TREATMENT OF PATIENTS WITH ADVANCED CANCER FOLLOWING CHEMOTHERAPY AND TRADITIONAL MEDICINE-LONG TERM FOLLOW UP OF 75 CASES

Traditional systems of medicine all over the world even traditional medicine and cancer have been using plants and plants products for therapeutic intention. The purpose of these retrospective trials is to assess the clinical efficacy of chemotherapy in conjunction with TCM for a broad variety of cancers. 75 patients with available cancers were concluded in the study during September1993 – May 2018.The sex ratio of male: female was 50:25 respectively. The mean age at onset was 46.9 years(range 10-79 years. All patients were treated with different dosage of various chemotherapy in combination with TCM or traditional medicine alone. The basic chemotherapeutic regimen consisted of vincristine(VCR, 1-2 mg/week)、cyclophosphamide(CTX, 200-1, 000mg/ week), mitomycin C(MMC, 2-4mg/week) and 5-fluorouracil(5-Fu,250-500mg/ day). In addition, according to patient condition, the additional drug doxorubicin(ADM, 20mg/ week)in lymphoma and metastatic breast cancer, demethylcantharidin in liver cancer and cisplatin (DDP) or interleukin-2(PHA)or gefitinib in lung cancer. The detail prescription of TCM varied among a broad variety of carcinomas. The criteria of complete remission(CR)and/or partial remission(PR)is according to the rules where physicians have in common with in clinics. In 75 cases, the CR was obtained in 33(44%) advanced cancers, a short CR in 11(14.7%) cases, PR in 25 (33.3%) cancers, stable disease in 6 cases. In differential types of 20 patients over ten years, lymphoma occupied 8 cases (40%). As to approach to the schedule of drug administration, 16 lymphoma obtained CR via COMA (CTX, VCR, MMC, and ADM) regimen and TCM or antibiotics and immunotherapy. Five advanced gastric cancer were successfully treated using MFC and cinobufacini/ cantharidin, and TCM. In follow up, one HCC accompanied with colon polyps obtained CR via hepatectomy and targeting oncogenic receptor tyrosine kinase inhibitor sorafenib. Among two lung cancer, one female with metastatic lung cancer was given targeting oncogenic receptor EGFR gefitinib therapy after the combination chemotherapy, which was stable disease for 8+months. CR can also be achieved in one advanced cholangicarcinoma and one advanced gallbladder cancer through major protocol of TCM and the addition of small dosage of chemotherapy. Thyroid cancer was placed on the primary use of TCM. The crude herbs consisted of sargassum, tangle, Oyster(mussels), Poria cocos, Ophiopogon japonicus, Prunella vulgaris, Taraxacum, Scrophularia ningpoensis, Cremastra appendiculata, Trichosanthes Kirilowii, Sophora subprostrata, Houttuynia cordata, Scutellaria barbata d. don and Oldenlandia diffusa roxb. Among those long-term survivors, 31 carcinomas obtained in disease-free survival over 5 years, 20 cancers were survival over 10 years, the longest four patients over 25 years. In this study, it was experienced that a CR was a pivotal influencing factor in those longest survival patients, and traditional medicine was also recommended. Down regulating oncogenic receptors may be useful paradigm and perspective in currently the third line setting of clinical target therapy and in rendering our better understanding of cancer biology.


