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Recurrent Small-Cell Carcinoma of the Lung

Recurrent Small-Cell Lung Cancer

Small cell lung cancer (SCLC) is an aggressive form of lung cancer that usually presents with local or distant metastases. This tumor has a poor prognosis.

The reappearance of SCLC after treatment, whether it is within or outside the lungs (e.g. in the central nervous system) is defined as relapsed small cell lung cancer.

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Presentation

The clinical presentation of SCLC depends on the local tumor size, its spread within the lungs, the development of distant metastases and their location as well as the presence of paraneoplastic syndrome(s). Typical presenting signs and symptoms of SCLC include dyspnea, cough, fatigue, weight loss, bone pain and neurological problems for an average duration of 8-12 weeks.

As small cell lung cancer has a tendency for rapid progression and early spread, patients usually have mediastinal masses on radiographs at the time of diagnosis. Identification of the sites of distant metastases becomes the key for staging the disease. The symptoms vary depending on the location of the metastases. Common sites of metastatic spread include brain, bones, adrenal glands, and liver. The distinction between the primary and the metastatic process is not always possible.

The local tumor growth process may be represented by a cough, dyspnea, and hemoptysis. Obstruction of large airways is a typical consequence of SCLC local growth, resulting in distal collapse and lung parenchymal infections.

Brain metastases or pressure exercised over the spinal cord may lead to neurological symptoms including an elevated intracranial pressure. Symptoms may include one or more of the following: a headache (that worsens in the morning), blurred vision, nausea, vomiting, confusion, speech problems, photophobia.

Small cell lung carcinoma tends to metastasize early to the mediastinal lymph nodes. At the time of diagnosis, patients may already have large mediastinal tumors. The tumor may compress the contents of the mediastinum, manifesting as:

