Oncology

Small cell lung cancer

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Small Cell Lung Cancer

What every physician needs to know:

Small cell lung cancer (SCLC) is an aggressive epithelial tumor with neuroendocrine characteristics, which accounts for 15% of all lung cancer diagnoses. SCLC has a rapid doubling time and predilection to metastasize early; approximately two-thirds of patients present with metastatic disease.

Treatment should be initiated as soon as possible. Except for rare patients with extremely poor performance status, treatment includes systemic chemotherapy for all patients; staging further identifies patients who may benefit from local therapy such as radiation or surgery. The prognosis for SCLC is poor; the average survival of patients diagnosed with localized SCLC (Limited Disease, LD) is less than 2 years, while that of patients with metastatic SCLC (Extensive Disease, ED) is less than one year.

The WHO definition of SCLC includes SCLC and combined SCLC. In combined SCLC, non-small cell lung cancer components are admixed with small cell lung carcinoma and should represent at least 10% of the cells. Patients with combined SCLC should be treated along the same paradigm those with (pure) SCLC.

Genetics of small cell lung cancer

Genetically, SCLC is hallmarked by discrete abnormalities of several tumor suppressor genes. TP53 is mutated in 70-90% of SCLC cases. Similarly, the retinoblastoma (Rb) gene product is absent in a vast majority of cases. Deletion of the short arm of chromosome 3 (3p) is commonly deleted in SCLC; three putative tumor suppressor genes are located in this chromosomal region, including fragile histidine triad and RASSF1A.

Are you sure your patient has small cell lung cancer? What should you expect to find?

Common presenting symptoms

The diagnosis of SCLC is made by light microscopy. The classic description of SCLC is of small round blue cells with scant cytoplasm, nuclear molding and a high mitotic rate. SCLC stains positively for epithelial markers (AE1/3) and are usually TTF-1 positive.

SCLC often displays neuroendocrine differentiation and over 90% of SCLC tumors stain positively for at least one of the following markers:

  • neuron-specific enolase (NSE)

  • neural cell adhesion molecule (NCAM, CD56)

  • synaptophysin

  • or chromogranin.

Less common presenting symptoms (paraneoplastic syndromes)

Patients with SCLC may present with signs and symptoms of endocrine or neurologic paraneoplastic syndromes, which occur in up to 15% of patients including:

  • Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

  • Cushing’s syndrome

  • Lambert-Eaton syndrome

Syndrome of Inappropriate secretion of Antidiuretic Hormone

SIADH is a euvolemic, hypo-osmotic, hyponatremia due to inadequate suppression of antidiuretic hormone secretion. This syndrome affects 1-2% of all cancer patients, but is observed in 10-50% of SCLC patients at some point in their disease process.

The majority of patients are asymptomatic or have mild symptoms including headache, fatigue, weakness and mild cognitive changes. Severe symptoms such as seizures and coma may occur in patients whose serum sodium has fallen below 120 mEq/L in less than 48 hours.

Management:

  1. Treatment of the underlying tumor; resolution may be slow over the course of weeks.

  2. Acute management may include:

  • Fluid restriction with a goal intake of under 800 mL per day

  • Administration of intravenous saline for patients with severe, symptomatic or resistant hyponatremia. To effectively raise serum sodium, the osmolality of the intravenous fluid must be greater than the patient’s urine osmolality.

  • Initiation of oral salt tablet with or without a loop diuretic.

  • Pharmacologic agents such as demeclocycline or vasopressin receptor antagonists such as conivapan (parenteral) or tolvaptan (oral).

Cushing's syndrome

Cushing’s syndrome is classically associated with a constellation of symptoms secondary to glucocorticoid excess. Ectopic ACTH (adrenocorticoid stimulating hormone; corticotropin) syndrome is the second most-common cause of Cushing’s syndrome.

SCLC accounts for 50% of all cases of ectopic ACTH production; the prevalence of this syndrome among SCLC patients is approximately 1%. Patients typically present with hypertension, hypokalemia, weakness or edema, while other findings associated with Cushing’s syndrome such as truncal obesity are less often observed.

