# Small-Cell Lung Cancer: 8 Years Experience of a Single Multidisciplinary Team

Authors: Loaie M. El-Helw; Trevor K. Rogers; Matthew Q. F. Hatton
Journal: Journal of Oncology
 (2008)

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## Abstract

Aims. We have audited the changes in treatment
practice for small-cell lung cancer (SCLC) presented to a single
multidisciplinary team (MDT) at Doncaster and Bassetlaw Hospitals
between January 1998 and December 2005. Materials and
Methods. The MDT database was used to identify all
patients with SCLC. Anonymised demographic, treatment, and outcome
details were extracted from the database supplemented by patient
records. Results. 235 patients were identified.
112 (48%) had limited disease at presentation. Chemotherapy
was the initial treatment for 195 patients, 77% of whom had a
documented radiological response with a complete response in
24%. Chemotherapy regimes evolved during the study period with
the increasing use of platinum-based chemotherapy. Anthracycline-based
chemotherapy was most used before 2004 and was given to 57% of
all patients. 42% received consolidation thoracic radiotherapy
and 24% prophylactic cranial irradiation. The median and
2-year survival were 8 months and 18%, respectively, for
patients with limited disease and 5 months and 5%, respectively,
for extensive disease. Conclusion. We have
documented changes in treatment practice and service delivery of
SCLC over the 8 years during which the MDT has been operating. However,
there has not achieve any significant improvement in outcome for the
population of patients with SCLC.


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## Body

## 1. Introduction

It has been recognised that cancer
survival in the UK has
lagged behind the USA and other European countries. This recognition triggered the Calman-Hine report
in the mid 1990s, which started a major reorganisation of cancer services in
the UK. In 1998, the NHS executive  published guidance on Improving Outcomes in Lung
Cancer [1]. One aspect of
this guidance examined was the effectiveness of multidisciplinary teams (MDTs)
and supported the recommendation that all patients with lung cancer have their
case reviewed by a specialist MDT and targeted investment was made to develop
team working. In 2000, the NHS cancer plan looked to introduce more radical
changes and cover the whole cancer care pathway. This led to significant
investment aimed at reducing waiting times and improving access to treatment.The Doncaster lung cancer MDT was set up
and in 1997 started to review the management of all patients with lung cancer
who presented to three district general hospitals
that cover a population of 450000 patients in South Yorkshire and North Nottinghamshire . From the outset, a database was designed to prospectively record data for all patients reviewed by the MDT and
included demographic, staging, and treatment details. The MDT has now been
operational for 10 years and we have started to review our experience over that
time particularly looking to document the trends in treatment and outcome that
have occurred during this period of cancer service reorganisation in the UK.This paper has looked specifically at
patients with small-cell lung cancer (SCLC) which compromises approximately 20%
of all cases of lung cancer. The disease is characterised by early metastatic
spread, sensitivity to chemotherapy, and early development of resistance [2].
Untreated the median survival in limited stage is 3 months, and in extensive
stage 1.5 months. With single-agent chemotherapy, trials indicate a median
survival of 6 and 4 months and with combination chemotherapy, 10–20 and 7–11 months,
respectively [3–6].Improving outcomes in lung cancer,
published in 1998, [1] reviewed the research
evidence and recommended the use of combination chemotherapy. This guidance was
able to suggest an optimal duration of chemotherapy but concluded there was
little clear evidence to guide the choice of drugs. The guidance also felt
there was sufficient evidence to support the use of thoracic radiotherapy and
prophylactic cranial irradiation in limited stage disease. The National
Institute for Clinical Excellence commissioned an update, which was published
as the “The Diagnosis and Treatment of Lung Cancer Guidelines” in 2005 [7]. This
guidance built on the previous recommendation indicating the superiority of
platinum-based chemotherapy as first line treatment and indicating a role for second
line treatment in selected patients. No new recommendations were made for
radiotherapy, though its timing and sequencing with chemotherapy was
discussed.Therefore, we have chosen to study the
whole population of patients with SCLC presenting to our MDT and audit the
changes in treatment practice that have occurred between 1998 and 2005 and
monitored the effect that the investment made following the NHS cancer plan has
had an outcome.


## 2. Materials and Methods

The MDT database has prospectively recorded
all patients with a histological or radiological diagnosis of lung cancer since
the Doncaster Lung cancer MDT was formed. This database has been used to
identify all patients with a confirmed histological diagnosis of SCLC between
January 1998 and December 2005. The demographic and treatment data on the
database, supplemented by information from the patient records, has been
anonymised and subjected to statistical analysis. To examine for time trends we
divided patients into 3 chronological groups (1998–2000, 2001-2002, and 2003–2005) each
containing approximately 80 patients. Kaplan Myer survival analysis was
performed using SPSS statistical package version 12.0.1.


