MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Relaps

Amrubicin

  • Impressive results for the second-line treatment of relapsed SCLC
  • High response rates (37–60%) for single-agent amrubicin in three Japanese phase II trials
  • Response rate and median survival were similar in both sensitive and resistant patients.

A phase II trial in the USA single-agent amrubicin in patients with refractory or resistant SCLC

  • Activity was observed,
  • Most frequently observed toxicity was myelosuppression
    • But no anthracycline-induced cardiotoxicity was noted.

Randomised phase II trial has compared amrubicin and topotecan in previously treated SCLC

  • Study further supports the efficacy of amrubicin in both sensitive (overall response 53%) and resistant patients (overall response 17%)
  • A higher response rate was achieved with amrubicin than with topotecan
  • Further evaluation is currently ongoing within a phase III setting
  • erj.ersjournals.com/content/35/1/202

Chemotherapy drugs

  • Irinotecan, cyclophosphamide, adriamycin, and vincristine (CAV)
    • Have been used as second-line therapy
    • Have only produced minor effects
  • With increased research into surgery, radiotherapy, chemotherapy, and targeted therapy
    • The emergence of immunotherapy may become a new pillar of cancer treatment

International randomized controlled trials (RCTs)

  • Immunotherapy has been shown to be a safe and effective strategy
    • To restore the antineoplastic activity of T lymphocytes at key immune checkpoints,
    • Can be used in patients with advanced or metastatic malignancies
  • apm.amegroups.org/article/view/56721/html

Lorlatinib (LOR)

  • Third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors
  • ALK-positive metastatic and advanced non-small cell lung cancer (NSCLC)
    • First-line treatment option after it was given the approval by “the Food and Drug Administration (FDA)”.
  • Limits of detection and quantitation of MW-SPA were 1.8 and 5.5 mcg/well
  • Assay was applied with great success for determining LOR in its tablets
  • www.mdpi.com/1648-9144/59/4/756

Lurbinectedin-atezolizumab



Lurbinectedin


Lurbinectedin

  • A novel RNA polymerase II inhibitor has become a second-line treatment for SCLC.

Experimental animal models

  • Lurbinectedin induces ICD and generates a powerful synergistic effect with ICIs

ZEPZELCA® (lurbinectedin)



PARP inhibitors with temozolomide

  • To date, a limited number of trials have included SCLC patients but the available data indicate the potentially promising activity of PARP inhibitors in relapsed SCLC patients
  • Multiple combination trials of PARP inhibitors with temozolomide in patients with relapsed SCLC have yielded encouraging overall response rates in the 40% range
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC10452729/


Paclitaxel

  • Taxane family
  • Some evidence of non-cross-resistance to paclitaxel from phase II studies
  • 29% response rate to paclitaxel in chemotherapy-refractory ES-SCLC

Carboplatin + paclitaxel

  • Compared to a treatment with cyclophosphamide, doxorubicin and etoposide by de Jong et al.
  • Did not result in better survival,
  • Haematological toxicity was significantly lower with carboplatin/paclitaxel
  • Addition of paclitaxel to first-line treatment with EP
    • Did not improve the time to progression or survival in ES-SCLC compared with EP alone
    • Was associated with unacceptable toxicity
  • erj.ersjournals.com/content/35/1/202

Picoplatin

  • Platinum analogue
  • Designed to overcome platinum resistance
  • Activity in relapsed SCLC

Phase II trial conducted in refractory resistant and sensitive patients

  • Compared to other platinum agents, picoplatin causes much less nephro-, neuro- and ototoxicity in phase I and II trials

Phase III study (the Study of Picoplatin Efficacy After Relapse (SPEAR) trial)


