Modern chemotherapy (chemotherapy) for tumors began in the 1940s with the first successful treatment of Hodgkin’s lymphoma with nitrogen mustard by Yale University scientists Gilman and Philips. After 50 years, effective chemotherapeutic drugs such as 5-fluorouracil (5-Fu), methotrexate (MTX), cyclophosphamide (CTX) were discovered, followed by the discovery of new generation chemotherapeutic drugs such as cisplatin, adriamycin, violet, topoisomerase inhibitors, etc., together with the introduction of antiemetic drugs such as 5-hydroxytryptamine receptor blockers and drugs that elevate blood cells: colony cell stimulating factor, etc. As a result, the toxic side effects of chemotherapy drugs have been significantly reduced, and the efficacy of chemotherapy and patient tolerance have been significantly improved. Even now, chemotherapy is still the cornerstone of tumor treatment. Therefore, how to select the right patient and apply the right mode, the right dose and the right course of chemotherapy at the right time is very important for the efficacy of tumor treatment and the prognosis of patients.
I. Indications and contraindications of chemotherapy
1 Indications for chemotherapy.
1.1 Malignant tumors of hematopoietic system, which are sensitive to chemotherapy and can be completely controlled or even cured by chemotherapy, such as leukemia, multiple-issue myeloma, malignant lymphoma, malignant histiocytosis, etc.
1.2 certain solid tumors with better chemotherapeutic effect, choriocapillary epithelial carcinoma, malignant staphyloma, germ cell tumors, etc.
1.3 solid tumors that have extensive or distant metastases and are not amenable to surgical resection and radiotherapy
1.4 Those whose solid tumors have recurred or spread after surgical resection or radiotherapy, and may be considered for palliative chemotherapy.
1.5 cancerous body cavity effusion, including thoracic cavity, pericardial cavity and abdominal cavity using intracavitary injection of chemotherapeutic drugs.
1.6 Tumor caused by superior vena cava compression, respiratory tract compression, spinal cord compression or brain metastasis resulting in increased intracranial pressure, usually chemotherapy is often chosen first to reduce the volume and symptoms, followed by radiotherapy.
2 Contraindications.
2.1 Patients with a KPS score <60, cachexia, coma.
2.2 Patients with a tendency to perforation of the esophagus and gastrointestinal tract.
2.3 Pregnant women.
2.4 patients with allergy to all anticancer drugs are contraindicated to chemotherapy and should be used with caution in allergic patients
2.5 For tumors with primary drug-resistant types or those who have undergone multiple chemotherapies and developed secondary drug resistance.
2.6 Serious chemotherapy toxic reactions should be stopped, such as serious gastrointestinal reactions: severe nausea and vomiting, diarrhea leading to electrolyte imbalance, severe mucositis, gastrointestinal obstruction, gastrointestinal bleeding, etc.; bone marrow suppression above II° (refer to NTCI toxicity criteria, including reduction of white blood cells, platelets and red blood cells).