A high-dose dexamethasone suppression test may help distinguish between Cushing's disease due to pituitary hypersecretion or ectopic ACTH syndrome. Failure to suppress 17-hydroxycorticosteroids to below 50% confirms an ectopic ACTH source.

Management:

  1. Treatment of the underlying tumor.

  2. Adrenal enzyme inhibitors can be used to decrease steroid production:

  • Ketoconazole 200mg po TID, can be increased to 400mg po TID. Measure cortisol levels at 24 hour intervals.

  • Metyrapone 250mg BID-TID may be added if 1200mg/day of ketoconazole is not sufficient to suppress cortisol.

Lambert-Eaton Syndrome

Approximately 5% of SCLC patients will develop neurologic paraneoplastic syndromes mediated by antibodies directed at onconeural antigens; 3% of SCLC patients will develop a Lambert-Eaton myasthenia syndrome (LEMS). Conversely, approximately 50% of LEMS cases are associated with malignancy, typically SCLC. The vast majority (95%) of LEMS patients develop progressive symmetric lower extremity proximal muscle weakness without atrophy. Ptosis may also be observed. Respiratory failure is rare but may present late in the course of this syndrome.

The diagnosis of LEMS is based on clinical findings and confirmed by the presence of antibodies directed against voltage-gated calcium channel (VGCC) and EMG.

Management:

Treatment of the underlying cancer may improve or stabilize symptoms. In many cases, however, neurologic damage may be permanent. Supportive measures include immunosuppressive agents and symptomatic management of neurologic symptoms.

1) For mild disease

  • Pyridostigmine 30-120mg every 3-6 hours.

  • 3,4-DAP 10-25mg TID-QID or guanidine 5-10mg/kg/d divided into TID or QID may be added if the response to pyridostigmine is inadequate.

2) For moderate or more symptomatic disease consider:

  • IVIG 2mg/kg divided over 2-5 days.

  • Prednisolone 60-100mg orally every other day.

Beware of other conditions that can mimic small cell lung cancer:

Tumors that may be mistaken for SCLC including small round blue cell tumors (e.g. primitive neuroectodermal tumors, PNET) or other neuroendocrine tumors (atypical carcinoid, large cell neuroendocrine carcinoma). Small cell carcinoma may also arise from sites other than the lung (extrapulmonary small cell carcinoma), including the cervix, prostate and multiple GI organs (pancreas, small bowel).

Which individuals are most at risk for developing small cell lung cancer:

SCLC occurs almost exclusively in smokers, particularly heavy smokers. Of lung carcinomas, squamous cell and small cell have the highest associated risk with lifetime tobacco exposure.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Pathology

Biopsy of primary tumor or a metastatic site, including pleural or pericardial effusion, is acceptable. The diagnosis of SCLC is made by light microscopy; the classic description of SCLC is of small round blue cells with scant cytoplasm, nuclear molding and a high mitotic rate.

SCLC stains positively for epithelial markers (AE1/3) and is usually TTF-1 positive. SCLC often displays neuroendocrine differentiation and over 90% of SCLC tumors stain positively for at least one of the following markers:

  • neuron-specific enolase (NSE)

  • neural cell adhesion molecule (NCAM, CD56)

  • synaptophysin

  • and/or chromogranin

Radiographic studies

Recommended studies include the following:

  • CT scan of the chest, abdomen and pelvis.

  • PET scan, or if PET is not available, bone scan. Bone metastases are observed in up to 30% of patients with SCLC and are often asymptomatic.

  • Brain MRI with gadolinium (preferred) or head CT with contrast. Up to 15% of patients have brain metastases at the time of diagnosis.

  • Laboratory studies.

  • Chemistry panel. Adequate renal function is a determinant of whether patients will be eligible for particular chemotherapy regimens.

  • CBC with differential.

  • LDH is not essential but when elevated portends a poorer prognosis.

Other studies

  • Pulmonary Function Tests for patients who are candidates for radiation or surgery.

  • Bone marrow biopsy or aspirate: bone marrow involvement as the only site of extrathoracic disease is rare (5%). Consider bone marrow evaluation in patients with limited stage disease in whom bone marrow involvement is suspected, e.g. the presence of nucleated RBCs on peripheral blood smear.