### 2.1. Patients Characteristics

Two hundreds and thirty five patients with
SCLC were identified; 120 (51%) females and 115 (49%) males. The median age was
66 years (range 25–87), there were
83 patients (35%) ≥70 years old at the time of diagnosis. A histological
diagnosis was made at flexible bronchoscopy in 83%, the remaining 17% required fine
needle aspiration for cytology or CT guided biopsy.110 patients had a performance status of 0
or 1 at diagnosis and staging investigations showed 112 patients had limited
stage disease confined to the ipislateral lung and mediastinum. Applying the Manchester
prognostic scoring
system [8], 91 patients (39%) fell into the good prognosis category, 122 (52%)
the intermediate, and 22 (9%) were in the poor prognosis group.We analysed the time from GP referral to starting
definitive treatment as a measure of the early diagnostic part of the patient
pathway. The duration was shortest between 2003–2005 compared to
those of 2001-2002 and 1998–2000 (mean 27, 37,
and 34 days and median of 26, 33, and 31 days, resp.)
(P<.001 using one way ANOVA test) (Figure 1).Figure 1
Mean time from referral to treatment.In Table1, the patient characteristics
and treatment outcome are summarised and  broken down into the three
chronological groups. For 83% of patients the initial treatment was
chemotherapy. The table also shows that anthracycline-based chemotherapy was most
commonly used overall, though over the study period there was increasing use of
platinum-based treatment, which became the most commonly used treatment in the
last three years of the study. The median number of chemotherapy cycles given was
6 (range 1–6) and seventeen
patients received chemotherapy as part of ongoing clinical trials.Table 1
Patients characteristics and treatment outcome over the study period.
VariablesNumber of patients (%)Total no. (%)Years (inclusive)January 1998 till December 2000January 2001 till December 2002January 2003 till December 2005Patients number768277235GenderFemales35
(46)44
(54)41 (53)120
(51)Males41
(54)38
(46)36
(47)115
(49)StageLD39
(51)38
(46)35
(45)112
(48)ED37 (49)44
(54)42
(55)123
(52)Mean
time from referral to starting treatment (days)343727Overall
31TreatmentChemotherapy63
(83)68
(83)64
(83)195
(83)Palliative RT4 (5)5 (6)4 (5)13
(5.5)Supportive  Care8 (11)9 (11)9 (12)26
(11)Resection and chemotherapy1 (1)——1
(0.5)ChemoregimensAnthracycline based38
(59)43
(63)30
(47)111
(57)Platinum based14
(22)25
(37)34
(53)73
(37)Others12 (19)——12 (6)RadiotherapyPCI19 (33)20 (35)18 (32)57 (24)Consolidation TRT32 (32.4)33 (33.3)34 (34.3)99 (42)To Metastases9 (21)22 (51)12 (28)43 (18)Median survivalFor all patients (m)4876(P=.143)For patients with LD (m)78108(P=.516)For patients with ED (m)3655(P=.006)P-values
were calculated using logrank testLD: limited disease, ED: extensive disease, RT: radiotherapy, PCI: prophylactic cranial irradiation, TRT: thoracic radiotherapy, m: months.The table also indicates that the use of
radiotherapy was constant over the study period. Around 5% of patients received
radiotherapy as initial palliative treatment and in a further 18% it was used
to palliate symptoms later in the course of the disease. Consolidation thoracic
radiotherapy (TRT) was given in 42% of patients who had shown a response to the
initial chemotherapy and prophylactic cranial irradiation (PCI) was given to 24%
of patients who presented with limited stage disease and responded to
chemotherapy or were treated in the trial setting.