2.7 Combination of serious complications or impairment of important organ functions (heart, liver, kidney, etc.)
2.8 Combined with infection, temperature of 38℃ or more is contraindicated for chemotherapy.
Second, the dose intensity of chemotherapy
Hryniuk in the 80s proposed the concept of dose intensity, that is, regardless of the route of administration, the method of administration, the dose of drugs given per unit time in the course of treatment. Since the dose intensity is the average weekly dose received during the whole course of treatment, so in chemotherapy, such as reducing the dose or extending the interval of drug administration, will reduce the dose intensity. Studies have shown that the dose intensity of chemotherapy is significantly correlated with the therapeutic effect. If the dose intensity of antineoplastic drugs is increased and the interval is even shortened as planned, the efficiency of treatment and the cure rate will be significantly improved, which has been confirmed in the treatment of breast cancer and lymphoma. In a study published online in the 2011 Annals of Oncology on March 8, results showed that patients with primary operable and locally advanced breast cancer receiving dose-intensive intensive neoadjuvant chemotherapy achieved better rates of pathologic complete remission (pCR) than standard neoadjuvant chemotherapy.CHOP-14 improved the efficacy of diffuse large B-cell lymphoma in older adults compared to CHOP-21 [1,2]. If the dose intensity is not sufficient, it will not only fail to kill cancer cells, but instead cause resistance due to reduced uptake of anti-cancer drugs or increased ability of cancer cells to repair damaged cells, etc., while delay in chemotherapy regimen will lead to repopulation of tumor cells, making chemotherapy more difficult and resulting in unsatisfactory patient outcomes. The main reason for treatment failure of some diseases that can be cured by chemotherapy is often due to inadequate dose rather than due to drug resistance. Animal experiments have also confirmed that the complete remission rate decreases significantly when the drug is administered at 80% of the conventional dose, and the recurrence rate increases when the drug dose is reduced by 20% in the consolidation therapy after complete remission is achieved. Therefore, in the treatment of patients with curative potential, such as trophoblastic tumors, testicular germ cell tumors, Hodgkin’s lymphoma, Burkitt’s lymphoma, childhood acute lymphoblastic leukemia, childhood neuroblastoma, Wilms’ tumor, etc., the maximum tolerable dose of chemotherapy should be used to ensure the efficacy. In recent years, the use of granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), autologous bone marrow transplantation (ABMT) and autologous peripheral blood to cell transplantation (PBSCT) has made it possible to increase the dose intensity of chemotherapy, e.g., the R-CHOP14 regimen for diffuse large B-cell lymphoma must be supported by GM-CSF to successfully complete chemotherapy. complete chemotherapy. In clinical work, it is possible to ensure the effectiveness of chemotherapy and avoid early drug resistance by giving full attention to the dose intensity and giving chemotherapy to patients according to the standard, taking into account the individual differences of patients. At the same time, large doses of drugs, due to the increase in dose intensity, is bound to bring greater toxic reactions, therefore, in the absence of appropriate measures to prevent the treatment of toxic reactions, should not blindly increase the dose intensity.
III. Timing of chemotherapy
Chemotherapy is one of the four pillars of tumor treatment (surgery, radiotherapy, molecular targeted therapy) and can be used alone or in combination with other therapies in order to improve the efficacy of tumor treatment. Neoadjuvant chemotherapy is a concept proposed by sKarin et al. in 1989, which refers to systemic chemotherapy applied before local surgery for malignant tumors. The main purpose is to reduce the clinical (TNM) stage to shrink the primary lesions and metastatic lymph nodes, to provide the possibility of surgery for patients without surgical conditions, to increase the resection rate of radical surgery, and to preserve the maximum amount of normal tissue. Several studies have shown that even in resectable tumors, the intervention of preoperative chemotherapy can have better outcomes. For example, studies have shown that preoperative neoadjuvant chemotherapy combined with radiotherapy in patients with resectable gastric cancer resulted in significant pathologic remission in 63%, complete pathologic remission in 11%, and eventual D2 radical surgery in 83%, resulting in significantly longer survival [3,4]. Preoperative neoadjuvant chemotherapy combined with radiotherapy is also required for operable T3 rectal cancer and lymph node positive rectal cancer to improve the rate of anus preservation and prolong PFS; the results of the NSABP B-18 trial showed that preoperative neoadjuvant chemotherapy increased the rate of breast-conserving surgery in breast cancer patients with large tumors of clinical IIA, IIB and IIIA (T3N1M0 only) [5], and neoadjuvant chemotherapy results in longer survival for patients who achieve complete pathological remission. Therefore, as an oncologist, you should make a comprehensive analysis and decision on which oncology patients will benefit more from preoperative neoadjuvant chemotherapy in accordance with evidence-based medicine.
