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10/8/22
20-pound weight loss within three months, although she
extension to the mediastinum and significant mediastinal
confirmed presence of that large mass and no other areas
of abnormality within the abdomen or pelvis. Patient also
had a brain MRI which showed no evidence of metastatic
patient was diagnosed with limited stage SCLC. Peripheral
M.W.’s chief complaints were heartburn and pain in the upper
right side of her abdomen, not necessarily common symptoms
an indicator of the invasiveness of the disease. Although M.W.
did not complain of cough, her presentation is representative
of patients diagnosed with this disease in that the tumor was
it is a symptom experienced by patients with rapidly growing
disease, and associated with appetite suppression.
CASE 94-3, QUESTION 2: What potential complications
might patients such as M.W. experience during the course
decreased physical activity, is a common complaint as well as
hemoptysis.62 Owing to the central location of most of these
tumors, approximately 10% of patients can experience superior
growing tumor impinging upon the superior vena cava. This can
restrict blood return to the heart, resulting in head and facial
For a visual of the superior vena cava
syndrome, go to http://thepoint.lww.
One-third of patients have some degree of atelectasis
present.65 A peripheral location or chest wall involvement by
the tumor is uncommon. Rarely, SCLC presents as a solitary
Patients with SCLC frequently experience paraneoplastic
syndromes as a result of their disease, and these often differ
from patients who have NSCLC. For example, patients with
serum concentrations of antidiuretic hormone are often elevated
in SCLC, but few of these cases fulfill the criteria for SIADH and
are mostly asymptomatic. In some cases, ectopic production of
atrial natriuretic factor contributes to the disorder in sodium
homeostasis. Because SCLC is usually responsive to cytotoxic
develops in only 5% of those with SCLC. Low serum sodium and
Cushing syndrome are both poor prognostic indicators for the
2220Section 17 Neoplastic Disorders
Unlike M.W., most patients already have metastatic disease at
diagnosis, and the most common sites include bone, liver, adrenal
glands, and brain. Bone pain may or may not occur, depending
on the nature of the metastases to the afflicted area. Patients with
hepatic and adrenal lesions do not usually experience symptoms,
even if they have elevations of bilirubin, alkaline phosphatase, or
with central nervous system complications (e.g., seizures) as the
TREATMENT MODALITIES FOR SMALL CELL
the three treatment modalities (i.e., surgery, radiation, and
chemotherapy) for the treatment of her disease?
As mentioned earlier, surgery has a very limited role as part of
the treatment for patients with SCLC. In general, patients with
tumors larger than 3 to 7 cm and presence of any disease in the
lymph nodes or distant metastases do not benefit from surgery.66
The percentage of patients who fit this category is less than 5%. If
surgery is chosen, the procedure usually includes lobectomy with
mediastinal nodal dissection and sampling. Thereafter, patients
would receive adjuvant radiation and chemotherapy and then
prophylactic cranial irradiation as described in the subsequent
of 2 to 4 weeks, and total dosage targets range between 45 and
multidimensional imaging to assure tumor movement of less
than 1 cm is achievable (movement as a result of breathing
during the procedure). See http://www.slideshare.net/fovak/
igrt-srt-for-lung-cancer for more information.67–69 In addition
to their cytotoxic effects, many chemotherapeutic agents also
sensitize tumors to radiation. Hence radiotherapy should start
concurrently with chemotherapy, usually at the first or second
cycle. Due to the high incidence of metastases to the brain (i.e.,
greater than 50% of patients with SCLC), prophylactic cranial
irradiation is the standard of treatment for patients with limited
stage and extensive stage diseases. The total dosage for this ranges
between 25 and 30 Gy given for 10 to 15 fractions.70,71
The proliferative indices for SCLC cells are high, and early
used representative first-line treatment regimens for limited stage
and extensive stage diseases. In general, most of the regimens
Representative Chemotherapy Regimens for Small Cell
Limited Stage SCLC (maximum 4–6 cycles)
Etoposide, days 1, 2, 3, and then every 21 days69
Etoposide, days 1–4, then every 21 days72
Extensive Stage SCLC (maximum 4–6 cycles)
Etoposide days 1–4, then every 21 days72
Etoposide, days 1, 2, 3, then every 21 days73
Irinotecan days 1, 8, 15, then every 28 days74
Irinotecan days 1, 8, then every 21 days75
Chemotherapy for Relapsed Disease58
If relapse occurs <2–3 months after first-line and PS 0–2: ifosfamide,
paclitaxel, docetaxel, gemcitabine, irinotecan, or topotecan
If relapse occurs >2–3 months up to 6 months: topotecan (oral or IV),
irinotecan, paclitaxel, docetaxel, oral etoposide, vinorelbine,
gemcitabine, or cyclophosphamide/doxorubicin/vincristine
If relapse occurs >6 months: original regimen
PS, performance status; SCLC, small cell lung cancer.