## 2.1. Patients Characteristics

Two hundreds and thirty five patients with
SCLC were identified; 120 (51%) females and 115 (49%) males. The median age was
66 years (range 25–87), there were
83 patients (35%) ≥70 years old at the time of diagnosis. A histological
diagnosis was made at flexible bronchoscopy in 83%, the remaining 17% required fine
needle aspiration for cytology or CT guided biopsy.110 patients had a performance status of 0
or 1 at diagnosis and staging investigations showed 112 patients had limited
stage disease confined to the ipislateral lung and mediastinum. Applying the Manchester
prognostic scoring
system [8], 91 patients (39%) fell into the good prognosis category, 122 (52%)
the intermediate, and 22 (9%) were in the poor prognosis group.We analysed the time from GP referral to starting
definitive treatment as a measure of the early diagnostic part of the patient
pathway. The duration was shortest between 2003–2005 compared to
those of 2001-2002 and 1998–2000 (mean 27, 37,
and 34 days and median of 26, 33, and 31 days, resp.)
(P<.001 using one way ANOVA test) (Figure 1).Figure 1
Mean time from referral to treatment.In Table1, the patient characteristics
and treatment outcome are summarised and  broken down into the three
chronological groups. For 83% of patients the initial treatment was
chemotherapy. The table also shows that anthracycline-based chemotherapy was most
commonly used overall, though over the study period there was increasing use of
platinum-based treatment, which became the most commonly used treatment in the
last three years of the study. The median number of chemotherapy cycles given was
6 (range 1–6) and seventeen
patients received chemotherapy as part of ongoing clinical trials.Table 1
Patients characteristics and treatment outcome over the study period.
VariablesNumber of patients (%)Total no. (%)Years (inclusive)January 1998 till December 2000January 2001 till December 2002January 2003 till December 2005Patients number768277235GenderFemales35
(46)44
(54)41 (53)120
(51)Males41
(54)38
(46)36
(47)115
(49)StageLD39
(51)38
(46)35
(45)112
(48)ED37 (49)44
(54)42
(55)123
(52)Mean
time from referral to starting treatment (days)343727Overall
31TreatmentChemotherapy63
(83)68
(83)64
(83)195
(83)Palliative RT4 (5)5 (6)4 (5)13
(5.5)Supportive  Care8 (11)9 (11)9 (12)26
(11)Resection and chemotherapy1 (1)——1
(0.5)ChemoregimensAnthracycline based38
(59)43
(63)30
(47)111
(57)Platinum based14
(22)25
(37)34
(53)73
(37)Others12 (19)——12 (6)RadiotherapyPCI19 (33)20 (35)18 (32)57 (24)Consolidation TRT32 (32.4)33 (33.3)34 (34.3)99 (42)To Metastases9 (21)22 (51)12 (28)43 (18)Median survivalFor all patients (m)4876(P=.143)For patients with LD (m)78108(P=.516)For patients with ED (m)3655(P=.006)P-values
were calculated using logrank testLD: limited disease, ED: extensive disease, RT: radiotherapy, PCI: prophylactic cranial irradiation, TRT: thoracic radiotherapy, m: months.The table also indicates that the use of
radiotherapy was constant over the study period. Around 5% of patients received
radiotherapy as initial palliative treatment and in a further 18% it was used
to palliate symptoms later in the course of the disease. Consolidation thoracic
radiotherapy (TRT) was given in 42% of patients who had shown a response to the
initial chemotherapy and prophylactic cranial irradiation (PCI) was given to 24%
of patients who presented with limited stage disease and responded to
chemotherapy or were treated in the trial setting.


## 3. Results

### 3.1. Response

A Total 196 patient received primary chemotherapy,
5 died following the first cycle of treatment leaving 191 assessable for
response (Table2). There was an overall response rate was 77% (24% CR and 53%
PR) with only 6% having documented progressed during chemotherapy. We found a
higher response rate for patients with limited disease, performance status 0/1,
and those less than 70 years old but none reached statistical significance (using
chi-square test, P-values were 0.090, 0.390, 0.702, resp.). There
was higher response rate with platinum-based treatments (87%) compared anthracycline
(78%). The high response rate for platinum-based treatment includes patients in
the poor prognostic group, particularly those with impaired hepatic function,
in whom single-agent carboplatin was used and had a response rate of 50%.Table 2
Response to chemotherapy among 191 assessable patients.
Response, no. (%)TotalCRPRSDPDVariableOverall response46
(24)101
(53)32
(17)12 (7)191StageLimited25
(27)52
(58)9 (10)5 (5)91Extended21
(21)49  (49)23
(23)7 (7)100Manchester   groupsGood27
(33)44
(55)6 (7)4 (5)81
(42)Intermediate19
(20)46
(49)22
(23)8 (8)95
(50)Poor—11
(73)4 (27)—15 (8)Age<70 years35
(27)68
(51)21
(16)8 (6)132
(69)≥70 years11
(19)33
(56)11
(19)4 (6)59
(31)GenderMales17
(17)54
(55)20
(20)7 (8)98
(51)Females29
(30)47
(48)12
(12)5 (5)93
(49)ChemotherapyAnthracyclines-based30
(28)54
(50)19 (18)5 (4)108
(57)Platinum-based regimens14
(30)27
(57)5 (11)1 (2)47
(25)Carboplatin2 (8)10
(42)6 (25)6 (25)24
(12)Others—12 (6)CR: complete response, PR: partial response, SD: stable
disease, PD: progressive disease.