Adjuvant chemotherapy is a systemic therapy administered after effective local treatment (surgery or radiotherapy) to eliminate possible micro-metastases in the body and prevent recurrence of metastases, thus improving the cure rate and prolonging survival. However, not every tumor patient needs adjuvant chemotherapy after radical surgery or radiotherapy, for example, for T1N0M0 gastric cancer patients, as long as they are followed up regularly after surgery, and for T2N0M0 gastric cancer patients without adverse prognostic factors (poorly differentiated and highly graded tumor cells, lymphovascular and vascular invasion, age less than 50 years) do not need to undergo postoperative adjuvant chemotherapy. Similarly for T1abN0 margin-negative lung cancer, T2abN0 and margin-negative lung cancer without high-risk features (poorly differentiated, vascular invasion, wedge resection, tumor near the margin, tumor larger than 4 cm, dirty pleural involvement, Nx), IA,IIA, low-risk stage IIB colon cancer, low-risk factors for stage IA/IB ovarian cancer (grade 1, non-clear cell carcinoma, junctional tumor ), stage IA cervical cancer, and stage I-III soft tissue sarcomas (non-highly malignant and limb sarcomas) do not require postoperative adjuvant chemotherapy. For patients with early lymph node negative invasive breast cancer, if the tumor is small (maximum diameter ≤ 0.5 cm) the prognosis is very good without adjuvant chemotherapy. For patients with invasive ductal or lobular carcinoma without lymph node metastasis of 0.6-1.0 cm in diameter, 21-gene analysis can be performed to assess the risk of recurrence and the benefit of chemotherapy to determine whether chemotherapy is needed. The administration of chemotherapy to patients at lower risk should be weighed against the expected reduction in absolute risk and the patient’s willingness to bear the corresponding toxic effects. Therefore, clinicians should perform accurate staging of the tumor and assessment of the risk of recurrence and benefit of chemotherapy, and master the indications for chemotherapy to avoid over-treatment that will bring physical, mental and financial burdens to the patient, as well as to avoid under-treatment that will lead to recurrence and metastasis of the tumor.
For advanced tumors with metastases in distant organs, palliative chemotherapy or salvage chemotherapy is given to relieve patients’ pain, improve quality of life and prolong survival time. The 2011 NCCN guidelines state that patients with solitary brain metastases from lung cancer can benefit from surgical resection, and the 5-year survival rate after surgical resection ranges from 10-20%. For the treatment of liver metastases from colorectal cancer, the 2011 NCCN guidelines state that if the primary tumor can be resected radically, there are no unresectable extrahepatic metastases, and adequate liver function can be preserved, the liver metastases should be resected R0 according to their distribution and anatomical location. The resectability of initially unresectable or potentially resectable liver metastases should be reassessed after neoadjuvant therapy. It can be seen that surgery also has an important place in the treatment of advanced tumors. For patients with distant metastases, the significance of surgery, chemotherapy and radiotherapy should also be evaluated comprehensively, and the best treatment measures and timing should not be lost due to the one-sided belief that tumors with distant metastases can only be given palliative treatment and surgery should be abandoned.
As an oncologist, it is very important to coordinate preoperative neoadjuvant therapy, surgical treatment and postoperative adjuvant chemotherapy, which will affect the efficacy of tumor treatment and determine the prognosis of patients. Before making each treatment decision, a comprehensive assessment should be made, and if necessary, multidisciplinary discussions should be held to decide the appropriate time for surgery, radiotherapy and chemotherapy, so as to maximize the therapeutic effect of tumor treatment.
