- What is chemotherapy?
- Duration of chemotherapy cycles
- Objectives of chemotherapy
- What is meant by first-line and second-line?
- First-line chemotherapy in patients that are negative for EGFR mutations, ALK translocations and ROS1 rearrangements, and are PD-L1 <50%
- Chemotherapy in frail and elderly patients
- How is the effectiveness of chemotherapy treated evaluated?
- Maintenance therapy
- Second-line chemotherapy in patients with no identified molecular target
- Other non-chemotherapy drugs
What is chemotherapy?
By antineoplastic drugs, more commonly called chemotherapy, we refer to anticancer drugs that interfere with the reproduction of cancer cells. Cancer cells replicate much faster than other cells and chemotherapy drugs kill cancer cells as they divide. This is precisely why they especially effective against rapidly-growing tumors.
Duration of chemotherapy cycles
The administration of chemotherapy drugs takes place in ‘cycles’. A treatment cycle consists of the days in which drug is administered as well as the rest period that follows, until the next cycle begins. The rest interval between the two cycles allows the body to recover from the side effects. Between one cycle and another, the patient performs blood tests to assess possible toxicities on white blood cells, red blood cells and platelets.
Chemotherapy should be performed in multiple cycles because not all cancer cells replicate at the same time. There are always cells in the quiescent (at rest) phase that are may not be affected during the first cycle of chemotherapy.
The duration of chemotherapy is variable but generally lasts from 3-6 months, with the administration of 3-4 to 6-8 treatment cycles.
Objectives of chemotherapy
- Neoadjuvant chemotherapy: it is performed before surgery, aiming to reduce tumor size.
- Adjuvant chemotherapy: it is performed after surgery to reduce the risk of recurrence, eliminating any cancer cells that may have spread to other body areas.
- Exclusive chemotherapy: it is administered as a single therapy
- Palliative chemotherapy: it is used to contain or delay tumor growth and prolong survival.
What is meant by first-line and second-line?
First-line is the chemotherapy given to patients with metastatic disease and who have never undergone chemotherapy.
Maintenance therapy refers to treatment subsequent to first line. It is administered in patients without evidence of disease progression after undergoing the first line of chemotherapy. Usually maintenance therapy involves one of the drugs used in first line. The goal is to maintain the maximum benefit obtained (usually after 4 first-line cycles).
Second-line is the chemotherapy given subsequent to first-line and is initiated at disease progression (during or after the course of first line therapy). Third- and fourth-line treatments, or subsequent lines, can involve other drugs.
First-line chemotherapy in patients that are negative for EGFR mutations, ALK translocations and ROS1 rearrangements, and are PD-L1 <50%
The choice of first-line therapy is based on the patient’s comorbidities (the presence of any concomitant pathologies, such as diabetes or heart problems), expected toxicities, patient’s compliance and the histology.
Patients in good general conditions usually receive the standard chemotherapy doublet based on platinum (cisplatin or carboplatin) associated with a second drug (gemcitabine, pemetrexed, docetaxel, paclitaxel or vinorelbine). They are given intravenously, with each cycle repeated every 3 weeks. In the event that the regimen contains gemcitabine or vinorelbine, the patient receives a booster consisting of the respective drug 7 days after cycle initiation.
The probability of obtaining a significant reduction in tumor size, using pharmacological treatment is around 35-40%.
Studies that compared cisplatin and carboplatin showed a greater efficacy for cisplatin, however it was also associated with greater renal and sensory peripheral neurological toxicities.
Comparative studies of different doublet combinations have demonstrated an almost comparable efficacy of gemcitabine, docetaxel, paclitaxel and vinorelbine. However, the comparison of cisplatin-gemcitabine with cisplatin-pemetrexed showed an advantage for pemetrexed in patients with non-squamous histology (adenocarcinoma and large cell carcinoma) compared to those with a squamous histology. The reason for this difference in effectiveness is due to the biology of the disease. While, patients with non-squamous histology have low levels of thymidylate synthetase (an enzyme involved in the mechanism of action of pemetrexed), patients with a squamous histology express high levels of the enzyme, thus conferring resistance to the drug.
Another therapeutic option is adding a third anti-vascular agent, bevacizumab to the original doublet chemotherapy. For safety reasons, bevacizumab can only be prescribed in patients with adenocarcinoma. In fact, since disease localization in patients with a squamous histology lie close to the main bronchi, it has been shown that bevacizumab administration increases the risk of pulmonary bleeding in these patients. Although there are data on the effectiveness of adding bevacizumab to the combination of cisplatin-pemetrexed or carboplatin-pemetrexed, it is still not possible to receive these drug combinations under the National Health Service in Italy, due to legislative reasons.
The results of 2 phase III trials (KEYNOTE 407 and KEYNOTE 189) have changed the therapeutic approach in these patients. Both studies were designed to evaluate the advantage of adding pembrolizumab to platinum-containing chemotherapy in first line.
The KEYNOTE 407 study enrolled 559 patients with squamous NSCLC who were randomized to receive carboplatin-paclitaxel (or nab-paclitaxel) along with pembrolizumab or placebo. The chemotherapy–immunotherapy combination showed a 36% reduction in risk of death and 44% reduction in risk of progression. This was observed independent of PD-L1 expression.