Fatigue
  • Grade 3/4 adverse events ( 5% incidence) included anemia, thrombocytopenia, neutropenia/leukopenia, diarrhea, fatigue, dehydration, and hypokalemia for topotecan; and thrombocytopenia, fatigue, and alanine aminotransferase/aspartate aminotransferase elevations[ncbi.nlm.nih.gov]
Weight Loss
  • Typical presenting signs and symptoms of SCLC include dyspnea, cough, fatigue, weight loss, bone pain and neurological problems for an average duration of 8-12 weeks.[symptoma.com]
  • More generalized symptoms, such as fatigue and unintentional weight loss, may also signal a recurrence. Treatments Treating a lung cancer recurrence will depend on the site where the cancer recurs.[verywell.com]
  • Treatment may not be as effective for patients with small cell lung cancer that has spread to the bones or liver, excessive weight loss, ongoing cigarette use, or pre-existing medical conditions, such as heart disease or emphysema.[cancer.net]
  • Most patients with SCLC present with unspecific symptoms, such as new cough, a change in the pattern of their chronic cough or weight loss. This delays the time to diagnosis substantially.[breathe.ersjournals.com]
  • Performance status at diagnosis was poorly documented (unknown for 75% of cases) as was weight loss (unknown for 72% of cases) and was, therefore, not included in analysis.[bmjopen.bmj.com]
Malaise
Pleural Effusion
  • The most common grade 3 or worse treatment-related adverse events included thrombocytopenia (11%), pleural effusion (8%), and increased lipase (7%).[targetedonc.com]
  • This is called pleural effusion. In people who have cancer, this fluid may contain cancer cells. The fluid is removed by a needle and examined for the presence of cancer cells.[webmd.com]
  • Patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from LD by various groups.[cancer.gov]
  • The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure.[mrknewsroom.com]
  • Methods Patients To be included in the study, patients had to have cytologically or histologically confirmed small-cell lung cancer; extensive disease (defined by distant metastasis, contralateral hilar-node metastasis, or both; those with pleural effusion[nejm.org]
Dyspnea
  • No unexpected toxicities were noted, and grade 3/4 toxicities were limited to neutropenia, fatigue, and dyspnea. None of the vascular endothelial growth factor polymorphisms evaluated were significantly associated with response.[ncbi.nlm.nih.gov]
  • Typical presenting signs and symptoms of SCLC include dyspnea, cough, fatigue, weight loss, bone pain and neurological problems for an average duration of 8-12 weeks.[symptoma.com]
Cough
  • Typical presenting signs and symptoms of SCLC include dyspnea, cough, fatigue, weight loss, bone pain and neurological problems for an average duration of 8-12 weeks.[symptoma.com]
  • They are used to treat and prevent symptoms caused by recurrent non–small cell lung cancer, such as coughing, problems breathing, bleeding and pain. The type of endobronchial therapy used will depend on how quickly the symptoms must be treated.[cancer.ca]
  • Continued When to Seek Medical Care Consult a doctor if any of the following symptoms are present: Shortness of breath Coughing up blood Unexplained weight loss Voice change New cough or change in the consistency of a cough Unexplained persistent fatigue[webmd.com]
  • If it is a local recurrence, or in lymph nodes near the original tumor, symptoms may include a cough, coughing up blood, shortness of breath, wheezing, or pneumonia.[verywell.com]
  • Most patients with SCLC present with unspecific symptoms, such as new cough, a change in the pattern of their chronic cough or weight loss. This delays the time to diagnosis substantially.[breathe.ersjournals.com]
Hoarseness
  • Some of the symptoms of less advanced cancer include chronic cough, coughing up blood, chest pain, hoarseness, shortness of breath, wheezing, chest pain, weight loss, and loss of appetite. [14] A few more symptoms associated with the early progression[en.wikipedia.org]
  • Symptoms due to local growth of the tumor include the following: Cough Coughing up blood Shortness of breath Chest pain worsened by deep breathing Symptoms due to spread of the cancer to nearby areas include the following: Hoarse voice, resulting from[webmd.com]
  • Hoarseness. Malaise. Anorexia. Weight loss. Hemoptysis.[cancer.gov]
Stridor
  • […] mediastinum, manifesting as: Syndrome of superior vena cava (SVC) obstruction Changes in voice if the recurrent laryngeal nerve is compressed Hemi-diaphragmatic paralysis when the phrenic nerve is involved Dysphagia as a result of esophageal compression Stridor[symptoma.com]
  • […] areas include the following: Hoarse voice, resulting from compression of the nerve that supplies the vocal cords Shortness of breath, resulting from compression of the nerve that supplies the muscles of the diaphragm, or the lungs filling with fluid and stridor[webmd.com]
Nausea
  • Treatment was generally well tolerated and the most frequent adverse events were neutropenia, fatigue, nausea, vomiting, and constipation. BI 2536 is not effective in the treatment of sensitive relapsed SCLC.[ncbi.nlm.nih.gov]
Vomiting
  • Treatment was generally well tolerated and the most frequent adverse events were neutropenia, fatigue, nausea, vomiting, and constipation. BI 2536 is not effective in the treatment of sensitive relapsed SCLC.[ncbi.nlm.nih.gov]
Dysphagia
  • The tumor may compress the contents of the mediastinum, manifesting as: Syndrome of superior vena cava (SVC) obstruction Changes in voice if the recurrent laryngeal nerve is compressed Hemi-diaphragmatic paralysis when the phrenic nerve is involved Dysphagia[symptoma.com]
  • Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior[cancer.gov]
Bone Pain
  • Typical presenting signs and symptoms of SCLC include dyspnea, cough, fatigue, weight loss, bone pain and neurological problems for an average duration of 8-12 weeks.[symptoma.com]
  • Radiation therapy may be used for relief of the following symptoms: Bone pain Compression of the food pipe (esophagus), windpipe, spinal cord, or superior vena cava caused by tumors Obstructive pneumonia caused by the tumor Treatment of relapse of small-cell[webmd.com]
  • pain, nervous system changes (headache, weakness, dizziness, balance problems, seizures), jaundice, lumps near the surface of the body, numbness of extremities due to Pancoast Syndrome, and nausea, vomiting and constipation brought on by hypercalcemia[en.wikipedia.org]
Blurred Vision
  • Symptoms may include one or more of the following: a headache (that worsens in the morning), blurred vision, nausea, vomiting, confusion, speech problems, photophobia.[symptoma.com]
Photophobia
  • Symptoms may include one or more of the following: a headache (that worsens in the morning), blurred vision, nausea, vomiting, confusion, speech problems, photophobia.[symptoma.com]
Headache
  • As a result of severe headaches, rhIL-3 administration was discontinued in one patient at 8 micrograms. RhIL-3 during this chemotherapy regimen for relapsed small cell lung cancer did not enhance myelotoxicity but did improve bone marrow recovery.[ncbi.nlm.nih.gov]
  • Symptoms may include one or more of the following: a headache (that worsens in the morning), blurred vision, nausea, vomiting, confusion, speech problems, photophobia.[symptoma.com]
  • A fourth patient had unrelated toxicity; he had worsening of prior headaches (grade 3) which were found to be due to new ocular metastases; he declined further chemotherapy and study drug was discontinued.[journals.plos.org]
  • […] disease are feeling weak, being very tired, having trouble swallowing, swelling in the face or neck, and continuous or recurring infections like bronchitis or pneumonia. [4] [14] [15] Signs of more advanced cases include bone pain, nervous system changes (headache[en.wikipedia.org]
Confusion
  • Symptoms may include one or more of the following: a headache (that worsens in the morning), blurred vision, nausea, vomiting, confusion, speech problems, photophobia.[symptoma.com]
  • Tumors in the liver may result in abdominal pain, jaundice (a yellowish discoloration of the skin), itching or confusion. Recurrences in the bones most commonly present with deep pain in the chest, back, shoulders, or extremities.[verywell.com]
  • Unfortunately, there are different versions of this system in use, which may lead to confusion or discrepancies between centres. Most patients have extensive disease at the time of diagnosis.[breathe.ersjournals.com]
  • This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[ 19 ] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis[cancer.gov]