IV. Number of chemotherapy cycles
Most cycles of postoperative adjuvant chemotherapy are 4-6, mostly based on the results of different clinical trial studies. For example, a phase III clinical trial study conducted by Winton [6] et al. laid the foundation that only 4 cycles are required for adjuvant therapy in postoperative NP regimens for lung cancer; 6 cycles are required for the TAC (docetaxel, doxorubicin, cyclophosphamide) regimen, a postoperative adjuvant regimen for breast cancer, and 4 cycles are required for AC (doxorubicin + cyclophosphamide) sequential T (paclitaxel) in the AC regimen, and sequential T is given once a week after the end of AC, requiring 12 weeks of treatment. The NCCN guidelines for ovarian cancer (stage II-IV) recommend giving 6-8 cycles of chemotherapy, while early stage (IC, clear cell carcinoma, G2) recommends 3-6 cycles of chemotherapy. The Japanese ACTS-GC, a phase III randomized controlled clinical study, showed that patients with stage II and III gastric cancer after D2 radical surgery given tegeo adjuvant chemotherapy for 1 year had a 3-year survival rate of 80.5% versus 70.1% in the surgery-only group, and the risk of death decreased by 32% in the adjuvant chemotherapy group. This was further confirmed by the updated 5-year survival results reported at the 2010 European Society of Medical Oncology (ESMO) annual meeting and published in the Journal of Clinical Oncology (J Clin Oncol). In contrast, the Korean-based CLASSIC study with Chinese participation using a two-drug combination regimen of capecitabine combined with oxaliplatin (XELOX regimen) for 8 cycles of chemotherapy improved the 3-year disease-free survival (DFS) rate from 60% to 74% and reduced the risk of postoperative recurrence by 44%. Therefore, in clinical practice, a proven adjuvant chemotherapy regimen and a set number of chemotherapy cycles should be selected based on individual patient circumstances and clinical evidence, rather than arbitrarily subjecting patients to 4 or 6 cycles of adjuvant chemotherapy. The results of different clinical trials should also be carefully analyzed. For example, subgroup analysis of the ACTS-GC and CLASSIC studies found that tegeo failed to show significant benefits in stage IIIB patients, while XELOX showed similar benefits in stage II and III patients.
Palliative chemotherapy for metastatic or recurrent tumors that are lost to surgery should be given for a maximum of 6 cycles of first-line chemotherapy if tolerated by the patient with established efficacy. The efficacy of such chemotherapy must be evaluated prior to the start of the third cycle after two cycles of chemotherapy, and the chemotherapy regimen should be changed immediately if tumor progression occurs. Metastatic tumors are incurable, and the disease is more likely to progress after stopping treatment, so objectively it is necessary to adopt the strategy of “long flow and prolong life” rather than “pursuing with vigor and fervor”. On this basis, the concept of “oncology maintenance therapy” was born. The PARAMOUNT study, a randomized, double-blind, placebo-controlled phase III clinical study of maintenance therapy for non-small cell lung cancer, showed that four cycles of pemetrexed + cisplatin were associated with a significant increase in the number of patients in complete remission (CR), partial remission (PR), or stable disease (SD). The JMEN study further confirmed the value of pemetrexed maintenance therapy. The study showed that in the adenocarcinoma group, the PFS was 4.4 months with pemetrexed maintenance therapy, significantly longer than the 1.8 months in the placebo control group, and the OS was 15.5 months in the pemetrexed group, also significantly longer than the 10.3 months in the placebo control group. Therefore, on September 6, 2011, ASCO focused on revising and updating the guidelines for the treatment of stage IV non-small cell lung cancer (NSCLC) recommending maintenance therapy for patients with stage IV NSCLC who have a stable outcome or better after 4 cycles of first-line therapy and whose PS score can tolerate further treatment, and choosing according to cytologic type, such as adenocarcinoma choosing pemetrexed as the drug for maintenance therapy and other cell Other cell types are recommended to choose docetaxel as maintenance therapy. There are also many studies on breast cancer maintenance therapy, for example, in the GEICAM 2001-01 study, 288 patients with metastatic breast cancer were divided into maintenance and observation groups after using the A→T (doxorubicin→doxorubicin) regimen sequentially as first-line treatment. The maintenance treatment was liposomal doxorubicin 40 mg/m2 in 1 cycle every 28 days for 6 cycles. Maintenance treatment group significantly prolonged PFS (16.04 months versus 9.96 months, P=0.0001), and there was no significant clinical toxicity. The study of GOG 178 in ovarian cancer also supports that better progression-free survival was obtained with 12 months of maintenance paclitaxel given to patients who achieved complete remission after 6-8 cycles of chemotherapy. Both the OPTIMOX-1 and CONcePT studies of intermittent maintenance therapy with oxaliplatin in colorectal cancer have also demonstrated the benefits of 5-FU+LV maintenance therapy. However, not every tumor benefits from maintenance therapy and the choice of maintenance agents is stringent. In a MANTA1 study of maintenance therapy in breast cancer, 459 patients with recurrent metastatic breast cancer did not achieve PFS and OS benefits with paclitaxel maintenance therapy after first-line AT regimens. No survival benefit was seen with pemetrexed maintenance therapy in patients with squamous lung cancer. Therefore, the decision of which patients should be treated with maintenance therapy should also be made based on individual patient differences and clinical evidence.