The KEYNOTE 189 study enrolled 616 patients with non-squamous NSCLC who are negative for EGFR mutations and ALK rearrangements. The patients were randomized between chemotherapy (platinum-pemetrexed) combined with either pembrolizumab or placebo. A significant advantage in terms of overall survival and progression-free survival was also seen in this case. Patients who received the chemotherapy and immunotherapy (pembrolizumab) combination showed a reduction of 51% and 48% for risk of death and risk of progression, respectively. This was observed independent of PD-L1 expression.
Thus, the combination of chemotherapy and immunotherapy becomes another therapeutic option. Despite the advantages observed even in patients with PD-L1≥50%, no studies have been performed comparing this combination to monotherapy with pembrolizumab. Consequently, the Italian Drug Regulatory Agency (AIFA) decided not to approve the combination for patients who are PD-L1≥50%, where the standard treatment remains monotherapy with pembrolizumab.
Chemotherapy in frail and elderly patients
In the case of frail patients due to concomitant comorbidities, or in elderly (>75 years old) subjects, therapy should be based on drugs with a low toxicity profile. Therefore, it is preferred to start chemotherapy with a single drug, either Gemcitabine or Vinorelbine, or with a doublet including Carboplatin (but a lower dosage than standard) and Gemcitabine, Pemetrexed, Vinorelbine or Taxol, selected based on histology and expected toxicities.
How is the effectiveness of chemotherapy treated evaluated?
To evaluate the effectiveness of the chemotherapy undergone by the patient, the disease is re-evaluated by means of a chest and abdomen CT scan with contrast or PET every 2-3 cycles. The choice between CT and PET depend on what examination was performed before starting the first chemotherapeutic cycle, which will be used as comparison. PET is more rarely used as it is not recommended by guidelines, mainly due to their high costs, but they are preferred in cases of disease that are limited to the chest or in patients with renal insufficiency.
PET is not indicated in patients with decompensated diabetes as the accuracy of the test in those patients is lower. If the examinations show stability or reduction in number and size of lesions, the same drugs may be continued up to a maximum of 4 cycles (rarely for 6 cycles in patients responsive after 2 and 4 cycles and without major side effects).
Maintenance Therapy
In patients with a non-squamous histology undergoing their first line chemotherapy treatment (a combination of a platinum drug and Pemetrexed) with a stable disease or responsive after 4 cycles, a maintenance therapy with pemetrexed alone may be initiated according to the clinician’s discretion. This may be continued up to the possible onset of an unacceptable toxicity or in case of disease progression. In fact, maintenance therapy with Pemetrexed at the end of 4 platinum + pemetrexed cycles significantly increases survival.
Alternatively, patients receiving bevacizumab in addition to the doublet, can continue a maintenance therapy with bevacizumab only at the end of the 4 cycles of chemotherapy. Studies that evaluated efficacy of bevacizumab have demonstrated an increase in overall survival and progression-free survival. Progression-free survival refers to the time between start of first line chemotherapy and possible disease progression, which requires the beginning of a different chemotherapy regiment with a second-line drug.
Second-line chemotherapy in patients with no identified molecular target
When the diseases progresses following a first-line treatment, a second-line treatment is considered. The disease progression can occur during first-line, maintenance (for those indicated), or after a period of follow-up following the end of first-line (maximum of 4-6 cycles). The drugs, currently approved by the Italian Drug Regulatory Agency (AIFA) are Taxotere/Docetaxel, Pemetrexed, Erlotinib, Nivolumab, Pembrolizumab, Atezolizumab and the combination of Docetaxel with Nintedanib. Their prescription depends on the disease histology.
The choice between docetaxel and pemetrexed (both intravenous drugs administered every 3 weeks) depends on the histology and type of drug used in the first-line doublet with platinum. In fact, pemetrexed is indicated in adenocarcinoma and in terms of efficacy, is similar to docetaxel in second-line.
If Pemetrexed was used in first line, then the choice for second line would be docetaxel. If instead, it had not been used, Pemetrexed would be preferred considering that it cannot be prescribed after second line (legislative reasons) and because it is better-tolerated than docetaxel. Docetaxel can also be used on a weekly basis and appears to be a better option in terms of tolerance than every 3 weeks.
Nintedanib is an inhibitor of the vascular endothelial growth factor receptor (VEGFR), fibroblastic growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR). Nintedanib can be used in combination with Docetaxel as a second line for patients with lung adenocarcinoma with disease progression after chemotherapy. This combination derives from the results of the Lume-Lung 1 study (phase III), which compared it to docetaxel alone and showed an increase in overall survival and no difference in side effects for the combination of Nintedanib and Docetaxel.
To learn more about the effects of Nivolumab, Pembrolizumab and Atezolizumab their prescriptions, see Immunotherapy.
To learn more about the side effects of the various drugs, see Side Effects.
Other non-chemotherapy drugs
Erlotinib works through a different mechanism of action than Docetaxel and Pemetrexed as it works molecularly against the EGFR receptor. Its benefit is maximal in patients with an EGFR gene mutation. When compared with chemotherapy, it was less effective in terms of progression free survival. Progression-free survival refers to the time between start of first line chemotherapy and possible disease progression, which requires the beginning of a different chemotherapy regiment with a second-line drug.
Only one study demonstrated a better overall survival for Docetaxel compared to Erlotinib in patients without an EGFR gene mutation. However, erlotinib is associated to a batter survival compared to supportive care alone even in a population of patients with non-EGFR mutated non-small cell lung cancer.
To find out the side effects of chemotherapy drugs, go to the Side Effects page.