treatment beyond six cycles is usually not recommended for
this disease because the maximum effect of the treatment is
achieved in this time frame. Further, toxicity after treatment
usually stopped after four to six cycles and the patient is closely
monitored for recurrence of the disease afterward.
Several choices of agents are available as shown in Table 94-7, and
the selection is dependent on the overall condition of the patient
(e.g., performance status, toxicity from previous regimen) and
the length of time after the first line regimen was completed.
Many of these agents are given as single agent therapy except
for the CAV regimen. In general, a recurrence that occurs within
6 months, then the same agents used for the first-line regimen
may be used again. To date, no targeted agents are approved for
In conclusion, M.W.’s disease would not be a good candidate
for surgical removal because there is lack of proven benefit. Small
systemic therapy would also be favored because the tumor tends
to metastasize quickly and it provides a way to eradicate disease
Drug Administration (FDA), investigators noticed that patients
who were women, Asian, and nonsmokers tended to respond to
EGFR was a better predictor of response to erlotinib therapy
than demographic factors and smoking status. The prevalence
nonsmokers.47 Hence, the probability that L.L., a nonsmoking
white woman, has a tumor with this somatic mutation is higher
than for other categories of patients such as smokers or men.
Further, the observed incidence of these mutations is less than
3% for patients with squamous cell histology; therefore, it is not
and mutation testing is thus warranted on that basis alone.
The question arises that patients who fall into the category
with multiple clinical predictors of response could be started
empirically on erlotinib therapy without the need to test for
adenocarcinoma. However, studies with populations of patients
from developed countries with NSCLC showed that those who
had three or more of these characteristics experienced a 49%
response rate, whereas those with sensitizing EGFR mutations
experienced much higher 67% response rate.35 This indicates
that EGFR mutation is a better predictor of response to erlotinib
therapy than presence of multiple clinical predictors.
Application of this EGFR testing is useful for small molecule
tyrosine kinase inhibitors (e.g., erlotinib), but not for antibody
molecules (e.g., cetuximab) that also block EGFR. The antibody
tumor. It is likely that even without presence of the mutation(s),
the antibody molecule still binds, and can function through
several mechanisms to promote an anti-tumor effect. Small
molecule inhibitors, however, also bind receptor internally to
the cell surface and can inhibit the active ATP binding region,
which is constitutively activated in tumors with EGFR mutations.
For L.L., it is standard of care to send the tumor specimen for
CASE 94-2, QUESTION 3: Analysis of tumor tissue detected
L858R mutation in exon 21, which is commonly associated
with high sensitivity to the EGFR tyrosine kinase inhibitor
(TKI) erlotinib.35 L.L. was then started on erlotinib therapy
expect in terms of prolonged survival?
if there is a longer-term benefit. The response rate for erlotinib
treatment is approximately 67%, time to disease progression is
11.8 months, and overall survival is approximately 24 months.
As of yet, there are no data to support that treatment with
small molecule inhibitors prolongs overall survival, relative to
because study subjects who are randomly assigned to one arm
that addition of erlotinib to chemotherapy is superior to either
CASE 94-2, QUESTION 4: As mentioned earlier, patients
with stage IV NSCLC should receive radiotherapy prior to
characteristic about this patient might preclude her from
receiving radiation prior to erlotinib?