Workup

The diagnostic process starts with the patient's history and physical examination. A number of laboratory tests must be performed before beginning the therapy in order to evaluate the functionality of different organs and their ability to tolerate chemo- or radiotherapy. These include complete blood cell count (CBC), differential blood cell count, serum electrolyte levels, renal and liver function tests. Laboratory analyses may also be useful for detection of distant metastases- e.g. elevated serum calcium and alkaline phosphatase levels correlate with bone metastases.

The key step of the patient's workup is to identify the histologic type of the lung cancer in order to determine the treatment approach as well as its prognosis. This can be achieved by numerous techniques, bronchoscopy being the most convenient and easy to perform amongst them. Other techniques used for lung biopsy include mediastinoscopy, endobronchial ultrasound (EBUS), endoscopic ultrasound, transthoracic needle aspiration, thoracoscopy etc.

The lungs and other organs of possible metastases are examined using various methods in order to stage the disease and to select the most appropriate treatment scheme for SCLC. Furthermore, some of the enumerated techniques may be applied: chest X-ray, CT scan (including CT-scan of the chest, brain, and abdomen), PET-scan, sputum cytological tests, bronchoscopy, fine-needle aspiration biopsy, thoracoscopy, pleural puncture etc.

In cases where the metastases are more easily accessible, they can be biopsied instead of the primary focus of the lung cancer [11].

10-15% of the patients present with brain metastases at the time of diagnosis. Hence, magnetic resonance imaging (MRI) of the brain should be performed in both symptomatic and asymptomatic patients. [12] Metastases to the bone may be visualized through radionuclide bone scans.

Hyponatremia
  • […] without hyponatremia. [19] Hyponatremia results from inappropriate secretion of antidiuretic hormone (ADH), which results in the inability of the kidneys to excrete free water.[emedicine.medscape.com]
  • The third patient had anorexia, nausea, and vomiting (each grade 2) contributing to dehydration (grade 3) and worsening chronic hyponatremia from malignant SIADH; study drug was discontinued.[journals.plos.org]
Pleural Effusion
  • The most common grade 3 or worse treatment-related adverse events included thrombocytopenia (11%), pleural effusion (8%), and increased lipase (7%).[targetedonc.com]
  • This is called pleural effusion. In people who have cancer, this fluid may contain cancer cells. The fluid is removed by a needle and examined for the presence of cancer cells.[webmd.com]
  • Patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from LD by various groups.[cancer.gov]
  • The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure.[mrknewsroom.com]
  • Methods Patients To be included in the study, patients had to have cytologically or histologically confirmed small-cell lung cancer; extensive disease (defined by distant metastasis, contralateral hilar-node metastasis, or both; those with pleural effusion[nejm.org]

Treatment

SCLC is usually treated with etoposide/platinum chemotherapy. The treatment of relapsed SCLC differs according to the classification of the patient as either sensitive or refractory to treatment.

Sensitive relapse patients are treated with the same medications used in the first-line therapy regime [13] [14] [15]. In contrast, refractory patients are usually chemoresistant and although a large number of chemotherapeutical agents have been tested during years of clinical research, no guidelines for refractory cases were established until 1999.