Temozolomide

  • Patients with small cell lung cancer, you can justify giving them almost anything because it’s a matter of life or death at almost every step of the way
  • Guidelines giving us a list of options for these patients.
  • Retreatment with platinum-based chemotherapy
    • If they’ve made it 6 months since their last dose of platinum
  • Topotecan and lurbinectedin
  • I offer and have utilized lurbinectedin
    • I don’t utilize topotecan a lot
      • Topotecan is a difficult drug to give practically and from a toxicity
  • I like temozolomide a lot
    • Also have brain metastases
    • Response rates and blood-brain barrier penetration are very good
Carl M. Gay, MD, PhD

Temozolamide

  • Oral alkylating agent
  • Proven efficacy in the treatment of malignant glioma

Phase II trial as a treatment for patients with relapsed SCLC


Temozolomide

  • Mainly in those patients with central nervous system lesions and methylated methylguanine-DNA methyltransferase

Verapamil

  • Reverser of P-glycoprotein (Pgp)-related resistance
  • Improve the efficacy of CyCAV combined chemotherapy
    • Cy, cyclophosphamide (CPA);
    • C, cisplatin (CDDP);
    • A, doxorubicin (ADM);
  • V, etoposide (VP16)
  • Administered to SCLC patients at Institut Gustave-Roussy, France

Treatment of nude mice implanted with these tumours

  • Pgp encoded by the MDR1 (multidrug resistance) gene
    • Not the only mechanism for multidrug resistance (MDR)
  • Not all drugs included in this regimen are recognised by Pgp
  • Four different SCLC lines, expressing the MDR1 gene and recently grafted into nude mice
    • SCLC-75, SCLC-6 and SCLC-41 originated from untreated patients, and SCLC-74T was derived from a patient treated with a combination of ADM, CPA and VP16
  • Efficacy of the CyCAV regimen, with or without verapamil
    • 24 h before CyCAV on days 1-5
  • Verapamil (25 mg/kg) improved the antitumour effect of CyCAV in mice bearing SCLC-6T, SCLC-41T and SCLC-75 tumours, although toxicity was observed
  • Verapamil modestly delayed the plasma clearance of ADM
  • Two daily injections of 10 mg/kg of verapamil, administered at a 3 h interval
    • Proved to be effective
  • The same total dose administered as a bolus was not
  • Results indicate that the association of some reversers of MDR, including drugs possibly interacting with Pgp
    • Might potentiate SCLC combined chemotherapy.
  • pubmed.ncbi.nlm.nih.gov/8541114/

Cyclophosphamide + vinorelbine

  • Better therapeutic effect compared with routine treatment, which can effectively inhibit the development of disease, with benefits to the prognosis of patients.
  • Quality of life in the study group was distinctly improved by the treatment of cyclophosphamide combined with vinorelbine
    • Indicating that cyclophosphamide combined with vinorelbine is effective and could significantly bring clinical benefits.
  • www.hindawi.com/journals/cmmi/2022/3104879/