Helpful immunostains

SCLC is an epithelial tumor and thus should be positive for cytokeratins (AE1/AE3). It also displays neuroendocrine differentiation and a high proliferative index. The following immunostains are often employed in the diagnosis of SCLC:

  • TTF-1

  • NCAM (CD56)

  • Synaptophysin

  • Chromogranin A

  • Ki-67

Up to 90% of SCLC cases are positive for TTF-1. Over 90% of SCLC cases stain positive for at least one of the following: NCAM, synaptophysin or chromogranin.

Staging

Frequently small cell lung cancer is characterized as limited or extensive stage (see below). Small cell lung cancer may also be characterized by TNM staging (see Table I).

Table I.

What therapies should you initiate immediately i.e., emergently?

SCLC doubles rapidly and metastasizes early. Even in the absence of symptoms patients should be initiated on therapy immediately - ideally within 1-2 weeks of diagnosis. For patients who presents with symptomatic disease, treatment should be initiated emergently.

Superior vena cava syndrome

The patient should be admitted for emergent treatment with chemotherapy and/or radiotherapy.

Symptomatic brain metastases

Refer the patient for whole brain radiotherapy at treatment doses. If significant edema is observed on imaging studies or the patient is symptomatic, consider initiating steroids.

Spontaneous tumor lysis

Spontaneous tumor lysis is extremely rare in patients with solid tumors. Follow guidelines for the management of tumor lysis syndrome.

Hemoptysis

Hemoptysis can range from blood-tinged sputum to gross blood and may be due to local infiltration by tumor. Massive hemoptysis refers to cases in which airway bleeding is potentially life-threatening.

Patients with blood-tinged sputum should be referred to a pulmonologist for airway evaluation and possible local management. Most of these patients can be started on therapy but their cell counts should be monitored closely as the development of thrombocytopenia may aggravate their condition.

Patients with gross blood or massive hemoptysis should be admitted for emergent management. This may include evaluation by an interventional bronchoscopist, airway protection and management of any coagulopathy. If gross hemoptysis is due to tumor invasion, radiotherapy may be instrumental in acute management.

Airway obstruction

Patients who present with airway obstruction should be admitted for emergent management. This may include evaluation by an interventional bronchoscopist, airway protection, and emergent initiation of chemotherapy and/or radiotherapy.

What should the initial definitive therapy for the cancer be?

Almost all patients diagnosed with SCLC should receive chemotherapy; those with early stage disease should also receive local therapy (radiation or surgery). Even patients with poor performance status, if that performance status is judged to be secondary to newly diagnosed SCLC, should be offered therapy, as the disease is highly responsive.

The recommendation of chemotherapy alone versus combined modality therapy is based on the patient’s stage at presentation. The VALSG (Veteran’s Administration Lung Cancer Study Group) classification has traditionally been employed and categorizes patients as having either:

  • Limited Disease (LD): disease restricted to a hemithorax and which can be encompassed within a tolerable radiation port.

  • Extensive Disease (ED): disease beyond the definition of LD, including malignant pleural or pericardial effusion.

Staging (VASLG versus TNM)

  • LD SCLC: TNM Stages I-III

  • ED SCLC: TNM Stage IV

Approximately 5% of SCLC patients will present with Stage I (parenchymal only) disease; these patients may be candidates for surgical resection.

Management of patients with limited disease small cell lung cancer (TNM Stages I-IIIB)

The addition of radiotherapy to chemotherapy improves survival and local disease control in patients with LD SCLC. With combined modality treatment, approximately 15% of LD SCLC patients will be disease free at 5 years.

Randomized clinical trials over the past two decades further established that:

  • Thoracic radiotherapy (TRT) should be given concurrently with chemotherapy.

  • TRT should be initiated early in therapy.

  • Hyperfractionated (twice daily) TRT provided better outcomes than standard fractionated (once daily) TRT.

Patients with stage I (parenchymal only) SCLC may also be candidates for surgical resection followed by chemotherapy.

Chemoradiotherapy for limited disease small cell lung cancer

Patients with LD SCLC should receive 4 cycles of platinum-based chemotherapy. Cisplatin should be given when possible. For patients who are not candidates for cisplatin, carboplatin can be administered. Every effort should be made to keep patients on schedule.