Topotecan, a topoisomerase I inhibiting agent, is now the only US Food and Drug Administration (FDA) approved second-line drug for patients with refractory SCLC [16]. Amrubicin, a topoisomerase II inhibitor, is used for SCLC relapses in Japan. Although it is considered as a drug with better antitumor activity compared to topotecan, no comparative studies between the two agents have been conducted to confirm this.

Since 2002, molecular agents such as erlotinib and gefitinib were implemented in SCLC relapse therapy. Another molecular drug, sunitinib malate showed promising results in terms of tumor growth inhibition during preclinical studies. Sunitinib is a tyrosine kinase inhibitor with multiple targets, including VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, and KIT; all of them play a role in tumor progression and angiogenesis. However, sunitinib didn't show any improved therapeutical results in comparison with topotecan .

Results of third-line chemotherapy for resistant SCLC are not very encouraging. Therapy after a second relapse may be considered in patients with a satisfactory general condition. There is still no evidence for the effectiveness of such therapy, although some authors disagree [17] [18].

Prognosis

Factors affecting prognosis include number and site of metastases as well as relapse-free intervals. Although SCLC is chemo- and radiosensitive, the tumor prognosis remains poor as the majority of the patients relapse within the first two years of the disease. An average duration of survival for a limited stage disease in patients with SCLC is 15-20 months with 5-year survival rates less than 15%. Patients with extensive stage SCLC survive 9.4- 12.8 months with barely 5-19.5% of them having a 2-year survival.

However, over the years, there has been a minimal but significant increase in median survival times in patients with limited stage SCLC in numerous countries in Europe as well as in North America and Japan [9] [10].

Survival rates are higher in patients who respond well to first-line therapy and in patients with longer disease-free intervals. Patients who fail to respond to medicaments of first choice (e.g. a combination of cisplatin and etoposide) or obtain a minimal period of remission have an extremely poor prognosis.

Etiology

SCLC is an aggressive subtype of lung cancer. Along with squamous cell lung carcinoma, SCLC is the other lung cancer most strongly associated with smoking. 98% of patients with SCLC may report a history of smoking [3] [4].

SCLC is sensitive to both chemo- and radiotherapy. Chemotherapy is known to affect both quality of life and life expectancy. These encouraging facts are compromised by the underlying tendency of SCLC to relapse within the first two years after treatment. In the case of non-effective initial therapy, a second-line treatment can lead to minor improvement of symptoms and duration of survival.

Epidemiology

Lung cancer is the leading cause of cancer deaths worldwide and is responsible for 25% of cancer deaths in women and 30% in men in the United States. In the United States, SCLC comprises almost 18 % of all lung cancer cases. 1.04 million cases and 921.000 deaths due to lung cancer were registered worldwide in 1990 [5]. SCLC as a highly aggressive form of lung cancer tends to have an early metastasis [6] [7].

Sex distribution
Age distribution

Pathophysiology

SCLC was initially named "oat cell carcinoma" in 1926 by Barnard. Previously, it was considered as a form of atypical sarcoma or lymphoid tumor [8]. SCLC is now known to be a neuroendocrine carcinoma characterized by diffuse necrosis and high mitotic activity (>10 mitoses/2 mm2), with 60-80 mitoses/2 mm2 on an average. SCLC occurs in peribronchial sites and invades the submucosa of the bronchi.

According to WHO, SCLC is currently defined as: "a malignant epithelial tumor consisting of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli. The cells are round, oval or spindle-shaped. Nuclear molding is prominent. Necrosis is typically extensive and the mitotic count is high.”

SCLC is also characterized by the possible presence of numerous paraneoplastic syndromes due to the endocrine activity of its cells. These may include the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or the syndrome of ectopic adrenocorticotropic hormone (ACTH) production. Various neurologic syndromes (e.g. Lambert-Eaton syndrome) may also appear due to autoimmune mechanisms seen in the context of SCLC. The common locations to which this cancer may metastasize include the regional lymph nodes, bones, liver, brain and adrenal glands.

Prevention

As tobacco is strongly associated with all types of lung cancer, including small cell lung cancer, the only possible preventive measure is to limit smoking.

Summary

Lung cancer has the highest rates of mortality amongst all cancer types, with small cell lung cancer its most aggressive variant. Characterized by its high rates of posttreatment relapse, it is estimated that 13% of all patients with lung cancer have small cell lung cancer [1].