6.1.2.1Local and regional progression - second-line therapyIf patients develop a second intrapulmonary tumor after surgical resection and adjuvant chemotherapy, the possibility of a second primary with a different histology must be considered. In case of a new nodular lesion without lymph node involvement or distant metastasis (by PET-CT and further mediastinal staging if appropriate), another primary resection can be considered. If again histologically SCLC is evident, it is unclear whether repeat adjuvant chemotherapy will be beneficial.If surgical resection is not performed, histologic confirmation should be sought pre-therapeutically. If SCLC histology is proven pre-therapeutically, simultaneous chemoradiotherapy can be performed as an alternative to surgery. If histology is different, histology- and stage-specific therapy should be initiated.
If patients develop a locoregional recurrence with mediastinal lymph node involvement after surgical resection and adjuvant chemotherapy, simultaneous chemoradiotherapy can be performed after histologic confirmation and exclusion of distant metastasis by PET-CT, analogous to the procedure for LD.
If complete remission of lymph node involvement is achieved in stage LD after simultaneous chemoradiotherapy, but the primary tumor persists or shows local progression again, surgical resection of the primary tumor may be considered in individual cases. Prior to this, PET-CT and, if appropriate, further mediastinal staging should be performed to exclude N2 or N3 involvement, as well as cranial MRI to exclude cerebral metastasis. A pneumectomy should be avoided. Stereotactic radiotherapy may also be considered in individual cases.
If locoregional recurrence with mediastinal lymph node involvement occurs after completion of concurrent chemoradiation therapy, systemic therapy with chemotherapy and immunotherapy analogous to first-line therapy in stage ED is recommended.
If local progression is observed in primary metastatic disease with stable distant metastasis, local irradiation of the progressive tumor can be performed. In this case, chemo-immunotherapy or immunotherapy can be continued initially and a switch to second-line chemotherapy can be made if systemic progression is observed again. It should be noted that primary tumor irradiation during ongoing immunotherapy has not been studied in larger trials and may cause a higher risk of pulmonary toxicity.
6.1.2.2Systemic progression - second-line therapyIf a solitary adrenal or brain metastasis occurs as a recurrence after the initial stage VLD or LD, there is an option of local therapy. In the case of an adrenal metastasis, this can preferably be performed as a resection, and in the case of a brain metastasis, it can preferably be performed as stereotactic radiotherapy. Whether subsequent systemic chemotherapy improves the prognosis is unclear. Given the metastatic disease situation now present and the positive data on chemo-immunotherapy, additional chemo-immunotherapy analogous to primary therapy in stage IV is recommended.As an alternative to a local approach followed by systemic chemo-immunotherapy, the latter can also be used primarily. Prospective studies on the value of the local approach are not available, the optional recommendation is based on individual case reports and clinical experience.
In case of disseminated progression or relapse, second-line systemic therapy is indicated in patients with ECOG PS 0-2 and those with disease-related ECOG PS 3. It results in symptom relief and prolongation of survival. Depending on the timing of re-progression, a distinction can be made between sensitive progression with freedom from therapy of more than 90 days and refractory progression with freedom from therapy of less than 90 days. This distinction is prognostically relevant and may have an impact on the choice of second-line therapy. The later the progression or relapse occurs, the more effective the second-line therapy and the longer the survival benefit can be expected.
The results for systemic therapy in Extensive Disease can be summarized as follows:
Second-line chemotherapy in ED-SCLC
Drugs with proven efficacy in the second-line setting include topotecan, irinotecan including the nanoliposomal formulation, paclitaxel, ifosfamide, anthracyclines (including amrubicin), and lurbinectedin.
A randomized trial compared topotecan vs. best supportive care [38]. Topotecan resulted in a significant prolongation of survival from 14 to 26 weeks. The benefit was seen in both sensitive and refractory relapse. Oral and intravenous administration of topotecan are equivalent.
Topotecan is the only therapy currently approved specifically for the second-line treatment of SCLC and has therefore been used in trials as the standard of care in the comparator arm.
In a study comparing cisplatin/etoposide/irinotecan vs. topotecan in patients with sensitive recurrence [39], combination therapy prolonged median survival from 12 to 18 months, but without achieving long-term survival beyond 3 years, and with significantly higher toxicity.