INTRODUCTION
Chemotherapy is a major skillful of cancer therapy. One of the most important advances in oncology has been increased acceptance of evidence that most patients with disseminated tumors were setted to the protocol of chemotherapy in conjunction with recent targeting oncogenic receptor 1-14 , traditional medicine( TCM) and/or adoptive immunotherapy (LAK cells, TIL therapy) 15, 16 . The experience in Ugandan children with Hodgkin's disease has been excellent and in a study of 14 adults with stage I and II Hodgkin's disease, mostly clinically staged, 13 patients (93%) achieved CR with combination chemotherapy and all were in CR 11 to 94 months after the completion of treatment 17 . Another, a disease-free survivors of 5 years (56.5-59.3% versus 22-24.3%) and 10 years (48.9%) was remarkably higher rate in those breast cancers with stage III following surgery plus chemotherapy than only surgery. More promising, in large trials of 48 HER2-positive early breast cancer patients, targeting the adjuvant trastuzumab treatment demonstrated highly favorable outcome. Five year overall survival rates and disease-free survival rates were 95.8% and 93.8% respectively 19 . Recently, neratinib was recently approved by FDA for extended adjuvant treatment of ER+/HER2+ breast cancer 20 . Others, advanced or metastatic gastric cancer constitutes the majority of patients in clinical practice. Systemic chemotherapies and combined regimens are currently available, provide palliation and prolong survival. In particular, high-quality clinical trials on TCM in cancer are generally lacking, except for Kampo medication for Japanese cancer patients 21, 22 , arsenic trioxide (As 2 O 3 ) in the role of acute promyelocytic leukemia 23 and cantharidin in treatment of liver cancer 24 . This paper will attempt to place in proper interpretative review from those patients with cancers under remission in this group.

MATERIALS AND METHODS
75 patients with available cancers were concluded in the study during September 1993-May 2018. The sex ratio of male: female was 50:25 respectively. The mean age at onset was 46.9 years ranging from 10 to 79 yrs. Among age distribution, although there is some uncertain about the type distribution of cancers, it was found 38.1 years as the mean age at onset for lymphoma, 44.0 years for liver cancer, while higher mean age at 60.1 years has been shown in lung cancer in this group. The clinical diagnoses in a broad variety of carcinomas consisted of metastatic nasopharyngeal cancer 5 cases, metastatic breast cancer 4, lung tumors 12,hepatocellular carcinoma(HCC) 12, stomach cancer 5,hematological malignancies 25 cases(acute leukemias FAB M1 type 2, M2 type 1, acute promyelocytic leukemia 1, chronic myeloid leukemia CML 2,chronic lymphocytic leukemia CLL 1,multiple myeloma 2,lymphoma 16), thyroid cancer 2, maxillary sinus carcinoma 1,carcinoma of mandibular sinus 2, laryngeal carcinoma 1, gallbladder cancer 1, cholangiocarcinoma 1, metastatic oral cancer 1, epidermoid carcinoma 1, replapsed vulvar cancer 1, and other metastatic sternal and spinal (T12) tumor 1 respectively. All other benign neoplasias were not statistically included. The basic chemotherapeutic regimen consisted of vincristine( VCR, 1-2 mg/wk), cyclophosphamide( CTX, 200-1, 000 mg/wk), mitomycin C( MMC, 2-4 mg/wk) and 5fluorouracil( 5-Fu, 250-500mg/day). In addition, the additional drug adriamycin (ADM, 20mg/wk) in lymphoma and metastatic breast cancer, demethyl cantharidin in liver cancer and cisplatin (DDP) or interleukin-2( PHA/ gefitinib in lung cancer. The detail prescription of TCM varied among a broad variety of carcinomas (see full text case reports).The criteria of complete remission (CR) and/or partial remission (PR) is according to the rules where physicians have in common with in clinics. Complete remission (CR): there was no more tumor or tumor complete regressed in patients for at least 1 month; Partial remission: the tumor decreased by more than 50% in patients for at least 1 month; Stable disease: the tumor decreased by less than 50% or increased by no more than 25% in patients; Disease progression: the tumor increased by more than 25% in patients, or new lesions emerged. The efficacy was evaluated according to the survival time from the day when patients were at onset. The clinical data for liver cancer 25, 26 and lung cancer 27,28 were previously described.