Patients with relapsed small cell lung cancer can be classified into two groups- refractory and sensitive cases. Refractory cases include patients in whom the first-line chemotherapeutic treatment had no desired results and patients appear with relapse within the first 60 days after the therapy. Sensitive cases are those who obtained results from the initial therapy and relapsed after more than two months after chemotherapy.

This division is necessary as sensitive patients have greater chances to respond to second-line treatment than refractory ones. As third-line treatment standards have not been established yet, the medical care for patients with more than one relapse is strongly limited [2].

Small cell lung cancer cases are usually treated with a combination of etoposide and platinum. Therapeutic approaches regarding recurring lung cancer also depend on the stage of the disease and include radiotherapy for early stage patients and chemotherapy with or without radiotherapy for advanced cases. However, no satisfactory results have been obtained in terms of relapse therapy.

Patient Information

Relapsed or recurrent small cell lung cancer is a tumor that has returned despite initial chemotherapy, radiotherapy or surgical treatment.
Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer, characterized by early regional or distant spread. First-line chemotherapy usually gives good results but for a short period of time. The prognosis of patients with recurrent SCLC is poor, although various treatment regimens have been studied. The therapeutic scheme for patients with relapse is determined by their overall condition, disease-free interval and results from first-line treatment. Topotecan is currently the drug of choice for patients with relapsed SCLC. Other drugs that can be considered include amrubicin and sunitinib.

References

Article

  1. Govindan R, Page N, Morgensztern D. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24(28):4539-4544.
  2. von Pawel J, Ardizzoni A, Thatcher N. The relationship between treatment-free interval (TFI) and outcomes to therapy in patients with relapsed small cell lung cancer (SCLC): a review of 631 patients treated with iv topotecan in 6 studies. Lung Cancer. 2003;41(Suppl. @):235.
  3. Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma; a study of 684 proved cases. J Am Med Assoc. 1950;143(4):329-336.
  4. Pesch B, Kendzia B, Gustavsson P, et al. Cigarette smoking and lung cancer--relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer. 2012;131(5):1210-1219.
  5. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin. 1999;49(1):33-64.
  6. Jemal A, Murray T, Samuels A, et al. Cancer statistics. CA Cancer J Clin. 2003;53:5-26.
  7. Murren J, Glatstein E, Pass HI. Small cell lung cancer. In: DeVita VT Jr HSRSe, ed. Cancer: Principles & Practice of Oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2001.
  8. Barnard WG. The nature of the “oat-celled sarcoma” of the mediastinum. J Pathol Bacteriol. Vol 29; 1926.
  9. Coleman MP, Forman D, Bryant H, et al. Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995–2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. Lancet. 2011;377:127.
  10. Walters S, Maringe C, Coleman M, et al. Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK: a population-based study 2004-2007. Thorax. 2013;68:551-564.
  11. Früh M, De Ruysscher D, Popat S, et al. Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;Suppl 6:99-105.
  12. NCCN Clinical Practice Guidelines in Oncology. Vol 1. Small Cell Lung Cancer National Comprehensive Cancer Network. 2016. http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed October 2, 2015.
  13. Rosti G, Bevilacqua G, Bidoli P, Portalone L, Santo A, Genestreti G. Small cell lung cancer. Ann Oncol. 2006;17(Suppl 2):ii5-ii10.
  14. Giaccone G, Ferrati P, Donadio M, Testore F, Calciati A. Reinduction chemotherapy in small cell lung cancer. Eur J Cancer Clin Oncol. 1987;23(11):1697-1699.
  15. Postmus PE, Berendsen HH, van Zandwijk N, Splinter TA, Burghouts JT, Bakker W. Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur J Cancer Clin Oncol. 1987;23(9):1409-1411.
  16. Kim YH, Mishima M. Second-line chemotherapy for small-cell lung cancer (SCLC). Cancer Treat Rev. 2011;37(2):149-150.
  17. Igawa S, Yamamoto N, Ueda S, et al. Evaluation of the recommended dose and efficacy of amrubicin as second- and third-line chemotherapy for small cell lung cancer. J Thorac Oncol. 2007;2(8):741-744.
  18. Asai N, Ohkuni Y, Matsunuma R, Nakashima K, Iwasaki T, Kaneko N.Efficacy and safety of amurubicin for the elderly patients with refractory relapsed small cell lung cancer as third-line chemotherapy. J Cancer Res Ther. 2012;8(2):266-271.

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Last updated: 2019-07-11 20:10