Recommended regimens:

  • Cisplatin 60mg/m2 IV on day 1 plus

  • Etoposide 120mg/m2 IV on day 1-3

  • Given every 21 days

  • Cisplatin 80mg/m2 IV on day 1 plus

  • Etoposide 100mg/m2 IV on days 1-3

  • Given every 21 days

Patients who cannot receive cisplatin:

  • Carboplatin AUC 5-6 IV on day 1 plus

  • Etoposide 100mg/m2 IV on days 1-3

  • Given every 21 days

Radiotherapy:

  • Should be started with cycle 1 or 2 of chemotherapy.

  • When possible hyperfractionated TRT (1.5Gy BID to a total dose of 45Gy) is preferred.

  • If the patient is not a candidate, then 1.8-2.0Gy once daily to a total dose of 60-70Gy is recommended.

Management of patients with extensive disease small cell lung cancer (TNM Stage IV)

Patients with ED SCLC should receive systemic chemotherapy only with palliative intent. Etoposide plus a platinum agent is considered the standard of care in the US. Up to 70% of ED SCLC patients will respond to first-line chemotherapy; however, these responses are rarely durable. Less than 2% of ED SCLC patients are alive at 5 years.

Chemotherapy for extensive disease small cell lung cancer

Patients with ED SCLC are recommended to receive 4-6 cycles of platinum-based chemotherapy. Treatment beyond 6 cycles has not been shown to be of benefit.

Recommended regimens:

  • Cisplatin 60mg/m2 IV on day 1 plus

  • Etoposide 120mg/m2 IV on days 1-3

  • Given every 21 days

  • Cisplatin 80mg/m2 IV on day 1 plus

  • Etoposide 120mg/m2 IV on days 1-3

  • Given every 21 days

  • Carboplatin AUC 5-6 on day 1 plus

  • Etoposide 100mg/m2 IV on days 1-3

  • Given every 21 days

Alternate regimens:

  • Cisplatin 60mg/m2 IV on day 1 plus

  • Etoposide 120mg/m2 IV on day 1 followed by

  • Etoposide 240mg/m2 PO on days 2-3

  • Given every 21 days

  • Cisplatin 60mg/m2 IV on day 1 plus

  • Irinotecan 60mg/m2 IV on days 1, 8, 15

  • Given every 28 days

  • Carboplatin AUC 5 on day 1 plus

  • Irinotecan 50mg/m2 IV on days 1, 8, 15

  • Given every 28 days

  • Cyclophosphamide 1000mg/m2 IV on day 1 plus

  • Doxorubicin 45mg/m2 IV on day 1 plus

  • Vincristine 2mg IV on day 1

  • Given every 21 days

  • Caution with doxorubicin lifetime dose

Surgical resection for patients with early stage small cell lung cancer (Stage I disease)

TNM staging is useful for patients who are being considered for surgical resection. Approximately 5% of SCLC will present with parenchymal only disease. All patients with resected SCLC should receive adjuvant platinum-based chemotherapy. For surgical resection, lobectomy is preferred along with thoracic lymphadenectomy.

Adjuvant chemotherapy for resected small cell lung cancer

Chemotherapy should be initiated once the patient has recovered from surgery, ideally within 4-6 weeks of resection. Four cycles of cisplatin-based chemotherapy is preferred.

Recommended regimens:

  • Cisplatin 60mg/m2 IV on day 1

  • Etoposide 120mg/m2 IV on days 1-3

  • Given every 21 days x 4 cycles

  • Cisplatin 80mg/m2 IV on day 1

  • Etoposide 100mg/m2 IV on days 1-3

  • Given every 21 days x 4 cycles

Patients who cannot receive cisplatin:

  • Carboplatin AUC 5-6 IV on day1

  • Etoposide 100mg/m2 IV on days 1-3

  • Given every 21 days x 4 cycles

Prophylactic cranial irradiation

Over 50% of SCLC patients will develop intracranial metastases. Prophylactic cranial irradiation (PCI) decreases the incidence of brain metastases. Several studies have also demonstrated a survival benefit in LD and ED SCLC patients who have had an objective response to primary therapy. At the conclusion of primary therapy, patients should have restaging CT scans and repeat brain imaging. Patients with PR or CR and no evidence of intracranial disease should be referred for PCI.