### 3.2. Survival

The overall  median survival, and 2- and
5-year survival rates for all patients were 6 months, 8%, and 2%, respectively.
In limited stage disease, survivals were 8 months, 15%, and 5%, respectively, and
in extensive stage disease 5 months, 5%, and 0%, respectively for(P<.0001).
Univariate analysis also showed good Manchester
prognostic group (Figure 2) and chemotherapy response to be associated with improved
survival, but no significant survival differences were seen with age, sex, and
year of treatment (Figure 3).Figure 2
Survival in relation to Manchester scores.Figure 3
Survival function in relation to chronological periods.


### 3.3. Toxicity

Five patients (2.5%) died in the 3 weeks
that followed the first cycle of chemotherapy, and were recorded as treatment
related deaths. Case-notes review indicated 14% were admitted for the treatment
of neutropenic sepsis episodes, with this complication being more common with
anthracycline-based treatment (10%) than platinum (4%).


### 3.4. Relapse

183 patients (96%) relapsed after primary
chemotherapy treatment, mostly with metastatic recurrence (70%), 40% of the
patients received second line chemotherapy which included CAV regimen, single-agent
carboplatin or carboplatin/etoposide +/− palliative radiotherapy. The median
survival following second line treatment was 2 months (range 1–12 months).


## 3.1. Response

A Total 196 patient received primary chemotherapy,
5 died following the first cycle of treatment leaving 191 assessable for
response (Table2). There was an overall response rate was 77% (24% CR and 53%
PR) with only 6% having documented progressed during chemotherapy. We found a
higher response rate for patients with limited disease, performance status 0/1,
and those less than 70 years old but none reached statistical significance (using
chi-square test, P-values were 0.090, 0.390, 0.702, resp.). There
was higher response rate with platinum-based treatments (87%) compared anthracycline
(78%). The high response rate for platinum-based treatment includes patients in
the poor prognostic group, particularly those with impaired hepatic function,
in whom single-agent carboplatin was used and had a response rate of 50%.Table 2
Response to chemotherapy among 191 assessable patients.
Response, no. (%)TotalCRPRSDPDVariableOverall response46
(24)101
(53)32
(17)12 (7)191StageLimited25
(27)52
(58)9 (10)5 (5)91Extended21
(21)49  (49)23
(23)7 (7)100Manchester   groupsGood27
(33)44
(55)6 (7)4 (5)81
(42)Intermediate19
(20)46
(49)22
(23)8 (8)95
(50)Poor—11
(73)4 (27)—15 (8)Age<70 years35
(27)68
(51)21
(16)8 (6)132
(69)≥70 years11
(19)33
(56)11
(19)4 (6)59
(31)GenderMales17
(17)54
(55)20
(20)7 (8)98
(51)Females29
(30)47
(48)12
(12)5 (5)93
(49)ChemotherapyAnthracyclines-based30
(28)54
(50)19 (18)5 (4)108
(57)Platinum-based regimens14
(30)27
(57)5 (11)1 (2)47
(25)Carboplatin2 (8)10
(42)6 (25)6 (25)24
(12)Others—12 (6)CR: complete response, PR: partial response, SD: stable
disease, PD: progressive disease.


## 3.2. Survival

The overall  median survival, and 2- and
5-year survival rates for all patients were 6 months, 8%, and 2%, respectively.
In limited stage disease, survivals were 8 months, 15%, and 5%, respectively, and
in extensive stage disease 5 months, 5%, and 0%, respectively for(P<.0001).
Univariate analysis also showed good Manchester
prognostic group (Figure 2) and chemotherapy response to be associated with improved
survival, but no significant survival differences were seen with age, sex, and
year of treatment (Figure 3).Figure 2
Survival in relation to Manchester scores.Figure 3
Survival function in relation to chronological periods.


## 3.3. Toxicity

Five patients (2.5%) died in the 3 weeks
that followed the first cycle of chemotherapy, and were recorded as treatment
related deaths. Case-notes review indicated 14% were admitted for the treatment
of neutropenic sepsis episodes, with this complication being more common with
anthracycline-based treatment (10%) than platinum (4%).


## 3.4. Relapse

183 patients (96%) relapsed after primary
chemotherapy treatment, mostly with metastatic recurrence (70%), 40% of the
patients received second line chemotherapy which included CAV regimen, single-agent
carboplatin or carboplatin/etoposide +/− palliative radiotherapy. The median
survival following second line treatment was 2 months (range 1–12 months).