RESULTS
In 75 cancers, the rate of complete remission (CR) was achieved in 33(44%) advanced cancers. All CR patients with advanced cancers was survival over 5 years, 18 cancers was survival 10 years. Another, a short CR was obtained in 11 (14.7%) advanced cancers, the survival time varied from 20 months to 4 yrs. PR was obtained in 25(33.3%) patients with a broad variety of carcinoma, while three patients( 1 malignant lymphoma, 1 carcinoma of mandibular sinus, 1 metastatic tumor of bone) had survival 12, 18+ and 11+ years respectively, implicating a longer survivor in patients the survival with tumours. Otherwise, stable disease was 6 cases. Basic characteristics of studied population were summarized in Table 1. During the schedule of drug administration, all patients were treated with the different dosage of 1 to 4 courses of various combination chemotherapy in conjunction with traditional medicine. In statistically analysis, one patient with nasophyaryngeal cancer, the diplopia and unable version in his eye were recovered to "normal" visual acuity following the combination chemotherapy of VCMF( VCR, CTX, MMC and 5-Fu) plus traditional medicine. A patient with rodent ulcer( 8x5cm) once obtained complete response as to an approach of 5% Fu of retinoic acid ointment. A short CR was achieved by the protocol of MFC( MMC; 5-Fu; Ara C/ homoharringtonine, CTX) plus cantharidin or cinobufacini drug in 5 advanced gastric cancers. One of them was a long-term survivor for 6 yrs via mass incision and the combination of MFC with herbs Scutellaria barbata d. don. In view of cancer types, 10 lymphoma was setted to the major protocol of the combination conventional chemotherapy (COMA, VCR, CTX, MMC or ADM) in conjunction with traditional medicine which to relieve the chemotherapeutic toxicity, and reinforced the efficacy of chemotherapy. One lymphoma was regressed only by prednisone( 200#). Another 4 patients with thumb lymphadenopathy was treated by the use of antibiotics regimen in full dose with antiinflammatory herbal tablets or immunotherapy lymphocyte transfer factor. In 12 HCC, 6 HCC were treated mainly by 5-Fu (500-1,000mg/day) and TCM. 2 patients obtained CR through cantharidin and traditional medicine. The main protocol of TCM with adjuvant antibiotics regimen and low dose of dexamethasone was given in a primary liver cancer (AFP+, ascites +++, jaundice +++, liver tumor 3.2x3.0cm). One acute promyelocytic leukemia complicated with metastatic liver cancer (7x4.5cm) was in CR with all-trans retinoic acid (ATRA) and TCM. The detail prescription of TCM was mentioned before 25, 26 . In the follow up, one HCC accompanied with colon polyps obtained complete remission via hapatectomy and targeting oncogenic receptor tyrosine kinase inhibitor sorafenib. Dose intensity has proven to be critical in maximizing chemotherapeutic efficacy for numerous human cancers. Eight other patients with cancers were in remission through small dosage of chemotherapy and TCM or traditional medicine( TCM) alone. There were 4 lung cancers, 1 gallbladder cancer, 1 cholangicarcinoma and 2 thyroid cancers. Among targeting two metastatic lung cancer, one female with lung cancer was given the combination chemotherapy plus targeting oncogenic receptor EGFRv III gefitinib, which was stable disease for 8+ months. Thyroid cancer was placed on the primary use of traditional medicine. The crude herbs consisted of sargassum, tangle, Oyster (mussels), Poria cocos, Ophiopogon japonicus, Prunella vulgaris, Taraxacum, Scrophularia ningpoensis, Cremastra appendiculata, Trichosanthes kirilowii, Sophora subprostrata, Houttuynia cordata, Scutellaria barbata d. don and Oldenlandia diffusa roxb. The survival times in those patients with remission were less than 1 years 10 cases, 1 to 3 years 20 cases, over 3 to 5 years 12 cases, over 5 to 10 years 11 cases, over 10 to 20 years 13 cases, and over 20 years 7 cases. In differential types of 20 patients with over 10 years survivors, lymphoma occupied 8 cases( 40%). Among 7 patients with over 20 years, lymphoma occupied 3 cases, metastatic breast cancer 2 cases and hepatocellular carcinoma 2 cases.    