PCI should be initiated within 5-8 weeks of completion of primary therapy in these patients. The recommended dose is 25Gy delivered over 10 fractions or 30Gy delivered over 10-12 fractions. There is no data to support the role of PCI in patients with stable disease at the completion of primary therapy.

Patients with intracranial disease at the conclusion of primary therapy should be referred for whole brain radiotherapy.

Consolidation thoracic radiotherapy after initial response in patients with extensive disease small cell lung cancer

Patients who have had complete response in distant metastases after chemotherapy may benefit from consolidation radiotherapy. Improvement in median survival has been reported in ED SCLC patients who received consolidation TRT after initial complete response at distant sites of disease.

The role of consolidation TRT is currently being explored in a large, randomized trial. It is reasonable to refer patients who have a complete response in extrathoracic sites of disease for discussion of the risks and potential benefits of consolidation TRT.

What other therapies are helpful for reducing complications?

Aggressive hydration to induce diuresis may help prevent cisplatin-induced nephrotoxocity. We recommend hydration with 1 L NS prior to, and at least 500mL of NS following, cisplatin infusion. Mannitol 12.5gm IV prior to cisplatin may aid in inducing diuresis.

Cisplatin is highly emetogenic. We recommend aggressive management with substance P antagonists such as aprepitant or fosaprepitant along with steroids and 5HT3 antagonist.

Granulocyte colony-stimulating factors may aid in the management of chemotherapy-induced myelosuppression.

Tumor lysis syndrome

Tumor lysis syndrome (TLS) is an oncologic emergency characterized by metabolic derangements including hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia due to the rapid release of intracellular contents into the circulation.

The metabolites can cause acute renal failure and a wide range of symptoms including nausea, seizures, arrhythmias and tetany. TLS rarely occurs spontaneously in solid tumor patients, however, can be observed after the initiation of cancer therapy.

SCLC possesses intrinsic characteristics and may predispose to therapy-related TLS including a higher proliferative rate and responsiveness to therapy. SCLC patients who present with a large tumor burden should be monitored closely after therapy for signs of TLS.

Tumor Lysis Syndrome - Definitions

Laboratory (Cairo-Bishop) TLS is defined as two or more of the following:

  • Uric acid ≥ 8mg/dL

  • Potassium ≥ 6mEq/L

  • Phosphorus ≥ 4.5mg/dL

  • Calcium ≤ 7mg/dL

Clinial TLS is defined as laboratory TLS plus at least one of the following:

  • Creatinine ≥ 1.5 x ULN

  • Cardiac arrhythmia

  • Seizure

Tumor Lysis Syndrome - Management

Patients should be admitted and management focused on the identified metabolic abnormalities.

Hyperkalemia:

Moderate hyperkalemia (> 6mEq/L) and asymptomatic:

  • Cardiac monitoring

  • Sodium polystyrene sulfonate 15-30gm orally, repeat every 4-6 hours as needed.

Severe hyperkalemia (>7mEq/L) and/or symptomatic: as above plus temporizing measures to shift potassium intracellularly:

  • Regular insulin 10U plus 100mg of D50, may repeat after 30-60 min.

  • Sodium bicarbonate 50mEq IV.

  • Albuterol 10-20mg nebulized over 20 minutes or 10-20 puffs MDI.

  • QRS widening, loss of p-waves on EKG: Calcium gluconate 1gm IV, can repeat after 5-10 minutes for persistent EKG changes.

Hyperphosphatemia:

Moderate hyperphosphatemia (≥6.5mg/dL) - any of the following phosphate binders:

  • Sevelamer 800-1600mg with each meal.

  • Lanthanum carbonate 500-1000mg with each meal.

  • Aluminum hydroxide 300-600mg with each meal; avoid use in patients with renal insufficiency.

  • Preferred in hypocalcemic patients:

  • Calcium acetate 2-3 tabs with each meal.

  • Calcium carbonate 1-2 gms with each meal.

Severe hyperphosphatemia: dialysis

Hypocalcemia:

Asymptomatic hypocalcemia: no therapy

Symptomatic hypocalcemia: hyperphosphatemia should be corrected first:

  • Calcium gluconate 1gm slow IV infusion. May be repeated after 5-10 min if symptoms or EKG changes persist.