V. Route and sequence of chemotherapy administration.
Intravenous chemotherapy is the main route of chemotherapy. Local chemotherapy that infuses drugs directly into the area where the tumor is located can increase the chance of contact with antitumor drugs and reduce systemic adverse effects. For patients with malignant body cavity effusion give thoracic, abdominal and pericardial cavity infusion chemotherapy to control the disease and improve the treatment effect. Non-invasive bladder cancer needs to be treated with bladder irrigation after local electrodesiccation. The GOG172 study showed that patients with stage III ovarian cancer treated with standard intravenous chemotherapy combined with cisplatin/paclitaxel intraperitoneal chemotherapy after surgery had a longer survival time compared with the standard intravenous chemotherapy group. patients with stage III ovarian cancer had a 16-month longer survival time [7,8]. For tumors of the central nervous system the efficacy can be improved by intrathecal chemotherapy, and lymphomas in specific cases (testicular, sinus, epidural, bone marrow involvement (large cells), HIV lymphoma, extra nodal involvement at ≥2 sites), and lymphoblastic lymphoma must be given prophylactic intrathecal chemotherapeutic agents to prevent or delay central nervous system invasion.
Therefore, the specific choice of which form of local treatment is chosen for clinical application depends on the specific nature of the tumor site and the differences in local tumor and normal tissue blood supply.
In order to improve the efficacy of chemotherapy, the combination of two or more drugs is mostly adopted, then the order of administration also affects the efficacy and toxic reactions of chemotherapy. The general principle is to kill the tumor with cycle non-specific drugs first, and then use cycle specific drugs to kill the remaining tumor cells again, so that the killing effect of both drugs can be maximized, if the order is reversed, then the killing effect of cycle non-specific drugs is greatly reduced, which affects the chemotherapeutic efficacy. For example, the FP (5-FU+DDP) regimen applied in several tumors should be followed by cisplatin titration (cycle non-specific) and then 5-Fu maintenance (cycle specific), and it has been found that DDP leads to an increase in intracellular synthesis of methionine and a corresponding increase in reduced formyltetrahydrofolate and triplet complexes, enhancing the effect of 5-Fu. VCR in the CHOP regimen can cause cells to stagnate in the M phase after about 6-8 h CTX has the strongest effect on the killing of G1 stage cells, so VCR should be used first, and then CTX after 6~8h has better effect. The commonly used TP regimen (paclitaxel + cisplatin) in lung cancer and cervical cancer should be preceded by paclitaxel and then cisplatin, because cisplatin has a regulatory effect on cytochrome P450 enzymes, which can reduce the clearance rate of paclitaxel by 30%, thus increasing the blood concentration of paclitaxel. The common regimen of AT in breast cancer (Adriamycin + paclitaxel) should be followed by ADM and then paclitaxel, because paclitaxel and ADM are metabolized by a common pathway and compete with each other for metabolic pathways, and paclitaxel followed by ADM will increase its cardiotoxicity. II) expression, resulting in enhanced cytotoxicity of TOPO-II inhibitor (VP-16).
VI. Conclusion
After more than 70 years of development, the chemotherapy concept and protocols of oncology have been constantly updated under the guidance of numerous clinical studies. In clinical work, we must master the indications and contraindications of chemotherapy, and when formulating chemotherapy plans and protocols, we should not only clarify whether the tumor is chemotherapy-sensitive or chemotherapy-resistant, and whether the aim of treatment is curative or palliative, but also decide the treatment plan according to the individual characteristics of patients while following evidence-based medical evidence, in order to obtain the maximum therapeutic efficacy.