitive disease”) →

median survival = 4 - 5 months;

- pts not responding to initial chemotherapy or relapsing within 3 mos (“chemorefractory disease)” → median

survival of 2 - 3 months;

- pts with chemosensitive disease may be retreated with initial regimen (topotecan = modest activity as 2nd - line therapy; pts be entered onto clinical trials testing new agents)

TREATMENT OF SMALL CELL LUNG CARCINOMA

IX. Combination chemotherapy

(16)

* radiation therapy to thorax associated with small but significant ↑ in long - term survival for pts with limited - stage SCLC (5% at 3 yrs);

- chemotherapy given concurrently with thoracic

radiation > effective than sequential chemoradiation but associated with significantly more esophagitis and

hematologic toxicity

TREATMENT OF SMALL CELL LUNG CARCINOMA

COMBINED - MODALITY CHEMORADIOTHERAPY

(17)

* in one randomized study, twice - daily

hyperfractionated radiation compared with once - daily schedule (both administered concurrently with 4 cycles of cisplatin and etoposide)

- survival significantly ↑ higher with twice - daily

regimen (median = 23 vs 19 mos; 5 - yr survival = 26 vs 16%), with twice - daily regimen giving > G3 esophagitis and pulmonary toxicity

= pts be carefully selected for concurrent

chemoradiation therapy based on good performance status and pulmonary reserve

TREATMENT OF SMALL CELL LUNG CARCINOMA

COMBINED - MODALITY CHEMORADIOTHERAPY

(18)

*

selection criteria

=

limited - stage disease + PS

0 - 1 + initial good pulmonary function

:

-

CT

full dose RT given

without sacrificing too

much lung function;

* from some studies

twice - daily radiation

fractions

toxic and improve survival (compared

to once - daily treatment)

TREATMENT OF SMALL CELL LUNG CARCINOMA

COMBINED - MODALITY CHEMORADIOTHERAPY

(19)

TREATMENT OF SMALL CELL LUNG CARCINOMA

COMBINED - MODALITY CHEMORADIOTHERAPY

(20)

* initial chest RT usually not indicated;

* however,

addition of chest RT to CT considered for

favorable pts

” (PS 0 - 1 + good pulmonary function +

only one site of extensive disease

);

* radiotherapy

survival in pts with chemotherapy -

induced complete remission;

* for all pts, radiotherapy added if chemotherapy

inadequate to relieve local tumor symptoms

TREATMENT OF SMALL CELL LUNG CARCINOMA. XIV.

COMBINED - MODALITY CHEMORADIOTHERAPY

(21)

* cured ~ 20 - 30% pts with limited - and 1 - 5% pts with extensive - stage, respectively:

* complete remission in 50% with limited - and in 30% pts with extensive - stage disease (90 - 95% pts have complete or partial responses);

- responses median survival by 10 - 12 mos for pts with

extensive and by 14 - 18 mos for pts with limited - stage disease (as compared 2 - 4 mos for untreated pts);

- in addition, relief of tumor - related symptoms and of

performance status in most pts (however, maintenance of good performance status in pts receiving outpatient chemotherapy requires judgment and skill to avoid undue therapeutic toxicity)

TREATMENT OF SMALL CELL LUNG CARCINOMA

COMBINED - MODALITY CHEMORADIOTHERAPY

(22)

* prophylactic cranial irradiation

(PCI) significantly ↓ development of brain metastases (occuring in ~ 2 / 3 of pts not receiving PCI) and results in small survival benefit (~5%) in pts who obtained complete response to induction chemotherapy;

- deficits in cognitive ability

following PCI uncommon and often difficult to sort out from effects of chemotherapy or normal aging

TREATMENT OF SMALL CELL LUNG CARCINOMA

Prophylactic cranial irradiation in limited - stage disease

(23)

* palliative radiation therapy = important component of management of SCLC;

- with symptomatic, progressive lesions in chest or at other critical sites, be administered in full doses (e.g., 40 Gy to chest tumor mass, if radiotherapy not yet been

given to these areas)

TREATMENT OF SMALL CELL LUNG CARCINOMA

Radiation therapy for palliation

(24)

*

high - dose

radiotherapy

(40 Gy)

to whole brain when

documented brain

metastases or

symptomatic

progressive lesions in

chest or other critical

sites

TREATMENT

OF SMALL CELL LUNG CARCINOMA

(25)

* surgical resection not routinely recommended for SCLC; - occasional pts meet usual requirements for resectability

(stage I or II with negative mediastinal nodes);

- often histologic diagnosis made in some pts only on review of resected surgical specimen → they should receive standard SCLC chemotherapy;

* from retrospective series, high “cure” rates (> 25%) with

surgery + adjuvant combination chemotherapy (although unclear what outcome would be with chemoradiation

therapy alone, given relatively low bulk disease)

TREATMENT OF SMALL CELL LUNG CARCINOMA Surgery and adjuvant chemotherapy

(26)

* only

in context of approved clinical protocol

:

-

new drug combinations

;

- very

intensive initial or "reinduction" therapy with

autologous peripheral stem cell infusion

(“

bone

marrow transplantation

”) and

- novel ways of

combining chemotherapy,

radiotherapy, and surgery

TREATMENT OF SMALL CELL LUNG CARCINOMA

New treatments

(27)
(28)
(29)

* lung as

frequent site of metastases from

primary cancers outside lung

;

- metastatic disease

considered incurable

,

except

in two special situations

(30)

* metastasis or a new primary LC?;

* nodule can be surgically

resected (= treated as primary LC) because:

- natural history of LC usually worse than that of other

primary tumors;

- especially in smoker pt > 35 yrs, and

- no other sites of active cancer found

METASTATIC PULMONARY TUMORS. II.

1. Solitary pulmonary nodule on chest x - ray

in pt with known extrathoracic neoplasm

(31)

* resectable with curative intent

if, after careful staging:

- pt can tolerate pulmonary resection;

- primary tumor definitively and successfully treated, and

- all known metastatic disease encompassed by projected

pulmonary resection

METASTATIC PULMONARY TUMORS. III.

2. Multiple unilateral pulmonary nodules. I.

(32)

* key = excluding uncontrolled primary tumors and extrapulmonary metastases;

* primary tumors with curatively resected pulmonary

metastases include osteogenic and soft tissue sarcomas, colon, rectal, uterine, cervix and corpus tumors, head

and neck, breast, testis, salivary gland cancers, melanoma, bladder and kidney tumors;

- 20 - 30% 5 yr survival rates in carefully selected pts, especially with osteogenic sarcomas (where resection of pulmonary metastases is becoming a standard treatment approach)

METASTATIC PULMONARY TUMORS. IV. 2. Multiple pulmonary nodules. II

References

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