don, Oldenlandia diffusa roxb. In the follow up, she was a 15 years survivor. A 58-year-old man was diagnosed as having chronic lymphocytic leukemia (CLL) on January 16, 2011 because of recent leukocyte counts elevated to 118x109/l. The patient complained of his leukocytosis( 67-97x109/l) for more than one month duration. He was treated with hydroxycarbamide in another hospital and leukocytosis declined to 27x109/l. The most common physical signs revealed two thumb lymph nodes palpable in his left neck. Hemogram: Hemoglobin concentration( Hb) was 87g/l. Leukocyte count( WBC) 123.88x109/l. The leukocyte differential count: 9% segmented neutrophils, 90% small lymphocytes. The platelet count 131x109/l. Bone marrow aspiration revealed hypercellularity. Bone marrow differential count: 14% myeloid, 7.2% erythroid, approximately 76.8% of predominant cell was small lymphocytes. The diagnosis of CLL was made. CR was obtained by the use of chlorambucil tablets and traditional medicine. On April 9, 2011, repeat hemogram: Hb 112g/l, WBC 13.6x109/l, plt 128x109/l. On May 5 and July 28, 2011, Hb 104-112g/l; WBC 9.54-10.1x109/l, with a leukocyte differential count of 26.2% mature neutrophils and 63.8% lymphocytes; plt 101-112x109/l respectively. Bone marrow aspirates on May14, 2011 revealed normal cellularity. Bone marrow differential count: 34% myeloid, 31.2% erythoid, 33.6% lymphocytes. As an outpatient, he continued traditional herbs. He was well until on October 15, 2011 while an attack of stomach pain and tarry stools was admitted to another hospital. Routine hematologic studies at that time, Hb 69g/l; WBC 7.3x109/l with 70% mature neutrophils and 28% lymphocytes; plt 188x109/l. Repeat bone marrow aspirates on October 15, 2011 revealed normal cellularity. Bone marrow differential counts: 50% myeloid, 21% erythroid, 27.5% lymphocytes. He died of another stomach cancer.

DISCUSSION
In this study, a series of the long follow up of patients with cancers were reported. I experienced that a CR was a pivotal influencing factor in those longest survival patients, and traditional medicine was also recommended.
The traditional combination chemotherapy program for lymphomas of favorable histologic type has been CVP (CTX, VCR, Pred) given at 21-days intervals 29 . Cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) were used in the NCI study for patients with nodular mixed and nodular histocytic lymphomas 30 . More intensive CVP programs with the addition of Adriamycin or bleomycin, or both, known as BACOP or CHOP-bleo, resulted in overall complete remission rates for patients with diffuse lymphomas ranging from 48% to 89% 31-34 . The NCI program of this 5-drug program, complete remission rates with these approaches has ranged from 48% to 94% 33 . In this study, the CR rates was 63% in 16 lymphomas, 6 CR were used by CVP or COMA regimens. The use of chemotherapy to treat stomach cancer has no firmly established standard of care 35  These mutations, which commonly occur as either small in-frame deletions in exon 19 or point mutations T790M or L858R in exon 21 within the EGFR tyrosine kinase domain, confer constitutive activity and sensitivity to EGFR tyrosine kinase inhibitor( TKI) 49,50 . Konduri and colleagues reported five patients with metastatic lung cancer whose tumors harbored EGFR fusion, most commonly RAD5, are recurrent in lung cancer. Four of whom were treated with EGFR TKI erlotinib with documented antitumor response for 5, 6, 8, and 20 months respectively 51 . An early EGFR TKI trial randomized patients with EGFR mutation positive stage IIIb or IV adenocarcinoma to treatment with afatinib or gemcitabine and cisplatin, treatment with afatinib prolonged progression free survival to 11.0 months