Similarly, in the French study by Baize et al [40], an advantage for repeat therapy with carboplatin/etoposide over topotecan was observed in patients with sensitive recurrence and more than 90 days off therapy before relapse.
Orther studies showed no superiority for the ACO protocol and for single agents such as amrubicin, lurbinectedin, and nanoliposomal irinotecan compared with topotecan therapy.
The Atlantis study [41] comparing adriamycin plus lurbinectedin vs. topotecan or ACO in the control arm in 600 patients also showed no advantage for the combination. The preceding therapy-free interval had to be at least 30 days. Median survival was 8.6 months in the lurbinectedin arm and 7.6 months in the control. The survival curves were almost identical.
The RESILIENT trial comparing nanoliposomal irinotecan vs. topotecan in 450 patients also showed no advantage for the nanoliposomal encapsulated agent [42].
Second-line immunotherapy in ED-SCLC
The administration of immunotherapy in the second-line setting has achieved remission rates of approximately 12% in phase II trials (CheckMate-032) [43], but has not been successful in randomized trials. In the CheckMate-331 trial, there was no difference between nivolumab vs. topotecan in progression-free and overall survival in the overall population [44].
Due to the use of first-line immunotherapy, second-line immunotherapy is no longer important today.
Targeted substances
Antiangiogenic agents are not indicated in either first- or second-line settings after negative studies of aflibercept, bevacizumab, thalidomide, vandetanib, and others.
Furthermore, negative randomized phase II studies are available on mTOR inhibitors, HDAC inhibitors, BCL-2 antisense agents and PARP inhibitors.
The maintenance therapy trial with the PARP inhibitor niraparib showed no difference in either progression-free survival or overall survival between the two treatment arms.
Studies with rovalpituzumab tesirine (Rova-T), a drug conjugate directed against DLL-3, were also negative. TAHOE [45] included 442 patients and compared topotecan with Rova-T in DLL3 high-positive metastatic SCLC. Median survival was 6.3 months in the Rova-T arm and 8.6 months in the topotecan arm. The HR was 1.46. As a result, the study was terminated early. MERU [46] randomized 748 patients to Rova-T maintenance therapy or placebo after completion of chemotherapy and lack of progression. Again, the Rova-T arm tended to be less favorable than the placebo arm with a median of 8.5 vs 9.8 months. The drug was also associated with a higher rate of treatment-related adverse events, including pleural effusions in nearly 30% of patients, peripheral edema, and photosensitivity reactions.
Combinations of Rova-T with nivolumab with/without ipilimumab achieved remission rates of 30%, but were associated with high toxicities, leading to discontinuation of the studies.
A newer compound under investigation is AMG-757 (Tarlatamab), a bispecific antibody (BiTE molecule) that binds to DLL-3 on the surface of small-cell tumor cells on the one hand and to CD 3 on cytotoxic T cells on the other. The compound was used in 66 patients [47] and achieved a response rate of 20% in a heavily pretreated patient population. Main side effects were the occurrence of CRS (cytokine release syndrome) in 44% of patients. Further studies are currently ongoing in this regard.
Indication for therapy and differential therapy
In PS 0-1 patients, the use of repeat combination treatment in the second-line setting is warranted after outweighing the treatment goals against therapy-associated toxicity.
If progression occurs after a therapy-free period of more than (6-) 12 months, the first-line regimen can be used again.
With a therapy-free interval of 4-12 months, combination of cisplatin/irinotecan and etoposide can be used (see study results). Alternative combinations include cis- or carboplatin with irinotecan or topotecan, but also carboplatin with paclitaxel. Repeat therapy with carboplatin/etoposide is also an option. Platinum-free combinations include ACO or AIO (adriamycin, ifosfamide, vincristine) or ACE (adriamycin, cyclophosphamide, etoposide).
In cases of treatment refractoriness with progression during therapy or within 3 months after the end of therapy, topotecan is the only substance tested with an advantage over best supportive care. In this case, the value of repeated combination therapy is not certain.
In case of limited general performance or deliberate avoidance of renewed combination therapy, topotecan as monotherapy is the approved standard (cave myelosuppression). An alternative is weekly paclitaxel treatment.
If available, lurbinectedin and liposomal irinotecan are also alternatives.
If the general performance is severely reduced, a best-supportive-care approach is usually indicated. A possible option here is, at best, oral etoposide or trofosfamide administration with the aim of symptom relief.https://www.onkopedia-guidelines.info/en/onkopedia/guidelines/small-cell-lung-cancer-sclc/@@guideline/html/index.html

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Poslední aktualizace: 10. 12. 2023 2:01:52