The rationale for omitting radiotherapy has more to do
with the likely toxicity of the combination of radiation and
chemotherapy, rather than any characteristics of L.L. She clearly
inhibitor therapy may not be safe to give either sequentially or
together. Both studies were conducted with the EGFR small
given after a platinum-based concurrent radiotherapy regimen.
Enrollment for this phase III study was stopped early due to the
results of an interim analysis showing median survival time for
those getting placebo (35 months) was greater than for those
getting gefitinib (23 months). The gefitinib arm was associated
with an increased number of pulmonary deaths.48 The second
Dose-limiting pulmonary toxicity was observed in this second
Therefore, the toxicity may be the result of all three (cytotoxic
chemotherapy, radiotherapy, and EGFR inhibitor). Radiotherapy
delivered to the lungs is associated with pulmonary fibrosis and
small molecule EGFR inhibitor therapy is associated with the
development of pneumonitis. Though definitive proof does not
exist for this interaction, it would not be advisable to give L.L.
radiotherapy prior to her erlotinib treatment.
CASE 94-2, QUESTION 5: If L.L.’s tumor was classified as
having wildtype EGFR instead, what treatment should L.L.
If the biopsy results had shown that the tumor EGFR was
wildtype (i.e., no mutation), then L.L. would be considered for a
platinum-based doublet such as one shown in Table 94-6. Because
her disease is nonsquamous, the adjunct agent selected would
most likely be pemetrexed. Scagliotti et al. randomly assigned
patients with advanced-stage NSCLC to receive either cisplatin
plus gemcitabine versus cisplatin plus pemetrexed. Although
the median survival time was similar between the two arms,
there were differences depending on tumor histology. Patients
who received pemetrexed and had adenocarcinoma experienced
a median overall survival of 12.6 months, whereas those who
received gemcitabine had shorter survival. In contrast, those with
squamous carcinoma who received pemetrexed experienced a
9.4-month median overall survival, whereas those who received
gemcitabine had longer survival.31 Therefore, if L.L.’s tumor had
paclitaxel together with bevacizumab. As mentioned previously,
four to six cycles of cytotoxic therapy can receive maintenance
CASE 94-2, QUESTION 6: As discussed in Chapter 90,
Adverse Effects of Chemotherapy and Targeted Agents,
selected instead of erlotinib for L.L., what characteristics
about L.L. could be used to guide the selection of carboplatin versus cisplatin?
Cisplatin is predominantly associated with ototoxicity,
her first cycle of chemotherapy; therefore, she is not expected
2218Section 17 Neoplastic Disorders
would be considered to have moderate renal impairment. In this
case, carboplatin may be preferred over cisplatin because it is
associated with less renal toxicity and it is dosed according to the
Calvert formula, which accounts for renal function:
Total Carboplatin dose (mg) = AUC (GFR + 25) (Eq. 94-1)
AUC is the area under the concentration-time curve and GFR
is glomerular filtration rate.50 A typical dose of carboplatin in
this setting would be determined based on an AUC to account
for renal function instead of the typical weight (or m2)-based
dosing. AUC targets are commonly 4 to 6 mg/mL · minute for
a patient with normal renal function, then systemic exposure
would be higher. This higher exposure could result in greater
toxicity, notably greater myelosuppression. By dosing the drug
according to the patient’s renal function, the risk for overdosing
should be prepared. For example, if L.L.’s carboplatin dose is
ordered as 5 mg/mL · min, then her dose would be calculated as
dose = 5 mg/mL · minute (48 mL/min + 25), which is 365 mg.