What if scenarios.

What if a patient is found to have lymph node involvement after resection and thoracic lymphadenectomy for clinical Stage I SCLC? What if they have a positive-margin (R1/R2) resection?

Patients who are found to have lymph node involvement at the time of surgery or a positive-margin resection should receive adjuvant radiotherapy in addition to adjuvant chemotherapy.

What if a patient presents with superior vena cava syndrome due to SCLC?

Initiate treatment emergently with chemotherapy or radiotherapy.

What if a patient presents with symptomatic brain metastases?

Initiate whole brain radiotherapy. Oligometastatic disease in SCLC is rare, and micrometastatic disease should be assumed. There is no role for surgical resection of brain metastases from SCLC.

What if a patient is found to have brain metastases immediately after completion of front-line therapy?

Refer the patient for whole brain radiotherapy at treatment doses rather than prophylactic doses.

What if a patient presents with a paraneoplastic syndrome?

Symptoms related to the PNS may remit once treatment has been initiated. For some patients, symptomatic management may need to be initiated.

How should elderly patients diagnosed with SCLC be managed?

Elderly SCLC patients with a good performance status should be treated with optimal therapy.

How should patients with liver metastases be managed?

SCLC often metastasizes to the liver. Patients with normal liver enzymes and synthetic function despite hepatic involvement should be treated with full dose chemotherapy. Patients with abnormal liver function tests, particularly elevated bilirubin, may require dose reductions.

Follow-up surveillance and therapy/management of recurrences

After the completion of therapy, patients should be followed every 2-3 months with serial imaging studies, physical examination and bloodwork. The majority of patients will relapse and are generally categorized based on the duration of remission as having:

  • Chemotherapy-sensitive disease (recurrence > 2-3 months after completion of primary therapy).

or

  • Chemotherapy-refractory disease (recurrence < 2-3 months after completion of primary therapy).

Prognosis after relapse is poor.

Management of patients with chemotherapy-sensitive disease

Topotecan, a DNA topoisomerase I inhibitor, is FDA-approved for treatment of chemotherapy-sensitive SCLC. The intravenous and oral formulations are equally efficacious. The response rate of patients with chemotherapy-sensitive relapse is 18- 22%. Another DNA topoisomerase I inhibitor, irinotecan, may be a suitable alternative to topotecan. Irinotecan has been approved for use in Japan for SCLC and has a different dosing schedule and side effect profile from topotecan.

Recommended dosing (given until disease progression or signficant toxicities):

  • Topotecan 1.5 mg/m2 IV on days 1-5

  • Given every 21 days

  • Topotecan 2.3mg/m2 PO on days 1-5

  • Given every 21 days

  • Irinotecan 300mg/m2 IV on day 1

  • Given every 21 days

Patients that relapse over 6 months after primary therapy may respond to reinduction with platinum plus etoposide.

Management of patients with chemotherapy-refractory disease

There are no FDA-approved treatments of chemotherapy-refractory SCLC. Included in this patient population are those that have progressed through initial chemotherapy. Several agents have demonstrated activity in relapsed and refractory SCLC and may be offered to patients with good performance status but none have demonstrated a survival benefit in refractory disease.

Prior to the adoption of EP, CAV (Cyclophosphamide, Adriamycin and Vincristine) was considered the standard of care for SCLC and has activity in EP-resistant SCLC, though should be reserved for those with a good performance status.

Chemotherapy:

  • Paclitaxel 175mg/m2 IV on day 1

  • Given every 21 days

  • Temozolomide 75mg/m2 PO on days 1-21

  • Given every 28 days

  • Cyclophosphamide 1000mg/m2 IV on day 1 plus

  • Doxorubicin 45mg/m2 IV on day 1 plus

  • Vincristine 2 mg IV on day 1

  • Given every 21 days

Management of patients who progress during first-line therapy

Approximately 30% of SCLC patients will progress during treatment with first-line therapy. There are no FDA-approved drugs for primary-refractory SCLC. Agents used for chemotherapy-refractory patients should be considered.

What's the evidence?

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