## 4. Discussion

The Doncaster MDT serves an area with
significantly higher rates of lung cancer incidence and mortality than the
national average; the indirectly standardised registration rate (SRR) (2001–2003)
for Doncaster was 138 for men and 140 for
women [9]. Overall the
standardised mortality ratios (SMR) in Doncaster area were 114, 112 for males
and females, respectively, which  are among the highest SMR in
England and Wales
[10]. This indicates a poor general health
status for the population in the Doncaster area,  which would be expected to have an effect on outcome following a
diagnosis of small-cell lung cancer in various ways. Our population of patients
with SCLC will be different to the population of patients entering the trials
that provides our evidence base. An example would be a comparison of our demographics
with the Norwegian Lung Cancer Study Group Trial [11], which reported in the middle of our study period and has relatively
wide entry criteria that included limited and extensive disease. The age,
performance status, and stage of our patients are similar to those included in
the trial but we note we treated a significantly higher proportion of female
patients (51 vs. 36%) with worse performance status (PS 0/1 47% vs. 65%).The treatment response rates documented in
this study are comparable to those reported in trials, but these trials [12]
have reported better survival outcomes. The Norwegian study [11], for example, compared
anthracycline and platinum-based chemotherapy and demonstrated a survival
advantage in favour of the platinum-based treatment (median survival 7.8 vs.
10.2) months. Although the entry criteria for this study were relatively broad,
our population included a number of patients who would not meet the trial
inclusion criteria, the biggest group being the 17% of our patients who were
not considered fit for primary chemotherapy treatment.The national LUCADA database has
been developed to collect more detailed demographic information on patients
with lung cancer, to allow adjustments for comorbidity and other factors to be
made when comparing outcome across England and Wales
and has published its first report [13] with
coverage extending to the majority of the population. The data collected by
this report covers a different, but overlapping, period to our audit and comparison
suggests the median survival reported in our series is a typical outcome for UK
as
a whole (6 vs. 5.6 months), using current guidelines. During the period of our audit,
our unit reached the current national guidance recommendations with 100% of
patients being reviewed by the MDT and histological confirmation rate of 83% and
this compares favourable with the LUCADA averages
in 2005 of 78% and 65%, respectively. In addition, treatment rates compare favourably,
83% of our patients received chemotherapy; the LUCADA average being 54%. Therefore,
with median age, sex ratio, performance status, stage of disease, and
comorbidities being similar, we are disappointed that at best we demonstrate a
marginal improvement in the median survival of our patients with SCLC (6
months) compared to LUCADA report (5.6 months).Over the 8-year study period there
were no significant demographic changes, though we did notice a trend towards a
higher female incidence and extensive stage disease at initial presentation, the
latter probably reflecting increased accuracy of staging with the increased use
of CT scanning. During the audit period there was accumulating evidence
indicating the superiority of platinum-based treatment over anthracyclines [11, 14, 15]. This was reflected in the guidelines published in 2005 [7] and our
practice with a clear trend towards the increased use of platinum treatment in
the third cohort of patients. There was no change in the guideline advice on
the use of radiotherapy over the study period as the evidence demonstrating the
benefit of thoracic radiotherapy [16], and prophylactic cranial irradiation [17] had accumulated during the 1990s and was being applied at
the start of the audit period. There was no change in the proportion of
patients receiving radiotherapy over time, though from 2003 we did participate
in a study of PCI in extensive stage patients and considered concurrent rather
than sequential thoracic radiotherapy [18, 19].The
changes in treatment practice that have occurred over the 8 years have
been small; so perhaps it is unsurprising that they have not fed through to any
measurable effect on outcome for the total population with small-cell lung
cancer. However, the bigger changes that
occurred during our audit period were driven by the NHS cancer plan, which
revolutionised the delivery of cancer treatment across the UK. The plan
focused attention on target times for access, diagnosis, and waiting times, and
significant investment was made to reduce the intervals between referral, first
hospital appointment and treatment. These targets are now being met for 96–99% of cancer
patients and this audit was able to document an improvement in the patient
pathway. Comparing in 1998–2000
with 2003–2005 there was  a reduction in the
mean time from GP referral to a management plan being agreed (from 31 to 18 days)  and
in the mean time from referral to initial treatment
(from 34 days 27 days. The disappointment is that we are unable to
document any significant improvement in outcome to
correspond with this improvement.


## 5. Conclusion

We feel that these data reflect the
evolution of evidence-based treatment, delivered to an unselected cohort of
patients presenting to a single cancer unit. Disappointingly, we could not
document any significant improvement in outcome for patients over the 8-year
audit period. It remains difficult to translate the survival benefits reported
in trials. We feel that improvements in outcome will only come with earlier
diagnosis and improvements in the general health of our population.



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