In contrast, if her renal function were within normal range for
according to the method chosen. Usually, the choice of method
is institution-specific, because there is no evidence to show that
one estimation method is superior to the other. By consistently
using the same formula, providers reduce variability in systemic
exposure and thus increase the predictability of tolerance to the
patients. The FDA issued this safety alert to avoid administration
of high doses to patients with normal renal function and thus
likely avoiding drug-related toxicity.51
mutant), or if her disease becomes refractory to erlotinib, then
a platinum-based doublet (i.e., cisplatin or carboplatin) could be
considered. She has moderate renal impairment; therefore, an
be a safer choice because the dose would be selected based upon
her renal function, and is associated with a lower incidence of
renal toxicity than cisplatin.
CASE 94-2, QUESTION 7: L.L. experienced minor grade
diarrhea and skin rash and otherwise tolerated erlotinib
at 9 months there is no evidence of disease progression. The
plan is to continue this therapy until the disease relapses.
In general, therapy with erlotinib is well tolerated, especially
relative to cytotoxic chemotherapy. Diarrhea and rash are the
two most common adverse effects of EGFR TKI therapy.52 The
diarrhea can be treated with loperamide in most cases. Rash
requires intervention in approximately one-third of cases, and it
is desirable to treat it with agents such as 2% topical clindamycin,
minocycline, or doxycycline, and topical 1% hydrocortisone
(discussed in Chapter 90, Adverse Effects of Chemotherapy and
shorten the anticancer benefit experienced with this agent.53
As mentioned earlier, NSCLC is primarily a disease in those
older than 60 years. L.L. is 85 years old, and there is concern
elderly patients are often undertreated. However, recent studies
suggest that survival benefits are greater in elderly patients who
receive doublet therapy versus single agent.54 More studies of
various regimens are needed that would focus on treatment of
elderly patients, particularly effects on survival, quality of life,
and tolerability. Such studies would investigate the best clinical
parameters that enable prediction of response and tolerability
cytotoxic chemotherapy is first-line. Therefore, considerations
from diarrhea or vomiting, febrile neutropenia, etc.) would be
an essential consideration, particularly in this population. Even
though L.L. is able to continue treatment beyond 9 months, most
patients eventually exhibit progressive disease within 1 to 2 years.
These patients can often be re-biopsied. Approximately 40%
of these cases develop secondary mutations in EGFR (T790M)
that render the tumor resistant to erlotinib treatment.55 At such
time, consideration can be given for second-line treatment, and
Small cell lung cancer (SCLC) accounts for approximately 15%
decreased in the United States since its peak in the 1960s, the
incidence of SCLC has also declined. Relative to NSCLC, these
tumors generally have a more rapid doubling time, a higher
specimens such as bronchoscopic biopsies, fine needle aspirates,
core biopsies, and cytology. As the name suggests, these tumors
consist of small cells with limited volume of cytoplasm, poorly
defined cell borders, and finely granular chromatin.58 The cells
microscopic evaluation of tissue histology, and tests for presence
of molecular markers may also aid in the diagnosis.1
SCLCs usually arise centrally (i.e., in the chest region) and present
as a large hilar mass with bulky mediastinal lymphadenopathy
lung periphery, as can be the case with NSCLC. Due to smoking,
these previously existing symptoms may not prompt patients to
seek medical attention except in the further management of the
DIAGNOSIS AND OVERVIEW OF TREATMENT
In general, diagnostic procedures are similar to those used to
with limited stage disease ranges from 17 to 26 months and, for
extensive stage, 3 to 12 months.59 (These data were collected
from an analysis of 14 studies of SCLC, thus wide ranges for
the use of a simple two-stage system instead of the TNM system
used for other solid tumors. In the Veterans Administration Lung
Study Group staging system, limited stage disease is defined as
disease confined to the ipsilateral hemithorax and encompassed
in a tolerable radiation field, and extensive disease is defined as
disease beyond the ipsilateral hemithorax including malignant
pleural, pericardial effusion or hematogenous metastases.60 As
discussed subsequently, patients with limited stage disease are
treated with a combined modality approach (i.e., chemotherapy
with extensive stage disease.61
CLINICAL PRESENTATION AND PATHOPHYSIOLOGY
QUESTION 1: M.W. is a 63-year-old woman who presented
to her primary doctor with complaint of heartburn and pain
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