as opposed to 5.6 months with gemcitabine and cisplatin 6 . In the phase III trial of 419 patients with advanced T790M positive NSCLC with osimertinib vs platinum based therapy, progression free survival in the osimertinib group was 8.5 months, compared to the platinum-based therapy group at 4.2 months 6 . Serra reported the clinical response of a lapatinib-based therapy in lung metastatic lesions of a Li-Fraumeni syndrome patient with oncogenic HER2V659E mutation and an EGFR-exon 20 insertion. A symptomatic and radiologic clinical response was achieved using oral daily lapatinib at a dose of 1,000mg in combination with intravenous weekly paclitaxel 80mg/m 2 , lately, trastuzumab initial dose of 8mg/Kg intravenously, and then followed by 6mg/kg every three weeks 52 . In total, the clinical benifits lasted over 9 months. In Cuba, CimaVax-EGF, promising, an active vaccine targeting EGF as the major ligand of oncogenic EGFR, it is in use as a cancer therapy against non-small cell lung cancer( NSCLC) 53, 54 . In this study, we use gefitinib in keeping stable disease for 8+ months in a woman with lung adenocarcinoma, and using gefitinib in more patients are under investigation. Interesting, in an APL complicated with secondary HCC, It has been demonstrated previously that nuclear RARB has been shown to be rearranged as a result of insertion of HBV sequences 55 . Recent promising, these oncogenic receptor derivatives 23,56-58 , in addition to pml/RARA, oncogenic TBL1XR1-RARB 59 , and NUP98/RARG 60,61 , and PML-RARG 62 were also detected in APL rare cases. The involvement of RARB may explain why the disappearance of malignant hepatic tumour cells via the use of ATRA agent. In this case, ATRA (80-100mg/ day) was resistance to the relapse episode. In the presence of genetic mutation in RARA LBD and the PML-B2 domain of PML-RARA, one explanation for ATRA resistance is that the N-CoR/ SMAT-corepressor complex tightly interact with pml/ RARA or PLZF, even under pharmacological concentration of ATRA, so that transcriptional derepression cannot occur at RARA target gene promoter, ATRA binding LBD impaired, degradation of pml/ RARA by proteasome pathway are inhibited 23, 63 . Previous studies uncovered that the ATRA and 13-cis forms of retinoic acid, two isomers of RA, are equally effective inhibiting proliferation 64 . In addition, new emerging aberrant pml/ RARA in relapsed APL returned to act as a constitutive transcriptional repressor 1,23,58,63,77-92 by pertubing normal retinoid signaling and RAR function, suppressing (the blockade of) differentiation, possessing an altered specifity for DNA response element, these DNA recognition changes target a distinct set of "neoplastic" genes that differ from the genes normally targeted by normal RARA. In literature alternative strategy, an APL obtained CR after treatment with 13-cis retinoic acid first and repeated CR with ATRA in relapse 65 . And more, 80% (4/5) CR in newly APL and 33% (4/12) CR in relapsed APL were achieved after treatment with 9-cis retinoic acid (LGD1057) alone 66 . Nowadays, a lot of cohort trials, 61.5% (24/39) achieved CR using tamibarotene including 5 newly APL and 13 relapse APL twice or more 67-73 . Among 269 APL with CR underwent maintenance random, four year relapse-free survival rate was 84% (ATRA) and 91% (Tamibarotene). In 52 high risk patients, this became significant (50% for ATRA, 87% for tamibarotene) 72 . In comparative analysis among those relapsed APL 74  leukocytosis with development of retinoic acid syndrome, an important adverse reaction during treatment of APL. Thus, Tamibarotene demonstrated more efficacy in both untreated APL patients and relapsed who have been treated ATRA and chemotherapy, especially as novel strategy in relapsed APL in Japan and others 74-76 . This is encouraging perspective.

CONFLICTS OF INTEREST
The author declares that there is no conflict of interest regarding the publication of this paper.